Alkaloid Synthesis

309
Topics in Current Chemistry
Editorial Board:
K.N. Houk C.A. Hunter M.J. Krische J.-M. Lehn
l l l
S.V. Ley M. Olivucci J. Thiem M. Venturi P. Vogel

l l l l
C.-H. Wong H. Wong H. Yamamoto

l l
Recently Published and Forthcoming Volumes
Alkaloid Synthesis Luminescence Applied in Sensor Science

Volume Editor: Hans-Joachim Knölker Volume Editors: Luca Prodi, Marco Montalti,
Vol. 309, 2012 Nelsi Zaccheroni
Vol. 300, 2011
Fluorous Chemistry Chemistry of Opioids
Volume Editor: István T. Horváth Volume Editor: Hiroshi Nagase
Vol. 308, 2012 Vol. 299, 2011
Electronic and Magnetic Properties of Chiral
Multiscale Molecular Methods in Applied
Molecules and Supramolecular Architectures
Chemistry Volume Editors: Ron Naaman,
Volume Editors: Barbara Kirchner, Jadran Vrabec David N. Beratan, David H. Waldeck
Vol. 307, 2012
Vol. 298, 2011
Natural Products via Enzymatic Reactions
Solid State NMR
Volume Editor: Jörn Piel
Volume Editor: Jerry C. C. Chan
Vol. 306, 2012 Vol. 297, 2010
Nucleic Acid Transfection
Prion Proteins Volume Editors: Wolfgang Bielke,
Volume Editor: Jörg Tatzelt Christoph Erbacher
Vol. 305, 2011 Vol. 296, 2010
Carbohydrates in Sustainable Development II
Microfluidics: Technologies and Applications Volume Editors: Amélia P. Rauter,
Volume Editor: Bingcheng Lin Pierre Vogel, Yves Queneau
Vol. 304, 2011 Vol. 295, 2010
Carbohydrates in Sustainable Development I
Photocatalysis Volume Editors: Amélia P. Rauter,
Volume Editor: Carlo Alberto Bignozzi Pierre Vogel, Yves Queneau
Vol. 303, 2011 Vol. 294, 2010
Computational Mechanisms of Au and Pt Functional Metal-Organic Frameworks: Gas

Catalyzed Reactions Storage, Separation and Catalysis
Volume Editors: Elena Soriano, Volume Editor: Martin Schröder
José Marco-Contelles Vol. 293, 2010
Vol. 302, 2011 C-H Activation
Volume Editors: Jin-Quan Yu, Zhangjie Shi
Reactivity Tuning in Oligosaccharide Vol. 292, 2010
Assembly
Volume Editors: Bert Fraser-Reid, Asymmetric Organocatalysis
J. Cristóbal López Volume Editor: Benjamin List
Vol. 301, 2011 Vol. 291, 2010
Alkaloid Synthesis
Volume Editor: Hans-Joachim Knölker
With Contributions by
S.K. Adla M.G. Banwell I. Bauer H. Fujioka N.(Y.) Gao

T. Hudlicky M. Kitajima Y. Kita H.-J. Knölker T. Lindel
N. Marsch U. Rinner B.D. Schwartz H. Takayama L.V. White
Editor
Prof. Dr. Hans-Joachim Knölker
Department of Chemistry
Technical University Dresden
Bergstraße 66
01069 Dresden
Germany
[email protected]
ISSN 0340-1022 e-ISSN 1436-5049

ISBN 978-3-642-25528-1 e-ISBN 978-3-642-25529-8
DOI 10.1007/978-3-642-25529-8
Springer Heidelberg Dordrecht London New York
Library of Congress Control Number: 2011943173
# Springer-Verlag Berlin Heidelberg 2012

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,
reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication
or parts thereof is permitted only under the provisions of the German Copyright Law of September 9,
1965, in its current version, and permission for use must always be obtained from Springer. Violations
are liable to prosecution under the German Copyright Law.
The use of general descriptive names, registered names, trademarks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
Printed on acid-free paper
Springer is part of Springer Science+Business Media (www.springer.com)

Volume Editor
Prof. Dr. Hans-Joachim Knölker
Technical University Dresden
Bergstraße 66
01069 Dresden
Germany
[email protected]
Editorial Board
Prof. Dr. Kendall N. Houk Prof. Dr. Steven V. Ley
University of California University Chemical Laboratory
Department of Chemistry and Biochemistry Lensfield Road
405 Hilgard Avenue Cambridge CB2 1EW
Los Angeles, CA 90024-1589, USA Great Britain
[email protected] [email protected]
Prof. Dr. Christopher A. Hunter Prof. Dr. Massimo Olivucci

Department of Chemistry Università di Siena
University of Sheffield Dipartimento di Chimica
Sheffield S3 7HF, United Kingdom Via A De Gasperi 2
[email protected] 53100 Siena, Italy
[email protected]
Prof. Michael J. Krische Prof. Dr. Joachim Thiem
University of Texas at Austin
Institut für Organische Chemie
Chemistry & Biochemistry Department
Universität Hamburg
1 University Station A5300
Martin-Luther-King-Platz 6
Austin TX, 78712-0165, USA
20146 Hamburg, Germany
[email protected]
[email protected]
Prof. Dr. Jean-Marie Lehn Prof. Dr. Margherita Venturi

ISIS Dipartimento di Chimica
8, allée Gaspard Monge Università di Bologna
BP 70028 via Selmi 2
67083 Strasbourg Cedex, France 40126 Bologna, Italy
[email protected] [email protected]
vi Editorial Board
Prof. Dr. Pierre Vogel Prof. Dr. Henry Wong

Laboratory of Glycochemistry The Chinese University of Hong Kong
and Asymmetric Synthesis University Science Centre
EPFL – Ecole polytechnique féderale Department of Chemistry
de Lausanne Shatin, New Territories
EPFL SB ISIC LGSA [email protected]
BCH 5307 (Bat.BCH)
1015 Lausanne, Switzerland Prof. Dr. Hisashi Yamamoto
[email protected]
Arthur Holly Compton Distinguished
Prof. Dr. Chi-Huey Wong Professor
Professor of Chemistry, Scripps Research The University of Chicago
Institute 5735 South Ellis Avenue
President of Academia Sinica Chicago, IL 60637
Academia Sinica 773-702-5059
128 Academia Road USA
Section 2, Nankang [email protected]
Taipei 115
Taiwan
[email protected]
Also Available Electronically
Topics in Current Chemistry is included in Springer’s eBook package Chemistry

and Materials Science. If a library does not opt for the whole package the book series
may be bought on a subscription basis. Also, all back volumes are available
electronically.
For all customers with a print standing order we offer free access to the electronic
volumes of the series published in the current year.
If you do not have access, you can still view the table of contents of each volume
and the abstract of each article by going to the SpringerLink homepage, clicking
on “Chemistry and Materials Science,” under Subject Collection, then “Book
Series,” under Content Type and finally by selecting Topics in Current Chemistry.
You will find information about the
– Editorial Board
– Aims and Scope
– Instructions for Authors
– Sample Contribution
at springer.com using the search function by typing in Topics in Current Chemistry.
Color figures are published in full color in the electronic version on SpringerLink.
Aims and Scope
The series Topics in Current Chemistry presents critical reviews of the present and
future trends in modern chemical research. The scope includes all areas of chemical
science, including the interfaces with related disciplines such as biology, medicine,
and materials science.
The objective of each thematic volume is to give the non-specialist reader, whether
at the university or in industry, a comprehensive overview of an area where new
insights of interest to a larger scientific audience are emerging.
vii
viii Topics in Current Chemistry Also Available Electronically
Thus each review within the volume critically surveys one aspect of that topic
and places it within the context of the volume as a whole. The most significant
developments of the last 5–10 years are presented, using selected examples to illus-
trate the principles discussed. A description of the laboratory procedures involved
is often useful to the reader. The coverage is not exhaustive in data, but rather
conceptual, concentrating on the methodological thinking that will allow the non-
specialist reader to understand the information presented.
Discussion of possible future research directions in the area is welcome.
Review articles for the individual volumes are invited by the volume editors.
In references Topics in Current Chemistry is abbreviated Top Curr Chem and is
cited as a journal.
Impact Factor 2010: 2.067; Section “Chemistry, Multidisciplinary”: Rank 44 of 144
Preface
Natural product chemistry very often stimulates the development of novel pharma-
ceutical drugs. In fact, the vast majority of new lead structures in medicinal
chemistry are derived from frameworks of naturally occurring compounds. In this
respect alkaloids lead the way and consequently a breathtaking progress in the
chemistry of alkaloids has taken place over the last century. Especially over the past
decades, we can follow the evolution of numerous novel synthetic methodologies
for the total synthesis of biologically active alkaloids. Due to space limitation, of
course only a few aspects of some recent developments in “Alkaloid Synthesis”
could be highlighted in the present volume of Topics in Current Chemistry. In six
contributions, different research teams from Austria, Australia, Canada, Japan and
Germany have summarized important achievements of the past decade.
In the first chapter, Mariko Kitajima and Hiromitsu Takayama from the Gradu-
ate School of Pharmaceutical Sciences at Chiba University in Japan describe the
isolation and asymmetric synthesis of Lycopodium alkaloids. The following chapter
is a joint contribution by Uwe Rinner from the Institute of Organic Chemistry at the
University of Vienna in Austria and Tomas Hudlicky from the Department of
Chemistry and Centre of Biotechnology at Brock University in St. Catharines,
Canada. They discuss recent developments in the synthesis of morphine alkaloids
and derivatives. Thomas Lindel, Nils Marsch and Santosh Kumar Adla from the
Institute of Organic Chemistry at the Technical University of Braunschweig de-
scribe important aspects of indole prenylation in alkaloid synthesis. Yasuyuki Kita
from the College of Pharmaceutical Sciences at Ritsumeikan University in Shiga,
Japan, and Hiromichi Fujioka from the Graduate School of Pharmaceutical
Sciences at Osaka University in Japan compiled in their joint chapter the synthesis
of marine pyrroloiminoquinone alkaloids. The penultimate chapter by Martin G.
Banwell, Nadia Gao, Brett D. Schwarz and Lorenzo V. White from the Research
School of Chemistry and Institute of Advanced Studies at The Australian National
University in Canberra, Australia, report on Amaryllidaceae and other terrestrially-
derived alkaloids. Finally, an article with Ingmar Bauer as co-author from our own
laboratories of the Department of Chemistry at the Technical University of Dresden
ix
x Preface
in Germany outlines recent developments in the synthesis of pyrrole and carbazole

alkaloids.
I am very grateful to all authors and co-authors of this special volume of Topics
in Current Chemistry for their contributions and for their efforts to meet the time-
lines. I am convinced that the present compilation of recent developments in
“Alkaloid Synthesis” represents a useful and stimulating reference source not
only for researchers active in this field but also for young scientists and students.
Dresden Hans-Joachim Knölker

August 2011
Contents
Lycopodium Alkaloids: Isolation and Asymmetric Synthesis . . . . . . . . . . . . . . . 1

Mariko Kitajima and Hiromitsu Takayama
Synthesis of Morphine Alkaloids and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Uwe Rinner and Tomas Hudlicky
Indole Prenylation in Alkaloid Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Thomas Lindel, Nils Marsch, and Santosh Kumar Adla
Marine Pyrroloiminoquinone Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Yasuyuki Kita and Hiromichi Fujioka
Synthetic Studies on Amaryllidaceae and Other Terrestrially

Derived Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Martin G. Banwell, Nadia (Yuqian) Gao, Brett D. Schwartz,
and Lorenzo V. White
Synthesis of Pyrrole and Carbazole Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Ingmar Bauer and Hans-Joachim Knölker
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
xi
Top Curr Chem (2012) 309: 1–32
DOI: 10.1007/128_2011_126
Published online: 31 March 2011
Lycopodium Alkaloids: Isolation

and Asymmetric Synthesis
Mariko Kitajima and Hiromitsu Takayama
Abstract Lycopodium alkaloids have attracted the attention of many natural

product chemists and synthetic organic chemists due to their important biological
activities and unique skeletal characteristics. In this review we describe isolation
and asymmetric syntheses of several new alkaloids such as lycoposerramines-C,
-V, -W, and cernuine, and show that asymmetric total synthesis played a key role in
elucidating the structures of these complex natural products.
Keywords Alkaloid Asymmetric synthesis Isolation Lycopodium Structure

elucidation
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 Fawcettimine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.1 Lycoposerramine-A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2 Lycoposerramine-B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.3 Lycoposerramine-C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3 Phlegmarine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.1 Lycoposerramine-V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.2 Lycoposerramine-W . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.3 Lycoposerramines-X and -Z . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4 Cernuine and Related Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.1 Establishment of an Efficient Route to a Common Synthetic Intermediate . . . . . . . . . . 21
4.2 Quinolizidine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4.3 Cernuane-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
M. Kitajima and H. Takayama (*)

Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba
263-8522, Japan
e-mail: [email protected]
2 M. Kitajima and H. Takayama
Abbreviations
AChE Acetylcholine esterase

CBS Corey–Bakshi–Shibata
CDI Carbonyl diimidazole
DIAD Diisopropyl azodicarboxylate
DMP Dess–Martin periodinane
DPPA Diphenylphosphinyl azide
dppf 1,10 -Bis(diphenylphosphino)ferrocene
DTAD Di-tert-butyl azodicarboxylate
IBX 2-Iodoxybenzoic acid
Ipc Isopinocampheyl
NMO N-Methylmorpholine oxide
Ns Nosyl
TASF Tris(dimethylamino)sulfonium difluorotrimethylsilicate
Teoc 2-(Trimethylsilyl)ethoxycarbonyl
1 Introduction
Plants belonging to the genus Lycopodium, Family Lycopodiaceae, are widely

distributed all over the world. More than 500 species exist and many of them thrive
in tropical regions. Since B€ odeker isolated lycopodine (1) from Lycopodium com-
planatum in 1881 [1], chemical investigations of the constituents of Lycopodium
plants have been energetically carried out by many groups [2–12].
Among the alkaloids in Lycopodium plants, huperzine A (2) was isolated from
Lycopodium serratum Thunb. in 1986 and has been shown to have acetylcholine
esterase (AChE) inhibitory activity and to improve memory disorders in Alzheimer’s
disease [13–15]. In addition to these unique activities, it was recently reported that
some Lycopodium alkaloids possessing skeletons different from that of huperzine
A (2) are able to enhance nerve growth factor (NFG) mRNA expression and
production in human glial cells [16, 17]. Because of their useful biological activ-
ities, Lycopodium alkaloids are an attractive target in natural product chemistry,
synthetic chemistry, and medicinal chemistry.
Hemscheidt and Spenser conducted feeding experiments and found that
Lycopodium alkaloids are secondary metabolites of lysine (3) [18] (Scheme 1).
The decarboxylation of lysine (3) yields cadaverine (4), which consists of five
carbons, and this, in turn, is converted into D1-piperideine (5). The condensation of
D1-piperideine (5) with 3-oxoglutaric acid (6) produces 4-(2-piperidyl)acetoacetic
acid (7) and this is converted into pelletierine (8) after a decarboxylation reaction.
The biosynthetic process from this point to structurally complex Lycopodium
alkaloids, such as lycopodine (1) and huperzine A (2), is deduced from the structures
of the isolated alkaloids. The condensation of pelletierine (8) with 4-(2-piperidyl)
Lycopodium Alkaloids: Isolation and Asymmetric Synthesis 3
H COOH
NH2 NH2 3-Oxoglutaric acid (6)

–CO2
N O
NH2 NH2 CO2H
1-Piperideine (5)
Lysine (3) Cadaverine (4)
CO2H
–CO2
Me
O O
CO2H CO2H
O –CO2
H N Me N
N H H H
O
NH Pelletierine (8) 7
–CO2 7
Pelletierine (8) Me Me
Me
OH OH OH
7 H H
O N HO N N
13
12 4
N H N NH
9 10
Tandem cyclization Tetracyclic

basic skeleton
16
Me Me Me
15
8 14 H H
H 7 5 N 5 O
N 6
O H 1 H 4
H H 13
H 3
Me 12
NH 4 2 N
NH2 11 3 1 2
9
10
Huperzine A (2) Lycodine Lycopodine (1)
Scheme 1 Hypothetical biogetetic route of Lycopodium alkaloids
acetoacetic acid (7) and the successive oxidation would afford intermediate 9
having two enamine functions in the molecule. Intramolecular tandem cyclization
would produce plausible biosynthetic intermediate 10 having a tetracyclic basic
skeleton. From this key intermediate, more than 250 Lycopodium alkaloids would
be derived by further re-cyclization, oxidation, and/or rearrangement. Huperzine A
(2) mentioned above belongs to the lycodine-type alkaloids.
The highly diverse and unique skeletal characteristics of Lycopodium alkaloids
have inspired many groups to design total syntheses of these alkaloids. However,
there are very few reports of their biological activities. Recently, we have initiated a
chemical investigation of Lycopodium plants, including structure elucidation and
total syntheses, to find seed and lead molecules for drug development. In this
review we describe the results of our chemical investigation of some new alkaloids
isolated from L. serratum Thunb. and Lycopodium cernuum L., both of which were
collected in Japan.
2 Fawcettimine-Type Alkaloids
Fawcettimine-type alkaloids possess a C16N1 skeleton and are considered to be

derived from the lycopodine skeleton (Scheme 2). Initially, the nucleophilic attack
of water on C-13 of the lycopodine skeleton, followed by C-13–N bond scission,
would occur. Next, the Wagner–Meerwein rearrangement would proceed to form
the fawcettimine skeleton. Fawcettimine (11) exists as an equilibrium mixture of
the carbinolamine form and the keto-amine form. A number of fawcettimine-type
alkaloids derived from each form have been isolated from nature.
2.1 Lycoposerramine-A
New alkaloid 12, named lycoposerramine-A [19], was found to have the molecular
formula C18H29N3O2. In its 13C NMR spectra, the chemical shift of the carbonyl
carbon signal (dC 157.0) indicated the existence of a novel urethane function in the
molecule. Furthermore, the characteristic signal at dC 88.6 implied the presence
of an sp3 carbon that had an aminoacetal function. 1H-1H COSY, HMQC, and
HMBC spectral data (Fig. 1) enabled us to construct the basic skeleton of 12, which
consists of a fused tricyclic ring system with five- and six-membered cycloalkanes
and 1-azacyclononane, retaining the fundamental backbone of the known alkaloid,
fawcettimine (11) with the keto-amine form, as shown in Scheme 2. To construct
the final structure of 12 by incorporating the remaining elements, i.e., one carbonyl,
two nitrogens, and one oxygen atom, several candidates having the spectroscopic
data mentioned above could be nominated. Finally, X-ray crystallographic analysis
of 12 showed that lycoposerramine-A (12) is the first example of a natural product
that contains a novel 1,2,4-oxadiazolidin-5-one residue in the molecule.
Me Me
O H2 O O
Lysine (3) H H
X 13 X 12 4
(see Scheme 1) N O
H
H
lycopodine-type skeleton N
H
H O
H H O 5
15 O 7 H H
8 Me
16 H H 13 12 4
Me 3 O
14 13 12 4
N
1 2
9 N
10 H
Fawcettimine (11) Fawcettimine
carbinolamine form keto-amine form
Scheme 2 Hypothetical biogenesis of fawcettimine

OH
H 6 5
N N H N
O H 15 8 7
Me 16 H H
HN Me
O X 14 13 12 4 3
O
11 1 2
N N 10
Me Me 9 N
Me
1H-1H
Lycoposerramine-A (12) COSY Lycoposerramine-B (13)
HMBC
Fig. 1 Structures of lycoposerramines-A and -B
2.2 Lycoposerramine-B
The new alkaloid 13, named lycoposerramine-B [20], was deduced from NMR and
MS data to have a fundamental skeleton of the fawcettimine keto-amine form with a
ketone and an oxime function. The stereochemistry at C-7, C-12, and C-15 was
assumed to be the same as those in fawcettimine (11) based on biogenetic specula-
tion. The configuration at C-4 was inferred from J-resolved HMBC spectral data; an
anti relationship between H-4 and C-7 and a gauche relationship between H-4 and
C-13. To confirm the structure of 13 that was inferred by spectroscopic analysis, we
attempted its synthesis from serratinine (14) [21–24], the structure and absolute
configuration of which had been proven by X-ray analysis. Initially, according to
the procedure reported in the literature [21–24], monoacetate 15 was prepared from
serratinine (14) (Scheme 3). Then the free secondary hydroxyl group in 15 was
removed according to Barton’s procedure. Xanthate derivative 16 was exposed to
radical conditions by using n-Bu3SnH in the presence of AIBN to afford deoxy
derivative 17. Quaternary ammonium derivative 18, which was prepared from 17,
was treated with Zn powder in AcOH to give ring-opening product 19 in high
yield. The structure of 19 was established by X-ray crystallographic analysis,
revealing that the stereochemistry at C-4 was (S), which was opposite to that of
lycoposerramine-B (13). The epimerization at C-4 in 19 did not occur under basic
conditions. On the other hand, 19 was converted into alcohol 21 by oximation and
this was followed by deacetylation of resulting oxime 20. The conversion of the
hydroxy group at C-13 into the ketone failed in 21 due to a labile oxime function
under the attempted oxidation conditions.
Therefore, we adopted an alternative strategy that featured regioselective oxima-
tion (Scheme 4). Initially, diketone derivative 22 was prepared from 8-deoxy
compound 17 via removal of the acetyl group followed by oxidation of the resulting
secondary alcohol, and then 22 was subjected to the reductive ring-opening reaction
developed above. The conversion of 22 into a quaternary ammonium intermediate
and the subsequent treatment with Zn powder in AcOH afforded two C-4 epimeric
ring-opening compounds 23 and 24. More polar compound 23 showed the desired
H O Ac O
H O 1) Ac2O H O NaH, HMPA, THF;
8 pyridine, 98%
H H CS2
Me Me
13
N 2) 10% HCl N MeI, rt
OH OH
reflux, 84% 91% (brsm)
Serratinine (14) 15
H Ac O H Ac O
O MeOTf O
8
H H Zn, AcOH, rt
Me Me
N MeCN, rt N 99% (2 steps)
R
TfO Me
16: R=OC(=S)SMe n-Bu3SnH,AIBN 18
17: R=H toluene, reflux, 77%
Ac R NOH
H O H O
O
H H
H H
Me
4
NH2OH•HCl, AcONa Me 13
EtOH, reflux, 80%

N N
Me
19 (X-ray) Me
20: R=Ac NaOH, MeOH
21: R=H reflux, 52%
No epimerization at C-4
C-13 keto derivative
Scheme 3 Conversion of serratinine to tricyclic compounds
(R) configuration on C-4 (H-4b) by X-ray crystallographic analysis. On the other

hand, 24 could be epimerized at C-4 under basic conditions, enabling the conver-
gence of 24 having H-4a into desired 23 having H-4b. The oximation of diketone
23 with 1 equiv. of NH2OHlHCl under conventional conditions gave undesired
regioisomer 25 with an oxime function at C-13. This result suggested that the
carbonyl function at C-13 in 23 was more reactive than that at C-5 toward the
addition reaction of amine. On the basis of the difference in their reactivities, 23
was treated with Et2NH in EtOH, followed by the addition of NH2OHlHCl, to give
lycoposerramine-B (13) as expected. All of the spectroscopic data, including the
optical rotation of synthetic 13, were identical with those of natural lycoposerra-
mine-B. In this reaction, the geometrical isomer on the oxime function was also
obtained in 19% yield. The E/Z geometry of the oxime function was estimated by
comparing the chemical shifts of both protons and carbons. In the 1H NMR spectra,
the syn proton to the oxime hydroxy group showed a low-field shift compared to
the anti proton due to the anisotropy effect of the oxime oxygen. In addition, the
syn carbon showed a high-field shift compared to the anti carbon because of the
g-gauche effect of the oxime oxygen. According to this general rule, the E/Z
geometry of the oxime function in 13 and 26 was decided by comparing the
chemical shifts of the protons and carbons at C-4 and C-6.
H Ac O 1) KOH, MeOH H O 1) MeOTf

O reflux, quant
H H MeCN, rt
Me Me
13 13
N 2) Jones reagent O N 2) Zn, AcOH, rt
acetone, rt, 98% 23: 34%
17 22 24: 30%
H 5 O H 5 O
H H H H
Me NH2OH•HCl, AcONa Me
13 4 13
O N
EtOH, reflux, 70% HO
N N
Me 25 Me
23: H-4 (X-ray)
t-BuOK, t-BuOH, rt
24: H-4
H 2.20, 2.54
H 2.12, 2.40
C 28.7
C 31.3
OH Z
6 E 6
H N 3.18 H N
Et2NH, EtOH H OH
23 H H H H
Me Me H 3.59
H-4 then 4 42.9 4
NH2OH•HCl O C O C 39.6
+
N N
Me Me
Lycoposerramine-B (13): 46% 26: 19%
Scheme 4 Synthesis of lycoposerramine-B
2.3 Lycoposerramine-C
The structure of the new alkaloid 27, named lycoposerramine-C [25], was deduced
to be a fawcettimine-type alkaloid possessing a double bond at the C-6 and C-7
positions of fawcettimine (11), and was finally established by X-ray crystallographic
analysis (Fig. 2). Although our preliminary biological screening indicated that 27
possesses potent AChE inhibitory activity, further examination of the activity has
been restricted by its limited availability in nature. In order to develop an efficient
synthetic route to 27 for further examination, we planned the asymmetric total
synthesis of 27.
(S)-(+)-4-Phenyloxazolidinone (28) was acylated with crotonoyl chloride to give
crotonamide 29 (Scheme 5). Diastereoselective Hosomi–Sakurai allylation of
29 with allyltrimethylsilane in the presence of TiCl4 afforded compound 30 in a
sufficient yield with a diastereomeric ratio of ca. 8:1. Next, the direct conversion of
the oxazolidinone 30 into the Weinreb amide 31 was achieved using N,O-dimethyl-
hydroxylamine.
The absolute configuration of the stereogenic center in Weinreb amide 31
([a]D22 13.1 (c 0.23, CHCl3)) was confirmed to be (R) by direct comparison
with 31 ([a]D22 16.3 (c 0.08, CHCl3)) prepared from (R)-(+)-citronellic acid (32)
in six steps (Scheme 6).
H 6
HO O
Me 7
Lycoposerramine-C (27)
Fig. 2 Structure of lycoposerramine-C
O TMS
O O O
n-BuLi TiCl4
O NH + Cl O N Me
THF, –78 °C CH2Cl2, –78 °C
Ph Me 97% Ph
(S)-(+)-4-Phenyl-
29
oxazolidinone (28)
O AlMe3 O Me
O Me
NH(OMe)Me•HCl
MeO
O N N
THF, rt
93% (2 steps) Me
Ph 31
30 [ ]D22 –13.1 (c 0.23, CHCl3)
Scheme 5 Preparation of Weinreb amide 31
1) CDI
O Me Me NH(OMe)Me•HCl O Me
CH2Cl2, rt, 90% MeO
HO Me N CHO
2) RuCl3, NaIO4 Me
(R)-(+)-Citronellic acid (32) H2O, (CH2Cl)2 33
rt, 91%
1) NaBH4, EtOH, rt, 78% O Me

2) MsCl, Et3N, CH2Cl2 MeO
N
3) (PhSe)2, NaBH4, EtOH, 94% (2 steps) Me 31
4) H2O2, THF, 34%
[ ]D22 –16.3 (c 0.08, CHCl3)
Scheme 6 Alternative synthesis of Weinreb amide 31
The coupling reaction of Weinreb amide 31 with alkyne 34 using i-PrMgCl as a

base produced 1,7-enyne compound 35 in a quantitative yield (Scheme 7). The
diastereoselective reduction of alkynyl ketone 35 with (S)-Corey–Bakshi–Shibata
(CBS) reagent gave a propargyl alcohol and then the resulting secondary hydroxyl
group was protected with a TIPS group to afford substrate 36 for the Pauson–Khand
reaction [26–28]. After several attempts to use the intramolecular Pauson–Khand
reaction to construct a tetrahydroindenone core, we finally found that pretreatment
O Me
O Me OTBDPS 1) (S)-CBS,BH3•SMe2
34 THF, – 40°C, 97%
MeO
N
i-PrMgCl, THF, rt 2) TIPSOTf
Me 31 quant OTBDPS 2,6-lutidine, CH2Cl2
35 rt, 99%
NOE
TIPSO Me H
H
Co2(CO)8,CH2Cl2
15 O 7 Si(i-Pr)3
rt under Ar Me H
13 15
14 13 12 O
then
H H
OTBDPS NMO, CH2Cl2
2.4 Hz
rt under CO
36 87% TBDPSO 37
Scheme 7 Synthesis of bicyclic compound 37 by Pauson-Khand reaction
Fig. 3 Mechanistic consideration of Pauson-Khand reaction of 36
of 36 with Co2(CO)8 in CH2Cl2 at room temperature under Ar atmosphere, fol-

lowed by manipulation of the resulting coordination product with 4-methylmorpho-
line N-oxide (NMO) in CH2Cl2 at room temperature under CO atmosphere,
produced desired bicyclo compound 37 having H-7b in 87% yield as the major
product. The configuration at C-7 was determined from the NOE correlation
between H-7 and H-15. Major product 37 would be obtained via a pseudo-chair
transition state in which the methyl group took an equatorial orientation (Fig. 3).
Next, we turned our attention to the construction of a quaternary center at C-12
in the fawcettimine skeleton. For this purpose, we employed the vinyl Claisen
rearrangement providing an aldehyde functionality useful for extension of the
side chain (Scheme 8). Reduction of enone 37 with (R)-CBS reagent gave allyl
alcohol 38 in good yield with excellent selectivity (5H-a:5H-b ¼ 1:15).
Scheme 8 Synthesis of tricyclic compound 44
The stereochemistry of the resulting secondary alcohol was demonstrated by the

NOE correlation of H-7 to H-5. Allyl alcohol 38 was treated with phenyl vinyl
sulfoxide in the presence of NaH and a catalytic amount of KH to give sulfoxide 39

in quantitative yield [29]. Then 39 was heated at 170 C in 1,2-dichlorobenzene
in the presence of excess NaHCO3 to produce aldehyde 40 having an expected
(12S) quaternary carbon center. Synthesis of the tricyclic compound containing an
azonane ring from aldehyde 40 was achieved by applying the nosyl (Ns) strategy
[30–32]. Conversion of 40 into a,b-unsaturated nitro compound by the nitro-aldol
reaction, followed by reduction with LiAlH4, gave primary amine 41. Substrate 42
for the intramolecular Mitsunobu reaction was obtained via a one-pot operation
from 41, i.e., installation of the Ns group onto the primary amine and subsequent
removal of the TBDPS group. Under highly diluted conditions, azonane ring
compound 43 was obtained in excellent yield by treating 42 with diisopropyl
azodicarboxylate (DIAD). The protecting group on the secondary amine was
switched to the Boc group to afford desired tricyclic compound 44.
Then 44 was converted into ketone 45 by the conventional hydroboration-
oxidation procedure and the subsequent Dess–Martin oxidation (Scheme 9). At
this stage, X-ray crystallographic analysis of 45 enabled us to determine the
configuration of the stereogenic center at C-4 as (S). By applying the Ito–Saegusa
H H
TIPSO BH3•THF DMP TIPSO O
Me THF, rt CH2 Cl2 Me 4
then rt
3N NaOH aq 84%
44 NBoc 30% H2O2 45 NBoc
H2O, rt, quant (X-ray)
1) LDA, TMSCl
TIPSO O O
Et3N, THF 1) TBAF, AcOH
0 °C Me THF, rt, quant Me 4
O
2) Pd(OAc)2 2) DMP, CH2Cl2
CH3CN, rt 46 rt, 99% 47
NBoc NBoc
73% (2 steps)
H O H O
ZnBr2 HO t-BuOK
Me 12 Me
EtOH, rt 13 4 THF, 0 °C
N O N
91% 95%
Lycoposerramine-C (27) Phlegmariurine-A (48)
Scheme 9 Completion of the total synthesis of lycoporerramine-C and phlegmariurine-A
oxidation, 45 was regioselectively converted into a,b-unsaturated ketone 46.

Removal of the TIPS group in 46 and subsequent Dess–Martin oxidation of the
resulting alcohol gave desired diketone 47, which was a precursor of lycoposerra-
mine-C. Removal of the Boc group in 47 and simultaneous isomerization at C-4
[33, 34] to form the hemiaminal function were accomplished by treating 47 with
excess ZnBr2 in EtOH to give lycoposerramine-C (27) in high yield. Synthetic 27
was identical in all respects with the natural product, including the optical rotation,
thereby establishing its structure including its absolute configuration [35].
Phlegmariurine-A (48) isolated from L. serratum would be biogenetically
generated by a C-12–C-13 bond scission in lycoposerramine-C (27). In accordance
with this idea, we treated 27 with t-BuOK in THF to form 48 selectively in excellent
yield, as expected. This result supported the possibility that lycoposerramine-C (27)
might be a biogenetic precursor of phlegmariurine-type alkaloids.
3 Phlegmarine-Type Alkaloids
Phlegmarine-type alkaloids possess a C16N2 skeleton that consists of a piperidine

ring and a (decahydro)quinoline ring that are connected via a methylene group
(Scheme 10). They might be the biogenetic intermediates of lycodine (49). We next
describe the structure elucidation of this new class of alkaloids based on asymmetric
total syntheses.
Scheme 10 Hypothetical biogenesis of lycodine and phlegmarine-type alkalooids
3.1 Lycoposerramine-V
New compound 50, named lycoposerramine-V [36], had a phlegmarine skeleton

with the 5,6,7,8-tetrahydroquinoline moiety, the first of such to be discovered
among Lycopodium alkaloids, in contrast with common phlegmarine-type alkaloids
possessing a decahydroquinoline ring. The relative stereochemistry at H-7 and
H-15 was found to be cis by NOE analysis. However, it was not possible to
elucidate the relative stereochemistry between C-7 in the decahydroquinoline ring
and C-5 in the piperidine ring by spectroscopic analyses. Then we attempted the
asymmetric total synthesis of lycoposerramine-V to reveal its relative and absolute
configurations. The absolute configuration at C-15 was deduced to be (R) based on
the biogenesis of common Lycopodium alkaloids and, therefore, C-7 could be (R)
from the NOE data. As the asymmetric center at C-5 could not be determined from
spectroscopic analyses, we planned the synthesis of both stereoisomers with (5S)
(50) or (5R) (51) configuration (Fig. 4).
Initially, cyclohexenone 53 was prepared from commercially available
(R)-3-methylcyclohexanone (52) via a three-step operation in 49% yield (Scheme 11).
a-Iodination of cyclohexenone 53 with I2/pyridine gave iodide 54 in 85% yield.
Next, the installation of a 3-hydroxypropane side chain onto 54 was accomplished
with a tandem sequence involving the regioselective hydroboration of alkene 55
with 9-BBN, followed by coupling of the resulting borane under Pd-catalyzed
Suzuki–Miyaura conditions [37] in 83% yield. Regio- and stereoselective reduc-
tion of thus obtained enone 56 under Luche conditions gave allyl alcohol 57 as a
single isomer in 98% yield. Allyl alcohol 57 was subjected to the Johnson–Claisen
rearrangement to construct a C-7 stereogenic center by taking advantage of the
stereochemistry of the allyl alcohol function to yield 58.
By a conventional hydroboration-oxidation procedure [38], 58 was converted
into alcohol 59 as the major product in 75% yield with 82% de. Removal of the
3
2 4
5S 1 5R
N N 6
11
H H H H 12
7 8 7 10
15 15
16 9
Me N Me 14
13 N
50 51
Fig. 4 Structures of lycoposerramine-V and its C-5 epimer
1) LDA, PhSSPh
THF, –78 °C to rt
2) m-CPBA, CH2Cl2
I
–78 °C I2, pyridine
Me O 3) CaCO3, CCl4 Me O CCl4, 0 °C to rt Me O
52 65 °C 53 85% 54
49% (3 steps)
OTBDPS
1) 9-BBN, 55
THF, 0 °C to reflux OTBDPS NaBH4, CeCl3
2) Pd(dppf)Cl2, NaOH aq Me O MeOH, 0 °C

THF, rt to reflux 56 98%
83%
CH3C(OEt)3 EtO2C
OTBDPS o-nitrophenol 7
OTBDPS
Me OH xylene, reflux
92% Me
57 58
1) BH3•THF EtO2C 1) TBAF, THF

THF, 0 °C to rt rt, 99%
OTBDPS
2) H2O2 aq 2) (COCl)2, DMSO
NaHCO3 aq Me OH Et3N, CH2Cl2
0 °C to rt 59 –78 °C to rt
75%, 82% de
EtO2C EtO2C
NH2OMe-HCl
CHO AcOH LiAlH4,THF
toluene, reflux 0 °C to rt
Me O Me N
55% (2 steps) 98%
60 61
OHC
HO
(COCl)2, DMSO, Et3N
CH2Cl2, –78 °C to rt
Me N 98% Me N
62 63
Scheme 11 Synthesis of key intermediate 63

TBDPS group by TBAF and subsequent Swern oxidation of the resulting diol gave
keto-aldehyde 60. Next, 60 was subjected to Knoevenagel conditions with slight
modification using NH2OMelHCl to afford 5,6,7,8-tetrahydroquinoline 61. Reduc-
tion of the ester group in 61 with LiAlH4 and subsequent oxidation under Swern
conditions gave aldehyde 63.
Next, we employed Brown’s asymmetric allylation with B-allyldiisopino-
campheylborane [39, 40] to construct the C-5 stereogenic center (Scheme 12).
Treatment of aldehyde 63 with B-allyldiisopinocampheylborane prepared from
(+)-B-chlorodiisopinocampheylborane and allylmagnesium bromide furnished
homoallylic alcohol 64 in 97% yield with good diastereoselectivity (92% de).
The absolute configuration of the newly generated stereogenic center was assigned
as (R) based on a well-established reaction mechanism and confirmed later by X-ray
crystallographic analysis. The alcohol thus obtained was converted into azide 65
in 79% yield in two steps accompanying the stereoinversion at C-5 position via an
O-mesylated derivative. Using the Staudinger reaction, azide 65 was transformed
into primary amine, which, in turn, was directly acylated with acryloyl chloride to
give substrate 66 for RCM in 65% yield in two steps. X-ray crystallographic
analysis of 66 enabled the unambiguous assignment of all stereogenic centers as
(5S),(7R),(15R) configuration. RCM of 66 using first-generation Grubbs’ ruthenium
catalyst proceeded smoothly to generate unsaturated lactam 67 in 96% yield.
OHC
5
1) MsCl, Et3N
(+)-Ipc2BCl, allylMgBr CH2Cl2, 0 °C
HO
H
Et2O, THF, –100 °C 2) NaN3, DMF
Me N 80 °C
97%, 92% de
63 79% (2 steps)
Me N
64
1) PPh3, H2O, THF 5

N3 reflux O N 1st Grubbs cat.
H H H
2) ClCOCHCH2, Et3N CH2Cl2, rt
7
CH2Cl2, 0 oC to rt 15 96%
Me N 65% (2 steps) Me N
65 66 (X-ray)
5S
O N 1) H2, Pd/C, AcOEt, rt N
H H
2) BH3•THF, THF, reflux 7
15
76% (2 steps)
Me N Me N
67 Lycoposerramine-V (50)
Scheme 12 Completion of the total synthesis of lycoporerramine-V

Finally, reduction of the double bond with H2/Pd/C and subsequent reduction
of lactam with BH3lTHF to construct the piperidine ring afforded the desired
compound 50 with the (5S),(7R),(15R) configuration.
Starting from common intermediate 52, we achieved the asymmetric synthesis
of compound 51 possessing the (5R),(7R),(15R) configuration in 22% yield in seven
steps by using a sequence similar to that described above via a homoallyl alcohol
having the (5S) configuration, which was prepared by the asymmetric allylation
reaction of 63 using ()-B-chlorodiisopinocampheylborane.
Having both target compounds (50 and 51) in hand, we compared their physico-
chemical data with those of the natural product. As a result, compound 50 was
completely identical in all respects with natural lycoposerramine-V. Therefore,
the structure, including the absolute configuration of the stereogenic center, was
established to be 50 possessing the (5S),(7R),(15R) configuration [36].
3.2 Lycoposerramine-W
Compound 68, named lycoposerramine-W, was deduced to be an Na-methyl-

3-hydroxy derivative of lycoposerramine-V (50) from spectroscopic analyses
(Fig. 5). Its relative configuration between C-5 and C-7 and the absolute configura-
tion at C-5, C-7, and C-15 would be the same as those of 50 based on biogenetic
consideration. Furthermore, the remaining stereogenic center (C-3) would be (S),
that is, the hydroxy group is in an a-axial orientation, based on the coupling
constant of the proton on C-3 (d 4.08, dddd, J ¼ 4.9, 4.9, 3.7, 3.7 Hz). Then we
focused on the asymmetric synthesis of compound 68 having the 3(S),5(R),7(R),15
(R) configuration to elucidate the structure of lycoposerramine-W.
Azide 65, an intermediate of the synthesis of lycoposerramine-V, was converted
into primary amine by the Staudinger reaction and the resulting amine was directly
treated with methyl chloroformate to give methyl carbamate derivative 69
(Scheme 13). Reduction of the carbamate with LiAlH4 gave N-methyl derivative
70 and then the resulting secondary amine was acylated with chloroacetylchloride
H OH H 4.08
3S 3 H (J = 4.9, 4.9, 3.7, 3.7)
5R N 5 equatorial
N Me HO H
Me H 7
N
15R
7R axial
H 15
Me N
Me
Lycoposerramine-W (68)
Fig. 5 Structure of lycoposerramine-W

1) PPh3, H2O MeO

N3 THF, reflux O N LiAlH4 H N
H H H Me H
2) ClCO2Me, Et3N THF
CH2Cl2, 0 °C to rt reflux
Me N 96% (2 steps) Me N Me N
65 69 70
Cl Cl CHO
ClCOCH2Cl, Et3N OsO4, NaIO4 O N

O N Me H
CH2Cl2, 0 °C to rt Me H THF, H2O, rt
63% (2 steps) 84%
Me N Me N
71 72
H OH H OH
3 3
2 4
5 5
SmI2 BH3•THF
O N N
THF, 0 °C Me THF, reflux Me
40%, 79% de 83% 7
Me N Me 15 N
73 Lycoposerramine-W (68)
Scheme 13 Completion of the total synthesis of lycoporerramine-W
to yield amide 71. Oxidative cleavage of the terminal double bond in 71 under
Johnson–Lemieux conditions produced b-chloroacetamide-aldehyde 72. Next, the
samarium(II)-promoted stereoselective intramolecular Reformatsky reaction was
investigated. As far as we know, this reaction has been applied only to b-halo
acetoxy carbonyl substrates [41, 42], forming a lactone ring. None of the studies
that employed the intramolecular Reformatsky reaction used a b-haloacetamide-
carbonyl compound. After several attempts, we found that the use of samarium(II)
iodide freshly prepared from samarium metal and diiodomethane in THF gave the
best result, producing lactam 73 in 40% yield as the major product with good
diastereoselectivity (79% de). Careful analysis of the coupling constants of H-2
to H-5 demonstrated that H-3 was in an equatorial orientation and the relative
stereochemistry between C-3 and C-5 was trans. Having considered the reaction
mechanism [42], the stereochemistry of C-3 in 73 was determined to be (S), as
expected. Finally, the construction of a 4-hydroxy-2-substituted piperidine ring by
the reduction of lactam 73 with BH3lTHF afforded target compound 68 having the
(3S),(5R),(7R),(15R) configuration. Synthetic 68 was completely identical in all
respects, including the optical rotation, with natural lycoposerramine-W {synthetic
[a]D25 +21.5 (c 0.07, CHCl3)/natural [a]D25 +22.4 (c 0.14, CHCl3)}, thereby
establishing the absolute configuration of the natural compound as (3S),(5R),(7R),
(15R) [36].
3.3 Lycoposerramines-X and -Z
New alkaloids lycoposerramines-X (74) and -Z (75) are phlegmarine-type alkaloids

consisting of a piperidine ring with a novel nitrone residue and a decahydroquino-
line ring with four stereogenic centers [43] (Fig. 6). From spectroscopic analyses,
74 and 75 were found to be diastereomers at the C-13 position, but their absolute
configuration could not established. Then we planned the asymmetric total synth-
eses of 74 and 75 to confirm their structures, including the absolute stereochemistry.
The relative stereochemistry at C-7, C-12, and C-15 in the decahydroquinoline
ring in lycoposerramines-X (74) and -Z (75) is the same as that in compound 59,
the synthetic intermediate of lycoposerramines-V (50) and -W (68). Therefore,
compound 59 having four stereogenic centers in the cyclohexane ring was expected
to be a common intermediate for the divergent synthesis of lycoposerramines-X
(74) and -Z (75). Furthermore, we considered that a cis- or trans-decahydroquino-
line ring could be constructed by manipulating the hydroxy group at C-13. Based on
biogenetic consideration, the absolute configuration at C-15 in 74 and 75 was
deduced to be (R), similar to that of lycoposerramines-V (50) and -W (68). Initially,
the construction of a cis-decahydroquinoline ring in lycoposerramine-Z (75) was
carried out from common synthetic intermediate 59.
Acetylation of the secondary alcohol and deprotection of the silyl group of
the primary alcohol in 59, followed by replacement of the resulting hydroxy
group at C-9 with 2-nitrobenzenesulfonamide under Mitsunobu conditions and
removal of the acetyl group of the secondary hydroxy group at C-13, afforded
sulfonamide 76 (Scheme 14). Compound 76 was subjected to the intramolecular
Mitsunobu reaction with di-tert-butyl azodicarboxylate (DTAD) and PPh3 in THF
to give cis-decahydroquinoline 77.
After switching of the protecting group on the amine function in 77 from Ns to
2-(trimethylsilyl)ethoxycarbonyl (Teoc), reduction of the ester group afforded
alcohol 78 (Scheme 15). Oxidation of 78 with 2-iodoxybenzoic acid (IBX) gave
aldehyde 79. The installation of a C4 unit at C-5 was accomplished by treating 79
with an alkynyl anion that was prepared from 3-butyn-1-ol, producing diol 80 in
90% yield as a diastereomeric mixture. Selective oxidation of the hydroxy group on
the propargyl position with MnO2 gave a,b-unsaturated ketone 81. Mesylation
of the primary alcohol and subsequent reduction of the alkyne function afforded
keto-mesylate 82. Next, compound 82 was treated with 1.5 equiv. of NH2OHlHCl
Fig. 6 Structures of lycoposerramines-X and -Z

EtO2C 1) Ac2O, DMAP, Et3N EtO2C

CH2Cl2, rt, 92%
2) TBAF, THF, rt, 93%
9 9
Me 13 OH OTBDPS 3) NsNH2, DEAD, PPh3 Me OH NHNs
THF, rt, quant
59 4) NaOEt, EtOH, rt, 91% 76
EtO2C
12 H 12
DTAD, PPh3 H
14
N Ns
THF, rt 6 13
Me 13 N 15 H CO2Et
quant Me H
Ns
NOE
77
4.18 (ddd, J = 12.2, 4.6, 4.6)
Scheme 14 Synthesis of decahydroquinoline intermediate 77
EtO2C
1) PhSH, K2CO3 HO
DMF, rt IBX
Me N 2) Teoc-carbonate Me N DMSO, rt
DMAP, toluene 98%
Ns Teoc
rt, 80% (2 steps)
77 78
3) LiAlH4, THF
0 °C, 90%
5 OH
OHC OH
3-butyn-1-ol, n-BuLi MnO2
Me N HMPA, THF Me N CH2Cl2, rt

–78 °C to rt
Teoc 90% Teoc 75%
79 80
O
OH
1) MsCl, Et3N, CH2Cl2 MsO O
0 °C, 92%
Me N 2) H2, Pd/C, MeOH Me N

Teoc rt, 72% Teoc
81 82
1) NH2OH• HCl, K2CO3

EtOH/H2O (1:1) N
90 °C, 68% O 12
7
15
2) TASF, THF Me 13 N
0 °C, 78% R
Lycoposerramine-Z (75)
Scheme 15 Completion of the total synthesis of lycoporerramine-Z

in the presence of 0.5 equiv. of K2CO3 in EtOH/H2O (1:1) to yield the expected
cyclic nitrone in 68% yield. Finally, removal of the Teoc group with tris(dimethy-
lamino)sulfonium difluorotrimethylsilicate (TASF) in THF afforded lycoposerra-
mine-Z (75) in 78% yield. Synthetic 75 was identical in all respects with natural
lycoposerramine-Z, thereby establishing its structure as well as its absolute config-
uration as (7R),(12R),(13S),(15R) [44].
Next, we examined the construction of a trans-decahydroquinoline ring to
accomplish the synthesis of lycoposerramine-X (74) (Scheme 16). A nitrogen
function was introduced at C-13a in secondary alcohol 59 utilizing the Mitsunobu
reaction twice. After removal of the TBDPS group on the side chain, the resulting
primary alcohol was mesylated to yield substrate 84 for cyclization. Reduction
of the azide group in 84 led to the spontaneous cyclization. This was followed
by protection of the resulting secondary amine by the Teoc group to give trans-
decahydroquinoline 85 in 89% yield (two steps). According to the method for the
synthesis of 75 described above, trans-decahydroquinoline 85 was converted into
74. Synthetic 74 was identical in all respects with natural lycoposerramine-X,
thereby establishing its absolute configuration as (7R),(12R),(13R),(15R) [44].
EtO2C EtO2C 1) NaOEt, EtOH, rt, 94%

AcOH 2) DPPA, DEAD, PPh3
DTAD, PPh3 THF, –20 °C, 81%
Me 13 OH OTBDPS THF, rt Me 13 OAc OTBDPS 3) TBAF, THF, rt

65% 4) MsCl, Et3N, CH2Cl2
59 83
0 °C, 95% (2 steps)
EtO2C 1) H2, Pd/C EtO2C

N
EtOH, rt 12
steps 12
O
7
2) Teoc-carbonate 15
Me N3 OMs DMAP, toluene Me 13 N Me N13
rt Teoc H
84 89% (2 steps) 85 Lycoposerramine-X
(74)
Scheme 16 Completion of the total synthesis of lycoporerramine-X
Fig. 7 Common intermediate 59 for the syntheses of lycoposerramines-V, -W, -X, and -Z
As described above, we have achieved the asymmetric total syntheses of lyco-

poserramines-V (50), -W (68), -X (74), and -Z (75) using cyclohexanol 59 as
the common intermediate, which has enabled us to determine unambiguously the
structures, including the absolute configurations, of the four new phlegmarine-type
alkaloids (Fig. 7).
4 Cernuine and Related Alkaloids
From L. cernuum collected in Okinawa Prefecture, cernuine (86) and a new

alkaloid, cermizine C N-oxide (88), were isolated. Cernuine (86) is a representative
of cernuane-type Lycopodium alkaloids. It was isolated by Marion and Manske in
1948 and its structure was elucidated by Ayer et al. in 1967 [45, 46] (Fig. 8). Its
structure features a fused-tetracyclic ring system containing an aminal moiety that
is rare among Lycopodium alkaloids. The relative configuration of 86 was deter-
mined from the coupling constants in the 1H NMR spectra, but its absolute
configuration was deduced from CD spectra by comparison with those of related
alkaloids. Furthermore, the total synthesis of cernuane-type alkaloids has not been
reported to date, although those of various types of Lycopodium alkaloids have been
achieved. In 2004, Kobayashi et al. reported the isolation of cermizines possessing
a quinolizidine skeleton related to cernuine (86), in which some compounds
exhibited cytotoxicity to murine lymphoma L1210 cells [47]. However, the abso-
lute configuration of cermizines has not been clarified. Then, we attempted to
accomplish the first synthesis of cernuine (86) and to establish an efficient synthetic
route to these cernuane-type and quinolizidine-type alkaloids. Our endeavor has
enabled us to confirm their structures and absolute configurations. We focused on
the structure similarities between cernuane- and quinolizidine-type Lycopodium
16 Cernuane-type Quinolizidine-type H
15
14 H 12 Me
Me 11
13 N
H
8 NH 10 1
7 10
H 9 Me
6 N O Cermizine C (87)
5 1 H
4 2
C-1 & C-10 Me Reduction - Oxidation
3 H H
functionalization N 1 sequence Me
Cernuine (86)
N
10 O
H 12 HO
Me 15 Me O
13 Key intermediate Cermizine C
H
8 N 91 N-oxide (88)
HH 7 9
N H
1 5 Me
N
Cermizine D (90) 10
1
Me
Senepodine G (89)
Fig. 8 Divergent strategy for the total syntheses of cernuane-type and quinolizidine-type
Lycopodium alkaloids
alkaloids. As the target compounds have the same quinolizidine structure, we

envisioned that both cernuane- and quinolizidine-type alkaloids could have origi-
nated from a key intermediate that has the common quinolizidine core bearing
appropriate functional groups. Following a divergent strategy, we designed com-
pound 91 as the common key intermediate possessing the skeleton of cermizine
C (87) that was oxygenated at C-1 and C-10 positions.
4.1 Establishment of an Efficient Route to a Common

Synthetic Intermediate
The aldehyde in (+)-citronellal (92) was protected as an acetal function, and this
was followed by the Ru-catalyzed oxidative cleavage of the residual olefin function
to give aldehyde 93 (Scheme 17). Next, the organocatalytic a-amination of alde-
hyde 93 was investigated [48–50]. First we carried out the amination of 93 with
dibenzyl azodicarboxylate in the presence of a catalytic amount of an (S)-proline
derivative as organocatalyst. This was followed by in situ reduction to produce
oxazolidinone 94 under anhydrous conditions using K2CO3 in 94% yield with 84%
de. Next, reductive N–N bond cleavage in 94 was attempted. Sequential reduction
involving removal of the Cbz group under mild conditions (H2/Pd/C), followed by
hydrogenation of the resulting hydrazine with Raney Ni, gave cyclic carbamate 95
in good yield. Upon treatment of 95 with a catalytic amount of p-TsOH in refluxing
MeOH, cyclization occurred to give aminoacetal 96 as an allylation precursor.
Treatment of aminoacetal 96 with allyltrimethylsilane in the presence of TiCl4 at
low temperature gave 97 as the sole isomer at C-13, which would be formed by
stereoselective allylation of the acyliminium intermediate. The NOE correlation
between H-7 and the proton of the allyl group in 97 revealed that the allyl group was
introduced in an axial orientation. The stereoselectivity would be interpreted by the
axial attack of a nucleophile on the acyliminium intermediate that had a rigid
conformation defined by oxazolidinone. Hydrolysis of oxazolidinone in 97 under
basic conditions and subsequent acryloylation of resulting secondary amine 98 gave
acrylamide 99. The synthesis of key intermediate 91 was accomplished by RCM
with first-generation Grubbs catalyst, followed by hydrogenation of olefin. At
this stage, it was found that the conversion of hydrazine 94 into acrylamide 99
proceeded smoothly without purification, that is, the desired diastereomer of 99 was
obtained in pure form from 94 in six steps after a single chromatographic separation
from a concomitant diastereomer derived from the organocatalytic reaction of
aldehyde 93. Furthermore, it was found that the RCM reaction of 99 proceeded in
the presence of 1 mol% of catalyst to give 91. It is noteworthy that the present
procedure for the preparation of 91 required only two purification steps throughout
the eight-step conversion from 94 to 91 in 56% total yield. As described above, we
succeeded in the development of an efficient and practical synthetic route to pivotal
intermediate 91 in our divergent synthesis.
Me 1) cat. p-TsOH, ethylene glycol

Me
PhH, reflux
OHC
Me
2) RuCl3, NaIO4
(+)-Citronellal (92) (CH2Cl)2, H2O, rt, 87% (2 steps)
Ph Cbz
1) CbzN=NCbz, N Ph
H
HN
O Me CH2Cl2, rt
OTMS
O Me N Cbz
10 mol%
O OH
O then NaBH4 O
93 MeOH
Cbz
2) K2CO3 HN O H2N O
toluene O Me N 1) H2, 10% Pd/C O Me N
O O
reflux O EtOH, rt O
94% (2 steps) 94
84% de
O Me OMe
2) H2, Raney Ni p-TsOH TMS
O Me HN N
O O
EtOH 60 °C O MeOH TiCl4, CH2Cl2
reflux O
–78 to 0 °C
95 96
H 12.2 Hz
7 , Me Me H
N 15 13 15 14
O Me H
N N H
HO O H 13
Nu 7 O
O H7 O
97 NOE
H acryloyl chloride H
8M NaOH aq Me Et3N Me
H H
MeOH, reflux NH CH2Cl2, –78 oC N
56% (6 steps) O
HO HO
98 99
single diastereomer
1) 1st Grubbs cat. H
CH2Cl2 Me
H
2) H2, Pd/C N
EtOH, rt O
99% (2 steps) HO
91
Scheme 17 Synthesis of key intermediate 91

4.2 Quinolizidine-Type Alkaloids
Having developed an efficient route to the common intermediate 91, we next turned
our attention to the further transformation of 91 into quinolizidine-type alkaloids
(Scheme 18). The amido group in 91 was reduced with BH3lTHF in THF under
reflux to give amine 100. Without purification, 100 was treated with SOCl2 to yield
chloride 101, which was subjected to the next reaction without purification because
of instability on SiO2 gel. Reductive dehalogenation of chloride 101 with LiAlH4
afforded cermizine C (87) [51].
Next, cermizine C (87) was converted into cermizine C N-oxide (88) by
m-CPBA oxidation of 87. Synthetic 88 was identical in all respects with the new
alkaloid isolated from L. cernuum by us, thereby establishing its structure [51].
To synthesize senepodine G (89) [47], regioselective oxidation at C-9 position in
cermizine C (87) was required. We anticipated that cermizine C (87) and cermizine
C N-oxide (88) having a cis-quinolizidine skeleton would be suitable for the
regioselective oxidation to senepodine G (89). This is because among the protons
on C-1, C-5, and C-9, only the proton H-9 is situated at an anti-position to the N–O
bond in the activated intermediate that was prepared from cermizine C N-oxide (88)
in the Polonovski–Potier reaction. In fact, N-oxide 88 was treated with TFAA
in CH2Cl2 to give regioselectively senepodine G (89) in quantitative yield
H H H
Me Me Me
H BH3•THF H SOCl2 H
N N N
THF CHCl3
O reflux reflux
HO HO Cl
91 100 101
H H
Me Me
LiAlH4 m-CPBA 5
N N9
THF, reflux CH2Cl2, 0 °C 1
52% (3 steps) Me Me O
89%
(+)-Cermizine C (87) 88
O H
Me
TFAA Me O CF3
5 N
CH2Cl2, 0 °C Me N H
9 1 10
quant H Me CF3CO2
CF3CO2 (–)-Senepodine G (89)

TFA salt
Scheme 18 Completion of the total synthesis of quinolizidine-type alkaloids

(Scheme 18). In the 1H NMR spectra of synthetic 89, the signal for methyl protons
on C-10 was observed at d 2.45 (3H, s), confirming that the desired oxidation at C-9
position occurred. All of the spectroscopic data of synthetic 89 were identical with
the reported data of natural senepodine G in all respects [51].
4.3 Cernuane-Type Alkaloids
Next, we performed the syntheses of cernuane-type alkaloids, cermizine D (90) and

cernuine (86), from common key intermediate 91 (Scheme 19). The primary
alcohol in 91 was oxidized with IBX to give the aldehyde, which, in turn, was
subjected to the Wittig reaction without purification to afford 102. Mild acid
H H
Me 1) IBX, DMSO Me
H rt H 3M HCl
N N
2) Ph3PCH2(OMe)Cl THF
O KHMDS, THF MeO O rt
HO 62%
0 °C to rt
91 102 (3 steps)
t-Bu NH2
H S H
Me Me
H O H
N N
CuSO4, CH2Cl2, rt
O 93% t-Bu N O
OHC S 5
5
103 O H 104
1) MgBr
CH2Cl2, –78 °C
2) 3M HCl
MeOH, rt
54% (2 steps)
up to 60% de
H
NH2 Me
H
O N
106
H
H2N O
camphorsulfonic acid 5
(CH2Cl)2, rt 105
then NH2OH-AcOH
92%, 94% de
H Me H Me
N N
N 5 N
HO H HO H
O O
2-aza Cope rearrangement
Scheme 19 Stereoselective synthesis of homoallylamine 105

hydrolysis of the enol ether in 102 using 3M aq. HCl in THF gave carbon-elongated
aldehyde 103. To install allyl and amino groups onto aldehyde 103, we initially
adopted the Ellman protocol using a chiral sulfinimine [52]. Condensation of
aldehyde 103 and (R)-tert-butanesulfinamide in the presence of CuSO4 in CH2Cl2
afforded sulfinimine 104 in high yield. The addition of allylmagnesium bromide,
followed by the removal of the sulfinyl auxiliary, furnished desired homoallylamine
105 in good yield but with poor stereoselectivity (up to 60% de). In order
to improve the stereoselectivity, the transfer aminoallylation via the aza-Cope
rearrangement developed by Kobayashi and coworkers [53] was adopted for the
synthesis of homoallylamine 105. Treatment of aldehyde 103 with reagent 106
derived from (1R)-camphorquinone in the presence of a catalytic amount of CSA in
(CH2Cl)2, followed by treatment with NH2OH to liberate amine group, resulted in
the simultaneous and highly stereoselective installation of allyl and amine functions
onto C-5 in 103 to provide homoallylamine 105 in 92% yield and 94% de. The de
value of 105 was determined by HPLC analysis of its benzoylated products.
After examination of the conditions required to construct the aminal ring system,
amidine 107 was obtained by treating amine 105 with TiCl4 in refluxing xylene
(Scheme 20). The absolute configuration at C-5, which was constructed by the
transfer aminoallylation described above, was determined to be (S) from the NOE
correlation between H-7 and H-5. Amidine 107 was treated with 1 equiv. of AcOH
in EtOH and then the imine moiety in the resulting acetate was stereoselectively
reduced with NaBH4 to give aminal 108. Obtained aminal 108 was directly acylated
with acryloyl chloride and Et3N to provide acrylamide 109. The stereochemistry at
C-9 was confirmed by NOE experiment in which significant NOE between H-9 and
H-13 was observed. This stereoselectivity can be expected from the attack of
hydride from the convex face of 107. Thus, the characteristic cyclic aminal moiety
H H H H H NOE
Me Me NaBH4 Me acryloyl chloride Me
TiCl4 Et3N H13 H
H H AcOH H H
N N N N
H xylene 7
H EtOH H CH2Cl2 H 9
H2N O reflux NOE N rt NH –78 °C N O
5 5
80% 62% (2 steps)
105 107 108 109
acryloyl chloride 1) 2nd Grubbs cat.

Et3N CH2Cl2, rt, 78%
CH2Cl2, –78oC 2) H2, Pd/C, EtOH
82% rt, 96%
H H 1) LiAlH4 H H
Me 1) 1st Grubbs cat. Me THF, reflux Me Me
H CH2Cl2, rt H 60% H H H
N N N N
HH 2) H2, Pd/C HH 2) TFA HH H
O N O EtOH, rt O N O N TFA N O
95% (2 steps)
110 111 (+)-Cermizine D (90) (–)-Cernuine (86)
Scheme 20 Completion of the total synthesis of cermizine D and cernuine

Fig. 9 Structures of some Lycopodium alkaloids synthesized in recent years
of cernuine (86) could be stereoselectively constructed. Finally, RCM of 109 with

second-generation Grubbs catalyst in CH2Cl2 to construct the piperidone ring
and subsequent hydrogenation completed the first total synthesis of cernuine (86).
The spectroscopic data of synthetic 86 were in agreement with those of the natural
product in all respects. Therefore, the structure of cernuine (86), including the
absolute configuration, was confirmed [54].
Next, we investigated the synthesis of cermizine D (90) from homoallylamine
105. According to the synthesis of cernuine (86) described above, 105 was acylated
with acryloyl chloride to give acrylamide 110. RCM with first-generation Grubbs
catalyst and subsequent hydrogenation afforded bisamide 111. Reduction of bisa-
mide 111 with LiAlH4 in THF completed the synthesis of cermizine D (90).
As described above, the divergent asymmetric total syntheses of cernuane- and
quinolizidine-type Lycopodium alkaloids were accomplished. The first asymmetric
total synthesis of cernuine (86) was achieved starting from the easily available
(+)-citronellal in 9.6% overall yield in 21 steps. Furthermore, we have succeeded in
the syntheses of cermizine D (90), cermizine C (87), cermizine C N-oxide (88), and
senepodine G (89) from common key intermediate 91, and have established an
efficient synthetic route to cernuane- and quinolizidine-type Lycopodium alkaloids.
5 Conclusion
Lycopodium alkaloids have attracted the attention of many natural product chemists
and synthetic organic chemists due to their important biological activities and
unique skeletal characteristics. A number of elegant total syntheses of many
kinds of Lycopodium alkaloids have been reported in recent years (Fig. 9) (selected
reports on the total synthesis of Lycopodium alkaloids by other researchers in
recent years [28, 55–78]). In this review, we have shown that asymmetric total
synthesis played a key role in elucidating the structures of these complex natural
products.
References
1. B€odeker K (1881) Lycopodin, das erste alkaloid der gef€afskryptogamen. Ligbigs Ann
208:363–367
2. Manske RHF (1955) The Lycopodium alkaloids. In: Manske RHF (ed) The alkaloids, vol 5.
Academic, New York, pp 295–300, Chapter 47
3. Manske RHF (1960) The Lycopodium alkaloids. In: Manske RHF (ed) The alkaloids.
4. MacLean DB (1968) The Lycopodium alkaloids. In: Manske RHF (ed) The alkaloids, vol 10.
5. MacLean DB (1973) The Lycopodium alkaloids. In: Manske RHF (ed) The alkaloids, vol 14.
6. MacLean DB (1985) Lycopodium alkaloids. In: Brossi A (ed) The alkaloids, vol 26.
Academic, Orlando, pp 241–298, Chapter 5
7. Ayer WA, Trifonov LS (1994) Lycopodium alkaloids. In: Cordell GA, Brossi A (eds) The
alkaloids, vol 45. Academic, San Diego, pp 233–266, Chapter 3
8. Ayer WA (1991) The Lycopodium alkaloids. Nat Prod Rep 8:455–463

9. Ma X, Gang DR (2004) The Lycopodium alkaloids. Nat Prod Rep 21:752–772
10. Kobayashi J, Morita H (2005) The Lycopodium alkaloids. In: Cordell GA (ed) The alkaloids,
vol 61. Elsevier, Amsterdam, pp 1–57
11. Hirasawa Y, Kobayashi J, Morita H (2009) The Lycopodium alkaloids. Heterocycles 77:679–729
12. Katakawa K, Kogure N, Kitajima M, Takayama H (2009) A new Lycopodium alkaloid,
lycoposerramine-R, with a novel skeleton and three new fawcettimine-related alkaloids
from Lycopodium serratum. Helv Chim Acta 92:445–452 and references cited therein
13. Liu JS, Zhu YL, Yu CM, Zhou YZ, Han YY, Wu FW, Qi BF (1986) The structures
of huperzines A and B, two new alkaloids exhibiting marked anticholinesterase activity.
Can J Chem 64:837–839
14. Kozikowski AP, T€ uckmantel W (1999) Chemistry, pharmacology, and clinical efficacy of the
Chinese nootropic agent huperzine A. Acc Chem Res 32:641–650
15. Wong DM, Greenblatt HM, Dvir H, Carlier PR, Han YF, Pang YP, Silman I, Sussman JL
(2003) Acetylcholinesterase complexed with bivalent ligands related to huperzine A:
experimental evidence for species-dependent protein–ligand complementarity. J Am Chem
Soc 125:363–373
16. Ishiuchi K, Kubota T, Hoshino T, Obara Y, Nakahata N, Kobayashi J (2006) Lycopladines
B–D and lyconadin B, new alkaloids from Lycopodium complanatum. Bioorg Med Chem
14:5995–6000
17. Morita H, Ishiuchi K, Haganuma A, Hoshino T, Obara Y, Nakahata N, Kobayashi J (2005)
Complanadine B, obscurumines A and B, new alkaloids from two species of Lycopodium.
Tetrahedron 61:1955–1960
18. Hemscheidt T, Spenser ID (1993) Biosynthesis of lycopodine: incorporation of acetate via an
intermediate with C2v symmetry. J Am Chem Soc 115:3020–3021
19. Takayama H, Katakawa K, Kitajima M, Seki H, Yamaguchi K, Aimi N (2001) A new type of
Lycopodium alkaloid, Lycoposerramine-A, from Lycopodium serratum Thunb. Org Lett
3:4165–4167; (2002) 4:1243
20. Katakawa K, Kitajima M, Aimi N, Seki H, Yamaguchi K, Furihata K, Harayama T, Takayama
H (2005) Structure elucidation and synthesis of lycoposerramine-B, a novel oxime-containing
Lycopodium alkaloid from Lycopodium serratum Thunb. J Org Chem 70:658–663
21. Inubushi Y, Ishii H, Yasui B, Hashimoto M, Harayama T (1966) Serratinine: a novel skeletal
Lycopodium alkaloid. Tetrahedron Lett 7:1537–1549
22. Inubushi Y, Ishii H, Yasui B, Hashimoto M, Harayama T (1968) Serratinine: a novel skeletal
Lycopodium alkaloid. Chem Pharm Bull 16:82–91
23. Nishio K, Fujiwara T, Tomita K, Ishii H, Inubushi Y, Harayama T (1969) The crystal structure
of 13-acetyl-8-p-bromo-benzoyl serratinine: the revised configuration of C4-N bond of serra-
tinine. Tetrahedron Lett 10:861–864
24. Harayama T, Ohtani M, Oki M, Inubushi Y (1975) Total synthesis of the Lycopodium alkaloid
dl-serratinine. Chem Pharm Bull 23:1511–1515
25. Takayama H, Katakawa K, Kitajima M, Yamaguchi K, Aimi N (2002) Seven new Lycopo-
dium alkaloids, lycoposerramines, from Lycopodium serratum Thunb. Tetrahedron Lett 43:
8307–8311
26. Khand IU, Knox GR, Pauson PL, Watts WE (1971) A cobalt induced cleavage reaction and a
new series of arenecobalt carbonyl complexes. Chem Commun 36a
27. Ishizaki M, Hoshino O (2003) Pauson-Khand reaction of enynes bearing exo-olefin and its
application to total synthesis of Lycopodium alkaloid, magellanine. J Synth Org Chem Jpn
61:1166–1175
28. Kozaka T, Miyakoshi N, Mukai C (2007) Stereoselective total syntheses of three Lycopodium
alkaloids, (–)-magellanine, (+)-magellaninone, and (+)-paniculatine, based on two Pauson–
Khand reactions. J Org Chem 72:10147–10154
29. Mandai T, Ueda M, Hasegawa S, Kawada M, Tsuji J (1990) Preparation and rearrangement of
2-allyloxyethyl aryl sulfoxides; a mercury-free claisen sequence. Tetrahedron Lett 31:4041–4044
30. Fukuyama T, Jow CK, Cheung M (1995) 2- and 4-Nitrobenzenesulfonamides: exceptionally

versatile means for preparation of secondary amines and protection of amines. Tetrahedron
Lett 36:6373–6374
31. Kurosawa W, Kan T, Fukuyama T (2002) Preparation of secondary amines from primary
amines via 2-nitrobenzenesulfonamides: N-(4-methoxybenzyl)-3-phenylpropylamine [benze-
nepropanamine, N-[(4-methoxyphenyl)methyl]]. Org Synth 79:186–195
32. Kan T, Fukuyama T (2004) Ns strategies: a highly versatile synthetic method for amines.
Chem Commun 353–359
33. Heathcock CH, Smith KM, Blumenkopf TA (1986) Total synthesis of ()-fawcettimine
(Burnell’s base A). J Am Chem Soc 108:5022–5024
34. Heathcock CH, Blumenkopf TA, Smith KM (1989) Total synthesis of ()-fawcettimine.
J Org Chem 54:1548–1562
35. Nakayama A, Kitajima M, Kogure N, Takayama H (2009) First asymmetric total syntheses of
fawcettimine-type Lycopodium alkaloids, lycoposerramine-C and phlegmariurine-A. Org
Lett 11:5554–5557
36. Shigeyama T, Katakawa K, Kogure N, Kitajima M, Takayama H (2007) Asymmetric total
syntheses of two phlegmarine-type alkaloids, lycoposerramines-V and -W, newly isolated
from Lycopodium serratum. Org Lett 9:4069–4072
37. Miyaura N, Suzuki A (1995) Palladium-catalyzed cross-coupling reactions of organoboron
compounds. Chem Rev 95:2457–2483
38. Brown HC, Liotta R, Brener L (1977) Hydroboration. 46. The regio- and stereochemistry of
the hydroboration of representative cyclic olefins with 9-borabicyclo[3.3.1]nonane. J Am
Chem Soc 99:3427–3432
39. Brown HC, Jadhav PK (1984) B-Allyldiisocaranylborane: a new, remarkable enantioselective
allylborating agent for prochiral aldehydes. Synthesis of homoallylic alcohols approaching
100% enantiomeric purities. J Org Chem 49:4089–4091
40. Jadhav PK, Bhat KS, Perumal PT, Brown HC (1986) Chiral synthesis via organoboranes.
6. Asymmetric allylboration via chiral allyldialkylboranes. Synthesis of homoallylic alcohols
with exceptionally high enantiomeric excess. J Org Chem 51:432–439
41. Molander GA, Harris CR (1996) Sequencing reactions with samarium(II) iodide. Chem Rev
96:307–338
42. Molander GA, Etter JB, Harring LS, Thorel PJ (1991) Investigations on 1, 2-, 1, 3-, and 1,
4-asymmetric induction in intramolecular Reformatskii reactions promoted by samarium(II)
iodide. J Am Chem Soc 113:8036–8045
43. Katakawa K, Kitajima M, Yamaguchi K, Takayama H (2006) Three new phlegmarine-type
Lycopodium alkaloids, lycoposerramines-X, -Y and -Z, having a nitrone residue, from Lyco-
podium serratum. Heterocycles 69:223–229
44. Tanaka T, Kogure N, Kitajima M, Takayama H (2009) Asymmetric total syntheses of cyclic-
nitrone-containing phlegmarine-type Lycopodium alkaloids, lycoposerramines-X and -Z.
J Org Chem 74:8675–8680
45. Marion L, Manske RHF (1948) The alkaloids of Lycopodium species; Lycopodium cernuum
L. Can J Res 26b:1–2
46. Ayer WA, Jenkins JK, Valverde-Lopez S, Burnell RH (1967) The alkaloids of Lycopodium
cernuum L. I. The structures of cernuine and lycocernuine. Can J Chem 45:433–443
47. Morita H, Hirasawa Y, Shinzato T, Kobayashi J (2004) New phlegmarane-type, cernuane-type,
and quinolizidine alkaloids from two species of Lycopodium. Tetrahedron 60:7015–7023
48. Bøgevig A, Juhl K, Kumaragurubaran N, Zhuang W, Jørgensen KA (2002) Direct organo-
catalytic asymmetric a-amination of aldehydes – a simple approach to optically active
a-amino aldehydes, a-amino alcohols, and a-amino acids. Angew Chem Int Ed 41:1790–1793
49. List B (2002) Direct catalytic asymmetric a-amination of aldehydes. J Am Chem Soc
124:5656–5657
50. Kumaragurubaran N, Juhl K, Zhuang W, Bøgevig A, Jørgensen KA (2002) Direct l-proline-
catalyzed asymmetric a-amination of ketones. J Am Chem Soc 124:6254–6255
51. Nishikawa Y, Kitajima M, Kogure N, Takayama H (2009) A divergent approach for the total
syntheses of cernuane-type and quinolizidine-type Lycopodium alkaloids. Tetrahedron
65:1608–1617
52. Liu G, Cogan DA, Owens TD, Tang TP, Ellman JA (1999) Synthesis of enantiomerically
pure N-tert-butanesulfinyl imines (tert-butanesulfinimines) by the direct condensation of
tert-butanesulfinamide with aldehydes and ketones. J Org Chem 64:1278–1284
53. Sugiura M, Mori C, Kobayashi S (2006) Enantioselective transfer aminoallylation: synthesis
of optically active homoallylic primary amines. J Am Chem Soc 128:11038–11039
54. Nishikawa Y, Kitajima M, Takayama H (2008) First asymmetric total syntheses of cernuane-
type Lycopodium alkaloids, cernuine, and cermizine D. Org Lett 10:1987–1990
55. Ramharter J, Weinstabl H, Mulzer J (2010) Synthesis of the Lycopodium alkaloid
(+)-lycoflexine. J Am Chem Soc 132:14338–14339
56. De Lorbe JE, Lotz MD, Martin SF (2010) Concise total synthesis of ()-lycopladine A. Org
Lett 12:1576–1579
57. Yang Y-R, Lai Z-W, Shen L, Huang J-Z, Wu X-D, Yin J-L, Wei K (2010) Total synthesis of
(–)-8-deoxyserratinine via an efficient Helquist annulation and double N-alkylation reaction.
Org Lett 12:3430–3433
58. Canham SM, France DJ, Overman LE (2010) Total synthesis of (+)-sieboldine A. J Am Chem
Soc 132:7876–7877
59. Kozak JA, Dake GR (2008) Total synthesis of (+)-fawcettidine. Angew Chem Int Ed
47:4221–4223
60. Linghu X, Kennedy-Smith JJ, Toste FD (2007) Total synthesis of (+)-fawcettimine. Angew
Chem Int Ed 46:7671–7673
61. Tsukano C, Zhao L, Takemoto Y, Hirama M (2010) Concise total synthesis of ()-lycodine.
Eur J Org Chem 2010:4198–4200
62. Fischer DF, Sarpong R (2010) Total synthesis of (+)-complanadine A using an iridium-
catalyzed pyridine C-H functionalization. J Am Chem Soc 132:5926–5927
63. Yuan C, Chang C-T, Axelrod A, Siegel D (2010) Synthesis of (+)-complanadine A, an inducer
of neurotrophic factor excretion. J Am Chem Soc 132:5924–5925
64. Koshiba T, Yokoshima S, Fukuyama T (2009) Total synthesis of (–)-huperzine A. Org Lett
11:5354–5356
65. Yang H, Carter RG (2010) Development of an enantioselective route toward the Lycopodium
alkaloids: total synthesis of lycopodine. J Org Chem 75:4929–4938
66. Yang H, Carter RG, Zakharov LN (2008) Enantioselective total synthesis of lycopodine. J Am
Chem Soc 130:9238–9239
67. Liau BB, Shair MD (2010) Total synthesis of (+)-fastigiatine. J Am Chem Soc 132:9594–9595
68. Bisai V, Sarpong R (2010) Methoxypyridines in the synthesis of Lycopodium alkaloids: total
synthesis of ()-lycoposerramine R. Org Lett 12:2551–2553
69. Chandra A, Pigza JA, Han J, Mutnick D, Johnston JN (2009) Total synthesis of the Lycopo-
dium alkaloid (+)-serratezomine A. J Am Chem Soc 131:3470–3471
70. Nishimura T, Unni AK, Yokoshima S, Fukuyama T (2011) Concise total synthesis of (+)-
lyconadin A. J Am Chem Soc 133:418–419
71. Beshore DC, Smith AB III (2007) Total syntheses of (+)-lyconadin A and (–)-lyconadin B.
J Am Chem Soc 129:4148–4149
72. Bisai A, West SP, Sarpong R (2008) Unified strategy for the synthesis of the “miscellaneous”
Lycopodium alkaloids: total synthesis of ()-lyconadin A. J Am Chem Soc 130:7222–7223
73. Altman RA, Nilsson BL, Overman LE, Read de Alaniz J, Rohde JM, Taupin V (2010) Total
synthesis of (+)-nankakurines A and B and ()-5-epi-nankakurine A. J Org Chem 75:7519–7534
74. Nilsson BL, Overman LE, Read de Alaniz J, Rohde JM (2008) Enantioselective total
syntheses of nankakurines A and B: confirmation of structure and establishment of absolute
configuration. J Am Chem Soc 130:11297–11299
75. Cheng X, Waters SP (2010) Concise total syntheses of the Lycopodium alkaloids
()-nankakurines A and B via luciduline. Org Lett 12:205–207
76. Laemmerhold KM, Breit B (2010) Total synthesis of (+)-clavolonine, (–)-deacetylfawcettiine,

and (+)-acetylfawcettiine. Angew Chem Int Ed 49:2367–2370
77. Nakamura Y, Burke AM, Kotani S, Ziller JW, Rychnovsky SD (2010) Total synthesis of
(–)-lycoperine A. Org Lett 12:72–75
78. Snider BB, Grabowski JF (2007) Total synthesis of (–)-senepodine G and (–)-cermizine C.
J Org Chem 72:1039–1042
Top Curr Chem (2012) 309: 33–66
DOI: 10.1007/128_2011_133
Published online: 6 May 2011
Synthesis of Morphine Alkaloids and Derivatives
Uwe Rinner and Tomas Hudlicky
Abstract This review summarizes recent developments in the total synthesis of

morphine alkaloids and some of the semisynthetic derivatives. The literature is
covered for the period of 5 years after the publication of the last review in 2005.
The syntheses that appeared in this period are covered in detail and are placed in
the context of all syntheses of opiate alkaloids since the original one published
by Gates in 1952. The introduction covers the historical aspects of total synthesis
of these alkaloids. The synthesis of some of the medicinally useful derivatives is
reviewed in the last section along with some of the methodology required for their
preparation.
Keywords Alkaloids Analgesia Codeine Demethylation Morphine Total

synthesis
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2 Early Syntheses of Morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2.1 Gates (1952) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.2 Rice (1980) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3 Recent Syntheses of Morphine and/or Codeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.1 Fukuyama (2006) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
3.2 Hudlicky (2007) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3.3 Iorga and Guillou (2008) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.4 Chida (2008) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3.5 Hudlicky (2009) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.6 Magnus (2009) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
U. Rinner (*)
Institute of Organic Chemistry, University of Vienna, W€ahringer Straße 38, 1090 Vienna, Austria
T. Hudlicky (*)
Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Ave.,
St. Catharines, ON L2S 3A1, Canada
34 U. Rinner and T. Hudlicky
3.7 Stork (2009) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

3.8 Fukuyama (2010) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4 Medicinally Important Derivatives of Morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
5 Conclusion and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Abbreviations
2,4-DNPH 2,4-Dinitrophenylhydrazine
BHT Butylated hydroxytoluene
CSA Camphorsulfonic acid
DDQ Dichloro dicyano benzoquinone
DEAD Diethyl azodicarboxylate
DIAD Diisopropyl azodicarboxylate
DMAP 4-Dimethylaminopyridine
DNsCl 2,4-Dinitrobenzene-sulfonyl chloride
dpa Dibenzylidenacetone
dppf 1,10 -Bis(diphenylphosphino)ferrocene
dppp 1,3-Bis(diphenylphosphino)propane
EDCI 1-Ethyl-3-(3-dimetylaminopropyl)carbodiimide
IBX 2-Iodoxybenzoic acid
KHMDS Potassium bis(trimethylsilyl)amide
LiHMDS Lithium bis(trimethylsilyl)amide
MCPBA 3-Chloroperbenzoic acid
NaHMDS Sodium bis(trimethylsilyl)amide
NBS N-Bromosuccinimide
PAD Potassium azodicarboxylate
PPTS Pyridinium p-toluenesulfonate
TBAF tetra-n-Butylammonium fluoride
TCDI Imidazole 1,10 -thiocarbonyldiimidazole
TFA Trifluoroacetic acid
1 Introduction
Morphine (1) and its congeners, codeine (2), thebaine (3), and oripavine (4), Fig. 1,
as well as other minor constituents of the opium poppy latex, continue to garner
interest of the chemical community for a number of reasons. The focus on the total
synthesis of these alkaloids in the academic sector has not waned and now spans
almost 60 years since the seminal disclosure of the first synthesis by Gates in 1952
[1, 2].
Synthesis of Morphine Alkaloids and Derivatives 35
RO RO
1
A 3
B 12 10
O E D O 13 9
NMe 5 14 NMe
C
6
HO 8
MeO 7
morphine (1), R = H thebaine (3), R = Me
codeine (2), R = Me oripavine (4),R = H
Fig. 1 Morphine and congeners
AcO MeO HO
O O O
NMe NMe N
R OH
AcO O O
heroin (5) oxycodone (6), R = OH naltrexone (8)
hydrocodone (7), R = H
HO HO HO
O O O
N N N
OH OH
O MeO HO
naloxone (9) HO nalbuphine (11)
buprenorphine (10)
Fig. 2 Opiate-derived agonists and antagonists for legal and illicit (i.e., heroin) use
The medical community requires a constant supply of morphine and other analge-
sic agents for pain control. The unnatural derivatives of morphine, whether agonists or
antagonists, are all derived by semisynthesis from the naturally occurring alkaloids
harvested primarily in Asia and Tasmania for legal consumption. The extent of illicit
use of morphine and other derivatives, such as heroin (5), Fig. 2, can only be estimated
but likely exceeds $800 billion annually. Some opiate-derived products, such as the
analgesics oxycodone (6) and hydrocodone (7), enjoy a widespread legal as well as
illicit use. The antagonists and mixed agonists, all derived by semisynthesis, include
naltrexone (8) for treatment of alcohol addiction [3], naloxone (9) for treatment of
opiate overdose [4], buprenorphine (10), and nalbuphine (11), Fig. 2.
Naltrexone is an opioid receptor antagonist used primarily in the management
of alcohol and/or opioid dependence. It is marketed in generic form as its
hydrochloride salt, naltrexone hydrochloride, and sold under the trade names
Revia™ and Depade™. Naltrexone and its active metabolite 6-b-naltrexol are
competitive antagonists at m- and k-opioid receptors, and to a lesser extent at
d-opioid receptors [5]. Naloxone is a drug used to counter the effects of opioid
overdose, for example, heroin or morphine overdose. Naloxone is specifically used

to counteract life-threatening depression of the central nervous system and respira-
tory system. It is also used in combination drugs such as Suboxone™ (buprenor-
phine and naloxone, 4:1). Nalbuphine is a synthetic opioid used commercially as an
analgesic under a variety of trade names, including Nubain™. It is a mixed agonist/
antagonist, noteworthy in part for the fact that at low dosages it is much more
effective in women than in men, and may even increase pain in men [6], leading to
its discontinuation in the UK in 2003. Nalbuphine is indicated for the relief of
moderate to severe pain. It can also be used as a supplement to balanced anesthesia,
for preoperative and postoperative analgesia, and for obstetrical analgesia during
labor and delivery.
It is difficult to estimate accurately the worldwide requirements for these com-
pounds. In the US, the DEA manufacturing quota in 2007 for oxymorphone for
conversion to other medicinally important derivatives was 12 tons, compared to
1.8 tons for sale. Total consumption may be as high as 16.8 tons.1 Estimates for
combined naltrexone and naloxone production worldwide might therefore be
around 10 tons for 2007. The worldwide demand for the compounds, shown in
Figs. 1 and 2, whether legal or illicit, is tremendous and depends entirely on the
supply of natural opiates. The estimates for the production of opiates worldwide are
shown below in Tables 1 and 2.2
To date there is no practical source of morphine, either by chemical synthesis or
through fermentation, that would compete with the cost of isolation. Of course, part
of the reason that natural morphine is so inexpensive is the low-wage investment in
harvesting it, mostly in Afghanistan, Turkey, and India. Were the workers there
paid “western” wages, the price could never be as low as it is today (~$400–700/kg).
It is very likely that in the event of a natural or a political emergency in those
regions that produce morphine and other opiates the price of the medicinal deriva-
tives would climb sharply, and, at that time, the synthetic approaches would
receive enhanced credibility. The use of morphine and derivatives in medicine is
permanently entrenched in our society and the pricing of “synthetic” morphine,
however formidable, would not lead to a decrease in legal use.
Table 1 Worldwide production of raw materials. Designated as alkaloids contained in poppy

straw (tons) (see footnote 1)
Opiate 2003 2004 2005 2006 2007
Morphine (1) 349.9 300.8 333.4 333.8 287.5
Codeine (2) 13.1 12.9 10.9 14.7 23.7
Thebaine (3) 65.4 77.0 94.4 92.2 125.5
Oripavine (4) 19.1 21.8 24.7 22.0 23.6
1
http://www.incb.org/pdf/technical-reports/narcotic-drugs/2008/tables_of_reported_statistics.pdf.
2
The authors thank Dr. Phil Cox, Noramco, Inc. for providing the information in Tables 1 and 2.
Table 2 Worldwide production of opiates in tons (numbers in brackets represent production in

the US) (see footnote 1)
Opiate 2003 2004 2005 2006 2007
Morphine (1)a 376.7 (99.0) 354.7 (88.0) 397.6 (96.0) 415.8 (102.0) 440.0 (112.2)
Codeine (2)a 288.7 (67.9) 298.9 (63.7) 309.8 (70.4) 317.5 (73.4) 349.3 (77.0)
Oxycodone (6) 51.5 (41.1) 52.5 (40.3) 56.5 (40.3) 66.9 (49.7) 75.2 (55.7)
Hydrocodone (7) 29.8 (29.7) 32.1 (31.9) 35.6 (35.5) 39.7 (39.6) 38.2 (37.9)
a
Includes morphine/codeine for conversion to other products
a –
b + +
– HO
HO
+ + – –
– – + +
+ + – –
–O + – –O – +
– – + + + –
+ + NMe – – NMe
– – + +
HO + HO –
Fig. 3 Dissonant relationship in morphine connectivity (a ¼ phenol priority, b ¼ amine priority)3,4
Morphine has a fascinating history that can be gleaned by reading a number of

sources [7, 8], that discuss its pharmacology [9, 10] and societal and historical
impact on humans. The isolation of morphine precedes by some 25 years the
“official” beginning of organic chemistry, the synthesis of urea by W€ohler. Its
isolation from opium by Sert€ urner in 1805 [11–13] led to more than a century of
effort before the final structure elucidation was completed [14]. Sert€urner was
also the first person to document “animal and human trials” with the newly
isolated natural product [15]. Morphine, with its impact on chemists as well as
on society in general, is likely one of the very few chemical entities that everyone
recognizes.
Morphine’s synthesis remains a serious challenge to this day. Until recently, the
formal synthesis published by Kenner Rice [16] was its most efficient preparation.
In 2009, Magnus reported a route to codeine with a reported overall yield of
approximately 17% [17]. All academic syntheses reported in the literature, creative
as these may be, suffer from lack of practicality, with the sole exception of Rice’s
disclosure, which has potential for scale-up.
Morphine, although not particularly complex, suffers from a complete “dissonant
connectivity” (shown in Fig. 3) (Evans, 1972, Consonant and dissonant relationships.
An organizational model, unpublished manuscript) [20], as we have previously
3
Reprinted with permission from: Zezula J, Hudlicky T (2005) Synlett, 388–405. Copyright 2005
Georg Thieme Verlag Stuttgart, New York.
4
Hudlicky T, Reed, JW: the Way of Synthesis. Evolution of Design and Methods. Page 732.
Publication year 2007. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with
permission.
pointed out on several occasions [18, 19]. Starting from either the phenolic oxygen (a)
or the tertiary amine (b), it is not possible to draw a polarization assignment in which
all electronegative atoms avoid an incorrect positive charge or in which alternating
charges match. Because of this fact almost any strategy applied to the construction of
morphine skeleton will, sooner or later, require major tactical maneuvers leading to an
increase in the step-count and hence a decrease in practicality.
These issues have been addressed in detail in many previous reviews [18, 21–26].
Since our update on morphine synthesis was published 5 years ago in Synlett [18],
several new approaches have appeared in the literature. This review summarizes the
recent accomplishments and also provides for an update in methods used to
approach some of the semisynthetic opiates.
The summary of accomplishments in the total synthesis of morphine alkaloids is
depicted in Table 3. Most authors target codeine as the ultimate synthetic target;
its attainment represents a formal total synthesis of morphine as Rice demonstrated
its conversion to morphine by O-demethylation with BBr3 [55]. Such a strategy has
Table 3 Summary of syntheses of morphine and derivatives

Principal author Year Target Steps Overall
yield
(as reported)
Gates [1, 2] 1952 Morphine 31 0.06
Ginsburg [27, 28] 1954 rac-Dihydrothebainone 21 8.9
Grewe [29, 30] 1967 rac-Dihydrothebainone 9 0.81
Rice [16] 1980 Dihydrocodeinone 14 29.7
Evans [31] 1982 rac-O-Me-thebainone A 12 16.7
White [32] 1983 Codeine 8a 1.8
Rapoport [33] 1983 rac-Codeine 26 1.2
Fuchs [34, 35] 1987 rac-Codeine 23 1.3
Tius [36] 1992 rac-Thebainone-A 24 1.1
Parker [37, 38] 1992 rac-Dihydrocodeinone 11 11.1
Overman [39] 1993 Dihydrocodeinone 14 1.9
Mulzer [40] 1996 Dihydrocodeinone 15 9.1
Parsons [41] 1996 Morphine 5b 1.8
White [42] 1997 ent-Morphine 28 3.0
Mulzer [43] 1997 Dihydrocodeinone 18 5.7
Ogasawara [44, 45] 2001 Dihydrocodeineone ethylene ketal 21 1.5
Taber [46] 2002 Morphine 27 0.51
Trost [47, 48] 2002 Codeine 15 6.8
Fukuyama [49] 2006 rac-Morphine 25 6.7
Hudlicky [50] 2007 ent-Codeine 15 0.23
Iorga/Guillou [51] 2008 rac-Codeine 17 0.64
Chida [52] 2008 rac-Dihydroisocodeine 24 3.8
Hudlicky [15] 2009 Codeine 18 0.19
Magnus [17] 2009 rac-Codeine 13 20.1
Stork [53] 2009 rac-Codeine 22 2.0
Fukuyama [54] 2010 Morphine 18 4.8
a
N-Norreticuline was used as advanced starting material
b
Only the last five steps of the synthesis have been published in the cited journal
a historical basis as, in the early days of structure elucidation, chemists found
it easier to perform degradation on codeine because it was air stable. Morphine
is more difficult to handle for several reasons. First, it has the properties of an
amino acid, and, second, it is easily oxidized by air (hence the dark color of raw
opium). Once it was established that morphine and codeine differ only by the
absence or presence of the O-methyl group, all subsequent work was carried out
with codeine.
Modern approaches no doubt subscribe to a similar strategy for the same reasons
and thus most published syntheses stop at the stage of codeine. The syntheses are
listed chronologically, with the yields “as reported.” It is impossible to validate the
claimed yields, especially overall yields, in cases where the reactions are performed
on very small scales. Claims of reaction product yields above 94% are clearly
erroneous in nature and should be viewed with suspicion. Similarly, the credibility
of overall yields above 2 or 3% is questionable, as explained in a recent treatise on
accuracy in reporting isolated product yields [56]. An exception to this statement
are the yields reported in the synthesis of Rice [16], which was performed on a
multigram scale.
2 Early Syntheses of Morphine
The following section highlights two milestone achievements in morphine synthe-

sis. In 1952, Gates published the first total synthesis of the title alkaloid [1, 2] and
was thus able to prove the structure of morphine proposed by Robinson in 1925 to
be correct [57]. In addition, both enantiomers of morphine can be accessed follow-
ing the published route as Gates performed a resolution of an advanced intermediate
(see Scheme 2, compound 20). Although Gates did not benefit from modern
synthetic methods and structure elucidation techniques such as NMR spectroscopy,
he was able to determine the identity of synthetic intermediates by derivatization
and degradation studies of natural morphine. Written almost 60 years ago, the
original report demonstrates the amazing knowledge of reactions, purification,
and structure determination abilities of early synthetic chemists. Gates’s full
paper, as well as the earlier papers dealing with model studies, should be recom-
mended reading assignment for all students of organic synthesis.
The very short and highly efficient biomimetic synthesis of morphine [16, 32] by
Rice stands out in terms of overall yield and brevity; no subsequent contribution to
this area exceeds this milestone achievement. The route follows the biosynthetic
pathway and delivers dihydrocodeinone in almost 30% overall yield.
Although the syntheses of morphine by Gates and Rice have been reviewed on
several occasions [14, 19, 24], they are included in this review as they constitute
important highlights in the history of morphine research against which all other
approaches should be judged. (For clarity and better understanding, the key trans-
formations in featured syntheses are depicted in blue color within the schemes).
2.1 Gates (1952)
Gates utilized 2,6-dihydroxynaphthalene (12) as starting material and synthon for

the A,B-ring system of morphine [58]. As outlined in Scheme 1, monoprotection to
the corresponding benzoyl naphthol was followed by nitrosation (13) and formation
of ortho quinone 14. When treated with sulfur dioxide, cyclic sulfate 15 was formed
which upon exposure to dimethyl sulfate provided the methylated catechol. An
identical second nitrosation protocol delivered the B-ring of the alkaloid (16) for
conjugate addition of ethyl cyanoacetate and subsequent reoxidation (K3Fe(CN)6).
Decarboxylation under basic conditions gave nitrile 17, which served as precursor
for the key cycloaddition reaction. Diketone 18 (shown as enol) was obtained when
nitrile 17 was heated with butadiene and the material was subjected to a copper
chromite reduction, which provided amide 19. A sequence involving Wolff–
Kishner reduction, methylation, and LiAlH4 reduction then afforded morphinan 20.
With morphinan 20 in hand, the stage was set for the deracemization and functio-
nalization of the D ring of the alkaloid. Resolution of racemic amine 20 with dibenzoyl
tartrate (Scheme 2) afforded the isomer with correct configuration at C9 and C13 but
epimeric at C14. The identity of the synthetic material was unambiguously confirmed
HO HO O
1. PhCOCl, py 3. H2, Pd / C
A 2. NaNO2, AcOH 4. FeCl3
65 % N 88 % O
B
O
OH OBz OBz
12 13 14
SO2
MeO 1. NCCH2CO2Et 1. Me2SO4, K2CO3

MeO O
2. K3Fe (CN)6 2. KOH O
O 3. KOH 3.NaNO2 S
MeO O O
81 % MeO O
4. H2, Pd / C
O 5. FeCl3
O OBz
59 %
CN 17 16 15
50 %
Δ
MeO MeO MeO

1. NaOH, N2H4
Cu-Cr, H2, 2. MeI, NaH
O O
MeO 27 atm, 130 °C MeO 3. LiAlH4 MeO
CN O
50 %
OH 79 %
14 NH NMe
H H
18 20
19
Scheme 1 Gates’s synthesis of morphine – part 1

1. dibenzoyl Br
MeO MeO MeO 1
tartaricacid
(resolution)
MeO 2 . H2SO4, H2O HO Br2, HOAc HO
3. N2H4, KOH 13
NMe 4. tBuOK, Ph CO 9 NMe NMe
2 14
H 36 % H H
O O
Br
20 21 22
2,4-DNPH 41 %
(2 steps)
MeO Br MeO Br MeO Br
HO H2, Pt HO aq. HCl, acetone HO

80 % 60 %
5 NMe NMe 14 NMe
O O ArNHN
25 24 23
1. Br2 (2 equiv.)
26 %
2. 2, 4-DNPH
MeO Br MeO Br HO
1. LiAlH4, THF
aq. HCl, acetone 2. py, HCl
O O O
27 % 22 %
5 NMe NMe NMe
ArNHN O HO
26 27 morphine (1)
Scheme 2 Gates’s synthesis of morphine – part 2
by direct comparison with degradation products obtained from natural codeine, thus
confirming the structure of the morphinan skeleton as postulated by Robinson [57].
Furthermore, the remaining steps in the forward synthesis were facilitated by access to
larger amounts of material from natural sources. Regioselective hydration and selec-
tive monodemethylation with hydrazine and KOH in ethylene glycol were followed
by a modified Oppenauer oxidation and ketone 21 was obtained. a-Bromination
(along with bromination of the aromatic ring) afforded 22, which, upon reaction
with 2,4-dinitrophenylhydrazine (2,4-DNPH), gave 23 with concomitant epimeriza-
tion at C14 to the thermodynamically more favored natural configuration. Hydrolysis
of the hydrazone and hydration gave 25, which was brominated and treated
with 2,4-DNPH, resulting in the closure of the dihydrofuran ring (26). Hydrolysis of
the hydrazone delivered the a,b-unsaturated ketone 27, which was converted into
codeine via hydrogenation and reduction of the ketone and the aryl bromide. The use
of the unsaturated hydrazone for both epimerization and a-bromination of the C5
position was indeed ingenious and attests to the level of thought that Gates had given
to this protocol. Demethylation with hydrochloric acid in pyridine as described by
Rapoport [59] concluded the first total synthesis and the final structure proof of
morphine (1).
2.2 Rice (1980)
Rice achieved the shortest and the most efficient formal synthesis of morphine via
a biomimetic approach with a Grewe cyclization as the key step (Scheme 3).
Condensation of amine 28 and acid 29 is followed by a Bischler–Napieralski
reaction and sodium cyanoborohydride reduction to establish the C,D-ring of the
alkaloid (30). Birch reduction and subsequent N-formylation with phenyl formate
gave the methyl enol ether 31. Ketalization and bromination of the aromatic ring,
to protect the para position, afforded 32 as the precursor for the key electrophilic
cyclization reaction as described previously by Grewe [29]. This reaction
was achieved via treatment of 32 with formic acid to release the b,g-unsaturated
ketone and subsequent exposure to NH4F · HF in TfOH. Morphinan 33 was defor-
mylated and converted into 25 by reductive amination before the dihydrofuran
ring was established via bromination of the a-position of the ketone and deprotona-
tion of the phenol. The aryl bromide was removed by hydrogenation in the presence
MeO
MeO MeO
C 1. 200 °C, 2 h 1. Li, NH3,
NH2 2. POCl , MeCN D
3 NH THF, tBuOH NCHO
28 3. NaCNBH3, MeOH 2. PhOCHO, EtOAc, Δ
+ 85 %
82 %
COH2
A
MeO MeO
MeO
29 OH
OH OH
30 31
1. (CH2OH)2, THF,
MeSO3H
2. CH3CONHBr, 0 °C
O
MeO Br MeO Br
O C D
1. HCO2H, H2O A NCHO
HO 2. NH4F . HF, CF3SO3H HO Br
=
54 % from 31 D
NCHO NCHO
O C A
O MeO
O
33 32 OH
MeOH, HCl, reflux;

quant. NH3, H2O, iPrOH
MeO Br MeO HO
1. Br2, HOAc
2. NaOH, CHCl3 5 steps
HO 3. H2, HOAc, HCHO see refs. 55, 60
O O
79 % 36 %
NMe NMe NMe
O O HO
25 dihydrocodeinone (34) morphine (1)
Scheme 3 Rice’s biomimetic synthesis of morphine

of formaldehyde and dihydrocodeinone (34) was isolated. The conversion of

this material to morphine has been described before [55, 60] and the preparation
of dihydrocodeinone (34) constituted the formal synthesis of codeine and/or
morphine.
3 Recent Syntheses of Morphine and/or Codeine
This section summarizes all syntheses of morphine and codeine published since the
last major review in this area was published in 2005 [18]. A general overview of the
key strategic elements in all syntheses discussed within this section is provided in
Schemes 4 and 5.
Fukuyama (2006)
Heck
MeO
HO MeO MeO OMe
OMe
OMe
OMe
O O O O I NHCO2Me
NMe NR NHCO2Me
HO O Mannich reaction O
OTBS
morphine (1)
Hudlicky (2007)
MeO MeO MeO MeO
Br
CHO
O O O O Br
NMe NMeBoc NMeBoc
H H NMeBoc
C
HO TBSO Heck TBSO TBSO
amino- C-ring prepared
ent-codeine mercuration
(ent-2) by biocatalysis
Iorga and Guillou (2008)
MeO MeO MeO amination MeO

reduction Heck
O O
O O
NMe NMeBn NMeBn O
NMe2 Michael
HO O
O addition
codeine (2) hydro- Claisen OH
amination rearrangement
Chida (2008)
Claisen rearrange- MeO
HO MeO MeO
Friedel- ment cascade
Crafts Suzuki
MeO MeO
O O CHO CO2Et
HO
NMe CO2Et
C
HO TBSO HO
morphine (1) C-ring sugar derived
via Ferrier rearrangement
Scheme 4 Overview of strategies in the recent syntheses of morphinans – part 1

Hudlicky (2009)
MeO MeO
in analogy NMeBoc NMeBoc

to Scheme 4 CHO HO
O
O Br O C
NMe HO
epoxide NMeBoc
opening C-ring prepared
HO by biocatalysis
TBSO
codeine (2)
Magnus (2009)
MeO MeO MeO Henry- MeO

aldol
O O CHO
O O EtO
NMe NCO2Et NO2
EtO
Br Suzuki
HO SN2¢ o, p-phenol
codeine (2) Michael
oxidation O OTBS
Stork (2009)
MeO MeO MeO Heck

MeO
OMe
CO2Me O
O O O O
NMe O OTES I O
Diels-
Alder MeO MeO
HO
codeine (2) O OMe
Fukuyama (2010)
MeO MeO
HO MeO OMe
OMe
OMe OMe
O O O O I NHCbz
NMe NMeDNs NMeDNs
OMs Heck
1, 6-addition O O Mitsunobu
HO
AcO
morphine (1) aldol
Scheme 5 Overview of strategies in the recent syntheses of morphinans – part 2
3.1 Fukuyama (2006)
In 2006, Fukuyama presented an approach to codeine and morphine based on

a Tsuji–Trost coupling and intramolecular Heck reaction as key steps [49, 61].
The synthesis was carried out in the racemic manifold; however, by devising an
alternative stereoselective route to epoxide 41, access to either the natural or the
enantiomeric form of morphine could be achieved.
As outlined in Scheme 6, isovanillin (35) was converted to aryl iodide 36 via

MOM-protection, protection of the aldehyde, and subsequent iodination. Hydrolysis
of the acetal and Wittig olefination delivered phenol 37 after exposure of the
intermediate aldehyde to methanolic hydrochloric acid. Epoxide 41, the coupling
partner of phenol 37 in the key Tsuji–Trost-reaction, was synthesized from benzoic
acid following a procedure developed by Fukuyama for the synthesis of strychnine
[62]. Birch reduction of benzoic acid with subsequent isomerization of one double
bond into conjugation was followed by esterification and bromohydrin formation
(40). The ester was reduced and the bromohydrin was treated with base to provide
the epoxide. Silylation concluded the preparation of epoxide 41, the coupling
partner for iodide 37, and both fragments were reacted in the presence of palladium
to attain iodide 38.
The configuration of the secondary alcohol in 38 (Scheme 7) was inverted by
means of a Mitsunobu reaction with p-nitrobenzoic acid, and the silyl ether was
cleaved under acidic conditions. The primary alcohol was converted into nitrile 42
under Mitsunobu conditions utilizing the cyanohydrin derived from acetone.
Reductive cleavage of the p-nitrobenzyl ester was followed by TBS protection of
the resulting secondary alcohol and the installation of a methyl carbamate (43)
before the key Heck cyclization was achieved in excellent yield. The silyl enol ether
obtained after this crucial transformation was cleaved and ketone 44 was obtained
as single isomer. Next, the B and D rings were closed, presumably via an intra-
molecular Mannich-type reaction, by heating carbamate 44 to reflux in metha-
nolic hydrogen chloride. With morphinan 45 in hand, Fukuyama turned his
attention to the functionalization of the C-ring of the alkaloid. Epoxidation of the
a,b-unsaturated ketone obtained after a Segusa-oxidation protocol furnished alcohol
46 after sodium borohydride reduction. The hydroxy moiety was converted into
a thiocarbonate and subjected to radical reaction conditions resulting in epoxide
1. AcOH, THF, H2O

1. MOMCl, iPr2NEt
2. MeOCH2PPh3Cl,
2. CSA, HC(OMe)3
MeO MeO NaHMDS MeO
3. nBuLi; I2
3. HCl, MeOH, 40 °C OMe
A
72 % OMe 81 %
HO 4 CHO MOMO HO OMe
I OMe I
35 36 37
[Pd2(dba)3],
P(2-furyl)3, 91 %
41, 40 °C
MeO
OTBS OMe
COOH 1. Na, NH3, EtOH, -78 °C CO2Me 1. DIBAL-H A
13 2. AcCl, MeOH; NaOMe
OH 2. NaOMe, MeOH OMe
3. NBS, H2O, DMSO 3. TBSCl, imidazole
C O O I
62 % 45 %
Br OTBS
39 40 41
C
OH
38
Scheme 6 Fukuyama’s synthesis of morphine – part 1

MeO MeO
OMe OMe
1. p-nitrobenzoic 1. LiBH4 A
acid,DEAD, Ph3P 2. TBSCl, imidazole
OMe 3. DIBAL-H OMe
2. CSA, MeOH
38 O O I NHCO2Me
3. DEAD, Ph3P I 4. NaBH4, MeOH
HO CN CN 5. ClCO2Me, K2CO3
C
73 % (from 38)
O OTBS
43
42
O Ar 1. [Pd2(dba)3],
P(o-tolyl)3,
87 %
NEt3,MeCN
2. TBAF
MeO MeO MeO

OMe
1. TMSCl, LiHMDS HCl, MeOH
2. Pd(OAc)2, MeCN B reflux
O O E
OMe
D O
3. aq . H2O2, MeCN 94 %
NR NR NHCO2Me
4. NaBH4
6
OH 76 % 8 O O
O 7
46 R = CO2Me 45 R = CO2Me 44
1. TCDI, DMAP,
48 % ClCH2CH2Cl, 60 °C
2. Et3B, n-Bu3SnH
MeO MeO HO
1. Dess-Martin
2. LiAlH4, THF, BBr3,
reflux CH2Cl2
O O O
78 % 74 %
NR NMe NMe
HO HO HO
47 R = CO2Me codeine (2) morphine (1)
Scheme 7 Fukuyama’s synthesis of morphine – part 2
opening and formation of allylic alcohol 47. The synthesis of codeine (2) was
accomplished after inversion of the alcohol via the known oxidation/reduction
sequence [46, 60]. Morphine (1) was obtained after cleavage of the methyl ether
following a procedure published by Rice in 1977 [55].
3.2 Hudlicky (2007)
In 2007, Hudlicky and co-workers reported the preparation of ent-codeine (ent-2)

with the enzymatically derived cyclohexadiene diol 49 as the starting material
(Scheme 8) [50]. Key steps in this synthesis involve the introduction of the aryl
moiety via a Mitsunobu reaction, a Heck reaction to establish the carbon bond
between the aromatic ring and C13 followed by a second Heck reaction to close
MeO Br Br 1. MeNH2, K2CO3, -40 °C NMeBoc

A 1. PAD, AcOH, MeOH 2. (Boc)2O, NEt3, MeOH
OH OAc OH
2. Ac2O, NEt3, DMAP 3. TBSCl, imidazole, -78 °C
HO C
47 % 44 %
Br O OH OAc OTBS
48 49 50 51
n-Bu3P, DIAD,
THF, 48, 0 °C 55 %
MeO
MeO MeO
Br
PPh3CH2Br2, Pd(OAc)2, Ag2CO3, CHO
t-BuOK, THF, -60 °C CHO dppf, toluene, 110 °C
O O O Br
49 % 13 82 %
NMeBoc NMeBoc NMeBoc
TBSO TBSO TBSO

54 53 52
44 % Pd(OAc)2, Ag2CO3,
dppp, toluene, 110 °C
MeO 1. TBAF, THF MeO MeO

2. IBX, DMF 1. TFA, CH2Cl2
3. NaBH4, CeCl3, 2. Hg(OAc)2, NEt3,
B MeOH 10 3. LiAlH4
O O O
72 % 15 % D
NMeBoc NMeBoc NMe
H H H
TBSO HO 6
HO
55 56 ent-codeine
(ent-2)
Scheme 8 Hudlicky’s synthesis of ent-codeine
the B-ring with concomitant shift of the double bond into the position present in the
natural product and final closure of the D-ring.
Whole cell oxidation of b-bromoethylbenzene with recombinant Escherichia
coli JM109 (pDTG601A) [63] afforded cyclohexadiene-cis-diol 49, which was
selectively reduced with potassium azodicarboxylate (PAD) before the hydroxy
functionalities were protected as acetate 50. The bis-acetate was reacted with
methylamine and the corresponding secondary amine was obtained with concom-
itant cleavage of the acetate functionalities. N-Boc-protection and silylation of
the distal hydroxy functionality resulted in allylic alcohol 51, which served
as coupling partner in a Mitsunobu reaction with phenol 48. Intramolecular
Heck cyclization of aryl bromide 52 afforded aldehyde 53 in excellent yield as
a single isomer. A Wittig reaction was then used to introduce a vinyl bromide
moiety and served to prepare the substrate for the second Heck cyclization
reaction to close the B-ring and simultaneously shift the double bond in the
position present in the natural product. The configuration of the C6 hydroxy
group in 55 was corrected via the known oxidation/reduction sequence [46, 60]
after the cleavage of the silyl ether and 56 was isolated. The closure of the
D-ring concluded the synthesis of ent-codeine. All attempts to repeat the hydro-
amination protocol published by Trost for the same synthetic intermediate
[47, 48] failed and a different strategy for this operation had to be devised.
The D-ring was established by removal of the Boc-protecting group followed
by aminomercuration of the benzylic double bond and intramolecular trapping
of the resulting organomercurial species by the ethylamino sidechain. The final
steps required the reduction (LiAlH4) of the organomercury compounds formed
during the aminomercuration protocol.
Two years after the publication of ent-codeine, Hudlicky also presented a route
towards codeine (natural series) employing the same enzymatically derived starting
material (49) [15]. The synthesis of the natural isomer is outlined in Sect. 3.5.
3.3 Iorga and Guillou (2008)
Iorga and Guillou presented a route to racemic codeine with a lactone opening/
Michael addition sequence and an Eschenmoser–Claisen rearrangement as key
steps (Scheme 9) [51]. Acid 58, accessible by Birch reduction of p-methoxyphe-
nylacetic acid and subsequent ketalization with ethylene glycol, was esterified with
2-iodo-6-methoxyphenol (57). Subsequent Heck cyclization of ester 59 delivered
spirocyclic lactone 60. Hydrolysis of the ketal and oxidation of the corresponding
a,b-unsaturated ketone delivered lactone 61, which was allowed to react with
N-methylbenzylamine, resulting in lactone opening and amide formation. Upon
reduction with LiAlH4 in refluxing THF, the amine 62 was obtained. During
the course of this reaction the deprotonated phenol acted as the nucleophile in
a Michael-type addition with concomitant formation of the E-ring. Thus, the
exocyclic two-carbon chain in 58 served a dual purpose: it was used as a convenient
tether for the intramolecular Heck cyclization of 59 and later provided the ethyla-
mino bridge to complete ring D of morphine.
The allylic alcohol was subjected to an Eschenmoser–Claisen rearrangement
with dimethylacetamide dimethylacetal to introduce the C14 substituent in a stereo-
selective manner. Reduction of the amide to the corresponding aldehyde with
phenyl silane in the presence of Ti(OiPr)4 was followed by an acid-promoted
closure of the C-ring of codeine. In order to prevent N-oxidation, the amine
was converted to the corresponding tosylamide, via debenzylation and treatment
with tosyl chloride, before the allylic alcohol was introduced by the reaction of
the alkene with selenium dioxide (65). The stereochemistry of the C6 hydroxy
functionality was corrected by applying the well-known oxidation/reduction
protocol [46, 60] before the benzylic double bond was reductively removed under
Birch conditions. Codeine (2) was obtained in 17 steps with an overall yield of
approximately 0.6%.
MeO
MeO
A
HO MeO
57 O [Pd2(dba)3], NEt3,
I EDCl, DMAP DMF, 140 °C
+ I O
HO2C 80 % O
O O
C O
O O 60
O O 58 59
1. Ph3CBF4
2. (PhSeO)2O, 60 %
Na2CO3, 60 °C
MeO MeO OMe MeO

MeO
1. HNMeBn
NMe2 A
2. LiAlH4, THF,
decalin, 215 °C reflux O
O O E
49 % 77 %
13 NMeBn 13 14 NMeBn O C
14
NMe2 O
O 62 61
63
OH
1. Ti(OiPr)4, PhSiH3
40 % 2. pTSA, toluene
MeO 1. ClCO2CH(Cl)CH3, MeO MeO

(ClCH2)2 1. Dess-Martin
2. TsCl, NEt3 2. NaBH4, MeOH
80 % (2 steps) 3. Li / NH3, tBuOH
O O O
3. SeO2, tBuOOH 14 %
NMeBn NMeTs (4 steps) NMe
HO 6 HO
64 65
codeine (2)
Scheme 9 Iorga and Guillou’s synthesis of codeine
3.4 Chida (2008)
With the preparation of racemic dihydroisocodeine (79), Chida reported a formal

synthesis of morphine [52]. The synthesis is based on a cascade of sequential
Claisen rearrangements of an allylic vicinal diol derivative as key steps. The
Claisen rearrangement protocol, as an efficient strategy for the installation of
the C13 quaternary carbon, was successfully employed in the preparation of the
Amaryllidaceae alkaloid galanthamine, published 1 year before the synthesis of
dihydroisocodeinone [64].
With commercially available tri-O-acetyl-D-glucal (66) as the requisite chiral
starting material, dihydroisocodeine was obtained in 24 synthetic operations. The
route to the alkaloid is outlined in Schemes 10 and 11.
The C-ring of morphine was prepared from tri-O-acetyl-D-glucal (66) as shown
in Scheme 10. Saponification of the acetate moieties in 66 under basic conditions
was followed by treatment with p-anisaldehyde dimethylacetal before the C6
hydroxy functionality (morphine numbering) was protected as its silyl ether (67).
AcO 1. NaOMe, MeOH PMP O I

2. p-anisaldehyde 1. DIBAL-H, PhCH3, -20 °C
AcO dimethylacetal, 2. Ph3P . HBr, MeOH,
O PMBO
O PPTS, DMF, 45 °C O NaBr, DME, 0 °C O
3. TBSCl, imidazole 3. I2, imidazole, Ph3P
AcO 45 % TBSO TBSO OMe
69 %
66 67 68
t BuOK,
87 %
THF
OTf O 1. Hg(OCOCF3)2,
13
L-Selectride, -78 °C; PMBO acetone, buffer PMBO
PMBO
Comins’ reagent 2. MsCl, NEt3, DMAP O
5 C
89 % 91 %
TBSO 6 TBSO TBSO OMe
71 70 69
Scheme 10 Chida’s synthesis of dihydroisocodeine – part 1
MeO
A
MeO MeO MeO

1. Pd(OAc)2, Ph3P, EtCOOH,
B(OH)2 aq . Na2CO3, 1, 4-dioxane CH3C(OEt)3,
72 2. DDQ MeO 140 °C, 24 h MeO
+
OTf 83 % HO 87 %
14 CO2Et
PMBO
TBSO TBSO
C
73 74
TBSO 1. Bu4NF
71 1.Bu4NF 2. 2-nitrophenol
CH3C(OEt)3,
2. 2-nitrophenol, 140 °C, 120 h
CH3C(OEt)3, 55 %
1. DIBAL-H 140 °C, 72 h
MeO 2. montmoril- MeO 36 % MeO
lonite K-10
3. TBSOTf,
2, 6-lutidine 1. MCPBA MeO
O CHO O E CO2Et 13 CO2Et
75 % 2. TBSCl,
CO2Et imidazole 14 CO2Et
73 %
TBSO TBSO 6
77 76 75
1. MeNH2, MeNH3Cl,
MS 3A, 0 °C; then LiBH
86 % 2. TsCl, DMAP, py, 80 °C 4
3. Bu4NF, THF
MeO MeO HO
Li, tBuOH,
NH3,THF, -78 °C ref. 38
O O O
92 %
NMe NMe NMe
Ts
HO HO 6 HO
78 dihydroisocodeine (79) morphine (1)
Scheme 11 Chida’s synthesis of dihydroisocodeine – part 2

Reductive cleavage of the para-methoxyphenyl (PMP-) group released the primary

alcohol and the compound was converted into the corresponding methyl glycoside
upon reaction with methanol in the presence of Ph3P.HBr [65]. Subsequently, the
primary alcohol was replaced by iodine to yield 68 to pave the way for the intro-
duction of the exomethylene functionality required for the key Ferrier’s carbocy-
clization reaction. Carbocycle 70 was obtained after exposure of 5-enopyranoside
69 to Hg(OCOCF3)2 in acetone/acetate buffer and the subsequent b-elimination.
The synthesis of the C-ring of the alkaloid was completed by 1,4-reduction and
formation of the vinyl triflate 71 with the Comins’ reagent.
Suzuki coupling of vinyl triflate 71 with boronic acid 72 (Scheme 11) was
followed by the cleavage of the PMB ether by means of a dichloro dicyano
benzoquinone (DDQ) oxidation to afford allylic alcohol 73 in good yield. When
treated with triethyl orthoacetate, the first Claisen rearrangement of 73 took place
and ester 74 was obtained in nearly 90% yield as a single stereoisomer. The silyl
ether was then cleaved and the corresponding alcohol was used in a second Claisen
rearrangement, which delivered the bis-ester 75 in 55% yield. Bis-ester 75 could
also be obtained in a cascade Claisen sequence as shown in Scheme 11. To this end
the silyl group in 73 was cleaved to afford the corresponding diol which was then
treated with triethyl orthoacetate and heated to 140 C for 72 h in the presence of
2-nitrophenol, allowing the product of the double Claisen rearrangement, namely
compound 75, to be isolated in 36% yield.
The E-ring of morphine was installed via epoxidation of the C5–C6 double bond
and simultaneous dealkylating/epoxide opening sequence using MCPBA as oxi-
dant. Silylation of the secondary alcohol at C6 (76) was followed by elaboration of
the B-ring of the alkaloid. This was accomplished by DIBAL-H reduction of both
ester functionalities in 76 to the corresponding aldehydes and subsequent Friedel-
Crafts type cyclization reaction. Elimination of the resulting hydroxyl group
afforded alkene 77. Reductive amination and tosylation of the nitrogen gave 78
after cleavage of the C6 silyl ether. The D-ring was finally established upon treat-
ment of 78 under Birch conditions and dihydroisocodeine 79 was obtained. As this
material was previously successfully converted into morphine [38] this achieve-
ment formalized the synthesis.
3.5 Hudlicky (2009)
Two years after the synthesis of ent-codeine [50], Hudlicky published a route to the
natural enantiomer of the alkaloid [15]. With biocatalytically-derived cyclohexa-
diene-cis-diol 49 (Scheme 8), the same starting material in the synthesis of the
enantiomer of the natural product was utilized. The strategic difference between the
two syntheses is based on the preparation of epoxide 82 obtained via a Mitsunobu
inversion/elimination protocol of the diol 80 (Scheme 12).
The cyclohexadiene-cis-diol 49, derived enzymatically from b-bromoethylben-
zene, was converted into Boc-protected amine 80 as described previously and
NMeBoc 1. DIAD, PPh3, NMeBoc NMeBoc NMeBoc

pNO2C6H4CO2H
OH 2. TsCl, NEt3, DMAP OpNO2Bz NaOMe, 5
MeOH
C O = O
52 % 88 %
OH OTs 6
80 81 82
1. 84, DME, DMF

18-c-6, 80 °C 46 %
2. TBSCl, imidazole
MeO
MeO
MeO in analogy CHO

to Scheme 8
A O O Br
KO NMe NMeBoc
Br O
HO TBSO 6
84
codeine (2) 83
Scheme 12 Hudlicky’s synthesis of codeine
outlined in Scheme 8. Inversion of the allylic alcohol by means of a Mitsunobu

reaction was followed by tosylation of the remaining hydroxyl functionality (81).
Basic hydrolysis of the p-nitrobenzoate afforded epoxide 82, which served as the
electrophile in the reaction with the potassium salt of bromoisovanillin (84). Silyla-
tion of the C6 hydroxy group (morphine numbering) afforded aryl bromide 83 and
the remaining steps in the route to codeine were carried out in analogy to the
preparation of the enantiomer published in 2007. With this slight modification of
the synthetic strategy, the natural product and the enantiomeric series of the target
compound become available utilizing the same biocatalytically-derived starting
material.
3.6 Magnus (2009)
In 2009, Magnus published an approach towards codeine that also constitutes

a formal synthesis of the Amaryllidaceae alkaloid galanthamine by the preparation
of narwedine (90) via a common precursor [17]. Key step in the reaction sequence
is an o-p-phenolic oxidation resulting in the aforementioned common precursor of
galanthamine and codeine.
Commercially available bromoisovanillin (48) was reacted with the triarylbor-
oxine 85 in a Suzuki cross-coupling to afford biphenyl 86 as outlined in Scheme 13.
Reaction of this phenol with ethyl vinyl ether in the presence of bromine afforded
ether 87 which was converted into spirocycle 88 by treatment with cesium fluoride
in DMF at 130 C. Spirocycle 88 served as common intermediate in the syntheses
of both natural products mentioned above.
Ar
B
O O MeO MeO
B B ethyl vinyl ether,
MeO Ar O Ar
HO CHO Br2, iPr2NEt, 0 °C O
85 CHO
A EtO
[Pd2(dba)3], PCy3, 99 %
HO CHO BHT, K2CO3, 80 °C
Br dioxane, H2O,
Br
99 %
OTBS OTBS
48 86 87
CsF, DMF, 96 %
Ar = C OTBS 130 °C
MeO MeO MeO

1. MeNH2.HCl, A
iPr2NEt, NaCNBH3, 2 M HCl,
NMe AcOH, dioxane CHO dioxane, reflux O CHO
O O OH
2. MeSO3H, dioxane 93 %
O
72 % EtO C
O O O
narwedine (90) 89 88
Scheme 13 Magnus’s synthesis of codeine – part 1
Acid-catalyzed hydrolysis of 88 afforded 89, which upon reductive amination

conditions followed by treatment with methanesulfonic acid gave narwidine (90).
Racemic narwidine is known to yield enantiomerically pure galanthamine – the
corresponding allylic alcohol – by spontaneous resolution and subsequent L-selectride
reduction [66]. Thus, the preparation of narwidine concludes the formal synthesis of
the Amaryllidaceae alkaloid galanthamine.
The synthesis of codeine from the common intermediate 88 is shown in
Scheme 14. Reaction of enone 88 with nitromethane gave 91 via a Henry-aldol/
Michael addition cascade with cis-relationship between the newly formed B-ring
and the C-ring. The benzylic double bond in 91 was reductively removed with
sodium cyanoborohydride before the compound was treated with LiAlH4 to afford
allylic alcohol 92. Reductive amination established the morphinan skeleton and the
secondary amine was protected as carbamate (93). With the morphinan skeleton in
hand, the remaining operations were devoted to the functionalization of the C-ring
of the alkaloid. The double bond was shifted to the position present in the natural
product with concomitant installation of the hydroxy functionality, with the correct
stereochemical relationship, via epoxide 94. Treatment of alkene 93 with 5,5-
dimethyl-1,3-dibromohydantoin (96) resulted in the formation of the corresponding
bromohydrin, which, upon exposure to base, delivered the epoxide. As the bromo-
hydrin formation step also resulted in the bromination of the aromatic A-ring of
codeine, an additional reduction step had to be added to the reaction sequence.
Treatment of epoxide 94 with thiophenolate and subsequent oxidation with hydro-
gen peroxide in hexafluoroisopropanol (HFIP) completed the functionalization of
the C-ring (95) and codeine (2) was obtained after a final LiAlH4 reduction to
remove the aryl bromide.
MeO MeO 1. 1 M HCl,

MeO
1. NaCNBH3, NaCNBH3
MeNO2, NH4OAc AcOH, THF 2. EtO2CCl,
AcOH, reflux O 2. LiAlH4 O NEt3
88 B O
97 % 63 % 59%
EtO NO2 NH2 NCO2Et
EtO
O OH
91 92 93
1. 96
91 %
2. KOH
MeO MeO Br MeO Br

O
1. PhSNa, EtOH
LiAlH4 2. H2O2, HFIP
NBr O O O
BrN 87 % 75 %
NMe NCO2Et NCO2Et
O 6
6 8
96 HO HO 7
7
O
codeine (2) 95 94
Scheme 14 Magnus’s synthesis of codeine – part 2
3.7 Stork (2009)
Stork’s strategy towards racemic morphine comprises a Diels–Alder cycloaddition

reaction of a benzofuran to establish the B- and C-ring of morphine as the key step
[53]. The reaction sequence started with the ketalization of iodoisovanillin 97
(Scheme 15). Subsequently, the phenol was reacted with methyl propiolate to afford
98 as precursor for the installation of the benzofuran moiety via a palladium-
catalyzed Heck cyclization (99). Next, the key intermediate was prepared for the
Diels–Alder reaction. Hydrolysis of the acetal under acidic conditions and Wittig
homologation afforded aldehyde 100, which was converted to diene 101 via
hydrozirconation of acetylene 105 employing the Schwartz reagent and subsequent
reaction with aldehyde 100 followed by silylation of the secondary alcohol.
When heated to 240 C in decalin, Diels–Alder precursor 101 underwent the
desired cycloaddition reaction and afforded 102a as the major product. It is
noteworthy that four contiguous stereocenters in the correct relative configuration
required for the preparation of the natural product were established in this operation
and only a minor amount of 102b, diastereomeric at C9, was formed during the
course of the reaction. As the closure of the D-ring was envisaged to proceed via
mesylate 104, the diastereomeric mixture of 102a and 102b was not separated, as
the C9 alcohol had to be oxidized to the corresponding carbonyl at a later stage.
Before this oxidation was carried out, the ester was converted into an aldehyde as
precursor for a Wittig reaction to form the corresponding enol ether. Desilylation
and subsequent Dess-Martin oxidation of the C9-hydroxy moiety resulted in ketone
103, which was reduced and mesylated to afford selectively the required stereoiso-
mer for the formation of the D-ring. The methylamino functionality was introduced
via a reductive amination protocol after hydrolysis of the enol ether (103).
1. HO(CH2)3OH, MeO
pTSA MeO
2. methyl propiolate, Pd(OAc)2, Ph3P, NaOAc,
MeO O
NEt3, THF O nBu4NCl, DMF, 125 °C O
A
72 % I O 84 % O E
HO 13 13 O
I O CO2Me
O OMe 99
97 98
1. HCl, THF
OMe 2. Ph3PCH2OCH3Cl, 93 %
105 KHMDS
MeO MeO
OTES MeO
1. ZrCp2(H)Cl, 105
2. TESCl, imidazole
O CO2Me = O 95 % O
O
14 OTES CO2Me
6 CO2Me
MeO OMe
101 101 100
decalin, NEt ,
69 % 240 °C, 24 h 3
MeO 1. Super-hydride MeO MeO

2. Dess-Martin 1. L-Selectride
3. Ph3PCH2OCH3Cl, 2. MsCl, NEt
KHMDS OMe 3. HCl, THF 3 NHMe
CO2Me
O O O
R1 4. TBAF 4. NEt3, Ti(Oi Pr)4,
6 14 R2 O OMs
5. Dess-Martin MeNH2.HCl
51% 5. NaBH4
MeO MeO MeO
27 %
102a R1 = OTES; R2 = H 103
104
1 2
102b R = H; R = OTES
Scheme 15 Stork’s synthesis of thebaine and codeine – part 1
The closure of the D-ring succeeded under basic conditions via an SN2 displace-
ment of the mesylate by the secondary amine (Scheme 16). Morphinan 106 was
then successfully converted into thebaine (3) via manganese dioxide mediated
oxidation following a procedure by Rapoport [67].
Direct cleavage of the allylic methyl ether in 106 with boron tribromide afforded
codeine in only minor amounts. Better yields were obtained when 106 was con-
verted to the corresponding carbamate before a selenium dioxide mediated oxida-
tion delivered ketone 107. Stereoselective reduction of the ketone and concomitant
generation of the N-methyl group concluded the synthesis of codeine [60, 68]. This
synthesis reported by Stork and co-workers provided a closure to several years of
research, some of which has been reported in Ph.D. dissertations [69].
3.8 Fukuyama (2010)
In 2006, Fukuyama reported his first synthesis of morphine [49], followed 4 years
later by an improved route [54]. As shown in Scheme 17, cyclohexenone (108) was
MeO MeO MeO

K2CO3, γ-MnO2
NHMe benzene, 75 °C see ref. 67
O O O
73 % 80 %
OMs NMe NMe
MeO MeO MeO

104 106 thebaine (3)
1. ClCO2CH3
2. SeO2, tBuOOH 66 %
MeO MeO
LiAlH4
O O
82 %
NCO2Me NMe
O HO
107 codeine (2)
Scheme 16 Stork’s synthesis of thebaine and codeine – part 2
subjected to a-acetoxylation and subsequent iodination to afford iodoketone 109.

Enzymatic resolution of the racemic material with lipase AK yielded alcohol 110,
which was silylated before the a,b-unsaturated ketone was converted to allylic
alcohol 111 via Luche reduction. Palladium-catalyzed Suzuki-Miyaura coupling of
iodide 111 with boron reagent 119 afforded alcohol 112, which was used in
a Mitsunobu reaction with phenol 37 (for the preparation of this compound see
Sect. 3.1 of this review) to give the precursor for the intramolecular Heck reaction
with the requisite stereochemistry at C5 (113). The cyclization proceeded in high
yield and afforded 114. Reduction of the carbamate was followed by protection of
the secondary amine with 2,4-dinitrobenzene-sulfonyl chloride (DNsCl) before the
silyl group was cleaved and the resulting alcohol oxidized to the corresponding
ketone 115. Exposure of this b,g-unsaturated ketone to TFA resulted in hydrolysis
of the acetal and subsequent closure of the B-ring via an intramolecular aldol
reaction. Mesylation of the secondary hydroxy moiety furnished 116 and prepared
the compound for the elimination reaction and subsequent construction of the
D-ring of the alkaloid. Treatment of mesylate 116 with base resulted only in the
elimination of the b-epimer while the a-epimer remained unchanged and harsher
reaction conditions led to decomposition of the starting material. Therefore, the 2,4-
dinitrobenzene-sulfonyl group in 116 was cleaved with mercaptoacetic acid and
H€unig’s base resulting in elimination of both epimeric mesylates with subsequent
closure of the D-ring and a mixture of neopinone (117) and codeinone (118) was
obtained. Presumably, this closure proceeds via 1,6-addition of the amine to the
dienone 128 (Scheme 19) formed by the elimination of the mesylates. Such strategy
was used previously by Fuchs in his morphine synthesis [34, 35]. The synthesis of
morphine was completed by acid mediated conversion of the mixture of neopinone
and codeinone to pure codeinone [35] and subsequent sodium borohydride
1. Pb(OAc)4, 1. TBSOTf,
toluene,rf I lipase AK, I 2, 6-lutidine I
2. I2, DMAP, O 13 THF, phosphate O 2. NaBH4,
O HO
py, CCl4 buffer (pH 7.41) CeCl3, MeOH
C
70 %
AcO HO TBSO
108 109 110 111
[PdCl2(dppf)], 119
aq. NaOH, THF 84 %
MeO
MeO OMe
OMe [Pd2(dba)3], A NHCbz
P(o-tolyl)3,NEt3, n-Bu3P,DEAD
OMe HO
OMe MeCN, rf THF, 37
O O I
97 % 13 NHCbz 99%
NHCbz TBSO
5
C
TBSO
114 TBSO 113 112
1. LiAlH4, THF, rf
2. aq. NaOH, DNsCl
60 %
3. CSA, MeOH
4. Dess-Martin
MeO 1. aq. TFA, MeO MeO
OMe toluene, 50 °C
2. MsCl, HSCH2CO2H,
OMe iPr2NEt, 0 °C i Pr2NEt, 0 °C
O O O
14 71 %
NMeDNs 14 NMeDNs NMe
OMs
O O O
115 11 6 neopinone (8,14-dehydro; 117)
codeinone (7,8-dehydro; 118)
B 1. HCl, dioxane,
NHCbz 73 %
CH2Cl2
from 116
2. NaBH4, MeOH
HO MeO
119
BBr3,
MeO CH2Cl2
OMe O O
A 63 %
HO NMe NMe
OMe
I HO HO
37
for preparation see Scheme 6 morphine (1) codeine (2)
Scheme 17 Fukuyama’s synthesis of codeine and morphine
reduction to yield codeine. Morphine was obtained by reaction with boron tribro-
mide following the procedure first reported by Rice [55].
Fukuyama also presented an alternative route to the advanced intermediate 114
as shown in Scheme 18 with an early introduction of the protected amino function-
ality. Reaction of g-butyrolactone with the Grignard reagent derived from 1,4-
dibromobutane (120) afforded diol 121. Mesylation of the primary hydroxyl func-
tionality with concomitant elimination of the tertiary one was followed by reaction
with methylamine and protection of the resulting secondary amine to give alkene
122. Ozonolysis of the double bond in 122 and subsequent intramolecular aldol
condensation of the resulting ketoaldehyde afforded cycohexenone 123. Rubottom
oxidation and acetylation gave 124, which served as substrate in the lipase-
1. MsCl, NEt3
OH 2. MeNH2, MeOH, rf
Br Mg, THF, rf 3. DNsCl, aq. NaHCO3 DNs
Br HO N
61 %
O Me
120 121 122
O
79 % 1. O3, toluene;
Ph3P
2. aq. TFA
1. lipase AK,
NMeDNs THF, buffer NMeDNs 1.TMSOTf, NEt3; NMeDNs
2. TBSOTf, MCPBA
O O O
2,6-lutidine 2. Ac2O, py
5
C
42 % 89 %
TBSO AcO 6
125 124 123
NaBH4, THF
97 %
CeCl3.7H2O
1. 37, n-Bu3P, DEAD MeO

NMeDNs 2. [Pd2(dba)3], OMe MeO
P(o-tolyl)3, A OMe
HO A
MeCN, 85 °C
OMe
O HO 4 OMe
95 %
TBSO NHCbz I
126 C
37
TBSO for preparation see Scheme 6
114
Scheme 18 Fukuyama’s synthesis of codeine and morphine – alternative route to intermediate 114
MeO MeO MeO

O
O 2 steps
O O O
NMeAc NMeAc NMe
H
O O O
127 128 ent-codeinone
(ent-116)
9 steps from diol 49
2 steps form 53
Scheme 19 Hudlicky’s approach to ent-codeinone
catalyzed resolution in close analogy to the approach discussed above. Silylation

(125) and Luche reduction delivered allylic alcohol 126, which was used in a
Mitsunobu reaction with previously described phenol 37. The preparation of inter-
mediate 114 was achieved by intramolecular Heck cyclization forming the E-ring
of morphine.
At the time of Fukuyama’s publication a virtually identical approach was
nearing completion in the Hudlicky group. Enone 127 (Scheme 19), analogous to
115, was synthesized in the ent-series in nine steps from diol 49, previously used in
the synthesis of ent-codeine, Scheme 8. Cyclization of 127 to dienone 128 leaves
only two steps to complete ent-codeinone (ent-116) [70, 71].
4 Medicinally Important Derivatives of Morphine
The preparation of medicinally important derivatives of morphine has recently been

summarized in a review article [72]. Therefore, this section only provides a general
outline.
The commercial production of medicinally useful opiate-derived products is
faced with two major challenges. The first of these is the introduction of the C14
hydroxy group and the second is the formal exchange of the N-methyl group for
another alkyl group such as allyl (naloxone, 9), methylcyclopropyl (naltrexone, 8,
buprenorphine, 10) or methylcyclobutyl groups (nalbuphine, 11) as outlined in
Scheme 20 [72–77].
The oxidation of C14 is best accomplished by oxidation of either thebaine (3) or
oripavine (4) and the large-scale production of the corresponding ketones has been
adequately solved. Such methods include, for example, the addition of singlet
oxygen to thebaine (3) and subsequent reduction of the resulting endoperoxide
[78, 79] or treatment of (3) with formic acid and hydrogen peroxide [80]. The
preparation of hydrocodone, hydromorphone, and related derivatives can be accom-
plished via hydrogenation utilizing transition metal catalysts [81–83]. In 2007,
Hudlicky reported studies on regioselective hydrogenation of thebaine (3) with
rhodium and iridium catalysts to form 8,14-dihydrothebaine (130), which can be
converted to hydrocodone (7) via acidic hydrolysis of the enolether as shown in
Scheme 21 [84].
The second issue, the exchange of the N-alkyl group, is much more challenging.
The current methods include the use of reagents such as cyanogen bromide (von
Braun demethylation) [85, 86] or methyl chloroformate [87–91]. Neither is
RO RO
C14-oxidation
O O
14 NMe 14 NMe
OH
MeO O
oxycodone (6), R = Me
thebaine (3), R = Me oxymorphone (129), R = H
oripavine (4), R = H
1. N-demethylation
2. alkylation
HO
HO HO HO
O O N O
N N N
OH OH MeO OH
O O HO
HO
naltrexone (8) naloxone (9) buprenorphine (10) nalbuphine (11)
Scheme 20 Preparation of medicinally important morphine derivatives

MeO MeO MeO
H2, Ir- or Rh catalysts aq. HCl

O O O
14 NMe 14 NMe NMe

8 8
MeO MeO O
thebaine (3) 130 hydrocodone (7)
Scheme 21 Hudlicky’s transition metal catalyzed conversion of thebaine to hydrocodone
MeO
O
N+ Me
O–
O
MeO modified (131) MeO

Fe-Polonovski
reaction irradiation or
enzymatic methods
O O
NMe NH
Pd-catalyzed
demethylation /
O O
acylation MeO
hydrocodone (7) norhydrocodone (133)
O
N Ac
O
(132)
Scheme 22 N-Demethylation strategies of hydrocodone
particularly environmentally sound or efficient and the actual exchange of a methyl

group for any other alkyl group requires multiple steps. Demethylation under
irradiation was reported by Scammells [92]. Despite promising results on simple
substrates, the method fails to deliver demethylated derivatives of the more com-
plex alkaloids or derivatives in good yield. Once the N-demethylation is accom-
plished the secondary amine in O-protected noroxymorphone is alkylated with the
particular alkyl halide.
Among the more modern methods of N-demethylation of hydrocodone are
palladium-catalyzed N-demethylation/acylation as reported by Hudlicky [93, 94],
or iron-mediated reduction of N-oxides published by Scammells [95]. Scammells
developed different modifications of this variation of the Polonovski protocol and
the reaction can be carried out via a two step procedure (oxidation and in situ
demethylation of the activated alkaloid) [96] or under very mild conditions in
acetate buffer [97]. Quite recently, a protocol was reported utilizing ferrocene as
demethylation catalyst [98].
Alternative methods for the demethylation include biocatalytic protocols

mediated by fungal cytochromes [99, 100]. Scheme 22 summarizes the methods
discussed above.
5 Conclusion and Outlook
Eight total syntheses of morphine or congeners have been reported in the last
5 years, attesting to no shortage of new ideas or strategies. The interest in this
fascinating molecule will no doubt continue, yet a truly practical synthesis of the
title alkaloid still remains a distant dream. In order even to approach the current
price per kilogram, a synthesis would have to be five to six steps long starting with
commodity chemicals. A potential for a practical synthesis may exist in the realm of
fermentation provided the biosynthetic pathway could be coded into a single
plasmid and used to over-express the required enzymes in a robust bacterial carrier.
A proof of principle has been attained through the work of Kutchan with the cloning
and expression of codeinone reductase in E. coli [101].
Another possibility for practical synthesis could come from the combination of
fermentation for attaining specific steps with semisynthesis to complete the prepa-
ration. Currently, we are fully dependent on natural sources of morphine and
all medicinally useful derivatives are made by semisynthesis. Perhaps more impor-
tant goals for the future generations of chemists would be to focus on the de novo
total synthesis of the derivatives themselves rather than morphine or codeine.
Perhaps we will see some effort devoted to this most worthwhile task in the near
future.
Addition
After the manuscript has been accepted for publication, a synthesis of codeine
was published featuring a Claisen-rearrangement and a 1,3-dipoloar nitrone cyclo-
addition as key steps: Erhard T, Ehrlich G, Metz, P (2011) A Total Synthesis of
(þ/)-codeine by 1,3-Dipolar Cycloaddition. Angew Chem Int Ed doi: 10.1002/
anie.201007448.
Acknowledgments The authors are grateful to the following agencies for financial support:
Hudlicky group: Natural Sciences and Engineering Research Council of Canada (NSERC; Idea
to Innovation and Discovery Grants), Canada Research Chair Program, Canada Foundation for
Innovation (CFI), Research Corporation, Noramco, Inc., TDC Research, Inc., TDC Research
Foundation, and Brock University. In addition, the authors are most grateful to the co-workers
who participated in the various projects connected with the topic of this review between 2005 and
present; their names appear in the cited references. Rinner group: The Austrian Science Fund
(Fonds zur Förderung der wissenschaftlichen Forschung, FWF) is gratefully acknowledged for
financial support.
References
1. Gates M, Tschudi G (1952) The synthesis of morphine. J Am Chem Soc 74:1109–1110

2. Gates M, Tschudi G (1956) The synthesis of morphine. J Am Chem Soc 78:1380–1393
3. Altshuler HL (1979) Behavioral methods for the assessment of alcohol tolerance and
dependence. Drug Alcohol Depend 4:333–346
4. Mello NK, Mendelson JH, Kuehnle JC, Sellers MS (1981) Operant analysis of human heroin
self-administration and the effects of naltrexone. J Pharmacol Exp Ther 216:45–54
5. Shader RI (2003) Antagonists, inverse agonists, and protagonists. J Clin Psychopharm
23:321–322
6. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD (1999) The kappa
opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in
patients with postoperative pain. Pain 83:339–345
7. Booth M (1998) Opium: a history. St. Martin’s Press, New York
8. Kapoor LD (1995) Opium poppy: botany, chemistry, and pharmacology. Food Products
Press, New York
9. Rice KC (2003) In: Meldrum M (ed) Progress in pain research and management. IASP Press,
Seattle
10. Carr AS, Holtby HM, Hartley EJ, Cox P, Macpherson BA (1994) The dose-response of caudal
morphine in children undergoing open-heart-surgery. Anesthesiology 81:A1348–A1348
11. Sert€urner FW (1805) Trommsdorff’s J Pharm 13:229–235
12. Sert€urner FW (1806) Darstellung der reinen Mohns€aure (Opiums€aure) nebst einer
Chemischen Untersuchung des Opiums mit vorz€ uglicher Hinsicht auf einen darin neu
entdeckten Stoff und die dahin geh€ origen Bemerkungen. Trommsdorff’s J Pharm 14:47–93
13. Sert€urner FW (1817) Uber€ das Morphium, eine neue salzf€ahige Grundlage, und die
Mekons€aure, als Hauptbestandtheile des Opiums. Ann Phys Berlin 55:56–89
14. Butora G, Hudlicky T (1998) The story of morphine structure elucidation: one hundred
years of deductive reasoning. In: Hudlicky T (ed) Organic synthesis: theory and applications.
JAI Press, Greenwich
15. Leisch H, Omori AT, Finn KJ, Gilmet J, Bissett T, Ilceski D, Hudlicky T (2009) Chemo-
enzymatic enantiodivergent total syntheses of (þ)- and ()-codeine. Tetrahedron 65:
9862–9875
16. Rice KC (1980) Synthetic opium-alkaloids and derivatives – a short total synthesis of (þ/)-
dihydrothebainone, (þ/)-dihydrocodeinone, and (þ/)-nordihydrocodeinone as an
approach to a practical synthesis of morphine, codeine, and congeners. J Org Chem
45:3135–3137
17. Magnus P, Sane N, Fauber BP, Lynch V (2009) Concise syntheses of ()-galanthamine and
(þ/)-codeine via intramolecular alkylation of a phenol derivative. J Am Chem Soc 131:
16045–16047
18. Zezula J, Hudlicky T (2005) Recent progress in the synthesis of morphine alkaloids. Synlett
388–405
19. Hudlicky T, Reed JW (2007) The way of synthesis: evolution of design and methods for
natural products. Wiley-VCH, Weinheim
20. Wong HNC, Hon MY, Tse CW, Yip YC, Tanko J, Hudlicky T (1989) Use of cyclopropanes
and their derivatives in organic-synthesis. Chem Rev 89:165–198
21. Novak BH, Hudlicky T, Reed JW, Mulzer J, Trauner D (2000) Morphine synthesis and
biosynthesis – an update. Curr Org Chem 4:343–362
22. Taber DF, Neubert TD, Schlecht MF (2004) In: Harmata M (ed) Strategies and tactics in
organic synthesis. Academic, Oxford
23. Blakemore PR, White JD (2002) Morphine, the proteus of organic molecules. Chem
Commun 1159–1168
24. Hudlicky T, Butora G, Fernley S, Gum A, Stabile M (1996) A historical perspective of
morphine syntheses. In: Rahman AU (ed) Elsevier, Amsterdam
25. Waldmann H (1995) Synthesis of calicheamicin. In: Waldmann H (ed) Organic synthesis
highlights II. VCH, Weinheim
26. Maier M (1995) Syntheses of morphine. In: Waldmann H (ed) Organic synthesis highlights
II. VCH, Weinheim
27. Elad D, Ginsburg D (1954) Syntheses in the morphine series 6. The synthesis of morphine.
J Chem Soc 3052–3056
28. Elad D, Ginsburg D (1954) The synthesis of morphine. J Am Chem Soc 76:312–313
29. Grewe R, Friedriccsen W (1967) Die cyclisierung von octahydro-isochinolinderivaten durch
morphinan-ringschluss. Synthese Der Dihydrothebainons. Chem Ber Recl 100:1550
30. Grewe R, Fischer H, Friedric W (1967) Die Partielle Birch-Reduktion Von 1-Benzyl-
Isochinolin-Derivaten. Chem Ber Recl 100:1
31. Evans DA, Mitch CH (1982) Studies directed towards the total synthesis of morphine
alkaloids. Tetrahedron Lett 23:285–288
32. White JD, Caravatti G, Kline TB, Edstrom E, Rice KC, Brossi A (1983) Biomimetic total
synthesis of ()-codeine. Tetrahedron 39:2393–2397
33. Moos WH, Gless RD, Rapoport H (1983) Codeine analogs – synthesis of 4a-aryldecahy-
droisoquinolines containing nitrogen ring functionality and of octahydro-1 h-indeno[1,2,3-
ef]isoquinolines – a total synthesis of codeine. J Org Chem 48:227–238
34. Toth JE, Fuchs PL (1987) Syntheses via vinyl sulfones. 21. Total synthesis of dl-morphine.
J Org Chem 52:473–475
35. Toth JE, Hamann PR, Fuchs PL (1988) Synthesis via vinyl sulfones. 29. Studies culminating
in the total synthesis of (dl)-morphine. J Org Chem 53:4694–4708
36. Tius MA, Kerr MA (1992) A novel-approach to the synthesis of morphine alkaloids – the
synthesis of (D, L)-thebainone-A. J Am Chem Soc 114:5959–5966
37. Parker KA, Fokas D (1992) Convergent synthesis of (þ/)-dihydroisocodeine in 11 steps by
the tandem radical cyclization strategy – a formal total synthesis of (þ/)-morphine. J Am
Chem Soc 114:9688–9689
38. Parker KA, Fokas D (2006) Enantioselective synthesis of ()-dihydrocodeinone: a short
formal synthesis of ()-morphine. J Org Chem 71:449–455
39. Hong CY, Kado N, Overman LE (1993) Asymmetric-synthesis of either enantiomer
of opium-alkaloids and morphinans – total synthesis of ()-dihydrocodeinone and (þ)-
dihydrocodeinone and ()-morphine and (þ)-morphine. J Am Chem Soc 115:11028–11029
40. Mulzer J, Durner G, Trauner D (1996) Formal total synthesis of ()-morphine by cuprate
conjugate addition. Angew Chem Int Ed 35:2830–2832
41. Parsons PJ, Penkett CS, Shell AJ (1996) Tandem reactions in organic synthesis: novel
strategies for natural product elaboration and the development of new synthetic methodology.
Chem Rev 96:195–206
42. White JD, Hrnciar P, Stappenbeck F (1997) Asymmetric synthesis of (þ)-morphine. The
phenanthrene route revisited. J Org Chem 62:5250–5251
43. Mulzer J, Bats JW, List B, Opatz T, Trauner D (1997) The phenanthrenone approach to opium
alkaloids: formal total synthesis of morphine by sigmatropic rearrangement. Synlett 441–444
44. Nagata H, Miyazawa N, Ogasawara K (2001) A concise route to ()-morphine. Chem
Commun 1094–1095
45. Nagata H, Miyazawa N, Ogasawara K (2001) Tandem single-step construction of chiral
hexahydrophenanthrenes: a concise route to (þ)-ferruginol. Org Lett 3:1737–1740
46. Taber DF, Neubert TD, Rheingold AL (2002) Synthesis of ()-morphine. J Am Chem Soc
124:12416–12417
47. Trost BM, Tang WP (2002) Enantioselective synthesis of ()-codeine and ()-morphine.
J Am Chem Soc 124:14542–14543
48. Trost BM, Tang WP, Toste FD (2005) Divergent enantioselective synthesis of ()-galantha-
mine and ()-morphine. J Am Chem Soc 127:14785–14803
49. Uchida K, Yokoshima S, Kan T, Fukuyama T (2006) Total synthesis of (þ/)-morphine.
Org Lett 8:5311–5313
50. Omori AT, Finn KJ, Leisch H, Carroll RJ, Hudlicky T (2007) Chemoenzymatic total
synthesis of (þ)-codeine by sequential intramolecular Heck cyclizations via C-B-D ring
construction. Synlett 2859–2862
51. Varin M, Barre E, Iorga B, Guillou C (2008) Diastereoselective total synthesis of
(þ/)-codeine. Chem Eur J 14:6606–6608
52. Tanimoto H, Saito R, Chida N (2008) Formal synthesis of ()-morphine from D-glucal
based on the cascade Claisen rearrangement. Tetrahedron Lett 49:358–362
53. Stork G, Yamashita A, Adams J, Schulte GR, Chesworth R, Miyazaki Y, Farmer JJ (2009)
Regiospecific and stereoselective syntheses of (þ/) morphine, codeine, and thebaine via
a highly stereocontrolled intramolecular 4þ2 cycloaddition leading to a phenanthrofuran
system. J Am Chem Soc 131:11402–11406
54. Koizumi H, Yokoshima S, Fukuyama T (2010) Total synthesis of ()-morphine. Chem
Asian J 5:2192–2198
55. Rice KC (1977) Rapid, high-yield conversion of codeine to morphine. J Med Chem 20:
164–165
56. Wernerova M, Hudlicky T (2010) On the practical limits of determining isolated product
yields and ratios of stereoisomers: reflections, analysis, and redemption. Synlett 2701–2707
57. Gulland JM, Robinson R (1925) Mem Proc Manchester Lit Phil Soc 69:79
58. Gates M (1950) The synthesis of ring systems related to morphine. 3. 5,6-Dimethoxy-
4-cyanomethyl-1,2-naphthoquinone and its condensation with dienes. J Am Chem Soc 72:
228–234
59. Rapoport H, Lovell CH, Tolbert BM (1951) The preparation of morphine-N-methyl-C-14.
J Am Chem Soc 73:5900
60. Iijima I, Rice KC, Silverton JV (1977) Studies in (þ)-morphinan series. 1. Alternate
conversion of (þ)-dihydrocodeinone into (þ)-codeine. Heterocycles 6:1157–1165
61. Uchida K, Yokoshima S, Kan T, Fukuyama T (2009) Total synthesis of (þ/)-morphine.
Heterocycles 77:1219–1234
62. Kaburagi Y, Tokuyama H, Fukuyama T (2004) Total synthesis of ()-strychnine. J Am
Chem Soc 126:10246–10247
63. Zylstra GJ, Gibson DT (1989) Toluene degradation by pseudomonas-putida f1 – nucleotide-
sequence of the Todc1c2bade genes and their expression in Escherichia coli. J Biol Chem
264:14940–14946
64. Tanimoto H, Kato T, Chida N (2007) Total synthesis of (þ)-galanthamine starting from
D-glucose. Tetrahedron Lett 48:6267–6270
65. Bolitt V, Mioskowski C, Lee SG, Falck JR (1990) Direct preparation of 2-deoxy-D-gluco-
pyranosides from glucals without Ferrier rearrangement. J Org Chem 55:5812–5813
66. Shieh WC, Carlson JA (1994) Asymmetric transformation of either enantiomer of narwedine
via total spontaneous resolution process, a concise solution to the synthesis of ()-galantha-
mine. J Org Chem 59:5463–5465
67. Barber RB, Rapoport H (1975) Synthesis of thebaine and oripavine from codeine and
morphine. J Med Chem 18:1074–1077
68. Schwartz MA, Pham PTK (1988) Oxidative coupling of cis-3, N-bis(methoxycarbonyl)-
N-norreticuline – an approach to the asymmetric-synthesis of morphine alkaloids. J Org
Chem 53:2318–2322
69. Wu C (1991) Intramolecular Diels–Alder cyclizations in an approach to the morphine
skeleton. Diss Abstr Int B 53:2044
70. Hudlicky T, Duchek J, Piercy TG (2011) Can J Chem, in press
71. Piercy TG, Duchek J, Ilceski D, Hudlicky T (2010) Diverse approaches to chemoenzymatic
synthesis of (þ)-codeine. 93rd Canadian Chemistry Conference, Toronto, May 29 – June 2
72. Berenyi S, Csutoras C, Sipos A (2009) Recent developments in the chemistry of thebaine and
its transformation products as pharmacological targets. Curr Med Chem 16:3215–3242
73. Thavaneswaran S, McCamley K, Scammells PJ (2006) N-Demethylation of alkaloids. Nat
Prod Commun 1:885–897
74. McCawley EL, Hart ER, Marsh DF (1941) The preparation of N-allylmorphine. J Am Chem
Soc 63:314
75. Lewenstein MJ (1964) Br. Patent 955493
76. Blumberg H, Pachter IJ, Matossian Z (1967) U.S. Patent 3332950
77. Bentley KW (1968) Br. Patent 1136214
78. Lopez D, Quinoa E, Riguera R (1994) Photooxidation of thebaine – a route to 14-hydroxy-
morphinones and hydrodibenzofuran analogs of methadone. Tetrahedron Lett 35:5727–5730
79. Lopez D, Quinoa E, Riguera R (2000) The [4þ2] addition of singlet oxygen to thebaine:
new access to highly functionalized morphine derivatives via opioid endoperoxides. J Org
Chem 65:4671–4678
80. Krassnig R, Hederer C, Schmidhammer H (1996) Optimization of the synthesis of oxyco-
done and 5-methyloxycodone. Arch Pharm 329:325–326
81. Gindelberger DE (2010) Ruthenium catalysts for the production of hydrocodone, hydro-
morphone or a derivative thereof: PCT Int. Appl. 32 pp. CODEN: PIXXD2 WO 2010118273
A1 20101014 CAN 153:530729 AN 2010:1283630
82. Wang PX, Moser FW, Cantrell GL, Magparangalan DP, Bao J (2006) Method for the
catalytic production of hydrocodone, hydromorphone, and derivatives thereof: U.S. Pat.
Appl. Publ. 9 pp, Cont.-in-part of U.S. Ser. No. 973,031. CODEN: USXXCO US
2006155130 A1 20060713 CAN 145:124776 AN 2006:681645
83. Wang PX, White CR (2005) Process for the catalytic conversion of codeine and morphine
into hydrocodone and hydromorphone: U.S. Pat. Appl. Publ. 8 pp., Cont.-in-part of U.S. Ser.
No. 495,503. CODEN: USXXCO US 2005124811 A1 20050609 CAN 143:26767 AN 2005:
497544
84. Leisch H, Carroll RJ, Hudlicky T, Cox DP (2007) Studies on regioselective hydrogenation of
thebaine and its conversion to hydrocodone. Tetrahedron Lett 48:3979–3981
85. Kotick MP, Leland DL, Polazzi JO, Schut RN (1980) Analgesic narcotic-antagonists.
1. 8-beta-Alkyl, 8-beta-acyl, and 8-beta (tertiary alcohol) dihydrocodeinones and dihydro-
morphinones. J Med Chem 23:166–174
86. Yu H, Prisinzano T, Dersch CM, Marcus J, Rothman RB, Jacobson AE, Rice KC (2002)
Synthesis and biological activity of 8 beta-substituted hydrocodone indole and hydromor-
phone indole derivatives. Bioorg Med Chem Lett 12:165–168
87. Cooley JH, Evain EJ (1989) Amine dealkylations with acyl chlorides. Synthesis-Stuttgart
1–7
88. Hobson JD, McCluske JG (1967) Cleavage of tertiary boses with phenyl chloroformate –
reconversion of 21-deoxyajmaline into ajmaline. J Chem Soc C 2015–2017
89. Rice KC (1975) Improved procedure for N-demethylation of 6,7-benzomorphans, morphine,
and codeine. J Org Chem 40:1850–1851
90. Greiner E, Spetea M, Krassnig R, Schullner F, Aceto M, Harris LS, Traynor JR, Woods JH,
Coop A, Schmidhammer H (2003) Synthesis and biological evaluation of 14-alkoxymorphinans.
18. N-Substituted 14-phenylpropyloxymorphinan-6-ones with unanticipated agonist properties:
extending the scope of common structure-activity relationships. J Med Chem 46:1758–1763
91. Hamilton GL, Backes BJ (2006) Dealkylative functionalization of tertiary amines with
electron deficient heteroaryl chlorides. Tetrahedron Lett 47:2229–2231
92. Ripper JA, Tiekink ERT, Scammells PJ (2001) Photochemical N-demethylation of alkaloids.
Bioorg Med Chem Lett 11:443–445
93. Carroll RJ, Leisch H, Scocchera E, Hudlicky T, Cox DP (2008) Palladium-catalyzed
N-demethylation/N-acylation of some morphine and tropane alkaloids. Adv Synth Catal
350:2984–2992
94. Carroll RJ, Leisch H, Hudlicky T (2009) Conversion of thebaine to morphine derivatives:
U.S. Pat. Appl. Publ. 9 pp. Chemical Indexing Equivalent to 150:77839 (WO). CODEN:
USXXCO US 2009005563 A1 20090101 CAN 150:77838 AN 2009:1904, US patent #
7,928,234
95. McCamley K, Ripper JA, Singer RD, Scammells PJ (2003) Efficient N-demethylation of opiate
alkaloids using a modified nonclassical Polonovski reaction. J Org Chem 68:9847–9850
96. Kok GB, Pye CC, Singer RD, Scammells PJ (2010) Two-step iron(0)-mediated
N-demethylation of N-methyl alkaloids. J Org Chem 75:4806–4811
97. Kok G, Ashton TD, Scammells PJ (2009) An improved process for the N-demethylation of
opiate alkaloids using an iron(II) catalyst in acetate buffer. Adv Synth Catal 351:283–286
98. Kok GB, Scammells PJ (2010) N-Demethylation of N-methyl alkaloids with ferrocene.
Bioorg Med Chem Lett 20:4499–4502
99. Chaudhary V, Leisch H, Moudra A, Allen B, De Luca V, Cox DP, Hudlicky T (2009)
Biotransformations of morphine alkaloids by fungi: N-demethylations, oxidations, and
reductions. Collect Czech Chem Commun 74:1179–1193
100. Hailes AM, French CE, Bruce NC (1994) Morphinone reductase for the preparation of
hydromorphone and hydrocodone: PCT Int. Appl. 23 pp. CODEN: PIXXD2 WO 9400565
A1 19940106 CAN 120:128514 AN 1994:128514
101. Unterlinner B, Lenz R, Kutchan TM (1999) Molecular cloning and functional expression of
codeinone reductase: the penultimate enzyme in morphine biosynthesis in the opium poppy
Papaver somniferum. Plant J 18:465–475
Top Curr Chem (2012) 309: 67–130
DOI: 10.1007/128_2011_204
Published online: 14 September 2011
Indole Prenylation in Alkaloid Synthesis
Thomas Lindel, Nils Marsch, and Santosh Kumar Adla
Abstract Important biologically active indole alkaloids are decorated with prenyl
(3,3-dimethylallyl) and tert-prenyl (1,1-dimethylallyl) groups. Covering the litera-
ture until the end of 2010, this review article comprehensively summarises and
discusses the currently available technologies of prenylation and tert-prenylation
of indoles, which have been applied in natural products total syntheses or could
be applied there in the near future. We focus on those procedures which
introduce the C5 units in one step, organised according to the indole position to
be functionalised. Key strategies include electrophilic and nucleophilic prenylation
and tert-prenylation, prenyl and tert-prenyl rearrangements, transition metal-
mediated reactions and enzymatic methods.
Keywords Alkaloids Indole Prenylation Regioselectivity Total synthesis
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2 N-Prenylation and N-tert-Prenylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.1 N-Prenylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.2 N-tert-Prenylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
3 Prenylation and tert-Prenylation at C2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.1 Prenylation at C2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.2 tert-Prenylation at C2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
4 Prenylation and tert-Prenylation at C3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
4.1 Prenylation at C3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
4.2 tert-Prenylation at C3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
5 Prenylation and tert-Prenylation in the Benzene Section of Indole . . . . . . . . . . . . . . . . . . . . . . . 114
5.1 4- and 5-Prenylindoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Dedicated to Professor Gerhard Bringmann on the occasion of his 60th birthday.

T. Lindel (*), N. Marsch, and S. K. Adla
Institut f€ur Organische Chemie, TU Braunschweig, Hagenring 30, 38106 Braunschweig,
Germany
68 T. Lindel et al.
5.2 7-Prenyl- and 7-tert-Prenylindoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
1 Introduction
Indole alkaloids carrying 3,3-dimethylallyl (prenyl) or 1,1-dimethylallyl (tert-

prenyl) substituents constitute prominent secondary metabolites found in microbial
fungi, cyanobacteria, but also in marine bryozoans. A review on the structures and
chemoenzymatic syntheses of prenylated indole alkaloids has been published
recently by Li [1]. For earlier review articles, see Williams [2] and Winterfeldt
[3]. Given the importance of prenylated indole alkaloids for chemistry and beyond,
we thought it would be interesting to comprehensively summarise and discuss the
approaches employed for their total synthesis, aiming at identifying established,
investigated, and undeveloped areas of indole prenylation. Since natural product
synthesis drives and is driven by new synthetic methodology, this review also
includes recent advances in indole prenylation, even if no natural products have
been synthesised. The literature is covered until 2010.
prenylation electrophilic prenylation in buffer systems or

after N-deprotonation of C3-free indoles
use of iminium electrophiles
Pictet-Spengler condensation, if C2 blocked

Claisen rearrangement of 3-tert-
transition metal-mediated
prenylindolenine
chemoenzymatic
electrophilic prenylation after 2-
Ni- or Pd-mediated lithiation of N-protected indoles
Pictet-Spengler condensation
4
3
Ni- or Pd- 5 chemoenzymatic
mediated 2 acid-catalyzed prenyl shift from N1
6 N 1
H acid-catalyzed prenyl shift from C3
Ni-mediated 7 of pyrrolo[2,3-b]indolines
nucleophilic attack of tert-

prenylborane at 3-haloindolenines
chemoenzymatic
Claisen rearrangement of 6-
tert-prenyloxyindole electrophilic prenylation after N-
deprotonation, if C3 substituted
aza-Claisen rearrangement of
N-tert-prenylindole chemoenzymatic
Fig. 1 Major possibilities of one-step indole prenylation

Indole Prenylation in Alkaloid Synthesis 69
tert-prenylation Claisen rearrangement of 2-prenyloxy-

or -thioindole
nucleophilic tert-prenylation with

prenyl metal compounds
oxidative shift of tert-prenyl from C2
chemoenzymatic
not established transition metal catalysed coupling with tert-prenol
4
3 nucleophilic attack of prenylborane
not established 5 at 3-chloroindolenine and -indole
2
Claisen rearrangement of 3-
6 N1 prenyloxy- or -thioindole
not established H
7
metal-catalysed substitution
Claisen propargylation of indoline
rearrangement of 6-
prenyloxyindole chemoenzymatic
Fig. 2 Major possibilities of one-step indole tert-prenylation
Prenylations and tert-prenylations of indole most frequently occur at positions

N1, C2 and C3 (Sects. 2–4), with fewer indole alkaloids prenylated in the benzene
section (Sect. 5). There are no indole derivatives with prenylated or tert-prenylated
bridge head positions C3a or C7a. Regioselective introduction of prenyl or tert-
prenyl groups at the indole ring can be challenging, depending on the position.
Certain cases are simple, such as N-prenylation, others are still not reported, such as
6-tert-prenylation. Figures 1 and 2 give overviews of the major possibilities of
synthesising prenylated or tert-prenylated indoles, respectively, in one step.
We decided to sort the material according to the indole positions that are
prenylated or tert-prenylated. Methodology or natural product oriented section
headings would also have been possible. With a few exceptions, only those
approaches have been included in this review, which incorporate the entire C5 unit
within a single operation. Syntheses building up the indole systems are only briefly
mentioned, as are approaches constructing the prenyl or tert-prenyl unit stepwise.
2 N-Prenylation and N-tert-Prenylation
2.1 N-Prenylation
Electrophilic N-prenylation. Synthesis of N-prenylindole derivatives is usually facile

by deprotonation of N-unsubstituted indoles with NaH or, more rarely KH, in DMF
[4–17], DMSO [17], THF [18] or acetone [19], followed by reaction with prenyl
70 T. Lindel et al.
bromide or chloride. Yields normally reach more than 80%. Alkali hydroxides in the
presence of crown ethers, phase transfer catalysts [8, 20–23] or K2CO3 [24, 25] have
also been used as bases, if electron withdrawing groups (Ac, CHO) were present at C3.
N-Unsubstituted diketopiperazines and phthalimide-protected tryptophan derivatives
underwent partial epimerisation when working with NaH/DMF. As an alternative, it
was possible to N-prenylate unprotected tryptophan selectively by treatment with
prenyl bromide/Na in liquid ammonia via the disodium salt of tryptophan [16, 26].
N-Prenylation of 3-alkylindole can be combined in situ with Vilsmeier formylation of
the 2-position [27]. However, if the indole is not deprotonated prior to prenylation, e.g.
by working in slightly acidic buffer systems instead of using NaH/DMF, other
positions than the indole nitrogen are prenylated (see below).
Electrophilic N-prenylation of indole has, for instance, been employed in the synthe-
sis of N-prenylindolactam-V (3, Scheme 1) [18], where the yield is only moderate,
probably due to the simultaneous presence of the amide moiety. The natural product
()-indolactam V (1) is a potent inhibitor of protein kinase C isozymes [28]. Other
examples include the total syntheses of deformylflustrabromine B [11], of derivatives of
physostigmine and debromoflustramine B [22], or of vulcanine and borrerine [24]. The
key step of the synthesis of N-prenyltryprostatin B features N-prenylation with concom-
itant 3-prenylation (see Sect. 3.1) [29]. As a side reaction, prenylation of diketopi-
perazines, a frequent structural motif in prenylated indole alkaloids, was observed.
There are only a few cases in which the standard procedure did not work. One of
them concerns the behaviour of pyrroloindole 4 on treatment with NaH and then
prenyl bromide (Scheme 2). Prabhakar, Lobo and co-workers obtained mostly the
3-prenylated products 5 (30%) and 6 (28%) with minor amounts of 7 (10%)
[30, 31]. Perhaps in this special case Na+ is chelated by the deprotonated indole
nitrogen and the oxygen of the acetyl side chain, forming a six-membered ring,
thereby shielding N1 and paving the way for C3a to attack at prenylbromide.
As the other important exception to the applicability of the standard procedure,
N-prenylation is only the minor reaction if an alkylmercapto group is located at C2.
Via S-prenylation, a thia-Claisen rearrangement to the 3-position becomes the
major reaction, affording 3-tert-prenylindoles [4, 32], as exploited in the total
synthesis of amauromine [33–35] (see Chap. 4.2).
Chemoenzymatic synthesis. The synthesis of the Aspergillus fumigatus myco-
toxin fumitremorgin B (10) from 12,13-dihydroxyfumitremorgin C (9) is one of the
early, still recent, applications of enzyme-catalysed N-prenylation (Scheme 3).
H
H 1) Ac2O, pyridine N
N N
OH
N 2) i) NaH, THF, 0°C, 30min) O
OH
O
ii)
2 N
N Br
H
iii) 2 N KOH, rt, 3 h
36%
1:(−)-indolactam-V 3
Scheme 1 N-Prenylation of ()-indolactam-V (1) [18]

CO2Me i) NaH, DMF, 0 °C, 45 min

ii) prenyl-Br, 0 °C, 2 h
N
N
H
O
4
CO2Me CO2Me CO2Me

+ +
N N N
N N N
O O O
5: 30% 6: 28% 7: 10%
Scheme 2 Non-regioselective prenylation of an N-acetyl pyrrolo[2,3-b]indole [30]
HO HO O 8 HO HO O
O O
N OP2O6(NH4)3 N
N N N
N prenyl transferase FtmzPT2
H O O
9: 12,13-dihydroxyfumitremorgin C 10: fumitremorgin B
Scheme 3 Enzymatic synthesis of fumitremorgin B (10) by Li and co-workers [36]
Li and co-workers expressed the prenyltransferase His6-FtmPT2 from Aspergillus

fumigatus (2 mg/L culture) [36], which uses ammonium prenylpyrophosphate (8) as
prenyl source. After 2 h at 37 C, about one third of 9 had been converted to 10.
Since then, the Li group has contributed many more and higher yielding examples
of enzymatic indole prenylation (see below).
N-Prenylation of an indolo[2,3-b]quinoline. Working on the synthesis of the
communesins, Westwood and co-workers studied the possibility of introducing a
prenyl group on the indolo[2,3-b]quinoline system via a Claisen-Cope sequence
starting from the chlorinated precursor 11 (Scheme 4) [37]. Nucleophilic substitution
by allylic sodium alkoxides led to formation of intermediate 12, which could not be
isolated in any of the cases shown in Scheme 4 due to rapid Claisen rearrangement. The
prenol derivative afforded only N-prenyl product 14 in 88% yield, and it was not
possible to isolate the primary rearrangement product 13 with a tert-prenyl group at
C10b. The rate of the initial Claisen rearrangement is known to be increased by alkyl
substituents [38–40]. Product 13 experiences steric strain, which is released by forma-
tion of the N-prenylated product 14. However, if allyl or 1-methylallyl groups are used
instead of a prenyl group, quaternised primary products were isolated exclusively.
Interestingly, [3,3] sigmatropic rearrangement of an allyl group did not stop
at C10b and proceeded through to product 17 when starting from regioisomer
72 T. Lindel et al.
R3
R1 R2
Cl Na, allylic alcohol,
THF, rt, 18 h O
N
N N
N
11 12
O
R1 R2
O
THF, rf, 2.5 h R 3 N
10b
+
N
N R2 R1
N
R3
13 14
R1 R2 R3 13 14
H H H 89% 0%
H H Me 40% 16%
H Me Me 0% 88%
Me H H 83% 0%
O O O
PhMe, rf,
4 d, 93%
N N N
N N N
15 16 17
Scheme 4 Sequential Claisen and aza-Claisen rearrangements on the indolo[2,3-b]quinoline

system [37]
15, which is N-methylated at the indole instead of the quinoline moiety. Allylation
of the benzene section of the indole system was observed only as a very minor
reaction. By calculation, Westwood was able to confirm that when starting from 12
the barrier of the initial Claisen rearrangement is about 18 kJ/mol higher than that of
the subsequent aza-Claisen rearrangement, making it impossible to stop at the 10b-
allylated intermediate. In the case of 15, the second barrier is about 7 kJ/mol higher
than the first.
2.2 N-tert-Prenylation
Chemoenzymatic synthesis. Enzymatic prenylation of indole will probably soon

become practical in a chemical sense with general availability of indole prenyl-
transferases. N-tert-Prenylation of L-tryptophan (18) was possible employing the
cyclic dipeptide prenyltransferase CdpNPT from Aspergillus fumigatus affording
N-tert-prenyltryptophan 19 (38%, Scheme 5) [41]. A prenyl transferase from
Aspergillus oryzae catalysed the simultaneous N-tert-prenylation and 7-prenylation
of the diketopiperazine cyclo-L-Trp-L-Trp [43].
Moore and co-workers recently reported the identification of the prenyl trans-
ferase CymD from the marine actinobacterium Salinispora arenicola, which
catalysed N-tert-prenylation of L-tryptophan prior to its incorporation into the cyclic
O 8, CdpNPT (0.0016 O
OH equiv.), Tris-HCl (50 OH
mM, pH 7.5), CaCl2 (10
NH2 mM), water, 37 °C, 16 h NH2
N 38% N
H
18 19
O 21 O
OMe OMe
Pd(OAc) 2 (0.1 equiv.),
NHX AgOCOCF3 (2 equiv.), NHX
Cu(OAc)2 (2 equiv.),
N air, MeCN, 35 °C, 24 h N
H 61%
20 22
X = Fmoc
(i) DDQ
X = Boc NaBH3CN, HOAc (ii) H2 , Pd-C,
quinoline
O O
OAc
OMe 24 OMe
NHBoc NHBoc
CuCl, iPr NEt,
N 2 N
THF, rf
H
70%
23 25
Scheme 5 One-step N-tert-prenylation of tryptophan and derivatives, enzyme-catalysed

(CdpNPT: cyclic dipeptide N-prenyl transferase from Aspergillus fumigatus) [41] and Pd-
catalysed [42], compared with an earlier pathway
74 T. Lindel et al.
peptide cyclomarin A [44]. For comparison, a sample of N-tert-prenyltryptophan

had to be synthesised chemically.
Transition metal catalysed prenylation. There is a new one-step N-tert-
prenylation of indole developed by Baran and co-workers [42] which still outcom-
petes the chemoenzymatic approach (Scheme 5). Isobutene (21) as prenyl source is
reacted with side-chain Fmoc-protected tryptophan methyl ester 20 in the presence
of catalytic amounts of Pd(OAc)2 and superstoichiometric amounts of Ag(I)
trifluoroacetate and Cu(II) acetate. The protocol also requires the presence of
oxygen. After about 1 day at 35 C, the N-tert-prenylated indole is obtained in a
yield of about 60%. The mechanism has not been elucidated, but may involve a
p-allyl-Pd(II) complex which is coordinated by the indole nitrogen or by C3. In the
latter case, a Pd-Claisen rearrangement of a 3-palladated indole would follow. Ag
(I) functions as reoxidant of Pd(0).
Propargylation of indoline. Until 2009, N-tert-prenylation of tryptophan deriva-
tives at the indole nitrogen required four steps, beginning with the reduction of 20 to
the indoline 23 with NaBH3CN, followed by Cu(I)-catalysed N-propargylation with
propargyl acetate 24 [45–47], reoxidation to the indole (DDQ or MnO2 [48]) and
hydrogenation of the alkyne affording 22. The propargyl pathway may still be the
method of choice if indoline moieties instead of indoles are to be N-tert-prenylated.
The synthesis of the insecticidal indole alkaloid okaramine C (29) from Penicillium
simplicissimum [49] by the Ley group [50] (Scheme 6, endgame shown) features
a late stage introduction of the N-tert-prenyl group on an indoline moiety, which
would otherwise have been in danger of Claisen rearrangement to the indole
7-position, as observed by Ganesan and co-workers (Sect. 5.2). For N-propargylation
of 26, propargyl bromide 27 was used, whereas treatment with the corresponding
propargyl acetate/CuCl did not give satisfactory results. The indoline propargylation
O O
Br
HO 27 HO
NH NH
N N
N H CuCl, iPr2NEt, N H
H O rt, 4 d O
NH 70% NH
26 28
O
HO NH
H2, Lindlar,
N
MeOH-pyridine (99:1)
29: okaramine C
N H
95% O
NH
Scheme 6 Endgame of the Ley group synthesis of okaramine C (29) [50]

approach has also been used in the Corey synthesis of okaramine N (see Sect. 3.2)
[51] and in the Ganesan synthesis of okaramine J (see Sect. 5.2) [52].
Except for 3-bromoindole, it is necessary to proceed via the indoline, because
treatment of indole with 1,1-dimethylpropargyl chloride (31) in the presence of
base leads to product mixtures resulting from reaction of in situ formed dimethyl-
vinylidene carbene. Sheu and co-workers isolated the three products 32, 33 and 34
on reaction of indole-3-carbaldehyde (30) (Scheme 7) [53]. In the main reaction,
indole C3 attacks at dimethylvinylidene carbene forming a vinyl anion, which
is protonated to give the 3-allenylindolenine. Hydroxide then attacks the carbal-
dehyde moiety with loss of formic acid and formation of a 3-allenylindole. Addition
of a second equivalent of indole-3-carbaldehyde (30) affords 32 and 33.
After treatment of Boc-protected tryptophan methyl ester (20) with 1,1-
dimethylpropargyl chloride (31) / NaH in DMF, we isolated the five products 35,
36, 37, 38 and 39 (Scheme 8) [54]. Both the indole nitrogen and C3 had reacted as
nucleophiles towards C1 and C3 of the intermediate dimethylvinylidene carbene,
followed by cyclisation to the pyrrolo[2,3-b]indoles. Earlier, Hino and co-workers
had obtained a similar result when starting from achiral Nb-methoxycarbonyl-
tryptamin [55]. With 3-unsubstituted indoles, Wenkert and co-workers observed
formation of quinolines as side products, presumably via cyclopropanation of the
indole 2,3-double bond by dimethylvinylidenecarbene [56].
Pirrung and co-workers found that direct 1,1-dimethylpropargylation of
3-bromoindole at the indole nitrogen is possible in about 50% yield without
prior reduction to the indoline, simply by treatment of 3-bromoindole and
1,1-dimethylpropargyl chloride with NaH in DMF [57]. Joullié and co-workers
found that N-propargylation of indoline in boiling THF affords 40, followed by
cyclisation to tricycle 41, which can be prevented by carefully monitoring the
reaction (Scheme 9) [58]. It was also possible to fully convert 40 to 41 at higher
31
Cl
O O
KOH, cat. 18-c-6,
H2O, THF, rf
+
N N
H
N
H
30 32: 44%
O
N +
N
N H
H
33: 6% 34: 8%
Scheme 7 Treatment of indole with propargylic halides [53]

76 T. Lindel et al.
Cl
CO2Me 31 (2 equiv.) CO 2Me

CO2Me
HN Boc NaH (2.5 equiv.), HN Boc
DMF, 0 °C, 21 h N
N N + N
H H Boc
H
20 35: 9% 36: 8%
CO2Me CO2Me CO2Me

+ + +
N N N
N Boc N N Boc
H H H H Boc H H
37: 7% 38: 5% 39: 6%
Scheme 8 Product mixture obtained on reaction of tryptophan derivative 20 with

propargylchloride 31/NaH [54]
Scheme 9 Behaviour of
N-(1,1-dimethylpropargyl) 160 °C, 30 min
indoline (40) on heating [58] N N
40 41
temperature under microwave conditions. The cyclisation probably proceeds

in the same manner as for phenol derivatives, commencing with a thermal
Claisen rearrangement to the 7-allenylindole, followed by hydrogen shift and
6p electrocyclisation.
Other approaches. There is also a less efficient multistep procedure first
introducing a C3 substituent at N1 by reaction of the deprotonated indole with ethyl
a-bromopropionate, followed by a-methylation and reduction to the hydroxy tert-
butyl group, oxidation to the aldehyde and elongation to the tert-prenyl group by
methylenation. This strategy was employed by Yao and co-workers in their synthesis
of the marine bacterial natural product cyclomarin C [59, 60] and by Spinella and co-
workers for obtaining N-tert-prenyl-3-methoxycarbonylindole [61].
By building up the indole ring, N-tert-prenylindole is also accessible. Willis
and co-workers synthesised demethylasterriquinone A, isolated from the Congo
fungus Pseudomassaria sp., from N-tert-prenyl indole which had been constructed
via Pd-catalysed condensation of 1,1-dimethylpropargylamine and a dihalogenated
styrene derivative [62]. Ortho-chlorinated alkynylbenzenes have been employed
by Ackermann and co-workers in a Pd-catalysed N-arylation-hydroamination
sequence [63, 64]. Indole assembly was also used by Karchava and co-workers who
condensed methyl a-formyl-(o-bromophenyl)acetate with 1,1-dimethyl propargy-
lamine, followed by Cu(I)-catalysed cyclisation to N-tert-prenylindole [65].
3 Prenylation and tert-Prenylation at C2
3.1 Prenylation at C2
Electrophilic prenylation. By electrophilic prenylation with allyl halides, it is quite

difficult to access the indole 2-position, because the 3-position reacts faster if
unsubstituted. Westermaier and Mayr quantified the electrophilic prenylation of
excess indole or N-methylindole (5 equiv.) in 80% aqueous acetone in the presence
of NH4HCO3 which predominantly affords 3-prenylindole with minor amounts of
2-prenylindole (9:1) [66]. If substoichiometric amounts of indole were employed,
2,3-diprenylindole became the major product. On reaction of 3-methylindole with
prenyl bromide in acetate buffer, Casnati and co-workers obtained the 2-prenylated
product in 61% yield [67].
It is possible to lithiate the 2-position of N-protected indoles exploiting the ortho
effect employing LDA, as shown by Wenkert and co-workers, who obtained
1-benzenesulfonyl-2-prenylindole in 76% yield [56], which could be deprotected
by reduction with sodium amalgam.
Introduction of a 2-prenyl group as an electrophile can also be achieved via
Pictet–Spengler condensation of indoles with suitable C5 aldehydes. The cell cycle
inhibitor 6-demethoxyfumitremorgin C (47), isolated from Aspergillus fumigatus,
can be synthesised by condensation of L-tryptophan methyl ester (42) and prenal
(43) as the initial step [68–70]. It is possible to isolate the intermediate imine, which
reacts to a mixture of diastereomeric b-carbolines (44) under acidic conditions.
A problem is always the low diastereoselectivity of the cyclisation step, as observed
for 44 by the Ganesan and Bailey groups in their very similar three-step syntheses
of 47 (Scheme 10).
Use of a,b-unsaturated aldehydes such as prenal (43) tends to diminish the
yield of Pictet–Spengler condensations. Therefore, the Nakagawa group used
3-methyl-3-(phenylthio)butanal in their total synthesis of fumitremorgin B [8, 21].
A similar strategy was applied by the Danishefsky group in their synthesis of
spirotryprostatin A (see Chap. 4.1) [71, 72]. Thermal dehydrosulfenylation is possi-
ble after oxidation to the sulfoxide. Analogues of demethoxyfumitremorgin C (47)
have been synthesised on the solid phase [73]. The de Meijere group assembled
cyclopropanated analogues of demethoxyfumitremorgin C (47) [74].
Chemoenzymatic synthesis. Enzymatically, Li and co-workers converted
brevianamide F to tryprostatin B [41], employing recombinant FtmPT1 and
prenyl pyrophosphate as prenyl source. However, when changing the substrate to
L-tryptophan, regioisomeric 1-tert-prenylation occurred exclusively, pointing to sig-
nificant promiscuity of FtmPT1. There are still more substrates to be investigated.
78 T. Lindel et al.
O i)
43
OMe O CO2Me
DCM
NH 2 NH
ii) TFA (excess),
N CHCl3, −40 °C, 10 h N
H 58% H
42 44 (de 50%)
O
COCl CO 2Me
N
N
N piperidine,
Fmoc 45 N DMF, 40 °C N
N O O
Fmoc N
53% from 44
H H
46, not isolated 47: demethoxyfumitremorgin C
Scheme 10 Synthesis of demethoxyfumitremorgin C (47) [69, 70]
R3 R3 R2 R3
TFA, rt, 48 h
R1 R1
N N N R2
R 2 R1
H H
48 49 50
R1 R2 R3 % (48) % (49) % (50) ratio 49:50

H H Me 100 - - -
Me H Me 36 14 35 27 : 73
Me Me Me - 50 50 50 : 50
Me Me Pr 3 52 45 56 : 44
Scheme 11 TFA-mediated allyl shifts of N-allylindoles [75]
Prenyl rearrangement. It is possible to access the indole-2-position by prenyl

migration either from the indole-1- or from the indole 3-position. In early
publications, Casnati and co-workers reported on the behaviour of N-allylated
3-methylindoles (48) in TFA [75, 76]. It was found that the N-allyl group itself
does not migrate, whereas the prenyl group migrated quantitatively, affording
2-prenylated and 2-tert-prenylated indoles (49, 50) in roughly equal amounts
(Scheme 11). Furthermore, the product ratio proved to be rather invariant (70:30
to 30:70) against reaction time and temperature. N-Crotyl groups afforded the
corresponding regioisomeric products together with recovered starting material.
Casnati also used other Lewis acids (BF3-Et2O, AlCl3-hexane, SnCl4-hexane)
obtaining similar product mixtures when starting from 3-methyl-N-prenylindole.

Migration of the unsubstituted allyl group was achieved in the presence of AlCl3 in
boiling benzene [77], whereas nothing happened when using ZnCl2.
Prabhakar, Lobo and co-workers have been able to catalyse a regioselective
prenyl shift from N1 to C2 by BF3-Et2O (>20-fold excess) [16, 78]. Phthalimide-
protected N-prenyl tryptophan methylester 51 was converted to the corresponding
2-prenyl tryptophan derivative 52 at 4 C in the convincing yield of 61%
without epimerisation, paving the way for an efficient formal total synthesis of
the Aspergillus fumigatus alkaloid tryprostatin B (56, Scheme 12). According
to DFT calculations (B3LYP), BF3 coordinates to the indolic nitrogen (57) and
renders ionic character to the rearrangement. The authors favour a direct [1,5]-shift
over two consecutive [3,3] sigmatropic rearrangements with double inversion of the
prenyl group. The favoured transition state 57 exhibits an endo conformation with
the prenyl group being situated on top of the pyrrole section of the indole. The
barrier corresponds to those of facile thermal rearrangements.
In 1983, Nakagawa showed that 3a-prenylated pyrrolo[2,3-b]indoles rearrange
in high yield to 2-prenylindoles (59) with concomitant opening of the pyrrolidine
ring when exposed to TFA in DCM (Scheme 13) [79]. In acetate buffer (pH 2.7),
N 2H 4-H2 O
CO2 Me BF3-Et2 O (excess), CO 2Me (3.5 equiv.),
DCM (0.024 M), MeOH-DCM,
NPhth -4 °C, 18 h NPhth 24 h
61% (95% ee)
82%
N N
H
O
51 52
F
CO2 Me NBoc
MeO 2C
54 (1.5 equiv.), NBoc
NH 2 DCM, NaHCO 3, H2 O
HN H
94% O
N
H N
H
53 55
O
N
H
i) TMSI, MeCN, 0 °C R
H
ii) NH 3/MeOH, 20 h N
H O
N
67%
N BF3
H
56: tryprostatin B 57
Scheme 12 Total synthesis of tryprostatin B (56) via BF3-mediated prenyl shift by Prabhakar,
Lobo and co-workers [16]
80 T. Lindel et al.
NHAc
NAc TFA-DCM (3:2), rt, 4 h
N H N
89%
58 59
O
O
OEt OEt O
N
O 61 OEt
N
DCM, 20 °C, 24 h O + NOH
N N H
H H N
93%
60 62 2:1 63
O O
OEt OEt
TFA (5 equiv.),
DCM, 20 °C, 1 h NOH NOH
62 +
97%
N N
H H
64 1:9 65
O O
OEt OEt
N TFA (5 NOH
O equiv.),
N 61 , DCM, N H DCM, 20 °C, N
20 °C, 24 h 1h
87% 88%
66 67 68
Scheme 13 Studies on prenyl migration from the indole-3- to the -2-position by the Nakagawa
[79] and Ottenheijm [80] groups
nothing happens. As an example, the bisprenylated pyrrolo[2,3-b]indole 58 was

chosen with the N-prenyl group left untouched in the rearrangement reaction.
Plate and Ottenheijm published the efficient migration of a prenyl group from
C3 to C2 in the presence of TFA (Scheme 13) [80]. 3-Prenylindole (60) reacted as a
nucleophile with nitrosoacrylic ester 61 affording a 1:2 mixture of the Michael
alkylation product 63 and of the further cyclised tricycle 62. Compound 62 reacted
to a mixture of 2-tert-prenyl- and 2-prenylindoles 64 and 65 (1:9). The reaction
was also carried out starting from 1,3-diprenylindole (67) and provided 1,2-
diprenylindole 68 in high 88% yield. The N-prenyl group of 67 did not migrate.
The Menéndez first generation synthesis of tryprostatin B (56) utilises the shift
of a 3-prenyl group to C2 (Scheme 14) [81]. Starting material cyclo-(L-Trp-L-Pro)
(69) was subjected to prenyl bromide in the presence of magnesium nitrate,
a method which had been applied to the synthesis of pseudophrynaminol [82].
Menéndez isolated six products of which 22% was a mixture of tryprostatin B
(56) and the prenylated pentacycle 70. On treatment of 70 with TFA, additional
tryprostatin B was obtained in 96% yield by prenyl shift from C3 to C2 with
opening of the anellated pyrrolidine ring. Presumably, ring opening of 70 occurs
first, followed by [1,5] sigmatropic shift of the prenyl group.
In the second version of the synthesis, Menéndez and co-workers protected the
diketopiperazine nitrogen of 69 by a trimethylsilylmethyl group, before adding
prenyl bromide and LHMDS (Scheme 15) [29]. Diastereomers 74 and 75 were now
obtained in satisfying yields (66% and 11%, respectively). The authors propose that
deprotonation of intermediate 73 takes place at the methylene group leading to
O Mg(NO3 )2 (5 equiv.),
N
prenyl bromide O
(6 equiv.),
N HOAc-NaOAc- N
H O buffer, rt, 20 h N
N 22% (1:1) N H
H H O TFA (8.7
69 + byproducts equiv.),
70 DCM, rt, 20 h
+ 96%
monoprenylated byproduct: O
N
O
N
N H O
N
N
N H H
H O
71 (21%) 56: tryprostatin B
Scheme 14 Tandem-prenylation-cyclisation of the diketopiperazine cyclo-(L-Trp-L-Pro) (69) by

Menéndez and co-workers [81]
82 T. Lindel et al.
i) Si I
72
O
N
(1equiv.), NEt3 (1 equiv.),
69 N
DCM, 60 °C, 6 h O
TMS
N
H
73
O O
ii) LHMDS (1.5 equiv.),
prenyl bromide N N
(2.5 equiv.), THF, N N
−78 °C to rt,15h
N H + N H
O O
77%
74 (66%) 75(11%)
O
O N
Yb (OTf)3
N N
(0.1equiv.), O
N H
CH3NO2, rf, 43 h 70%
N N
O
Yb(OTf) 3
76 77 : N-prenyltryprostatin B
Scheme 15 Second generation synthesis of N-prenyltryprostatin B (77) by Menéndez and co-

workers [29]
liberation of trimethylsilylcarbene and the anion of the amide. Prenylation at C3

would be accompanied by nucleophilic attack of the amide anion at C2. Ytterbium
triflate-induced rearrangement of the prenyl group of both diastereomers 74 and 75
afforded N-prenyltryprostatin B (77). In the presence of Yb(III), the pyrrolidine ring
is assumed to re-open, paving the way for the [1,5] prenyl shift.
It is interesting to take a look at the synthesis of 2-prenylpyrroles by prenyl
rearrangement. Moody and Ward irradiated the N-allylpyrrolo[2,3-b]indoles 78
and 80 (Scheme 16) [83]. The major products 79 and 81, respectively, contain
a 2H-pyrrole moiety and result from 1,2- (or 1,5-)migration of the allyl group
without regioinversion. When the indole nitrogen was allylated and the pyrrole
nitrogen methylated instead, no products could be isolated after irradiation.
CO2Me CO2 Me R
N 300 nm, cyclohexane, 40 min N R

N N
R
MeO MeO
R
78: R = H 79: R = H (62%)

80: R = Me 81: R = Me (no yield reported)
Scheme 16 Photochemical 1,2-allyl shifts on pyrrolo[2,3-b]indole [83]
170 °C, 3-6 h 175 °C, PhH-

R2 R2 pyridine, 1-2 h
R 1 = H, R 2 = Et
1 R1 = Me, R2 = H R1
N R 1 = H, R 2 = H R 5 N N
H H
90% quant.
83 82 84
Scheme 17 Thermally induced crotyl migrations starting from 2H-pyrrole 82 [84]
Allyl rearrangements on 2H-pyrroles (82) have also been described. For

instance, aza-Claisen reactions to 83 take place, if C5 is not substituted, whereas
Cope rearrangement to 84 is favoured if C5 is substituted (Scheme 17) [84, 85].
Padwa and co-workers also induced the shift of prenyl groups on oxazolinone
systems [86].
Nucleophilic prenylation. Nucleophilic 2-prenylation of indoles was introduced
by Danishefsky and co-workers for the synthesis of tryprostatin B (56, Scheme 18)
[87, 88]. The key idea was to use double regioinversion of prenylstannane 86 via
conversion to the tert-prenylborane 88, which forms an N–B bond with the in situ-
generated 3-chloroindolenine 89. A second regioinversion affords 2-prenylindole
87. The reaction was only possible when employing BCl3 for transmetalation,
whereas 9-BBN derivatives did not work. Danishefsky proposes an ate-like six-
membered transition state derived form 89. Danishefsky’s general approach
became particularly useful for 2-tert-prenylations (see Sect. 3.2).
Attempts of Sakurai-type couplings employing prenyltrimethylsilane have
been made with indole-3-carbaldehyde, but gave only low yields due to competing
addition to the aldehyde carbon atom [89].
Other approaches. It is also possible to obtain 2-prenylindoles by Pd-catalysed
cyclisation of ortho-alkynylanilines with the prenyl unit situated at the other
terminus of the alkyne, as utilised by the Wood group in their work on the total
synthesis of the securines and securamines [90].
84 T. Lindel et al.
(i) tBuOCl,
CO2 Me CO2 Me
NEt 3, DCM-CCl4 ,
0 °C, then −78 °C
NPhth NPhth
(ii) 86
N SnBu3 N
H H
BCl3 , DCM
85 87
83%
via
Cl R
Cl2B
89
N
88 Cl2 B
1) N 2H 4-H2 O, MeOH-DCM (3:1), rt, 24 h

O
2) BocN N
54
F
N
O NaHCO 3, DCM, H 2O H O
87
3) TMSI, MeCN, 0 °C N
H
4) NH 3-MeOH, 20 h 20%
56: tryprostatin B
Scheme 18 Synthesis of tryprostatin B (56) via double regioinversion of a prenylstannane by

Danishefsky and co-workers [87]
3.2 tert-Prenylation at C2
Nucleophilic tert-prenylation. When using prenylboranes instead of tert-

prenylboranes, tert-prenylation of 3-chloroindolenines becomes possible. The
Danishefsky tert-prenylation has also been extensively used for the synthesis of
3-tert-prenylindoles which can be obtained from 2-tert-prenylated precursors (see
Sect. 4). The 1995 synthesis of the acyl-CoA-cholesterol acyltransferase inhibitor
gypsetin (94) [91, 92] was the first occasion to publish that elegant reaction
(Scheme 19) [88, 93]. On treatment of phthalimide-protected tryptophan methyl
ester (85) with tert-BuOCl, the 3-chloroindolenine is formed in situ, which is
nucleophilically attacked by prenyl-9-BBN with regioinversion of the prenyl
group. Hydrazinolysis afforded 2-tert-prenyltryptophan methyl ester (91).
The gypsetin synthesis features another interesting step, which is the oxidative
cyclisation of diketopiperazine 93 employing dimethyldioxirane, affording
gypsetin (94) as major stereoisomer in a yield of 40%. Interestingly, the tert-prenyl
group does not migrate to the 3-position, whereas the Davis oxaziridine has induced
tert-prenyl rearrangements after cyclisation (Sect. 4.2).
CO2Me 1) (i) tBuOCl, NEt 3, CO2Me 1) Boc2O, NEt 3,

THF, 1 h
THF, −78 °C, 30 min
NPhth NH 2
(ii) 90 2) LiOH, THF-
MeOH-H 2O, rt,
N [9-BBN] N 3h
H H
2) N 2H 4, EtOH, rt, 3 d 94%
85 91
63% CO2H
NHBoc
1) BOP-Cl, DCM, −78 °C to 0 °C N

2) TFA, DCM, rt, 1 h H
3) NH 3, MeOH, rf, 12 h 92
73%
O H
O O N
O
NH HO
NH N
HN HN N
OH
acetone, DCM,
-78 to 0 °C N
O H O
40%
+ other isomers
93 94: gypsetin
Scheme 19 Synthesis of gypsetin by Danishefsky prenylation and oxidative cyclisation by

DMDO [88]
In course of their elegant conversion of ()-hapalindole U (95) to (+)-ambiguine

H (98), both isolated from the cyanobacterium Fischerella sp., Baran and co-workers
were able to crystallise the 9-BBN adduct 97 featuring the earlier proposed N–B bond
(Scheme 20) [94]. On treatment with tert-BuOCl, the isonitrile ()-hapalindole U
(95) was not converted to the 3-chloroindolenine, but to the pentacyclic spiro
intermediate 96, in which the former isonitrile carbon is chlorinated and then attacked
by the indole 3-position. Isonitriles are more nucleophilic than indoles. Prenyl
rearrangement afforded the 2-tert-prenylindole 97 with the tert-prenyl group located
trans to the chloropyrroline ring (X-ray analysis). On irradiation of 97 in the presence
of base, (+)-ambiguine H (98) was formed. Baran proposes a Norrish-type cleavage
of the chloroimidate, followed by hydrogen migration to the imine carbon with
reconstitution of the indole 2,3-double bond, and heterolysis of the N–B bond after
intramolecular attack by chloride.
Remarkably, Zhun and Ignatenko used triprenylborane as prenyl source and
were able to attack indole in the 2-position without prior oxidation to the chloroin-
dolenine. The 2-tert-prenylindoline was obtained, which was then oxidised to the
marine natural product debromoflustrabromine [95].
When treating 3-unsubstituted indoles with tert-BuOCl, the resulting
3-chloroindoles such as 99 are usually isolated. Subsequent treatment with prenyl-
9-BBN affords the 2-tert-prenylated product (100). Examples are the syntheses of
86 T. Lindel et al.
H
H H N
(i) tBuOCl, DCM, -78 °C, 12 min
N
H C (ii) prenyl-9-BBN, -78 °C, 60 min Cl
60% N
N B
H
95: (-)-hapalindole U 96
H H
H N hn, NEt 3, PhH, 5 h N
H C
Cl 63%
based on recovered
N N
starting material
B H
97, crystallized 98: (+)-ambiguine H
Scheme 20 Protecting group-free conversion of ()-hapalindole (95) to (+)-ambiguine H (98) by

Baran and co-workers [94]
asterriquinone B1 (104) by Tatsuta and co-workers (Scheme 21) [96] and of

malbrancheamide by Williams and co-workers [97]. Recently, a prenyl borane
has also been produced in situ from 1,1-dimethylallene and 9-BBN [98]. Pirrung
and co-workers assembled various methylated derivatives of the asterriquinones
in a similar manner, starting from indoles synthesised following the Fischer or
Bartoli pathways [99]; see also [100]. The anti-diabetic asterriquinone B1 (104) has
also been synthesised via Danishefsky tert-prenylation by Liu and co-workers
[101]. There is also earlier work starting from aniline [102].
A creative strategy of tert-prenylation at C2 was applied by Corey and
co-workers in their synthesis of okaramine N (111, Scheme 22) [51]. After having
assembled the peptide 106 from the tryptophan-derived building blocks 22 and
105, treatment of 106 with Pd(OAc)2 in the presence of oxygen under acidic
conditions led to formation of the dihydroindolo azocine 107. Presence of HOAc
and water was necessary [103]. For the cyclisation of the remaining ring, the
Corey group had to protect the N-unsubstituted indole unit, which was accom-
plished by taking the indole 3-position temporarily out of the game by addition to
N-methyltriazolinedione (109, MTAD). Photooxidation of the remaining indole
unit became possible and led to cyclisation to intermediate 110, which lost MTAD
on heating.
O
Cl Br OMe
prenyl-9-BBN, NEt3,
THF, rt, 12 h 101
MeO Br
N 72% N
H H O
99 100 LHMDS, THF,
–78 °C to rt, 3 h
1) sBuLi, THF, 61%
–78 °C to rt, 2 h
OMe
O
N O NH
Br H
Br MeO
O 103
OMe
N 2) NaOH, MeOH, HN O
H rt, 4 h
51%
102 104: asterriquinone B1
Scheme 21 Synthesis of asterriquinone B1 (104) via 2-tert-prenylation of 3-chloroindole by

Tatsuta and co-workers [96]
Prenyl rearrangement. Prenyl rearrangements constitute the second general

approach to 2-tert-prenylindoles. The first example was published by Casnati and
co-workers (see Sect. 3) who obtained 2-tert-prenyl- together with 2-prenylindoles
by treatment of N-prenylindole in TFA [75, 76]. Similar results were obtained by
Grundon and co-workers [4].
There are several examples of Claisen-type rearrangements starting from
prenylated heteroatoms attached to the indole system. In 1971, Plieninger and
co-workers reported a study reacting 2-methoxycarbonyl-3-oxindole 112 with
tert-prenyl chloride in the presence of K2CO3 (Scheme 23) [104]. Three products
were obtained in similar amounts, of which the O-prenyl compound 113 could be
converted to the 2-tert-prenylated oxindole 115 simply by heating in cyclohexane.
Interestingly, addition of AlCl3 led to concomitant formation of 2-prenyloxindole
114 in equal amounts, pointing to an ionic process competing with the Claisen
rearrangement. For the corresponding allyl case, Plieninger experimentally deter-
mined an activation enthalpy of about 95 kJ/mol and an activation entropy of about
55 J mol1 K1, which is in good agreement with the values of the classical
Claisen rearrangement of allyl phenyl ether.
Similarly, Sakamoto and co-workers treated N-acetyl-3-oxindole (116) with
prenol (117) in the presence of CSA forming in situ compound 118 which underwent
Claisen rearrangement to a mixture of 2-tert-prenylated and 2-prenylated 3-oxindoles
120 and 121 with 120 being the major product (Scheme 23) [105]. After 10 h, tert-
prenylated compound 120 was the only product, pointing at the interconversion
88 T. Lindel et al.
O i)
43 O
OMe O OMe
DCM
NH2 HN
ii) NaBH4, MeOH,
N 0 °C, 30 min N
H H
42 105, not isolated
O
OMe
NHFmoc N
N
FmocHN O2, Pd(OAc)2 (1 equiv.),
22 MeO2C HOAc, dioxane, H2O,
25 °C, 16 h
N O
BOP-Cl, iPr2NEt, 0 °C, 3 h 38%
N
H 106 (70% from 42)
N N
FmocHN HNEt2 (excess), H

THF, 0 to 23 °C, 6 h O N
MeO2C
95%
N O N O
N N
H 107 H 108
109
O N
O , DCM, N
i) iii) 110 °C,
–5 °C OH
N N H 30 min
N O
ii) O2, sunlamp, 7.5 h, O O N
35%
MeOH, methylene blue, HN N
−28 °C; Me2S N O
110 N
H OH
O N
N O
111: okaramine N
N
H
Scheme 22 Efficient synthesis of okaramine N (111) by Corey and co-workers [51]

116
Cl
O K 2 CO 3, acetone, O
Br rf, 8 h Br
CO 2Me CO 2Me
N 113: 22% N
H 114 : 31% H
Br 115: 28% Br
112 113
AlCl3, cyclohexane,
cyclohexane, quant. rf, 24 h
rf, 24 h
O O
Br Br
+
N CO 2Me N CO 2Me
H H
Br Br
114 115
O 117 O
HO
CSA, MgSO 4,
N N
130 °C, 3 h
Ac Ac
120: 62%, 121: 11%
116 118
O O
119
HO
+
CSA, MgSO 4, N N
130 °C, 8 h Ac Ac
120: 27%, 121: 23% 120 121
Scheme 23 Claisen rearrangements of 3-prenyloxyindoles [104, 105]
of 121 to 120. The prenylated compound 121 appears to be formed from 118 by [1,3]
sigmatropic rearrangement. When tert-prenol (119) was used instead, the
same products 120 and 121 were obtained in almost equal yields. Ireland–Claisen
2-tert-prenylation has been achieved by Dunkerton and co-workers starting from
N-protected indoline 2-prenylcarboxylates on treatment with LDA in THF at 78 C
[106].
Plieninger also found that 3-mercaptoindoles (122) can be 2-tert-prenylated
(124) via thia-Claisen rearrangement after S-prenylation to 123 at 0 C [107].
90 T. Lindel et al.
SH S S
prenyl-Br, NaOAc, FSO3 Me, PhH,
acetone, 0 °C K 2CO3 , 2 h
N 88% N 53% N
H H H
122 123 124
Scheme 24 Thia-Claisen approach to 2-tert-prenylindoles [107]
At higher temperatures N-prenylated products were also obtained. The thia-Claisen

reaction itself was initiated by S-methylation of 123 employing methyl fluoro-
sulfonate (Scheme 24).
4 Prenylation and tert-Prenylation at C3
4.1 Prenylation at C3
Electrophilic prenylation. Electrophilic prenylation of C3-unsubstituted indole

occurs predominantly at C3 and can be carried out in good yield in aqueous buffer
systems (NH4HCO3) [66]. As far as 2-prenylated products were also obtained,
this has already been discussed in Sect. 3.1. For another example, see [108]. Use
of prenyl diisopropyl phosphate as biomimetic electrophile in the presence of
BF3-Et2O has afforded 3-prenylindole in a yield of only 21%, accompanied with
minor amounts of 3-tert-prenylindole [109]. Wenkert and co-workers treated indole
with tert-prenol in the presence of stoichiometric amounts of MeMgI and catalytic
amounts of [Ni(PPh3)2Cl2] and obtained a mixture of 3-prenylated and 3-tert-
prenylated indoles in 29% combined yield [56] via the Mg salt of indole. Later,
Yadav and co-workers have treated several N-unsubstituted indoles with prenylZnBr,
forming the indole Zn salt and obtaining 3-prenylindoles in more than 80% yield
[110]. Zhu and Ganesan found that unsubstituted indole is 3-prenylated by prenyl
bromide in the presence of Zn(OTf)2 [111] in moderate yield and, as a draw-
back, excess of precious indole. One may also try bromine/lithium exchange at
N-TBS-protected 3-bromoindole, followed by quenching with prenyl bromide
[112], which appears to be a little complicated.
Although not exactly being an installation of a free prenyl group, it should be
included here that Achenbach and co-workers reacted 7-prenylindole (103) with its
oxidised analogue, the butadienylindole 125 in the presence of catalytic amounts
of TFA (Scheme 25), obtaining the regioisomeric natural products annonidine A
(126) and C (127), isolated from the tropical plant Annonidinium manni, in good
yield [113]. The 3-methylbutadienyl group can also be generated in situ from the
N
H
TFA, petrol HN
125
ether, rt,1 h HN +
+
N N
H H
N
H
126: rac-annonidine A (44%) 127 : annonidine C (11%)

103
Scheme 25 Biomimetic formation of rac-annonidine A (126) and annonidine C (127) by

Achenbach and co-workers [108]
corresponding tertiary alcohol in the presence of HCl, which was exploited by Ohta
and co-workers in their synthesis of annonidine A (126) [114].
Pictet-Spengler condensation of C2-blocked indoles. Several syntheses of the
spirotryprostatins from the fungus Aspergillus fumigatus have been published. For a
review covering the literature until 2003, see [115]. ()-Spirotryprostatin B (133)
inhibits the G2/M phase of the mammalian cell cycle at micromolar concentrations.
Similar to a Pictet-Spengler condensation, but at C3 instead of C2, von Nussbaum
and Danishefsky utilised the condensation of prenal (43) and the tryptophan-
derived oxindole 128 (Scheme 26) [116]. This was possible due to the blocking
oxo substituent at C2, which at the same time enhances electron density at C3. The
spiro system 129 was obtained and elaborated further to ()-spirotryprostatin B
(133), although with the necessity to separate four diastereomers of peptide cou-
pling product 131. The double bond of the pyrroline unit of ()-spirotryprostatin B
(133) was introduced by phenylselenation of 131, oxidation with DMDO and
immediate elimination.
Horne and co-workers showed in their synthesis of spirotryprostatin A
that indole-2-chlorinated or -brominated tryptophan derivatives also undergo a
“spiro-Pictet-Spengler condensation” with participation of the indole 3-position
[117, 118]. Imine formation with prenal proceeded quantitatively. However, acid-
induced spirocyclisation afforded, as in the other syntheses of spirotryprostatins, a
mixture of diastereomeric spiro products in only moderate yield.
The Danishefsky group also developed a pathway to the spirotryprostatins via
ring contracting rearrangement of 2-dihydroprenylated indoles obtained by regular
Pictet-Spengler condensation [71, 72]. This approach was also chosen by Wang and
Ganesan who utilised a ring contracting prenyl rearrangement of compound 136,
which was constructed by the low yielding Pictet-Spengler condensation of
L-tryptophan methyl ester 42 and prenal 43 via imine 134 (Scheme 27) [119].
The oxidative ring contraction is, as in the case of the notoamides (see below),
biomimetic and was induced by treatment of b-carboline 136 with NBS in
92 T. Lindel et al.
CO2Me CO 2 Me
DMSO (1 equiv.), 12 N HCl,
NH 2 NH 2
HOAc, PhOH (5 mol%), rt, 4 h
O
N N
H H
42 128
43
O OH
H CO2CH3
NEt3, 3 Å MS, N N 130
pyridine, rt, 9h Boc O
73% from 42 O BOP-Cl (1.2 equiv.), DCM,

N NEt3,(2.5 equiv.), rt, 2 d
H
129 90%
Boc
N 1) LHMDS (2.2 equiv.), N Boc
THF, 0 °C, 30 min
O O
PhSeCl (2.2 equiv.),
CO2CH3 THF, 0 °C, 2 h CO2CH3
N N
2) DMDO (4 equiv.),
THF, 0 °C, 4 h
O 3) separation of O
N diastereomers 38% N
H H
131 132
1) TFA/DCM O N
rt, 30 min
N O
133: (−)-spirotryprostatin B
2) NEt3, DCM
rt, 4 h
O
86% N
H
Scheme 26 Synthesis of ()-spirotryprostatin B (133) via “spiro-Pictet–Spengler condensation”

by von Nussbaum and Danishefsky [116]
THF-HOAc-H2O. Spiro compound 137 had been obtained as the Boc analogue by
Danishefsky who devised the further pathway to spirotryprostatin B (133).
Transition metal-mediated prenylation. Use of transition metals allows
prenylation of indole in the 3-position starting from tert-prenol. In a stoichiometric
application, Nicholas and co-workers prenylated 2-methylindole at C3 with isolable
[(3-prenyl)Fe(CO)4]BF4 (in MeNO2), which had been obtained from tert-prenol
and Fe2(CO)9/CO in Et2O [120]. 3-Prenylindole was obtained in 70% yield,
accompanied by only traces of 3-tert-prenylindole. In a Mo(VI)-catalysed reaction,
a 4:1 mixture of 3-prenyl- and 3-tert-prenylindoles was obtained by Zhu and
Cl O
CO2 CH 3 CO 2CH3
135
N Fmoc O
N N
, pyridine
N N Fmoc
H H N
DCM, rt, 8 h
32 %
134 136
separation of
diastereomers
N Fmoc
NBS, THF/HOAc/
H 2O, rt, 12 h O
N CO 2CH3 137
68%
N O
H
Scheme 27 Oxidative ring contraction of Pictet–Spengler product 136 [119]
allyl-OH (3 equiv.), 9-BBN-(C6H13) (1.1

MeO equiv.), Pd2(dba)3 (2.5 mol%), 139 (7.5 MeO
mol%), DCM, rt, 20 h
N N
H
138 140
O
O N 139 85%, ee 84%
N H
H Ph P
2
PPh2
Scheme 28 Enantioselective allylation of a 3-prenylindole by Trost and Quancard [122]
co-workers on reaction of indole and prenol in the presence of MoO2(acac)2

(10 mol%)/NH4PF6 in MeCN [121].
C3-quaternised 3-prenyl indolenines are accessible in an enantioselective manner
by Pd-catalysed 3-allylation of 3-prenylindoles, as reported by Trost and Quancard in
2006 (Scheme 28) [122]. In addition to the Pd-source and the anthracene-derived
chiral ligand 139, an optimised bulky tertiary borane (9-BBN-C6H13) is added, which
coordinates to the indole nitrogen, prevents N-allylation and also enhances the
enantioselectivity of the reaction. The reaction from 138 to 140 is especially suitable
for electron-rich indoles and could be tried with prenol as allylic alcohol.
Echavarren and co-workers reported the Au(I)-catalysed introduction of oxy-
genated prenyl groups at C3 by treating indole with isoprenoid tert-propargyl esters
[123], obtaining double bond regioisomers in part. Propargylation of indole
derivatives has also led to the formation of bisindoles [53] and allenylated products
and quinoline derivatives [56].
94 T. Lindel et al.
The key step of the synthesis of spirotryprostatin B (133) by Trost and Stiles is
an enantioselective Pd-catalysed decarboxylation-allylation reaction starting from
the prenyl b-oxoester 145, which serves as a pre-nucleophile (Scheme 29) [124].
prenol (117,5 equiv.),

O PhMe, 85 °C, 2.5 h O O
MeO2C NCS Bu Bu
N O N
Bu
HN Bu Sn O Sn NCS HN
H Bu H
O SCN Sn O Sn Bu O
141 Bu Bu 143
NCS
142 (Otera's catalyst, 3 mol%)
73%
i) LDA (1.2 equiv.), THF, 0 °C to rt,10 min

OTs
O
O 144 (1 equiv.) O O O
N
H N
HN
ii) DMF, 0 °C, HN
then iPr2NEt (1.2 equiv.), to rt, 6h H
O
79% 145
O O
CsOAc
NH HN (7 equiv.),
146
O O SePhBr
PPh2 Ph2P HN (2 equiv.),
N HOAc, 2h
HN
Pd2(dba)3,CHCl3 (10 mol%), 146 (24 94%
mol%), PhMe, 5 min, then addition to a H
O
solution of 145 in PhMe (0.07 M)
81% 147
O O O
O
HN AlMe3 (0.5 M in DCE, HN N
N 2.2 equiv.), DCE, 75 min N
HN
45% H
H O
O
AcO
148 133: spirotryprostatin B
Scheme 29 Synthesis of spirotryprostatin B (133) by Trost and Stiles [124]

Originally, this reaction type was carried out under thermal conditions (Carroll
rearrangement). Saegusa [125] and Tsuji [126] discovered the possibility of using
Pd catalysts, Williams [127], Pfaltz and Helmchen [128] developed chiral Pd
ligands for that reaction. The Trost synthesis is the first example of submitting
prenyl groups to the key reaction and employed the C2-symmetrical bisphosphane
ligand 146. Initially, a b-oxocarboxylate is formed, subsequently undergoing
decarboxylation to the enolate, which nucleophilically attacks the chiral 3-Pd
complex of the prenyl group. The starting material 143 was synthesised from
diketopiperazine 141 (Scheme 29), which was transesterified with prenol (117)
employing Otera’s tin catalyst (142) [129]. After enolisation of 143, tosylated
oxindole 144 was added as electrophile affording 145. The endgame of the synthe-
sis converts the prenyl group of 147 to the allylic acetate 148 by treatment with in
situ-produced PhSeOAc. Allylic acetate 148 underwent cyclisation to 133 after the
rare conversion to the aluminium amide on treatment with AlMe3.
There are also excellent total syntheses of spirotryprostatins which do not apply
intermolecular functionalisation of the indole 3-position with a C5 prenyl-type
precursor and are, therefore, not discussed in detail. Carreira and co-workers started
from 3-diazo-2-oxindole, which was used in a Rh(I)-catalysed cyclopropanation of
1,3-pentadiene. The resulting cyclopropane was subjected to MgI2-catalysed
ring expansion and added to an imine affording the spiro[5.5] partial structure
[130, 131]. Overman and Rosen built up the indole system by intramolecular
Heck reaction of a functionalised iodoaniline [132, 133]. In a model study building
up the indole system, Cacchi and co-workers synthesised 3-prenylindoles via Pd-
catalysed cyclisation of ortho-alkynyltrifluoroacetanilides with prenyl esters [134].
Use of enamine or iminium electrophiles. In their synthesis of spirotryprostatin B
(133), Fuji and co-workers started from rac-3-prenyl-2-oxindole (149) with an
interesting enantioconvergent nitroolefination affording the C3-quaternised product
151 (ee 78%, Scheme 30). The proline-derived nitroenamine 150 was used with the
pyrrolidine section functioning as auxiliary [135, 136].
Iminium organocatalysis was key to the enantioselective total synthesis of
()-flustramine B (157) from the marine bryozoan Flustra foliacea by MacMillan
and co-workers (Scheme 31) [137], which is discussed here despite not incor-
porating the entire C5 unit in one step. On treatment of the Boc-protected
NO2
(i) BuLi, THF
(ii) ZnCl2 (1 equiv.)
O O
Ph
N Ph N
H N H
(iii) 150
OMe
149 151, ee 78%
NO2 88%
Scheme 30 Enantioconvergent step of Fuji’s synthesis of spirotryprostatin B (133) [135]

96 T. Lindel et al.
1) O , OH
NHBoc O N
tBu
Br Ph N 153 Br N
H
N N
(0.2 equiv.), TFA. H Boc
DCM, -84 °C, 72 h
2) NaBH 4, MeOH,
152 78% 154, ee 90%
0 °C, 15 min
1) MsCl, NEt3, DCM, Grubbs

0 °C to rt, 20 min catalyst, DCM,
Br N rt to 40 °C, 1h
2) (i) 2- NO2PhSeCN, NaBH4, N Boc
H
EtOH, 0 °C, 30 min; rt, 94%
3 h; (ii) H2O2, THF,
155
0 to 50 °C, 150 min
89%
i) TMSI, MeCN, rt, 15 min

ii) NaB(OAc)3H, (CHO)n,
Br THF, -10 °C to rt, 30 min Br
N N
N Boc N H
H 89%
156 157: (-)-flustramine B
Scheme 31 Enantioselective total synthesis of ()-flustramine B (157) by MacMillan and

co-workers [137]
tryptamine derivative 152 with acrolein in the presence of 20 mol% of the

imidazolidinone 153, the tricycle 154 was formed in high yield (78%) and enantio-
meric excess (90%). As intermediate, a reactive chiral iminium cation with a lower
LUMO than acrolein is formed by nucleophilic attack of the free imidazolidinone
nitrogen at the aldehyde carbonyl carbon, which is attacked in the b-position by the
indole C3 with subsequent cyclisation to the pyrrolo[2,3-b]indole tricycle. After
reduction to the alcohol 154, mesylation, conversion to the selenide and oxidative
elimination the allyl compound 155 was obtained, which was submitted to Grubbs
metathesis with isobutene completing the prenyl group. Deprotection and reductive
methylation afforded ()-flustramine B (157).
The Williams group published a three-component condensation reaction
starting from oxindolidene acetate 158 which reacted with the azomethine ylide
161 formed in situ from the diphenylmorpholinone 160 and the isoprenoid aldehyde
159 (Scheme 32) [138–140]. The spiro compound 162 was obtained by 1,3-dipolar
cycloaddition and converted further to the pentacyclic diketopiperazine 164.
O CO 2Et O
CO2Et
O 4 Å MS, O
PhMe, rt HN
HN N
HN O Ph O Ph
O 82 %
Ph Ph
158 160
OCH3
OCH3
161
159
CO2Et O 1) H 2, PdCl2, THF/EtOH,
O
60 psi, 36 h
HN O HN
163
N 2) BnO
Ph , BOP, Et3 N,
Ph O MeCN
3) H2, Pd-C, EtOH
OCH3 4) BOP, Et3N, MeCN
162 70%
CO2Et O
O CO2 Et
O O
HN N
pTsOH (1 equiv.) HN
N N
PhMe, rf
N
O 85%
O
OCH 3
164 165
O O
1) LiI, pyridine, D HN N
2) DCC, DMAP, BrCCl3, D, N NaOMe, MeOH
133:
O separation of spirotryprostatin B
HO N diastereomers
25%
S 65%
166
Scheme 32 Three component condensation of the spirocyclic core structure of the spirotry-
prostatins by Williams and co-workers [138]
Elimination of methanol generated the double bond of the prenyl unit. As in the other
syntheses, introduction of the double bond of the pyrroline system proved to be
difficult and gave only moderate yields. Diastereomers of 133 had to be separated.
4.2 tert-Prenylation at C3
Transition metal catalysed coupling with tert-prenol. Recently, several Pd- and
Ru-catalysed 3-tert-prenylations of indole have been published, all of which start
98 T. Lindel et al.
119 (3 equiv.), Pd(PPh 3) 4 (5

m ol%), Et 3B (30 mol%), THF,
50 °C, 12 h
168 (86%), 169 (9%)

Tamaru and co-workers
119 (3 equiv. ), [(allyl)Pd(cod)]BF4

(5 m ol%), 170 (10 mol%), PhMe,
80 °C, 24 h
OH 168 (75%), 169 (12%) N
H
Br eit and co-work er s
119 168
+ +
119 (1 equiv.),
[(allyl)Cp*Ru(MeCN) 2](PF6 )2
(5 mol%), MeCN, rt
N 168 (70%), 169 (5%) N
H H
Pr egosin and co-w or kers
167 169
119 (1.2 equiv.), 171 (2.5 mol%),

DCE, H 2O (5 mol%), 50 °C, 16 h
168 (76%), 169 (4%)
Br uneau and co-work er s
CF3
PF6
Ph
O N P CF3 Ph P Ru
H 170 171
O
S O
F3 C CF3 O
Scheme 33 Pd- and Ru-catalysed 3-tert-prenylations of indole
from 3-unsubstituted indole and thereby do not generate a stereogenic centre at C3.
In every case (Scheme 33), yields between 70% and 80% of 3-tert-prenylindole
(168) were obtained and 3-prenylindole (169) was formed as minor side product,
whereas N-prenylated products have not been observed. Tamaru and co-workers
reported a Pd-catalysed reaction employing Et3B as an in situ auxiliary, which did
not prenylate N-methylindole, pointing to the necessity of forming an N–B bond
[141]. In the case of allylation, Tamaru was also able to convert tryptophan methyl
ester to the corresponding 3a-allyl pyrrolo[2,3-b]indole. Breit and co-workers
utilise pyridone-containing, self-assembling Pd-catalysts. Ligand 170 proved
to be very effective for 3-tert-prenylation of indole [142]. A p-allylpalladium
intermediate was suggested. Pregosin and co-workers [143] and Bruneau and
O 2 2 NH4
O
H OP2O6H H
NH NH
HN AnaPT (0.25 mM, CaCl2 (10
N
mM), Tris-HCl (50 mM), pH
N 7.5, glycerol, 37 °C, 24 h N H
H O H O
172 73% 173: aszonalenin
Scheme 34 Enzymatic synthesis of aszonalenin (173) by Li and co-workers [147]
co-workers [144] employed Cp*Ru(IV) complexes to achieve 3-tert-prenylation of

indole in good yield and regioselectivity.
Chemoenzymatic synthesis. The transition metal-catalysed tert-prenylations of
indole will have to compete with enzymatic reactions. For instance, several pyrrolo
[2,3-b]indoles have been synthesised by tert-prenylation of tryptophan-derived
diketopiperazines employing the recombinant prenyltransferases AnaPT [145]
and CdpC3PT [146], respectively, from the fungus Neosartorya fischeri. Using
the enzyme AnaPT it was also possible to 3-tert-prenylate the benzodiazepindione
172, with subsequent cyclisation to the natural product aszonalenin (173)
(Scheme 34). When epi-172 was used as substrate, a mixture of the corresponding
epi-aszolenin and 2-tert- and 1-tert-prenylated products was obtained [147].
Nucleophilic tert-prenylation. The tert-prenyl group can also be introduced
as a nucleophile at the indole 3-position. Danishefsky and co-workers developed
a route via 3a-phenylseleno pyrrolo[2,3-b]indoles which were synthesised by
treating Na,Nb-bis-Boc-protected tryptophan methyl ester (174) with N-phenylsele-
nophthalimide (175, Scheme 35) [148, 149], a reagent introduced by the Nicolaou
group [150]. In the presence of pyridinium p-toluenesulfonate or p-TsOH, the
desired diastereomer 176 was formed almost exclusively, probably due to kinetic
reasons. For the synthesis of amauromine and ardeemin (184), 176 was treated with
methyl triflate and prenyl-SnBu3 in the presence of 2,6-di-tert-butylpyridine,
introducing the tert-prenyl group with inversion of regiochemistry. After peptide
coupling with an alanine unit, cyclisation of 180 to the diketopiperazine was carried
out. The remaining anthranilic acid-derived unit was introduced by acylation with
ortho-azidobenzoyl chloride (182), followed by Staudinger reduction to the amine
and cyclising condensation. The phenylselenide pathway for installing the 3-tert-
prenyl group was also employed by Joullié and co-workers in their synthesis of
roquefortine C [151, 152] and, with a less diastereoselective phenylselenation step,
by Omura and co-workers [153].
Tributylprenylstannane can also attack 3-brominated 2-oxindoles, as exploited
by Fuchs and Funk in their synthesis of rac-flustramine A (188, Scheme 36) [154].
After preparation of 3-bromoindolin-2-one 186 from the tryptamine derivative 185,
prenylstannane 86 acts as a nucleophile introducing the tert-prenyl group at C3
affording 187. After three more steps, rac-flustramine A (188) was obtained.
Joseph-Nathan and co-workers converted the indole-3-position into the
b-position of an a-cyanoacrylate (Scheme 37) [155–157]. Starting material 189
100 T. Lindel et al.
N SePh
SePh
CO2Me 175 (1.5 equiv.)
O
CO2Me
N NHBoc N N
p-TsOH (0.1 equiv.),
Boc Na 2SO 4, DCM Boc H Boc
174 78% 176
MeOTf (4.5 equiv.)

1) 86 177
,
SnBu 3 tBu N tBu
(4.5 equiv.) (4.5 equiv.) CO2H

N N
DCM, −78 °C to rf
Boc H Boc
2) NaOH, THF, MeOH, rf 59%
178
F
i)
N N (4 equiv.)
179 i) TMSI (3 equiv.), MeCN,
F N F 0 °C
pyridine, DCM, −15 °C H O
ii) NH 3-MeOH, DMAP
ii) 76%
(1 equiv.) N N NH
Cl H N
3 CO2Me Boc H Boc
MeO2C
NaHCO3 (2 equiv.),
H2O, DCM 180
71%
N3
(2.4 equiv.) N3
H H
O ClOC O
182
N N N N N
H H NH KHMDS (1.1 equiv.), H H
O
THF, −78 °C
O O
80% 183
181
H N
PBu 3 (1.2 equiv.), PhH
184: ardeemin
N N N
72% H H
O
O
Scheme 35 Synthesis of ardeemin (184) via nucleophilic tert-prenylation by Danishefsky and co-
workers [148]
Ns Ns
N N 86
t
NBS, BuOH, Br
THF, H2 O SnBu 3
Br Br
O Cs 2CO3 , DCM, rt
N N
H 83% H 74%
185 186
Ns
N 1) NaH, prenyl-Br,
THF
Br N
2) Cs 2CO3 , PhSH, N
Br H
O DMF, rt, 12 h
N
H 3) AlH 3, THF, rf , 2 h
45%
187 188: rac-flustramine A
Scheme 36 Synthesis of rac-flustramine A (188) by Fuchs and Funk [154]
NC prenyl-MgBr,
CN CN
Et2O, THF,
CO2Me
-78 °C, 2 h O O
+
Br Br Br
OH O O
N N H N H
CO2Me CO2Me CO2Me
189 190: 40% 191: 35%
Scheme 37 Key step of Joseph-Nathan’s synthesis of several flustramines [155]
was obtained from 3-cyanomethylindole and dimethylcarbonate, followed by oxi-

dation with HNO3/HOAc. In the key step, treatment of 189 with prenylmagnesium
bromide led to both tert-prenylation and prenylation in roughly equal amounts with
concomitant cyclisation to the oxofuro[2,3-b]indoles 190 and 191. No regiocontrol
was possible by the Grignard reaction in Et2O/THF. Rac-flustramine A (188) was
obtained after further steps (not shown).
Use of isatin (192) is another option. Prenylindium species attack isatin
derivatives at C3 as g-nucleophiles and in yields above 80% [158], even in aqueous
media [159]. Iminoisatins have also been employed as electrophiles, resulting in the
formation of quaternary 3-aminooxindoles [160]. Krische and co-workers achieved
interesting reductive Ru- or Ir-catalysed tert-prenylations of isatin (Scheme 38) [161,
162], employing 1,1-dimethylallene (193) as prenyl source. As reducing hydrogen
sources, formic acid or isopropanol are used. Biaryl ligands such as JohnPhos (194)
proved to be suitable. The reaction has potential to be applied in natural product
synthesis, because the generated tertiary alcohol can be elaborated further to
a carbon side chain via substitution of the hydroxy group by chloride, followed
R=H
RuHCl(CO)(PPh3) 3
(2.5 mol%), 194 (5 mol%) OH
HCO2 H (1 equiv.), THF, rf
N O
t
Bu2 P H
O
195: 74%
N O
194: JohnPhos
R
192
[Ir(cod)Cl] 2 (2.5 mol%)
+ OH
196 (5 mol%)
i
PrOH (2 equiv.), O
N
Cs 2CO3 (7.5 mol%), Bn
193 3-nitrobenzoic acid (7.5 mol%),
PhMe, 60 °C, 40 h 197: 90% (96% ee)
R=Bn
Ph2 P
N
MeO OMe
N
PPh2 196
Scheme 38 Krische’s 3-tert-prenylation of isatin [161]
O O N OH
N oxidations
N
Diels-Alder reaction O
HN tert.-prenyl migration
2
O O 3
N
N O
H
H
198 199: paraherquamide A
Scheme 39 Biosynthetic origin of paraherquamide A (199) with tert-prenyl migration according

to Williams and co-workers [164]
by C-nucleophiles such as cyanide, but also indole. Recently, an enantioselective

version has been reported reaching yields and ee values above 90% [163].
Prenyl rearrangement. Efficient total syntheses of 3-tert-prenylated indole
alkaloids employ prenyl shifts from C2, which can be considered biomimetic,
since it was shown by Williams that the biosynthesis of paraherquamide A (199)
from Penicillium sp. proceeds via tert-prenyl shift from C2 to C3 starting from
precursors like 198 (Scheme 39) [2, 165], in agreement with earlier proposals by
Barrow [166] and by Gorst-Allman [167] for the biosynthesis of roquefortine.
The 2-tert-prenyl group itself stems from the mevalonate pathway and is introduced
in a non-stereospecific manner, as shown by isotope labelling studies [164].
The order of oxidations, of Diels–Alder reactions and of the tert-prenyl migration
is still a subject of research on the individual alkaloids.
Williams and co-workers reported the non-enantioselective total syntheses
of the heptacyclic indole alkaloids notoamide B (227) and stephacidin A (225)
(Scheme 43) [168], and of their probable biogenetic precursor, notoamide C (213)
(Scheme 41) [169]. The notoamides are fungal indole alkaloids from Aspergillus
species collected from the common mussel Mytilus edulis off Noto Island in the Sea
of Japan [170, 171]. There is also a synthesis of the closely related notoamide J
(217) (Scheme 42) [172].
As advanced precursors in all syntheses, racemic 2-tert-prenylated tryptophan
derivatives were synthesised, which had to be oxygenated at C6 of the indole ring.
Batcho–Leimgruber synthesis afforded 6-OBoc-indole 200 in four steps from
4-methyl-3-nitrophenol employing the Danishefsky tert-prenylation (Scheme 40)
[88]. This procedure did not work for indoles substituted by electron donating
Cl
1) TFA, 97% Cl
2 N
BocO 6 N O
H 2) O H Δ, 17 h
95%
O O
201
200 202
, CuCl Ph
81%
1) EtO C N Ph
2
N 205 (1 equiv.),
HCHO, PBu3 (0.5 equiv.),
HNMe 2 MeCN, rf, 24 h
O N N 2) 1 N HCl, CH 2Cl2,
H 95% O
H
rt, 24 h
75%
203 204
CO2Et CO 2H
H2N FmocHN
1) FmocCl (1.1 equiv.), 1,4-dioxane,
10% aq. Na2CO 3, 0 °C to rt, 16 h
O N 2) Me3SnOH (10 equiv.), 1,2- O N

H H
dichloroethane, rf , 5-8 h
206 74% 207
Scheme 40 Conversion of O-Boc-protected 2-tert-prenyl-6-hydroxyindole 200 to the strategic

tryptophan derivative 207 [173]
alkoxy or silyloxy groups [174]. Towards notoamides B (227), C (213) and D (215),
the 6-oxy substituent was transformed further to the anellated pyran ring.
Deprotection and O-propargylation of the N-unsubstituted indole 200 with
1,1-dimethylpropargyl carbonate 201 in the presence of CuCl afforded aryl pro-
pargyl ether 202 [173], which underwent thermal Claisen rearrangement in dichlo-
robenzene under reflux [100, 175]. It can be assumed that initial allene formation is
followed by hydrogen shift and 6p electrocyclisation. For the installation of the
racemic amino acid functionality, a method developed by Somei and Kametani
[176, 177] was modified, which proceeds by coupling of the gramine 204 with
the benzophenone imine 205 of glycine ethyl ester in the presence of tributyl-
phosphane, followed by hydrolysis under acidic conditions. Amino acid ethyl ester
206 was Fmoc-protected and hydrolysed to the free acid 207 in high yield
by treatment with trimethyltin hydroxide, following a mild procedure developed
by the Mascaretti [178] and Nicolaou [179] groups.
The racemic tryptophan derivative 207 was condensed with optically pure proline
derivatives following the BOP-Cl protocol. For the synthesis of notoamides C (213)
and D (215), proline ethyl ester was used as coupling partner (Scheme 41), whereas
the synthesis of stephacidin A (225) and notoamide B (227) employed hydroxyproline
ethyl ester 219 (Scheme 43). Towards notoamides C (213) and D (215), the diaste-
reomeric diketopiperazines 210 and 211 had to be separated by chromatography. The
Fmoc can be replaced by a Boc protecting group and BOP-Cl by HATU [172].
The biomimetic key step of the synthesis of notoamides C (213) and J (217)
treats 2-tert-prenylated indoles with Davis’ oxaziridine (212) [180], which induces
oxidative rearrangement of the tert-prenyl group from the indole-2- to the -3-
position (Schemes 41 and 42). Formation of notoamides C (213) and J (217) was
accompanied by the corresponding 3-epi-compounds 214 (48%) and 218 (15%),
respectively, because the Davis’ reagent epoxidised the indole C2¼C3 double bond
with low facial selectivity. Epoxide opening appears to occur preferably at C3,
setting the stage for a [1,5] sigmatropic rearrangement of the tert-prenyl group and
thereby generating the oxo group at C2. The electron donating substituent at C6
probably stabilises the intermediate benzylic cation.
Formation of notoamide D (215), which was also formed together with its
3-epimer (10% combined yield), can be explained by cyclisation via nucleophilic
attack of the neighbouring diketopiperazine nitrogen at the intermediate indole
epoxide, retaining oxygenation of C3 and preventing migration of the 2-tert-prenyl
group. Williams and co-workers were able to selectively synthesise notoamide D
analogues starting from 6-OBoc-indoles by irradiation in the presence of molecular
oxygen and methylene blue [169].
It should be noted that ring contracting migration of the C5 unit is not restricted
to inverse prenyl systems, but also works if the double bond of the tert-prenyl group
has been removed. For the synthesis of the more complex natural products
notoamide B (227) and stephacidin A (225), the 2-tert-prenyl group underwent
intramolecular [4þ2]-cycloaddition to a dehydrogenated diketopiperazine unit,
before its rearrangement to the 3-tert-prenylated oxindole was induced by treatment
with Davis’ reagent (Scheme 43). Hydroxyproline-derived diketopiperazine 221
CO 2Et EtO 2C
N HCl
H O
(1.5 equiv.), N
208
iPr FmocHN
2NEt (3.9 equiv.),
BOP-Cl (1.5 equiv.), rt,
overnight
207 N
61% O
H
209
nBu
O O
H N N
S O
N O
H O
212 (2 equiv.),
morpholine, THF, rt,
5 h, then 60 °C, 1 h O N DCM, rt, 24 h
H
210: α-H (40%)

211: β-H (35%)
separation by chromatography
O O O
N N
HO N
N N N
H O H O +
O + O N
O O
O N N
O H
H H
213: notoamide C (28%) 214: 3-epi-notoamide C (48%) 215: notoamide D (<10%)
Scheme 41 Conversion of protected tryptophan derivative 207 to notoamides C (213) and D

(215) by Williams and co-workers [168, 169]
nBu
O
O N 212 O N
N S O
H H H
H O
N N O
(2 equiv.), rt, 13 h H
H O 3
O
HO N HO N
H H
217: notoamide J (31%)
216 + 218: 3-epi-notoamide J (15%)
Scheme 42 Conversion of 2-tert-prenyl-6-hydroxyindole 216 to notoamide J (217) by Williams

and co-workers [172]
OH EtO 2C
EtO2C OH
O
HCl HN N
219 (1.5 equiv.), FmocHN

iPr NEt (3.5 equiv.), DCM,
2
DCM, rt, 1 h, then 0 °C, morpholine,
BOP-Cl (1.5 equiv.), to rt, overnight N THF, rt, 2 h
207 O
H
95%
54%
220
O N OH
O N
H H i. DEAD (2.5 equiv.),
PBu3 (2.5 equiv.) H
N O
H DCM, rt, 3h N OMe
ii. Cs2CO3 (25 equiv.),

O N Me3OBF4 (5 equiv.),
H O N
DCM, rt, 6 h H
74%
221 222
O Me OMe
O O
N N N N
20% aq. KOH,

MeOH, 0 °C to rt,
6h
+
O N O N
H H
separation by
chromatography
223: 61% 224 25%
Bu
O O
O N
HN N S O
223, 0.1 M HCl
(3 equiv.), O
THF, 0 °C, 5 min, 212 (2.9 equiv.),
then aq. NaHCO3 DCM, rt, 16 h
O N
96% H 73%
225: stephacidin A
O O
O O
HN N HN N
[1,5] O
O
O N N
H H O
226 227: r ac-notoamide B
Scheme 43 Conversion of tryptophan derivative 207 to stephacidin A (225) and further to

notoamide B (227) by Williams and co-workers [168]
was subjected to Mitsunobu dehydration (DEAD, PBu3) affording the pyrroline.

It turned out to be possible to convert selectively only the a,b-unsaturated amide
partial moiety to the conjugated lactim ether 222. On treatment of 222 with base,
tautomerisation to an azadiene occurred which served as diene component of the
subsequent intramolecular hetero Diels–Alder reaction affording a separable mix-
ture of diastereomeric heptacycles 223 and 224. Acidic hydrolysis of the lactim
ether 223 provided the natural product stephacidin A (225).
Ring contraction of stephacidin A (225) to notoamide B (227) was possible by
treatment with Davis’ reagent (212) in high yield (73%). Diastereoselectivity of the
initial indole epoxidation was complete, presumably due to the less flexible structure
of 225, when compared to the precursors of notoamides C (213), D (215) and J (217).
The 2009 synthesis of (+)-versicolamide B (231) by Williams and co-workers
revealed that the order of Diels–Alder reaction and oxidative tert-prenyl shift can
be reversed (Scheme 44) [181]. This is important, because racemic intermediates
Bu O
O N
N 212 OH
H
S O N
3 H O
O
221 O
(2 equiv.), DCM, O N
H
rt, 18 h
228 (60%, + 20% 3-epimer)
O
N
DEAD (2.5 equiv.),
PBu 3 (2.5 equiv.) 20% aq. KOH,
N MeOH, 0 °C to rt, 12 h
DCM, rt, 3 h H O
O
71% O N
H
229
O
O O
N HN N
N 19
O
OH
O H
O N N
H H O
230 231: (+)-versicolamide B (42%)

+ 19-epimer (33%)
Scheme 44 Synthesis of (+)-versicolamide B (231) carrying out the Diels–Alder reaction after the
tert-prenyl migration by Williams and co-workers [181]
are avoided and the total synthesis can be conducted enantioselectively, although
separation of diastereomers is still necessary on two occasions. Moreover, a lactim
ether such as 222 was not required for the intramolecular Diels–Alder reaction,
which also runs starting from the amide 229, which is obtained from 228 via
Mitsunobu dehydration. Treatment of 229 with aqueous KOH apparently forms
the azadiene intermediate 230 followed by cycloaddition of the double bond of the
tert-prenyl group. Versicolamide B (231) is a diastereomer of notoamide B (227)
and occurs in both enantiomeric forms in Aspergillus species.
The discovery of 2-tert-prenylated deformylflustrabromine (235) as a major
metabolite of Flustra foliacea collected near Helgoland [182–184] prompted us to
investigate its presumably biomimetic conversion to the pyrrolo[2,3-b]indole
flustramine C (236) [185], which is tert-prenylated at the bridgehead C3a (Scheme 45).
For the synthesis of deformylflustrabromine (235), Nb-methyltryptamine (232)
was converted to Nb-formyl-Nb-methyltryptamine which cleanly underwent
1. (i) Ac2O-HCO2H (1:1), 60 °C O

NH (ii) 232, DCM N
H
2. (i) t BuOCl, NEt3, -78 °C;
(ii) prenyl-9-BBN, THF, -78 °C to rt;
N N
(iii) 3 M NaOH, 30% H2O2, 0 °C
H H
72%
232
O 233
4 N
NBS (1equiv.), H
HOAc-HCO2H (3:1) Br 5 M NaOH, EtOH, reflux
6
N 95%
H
234: flustrabromine (53%)
+ 4-bromo regioisomer (20%)
NH
NBS (1 equiv.),
THF, 0 °C, 1 h
Br
N 71% Br N
N
H
235: deformylflustrabromine 236: rac-flustramine C
DIBAL (1.8 equiv.),

THF, rt, 24 h
Br 237: rac-dihydroflustramine C
N
93% N H
H
Scheme 45 Synthesis of rac-dihydroflustramine C (237) by us [185]

Danishefsky’s inverse prenylation [93] on treatment with tert-BuOCl and freshly

prepared prenyl-9-BBN [186] affording 2-tert-prenylindole 233 in 72% yield over
two steps.
Monobromination of 233 proceeded on treatment with one equivalent of
N-bromosuccinimide (NBS) in HOAc/HCO2H (3:1) [187] affording the natural
product flustrabromine (234) in 53% isolated yield. As side product, the 4-brominated
analogue was obtained (20%). Alkaline hydrolysis of flustrabromine (234) afforded
deformylflustrabromine (235), which afforded rac-flustramine C (236) in one single
step on treatment with NBS (1 equiv.). Rac-flustramine C (236) was reduced
diastereoselectively to rac-dihydroflustramine C (237) with DIBAL-H [188].
Non-brominated indoles also underwent the 2-tert-prenyl migration induced
by NBS and methylation of the side chain nitrogen was not necessary. Na,Nb-
Dimethyl-2-tert-prenyltryptamine (238) afforded the N,N0 -dimethylamidinium
salt 239, which precipitated from EtOAc (63% yield, Scheme 46). When the side
chain was monoformylated, no cyclisation was observed. In the case of Nb,Nb-
dimethyl-2-tert-prenyltryptamine (240), oxidation with NBS was carried out in
acetone for solubility reasons affording 3-bromoindole 242 (21%) via bromoin-
dolenine 241, which was observed on NMR control. Loss of the side chain of the
3-bromoindolenine on alkaline work-up can be explained by nucleophilic attack of
hydroxide at the imine b-position.
Deformylflustrabromine (235) can also be converted to flustramine C (236) on
treatment with tert-BuOCl (1 equiv.) in the presence of NEt3 in THF at 78 C.
Here, it was possible to identify the first intermediate 243 of the reaction sequence,
which was N-chlorinated in the side chain (Scheme 47). The reaction could proceed
with intramolecular chlorination of the indole 3-position affording chloroin-
dolenine 244. Alternatively, azetidine 245 could be formed by nucleophilic attack
NH
NBS (1 equiv.),
THF, 0 °C, 20 min
63% N
N N
Br
238 239
N N
(i) NBS (1 equiv.), Br Br
acetone, 0 °C,
30 min (ii) NaOH
N N N
H H
240 241 242 (21%)
Scheme 46 Effect of methyl substitution on the NBS-induced tert-prenyl shift [188]

d N 30 d N 105 N Cl
NH
tBuOCl (1 equiv.),
Br Br
N N
d N 127 NEt3, THF, -78 °C to rt d N 127
H H
235 243
H
N
Cl
Br
N - Cl
H
CDCl3 244 Br N H
N
- Cl
N 246
Br
N
H
245
[1,5] NaOH
Br N Br N d N 90
N N
d N 217
H
247 236 (60%)
Scheme 47 Possible mechanisms of the tert-BuOCl-induced tert-prenyl shift. 15N NMR shifts are
referenced to ammonia [185]
of C3 at the chlorinated side chain nitrogen, since the polarity of an N–Cl bond is
not pronounced. Ring expansion of 245 would afford pyrroloindole 246 which
would then undergo [1,5] sigmatropic tert-prenyl rearrangement to form protonated
flustramine C (247), which was observed in the NMR spectrum.
Claisen rearrangement of 2-prenyloxy- or -thioindole. A viable strategy to
synthesise 3-tert-prenylindoles employs Claisen rearrangement starting from
2-prenyloxyindoles. The Sakamoto group published a total synthesis of rac-
flustramine C (236) featuring a domino olefination-isomerisation-Claisen rear-
rangement as the key step (Scheme 48) [189, 190]. Starting from 6-bromoindole
(248), 6-bromoindolin-3-one 249 was obtained in three steps by N-acetylation,
oxidation to the 2-methoxy-3-hydroxyindoline with MoO5-HMPA and elimination
of methanol on treatment with SnCl4. The prenyloxy group was introduced at C2
1) AcCl, 33% NaOH, Bu4NHSO4

O 1) Br2 (1 equiv.),
2) MoO5 HMPA (1.1 equiv.),
MeOH, rt, 7 d DCM, 20 °C
Br N 3) SnCl4 (1.3 equiv.), DCM, Br N

H
0 °C to rt, 30 min Ac 2)
HO
248 249
43% 4 Å MS
89%
NC
O
P NC
O O O
tBuOK, DMF,
O O
-78 °C to rt
Br N Br N
Ac 90%
Ac
250 251
1) Red-Al (5 equiv.),
0 °C, PhMe
CN
N N
O
2) MeI, Na2CO3, Br N
Br N Br N
acetone, rf
H
252 236: rac-flustramine C (34%) 253 (26%)
Scheme 48 Total synthesis of rac-flustramine C (236) by the Sakamoto group [189]
affording 250 after C2-bromination of 249 and nucleophilic substitution at C2 with

prenol in the presence of molecular sieves in high yield.
Horner–Wadsworth–Emmons reaction afforded 3-cyanomethylindole 251 as
reaction intermediate which underwent Claisen rearrangement under mild
conditions affording 3-tert-prenylindol-2-one 252 with concomitant deacetylation.
The nitrile group was chemoselectively reduced to the amine with Red-Al at 0 C,
followed by cyclisation to the pyrrolo[2,3-b]indole. The last step of the total
synthesis afforded the N-methylated regioisomers 236 and 253, substantially
diminishing the overall yield of rac-flustramine C (236). Regioselective introduc-
tion of the N-methyl group was achieved by Kawasaki and co-workers following
the indole N-prenylation after the Claisen rearrangement. The nitrile was then
converted to an N-methylated secondary amide paving the way for the total
synthesis of flustramide A and flustramine A (188) [191].
A similar Claisen rearrangement starting from 2-prenyloxyindolin-3-ones
was induced by treatment with DBU in toluene at 40 C [192]. The corresponding
reaction with the crotyl compound confirmed that a chair-like transition state is
favoured. The reaction is also possible in EtOH/KOH with decarboxylation if
an additional ethoxycarbonyl group is present at C2 [193]. Booker-Milburn and
co-workers started from 3-methoxycarbonylindole, which was first converted to the
chloroindolenine, followed by nucleophilic attack of prenol and subsequent

Claisen rearrangement to the 3-tert-prenylindole in trichloroacetic acid-DCM
(89% yield) [194].
Lower yields and more byproducts have in most cases been obtained by the
corresponding thia-Claisen rearrangement. Bycroft and Landon were the first to
report a thia-Claisen rearrangement starting from 2-methylthioxy-3-methylindole
254 (Scheme 49) [195], which was treated with prenyl bromide in the presence
K2CO3 affording 3-tert-prenylindole 255 as major product (no yield given) via the
indolylprenylmethylsulfonium cation. However, Ottenheijm and co-workers
published a less clean reaction of 2-ethylthio a-oximinoester 257, which, after
O-benzylation, afforded a mixture of three products on treatment with prenyl
bromide and base. The thia-Claisen product 260 was formed in only 16% yield
with N-prenylated indole 259 (48%) being the major product, together with the
3-prenylindolenine 261 (25%, Scheme 49) [32].
Takase and co-workers applied this reaction to the corresponding indolylacetic
acid methyl ester and synthesised rac-debromodihydroflustramine C with the thia-
Claisen step proceeding in about 30% yield and very good regioselectivity in favour
of the 3-tert-prenylindole [34]. A thia-Claisen rearrangement was also employed
for the synthesis of amauromine (266) [33, 35], originally isolated from the fungus
Amauroascus sp. (Scheme 50). Starting material 262 is thiomethylated in both
a:
prenyl-Br, K2 CO3
S S + S
N N N
H
254 255 256
b:
CO2 Et CO 2Et
i) BnBr, DME, rt, 4 h
NOH ii) prenyl-Br, K2 CO 3, NOBn
acetone, 14 d
S S
N N
H H
Br
257 258
CO2 Et
NOBn CO 2Et CO2Et
S + NOBn + NOBn
N S S
N N
259: 48% 260: 16% 261: 25%
Scheme 49 Thia-Claisen rearrangements starting from 2-alkylmercaptoindoles [32, 195]

H
MeS N
O prenyl-Br (8 equiv.), K2CO3 (4
NH equiv.), dioxane, rt, 7 d
HN
N SMe O
H
262
MeS N
O
NH
Br
HN
H
N SMe O
O MeS N
NH 264 (15%)
+
HN N
O MeS
N SMe O
NH
H
Br
HN
N SMe O
263 265 (18%)
15%
265, TiCl4 ,
LiAlH 4, THF, rf
O H
H N
N
N 266 : amauromine
N H
H O
Scheme 50 Synthesis of amauromine (266) via bis-thia-Claisen rearrangement by Takase and

co-workers [35]
indole 2-positions and was reacted with prenyl bromide in the presence of base,
which probably leads to formation of the bis-sulfonium salt 263 as intermediate.
A [3,3] sigmatropic rearrangement of the prenyl groups results in the installation
of tert-prenyl groups in the indole 3-positions. Takase isolated diastereomers 264
(15%) and 265 (18%) in relatively low yields, of which 265 was reduced and
cyclised to amauromine (266) employing TiCl4/LiAlH4 in THF [196], again in
low yield (15%).
Other approaches. The construction of a tert-prenyl group at C3 may also
proceed stepwise and finish with the introduction of the terminal carbon by
methylenation of an aldehyde. Kawasaki and co-workers followed that strategy in
their total synthesis of ()-flustramine A (188) [197], and Sabahi and Rainier in
their synthesis of debromodihydroflustramine C [198]. Qin and co-workers assem-
bled ()-ardeemin (184) in the same manner, after having installed an acetic acid
side chain at C3 by reaction of a tryptamine derivative with diazoacetate in the

presence of a CuOTf-toluene complex [199]. The indole ring itself can also be
assembled after having installed a tert-prenyl group in the 3-position, as shown by
Viswanathan and co-workers [200].
5 Prenylation and tert-Prenylation in the Benzene

Section of Indole
5.1 4- and 5-Prenylindoles
Prenyl rearrangement. To date, only 4-prenyl-, but no 4-tert-prenylindoles have

been synthesised. Rainier and co-workers exploited an interesting sequence of
sulphur ylide Claisen rearrangement and Cope rearrangement to achieve
C4-prenylation of 2-thioindoles (Scheme 51) [201]. Sulphur ylide intermediate
269 was generated by reaction of the thiane moiety of 267 with the rhodium
carbene complex formed from a-diazoester 268 and Rh2(OAc)4. The following
[3,3] sigmatropic rearrangement proceeded with high diastereoselectivity (21:1)
affording indolenine 270 with a substituted tert-prenyl group at C3. By treatment of
270 with HgCl2, Rainier and co-workers were able to induce a second [3,3]
sigmatropic rearrangement to the 4-prenylindole derivative 271.
Transition metal-mediated prenylation. The earliest example was reported in
1971 by Plieninger and Sirowej who were able to react 4-bromoindole with
stoichiometric amounts of preformed 3-(3,3-dimethylallyl)-nickel bromide at
NHBoc N2 268 NHBoc
CO2Et
S S
N Rh2 (OAc)4 , DCM , rt N
H H
81% EtO2 C
267 269
CO2 Et
EtO 2C
NHBoc NHBoc
HgCl2 , H 2O, MeCN
85%
S S
N N
H
270 271
Scheme 51 Sequential sulphur ylide Claisen and Cope rearrangements leading to C4-prenylation
of indole [201]
60 C accomplishing 4-prenylation in 67% yield. In the same manner and similar
yields 5- and 6-prenylindoles were synthesised [202].
In an in situ version of that reaction, Kn€ olker and co-workers prenylated
bromocarbazoles by treatment with excess prenyl bromide and Ni(cod)2, obtaining
the natural products glycomaurrol and micromeline [203]. Utilising Ni-based
prenylation methodology, Kn€ olker also synthesised the carbazole alkaloid rac-
neocarazostatin B (277) from Streptomyces sp. carrying a prenyl group in the indole
5-position (Scheme 52) [204]. The carbazole system itself had been assembled by
Kn€olker’s iron-mediated CC and CN bond formation affording iron complex 274,
which was demetalated and regioselectively brominated to 275. Treatment of 275
with [prenylNiBr]2 (2 equiv.) provided 276 which was reduced to the natural
product 277. The synthesis of carbazole alkaloids has been comprehensively
reviewed in an excellent article by Kn€ olker and Reddy [205].
Very recently, She and co-workers reported the total synthesis of the
5-prenylated indole alkaloids tardioxopiperazine A, isoechinulin A and variecolorin
C, via Pd-catalysed coupling of an in situ-produced prenylindium reagent with a
5-triflyloxytryptophan derivative in DMF at 100 C [206].
Yokoyama and co-workers installed a 4-prenyl group by Heck reaction of
tert-prenol (119) with 4-bromotryptophan (280), which was synthesised from
4-bromoindole (278) by reaction with rac-serine/Ac2O in HOAc (Scheme 53).
An Aspergillus acylase was employed for kinetic resolution of the racemic mixture
OAc AcO OMe

(OC)3Fe
OMe MeCN, rt, 4 d H
+ (Ar); 7 d (air)
OAc
(OC)3Fe
H2 N 69% N
BF4 OAc H H
272 273 274
1) Me3 NO, acetone, rf, 4 h

AcO OMe
2) Pd-C, o-xylene, rf , 4.5 h
3) NBS, cat. HBr, MeCN, [prenylNiBr]2 (2 equiv.),
25 °C, 1 h Br DMF, 65 °C, 17 h
OAc
74% N 80%
H
275
AcO OMe OMe

HO
LiAlH 4, Et2 O,
25 °C, 1 h
OAc OH
90%
N N
H H
276 277: rac-neocarazostatin B
Scheme 52 Synthesis of rac-neocarazostatin B (277) by Kn€

olker and co-workers [204]
H2 N CO2 H AcHN CO2 H

Br Br Aspergillus acylase,
OH pH 7.5, 37 °C, 2 d
Ac 2O (2 equiv.),
N N
H HOAc, 80 °C, 90 min H
278 58% 279
i)
H2 N CO2 H OH
119 H CO2H
Br N
Pd(OAc)2 , K 2CO3 ,
H 2O, 130 °C, 2 h
N
H ii) HOAc, 60 °C, 2 h N
H
91%
280: 49%, ee 99% 281: clavicipitic acid
Bn
BnHN i)
N Pd-C, HCO2 NH 4
43
O (4 equiv.), MeOH,
HO TfO
(3 equiv.) rt, 30 min
N rt, 10 h N 284 : 18%

H ii) Tf 2 O, NEt 3, DCM H 285: 35%
282 60% 283
H H
N N
+
TfO
N 284 N
H H
43%
285: rac-aurantioclavine
PdCl2 (PPh3 )2 , dppp, NEt 3,
HCO 2H, DMF, 100 °C, 2 h
Scheme 53 Synthesis of diastereomeric clavicipitic acids (281) by Yokoyama and co-workers

[207] and of rac-aurantioclavin (285) by Ishikura and co-workers [208]
with only the enantiomer (S)-279 being deacetylated. Acid-catalysed cyclisation

afforded diastereomeric clavicipitic acids (281) [207, 209], originally isolated from
Claviceps sp. A similar approach via a 4-iodoindole with a de of 60% in favour of
trans-clavipitic acid was published by Jia and co-workers [210].
Ishikura and co-workers achieved the same without having to brominate the
indole 4-position because of the presence of a 5-hydroxy group in their starting
indole 282 and of the tryptamine side chain which probably participates via imine
formation (Scheme 53) [208]. Pictet–Spengler-type condensation of 282 with
prenal (43) afforded the azepinoindole 283 which was N-debenzylated with
HCO2NH4/Pd-C leading to the ergot alkaloid rac-aurantioclavine (285) from Peni-
cillium aurantiovirens, together with the oxygenated compound 284. Side product
284 could be converted to further amounts of the natural product 285.
Chemoenzymatic synthesis. As for other indole positions, enzymatic prenylation
appears to become competitive. Li employed the 4-dimethylallyltryptophan
synthase FgaPT2 [211] and the 7-dimethylallyltryptophan synthase DMATS
[212] (both from Aspergillus fumigatus) to prenylate tryptophan derivatives (286)
on the 100 nanomolar scale. In all cases shown in Scheme 54, yields >90% were
obtained overnight, based on recovered starting material. As coupling partner,
ammonium prenylpyrophosphate (8) was used as always.
> 90%
O
8, FgaPT2 (0.001 OH
X
equiv.), Tris-HCl (50 4
m M, pH 7.5), CaCl2 (5 NHR 1
m M), water, 37 °C
N
R2 287
1 2
O R =H, R =H, X=H
X OH R 1=Me, R2 =H, X=H
R 1=H, R2 =Me, X=H
NHR 1 OP 2 O6 (NH4 )3 R 1=H, R2 =H, X=O H
8
N O
R2 286 X OH
R 1 =H, R 2=H, X=H
R 1 =Me, R 2=H, X=H NHR 1
R 1 =H, R 2=Me, X=H 8, His 6 -7-DMATS 7 N
R 1 =H, R 2=H, X=OH (0.0006 equiv.), Tris- R2
HCl (50 mM, p H 7.5), 288
CaCl2 (10 mM), water,
37 °C R1 =H, R 2 =H, X=H
R1 =M e, R 2=H, X=H
> 90% R1 =H, R 2 =Me, X=H
R1 =H, R 2 =H, X=OH
Scheme 54 Chemoenzymatic 4- and 7-prenylations of tryptophan derivatives 286 (FgaPT2: 4-

dimethylallyltryptophan synthase, DMATS: 7-dimethylallyltryptophan synthase from Aspergillus
fumigatus) by Li and co-workers [211, 212]
The exact mechanism of enzymatic prenylations is still subject to debate. On the

basis of isotopic labelling, Luk and Tanner recently provided evidence that the
reaction proceeds via an allylic cation intermediate, rather than via an SN2-type
mechanism [213]. The ergot alkaloid producing fungus Claviceps purpurea was the
source of the first characterised prenyltransferase, isolated by the Floss group [214],
followed by identification of its gene [215]. Since then several new members of
the family have been characterised [216]. 4-tert-Prenylated indoles have not been
synthesised. However, the partial structure occurs in the natural product alfatrem
[217]. A 6-tert-prenylindole moiety occurs in the natural products sulpinine A and
B from Aspergillus sulphureus [218]. Surprisingly, there are no one-step syntheses
of 6-tert-prenylated indoles.
5.2 7-Prenyl- and 7-tert-Prenylindoles
Chemoenzymatic synthesis. In parallel to the work of the Li group on C7 [43, 219],

Edwards and co-workers recently identified, expressed and characterised the
bacterial tert-prenyltransferase LtxB from the marine cyanobacterium Lyngbya
majuscula [28]. It was possible to catalyse the 7-tert-geranylation of indolactam
V (1) with geranylpyrophosphate (289) affording the natural product lyngbyatoxin
(290) (Scheme 55).
Prenyl rearrangement. By boiling 6-geranyloxyindoles in N,N-dimethylaniline/
Ac2O, Moody introduced the tert-geranyl substituent in the indole-7-position via
Claisen rearrangement [220, 221]. Similarly, boiling a 6-prenyloxyindole in
bromobenzene (156 C) afforded a 7-tert-prenylindole (60%). In the presence of
water-containing Montmorillonite KSF, refluxing of 6-prenylindole derivatives
in toluene afforded 7-prenylindoles without regioinversion [222]. Prenylations
of the indole 7-position have also been achieved by Claisen rearrangement of 6-
tert-prenyloxyindoles and by aza-Claisen rearrangement from N-tert-
prenylindoles. Key step of Moody’s synthesis of murrayaquinone B (296) from
the Rutaceae plant Murraya euchrestifolia is a sequential indole formation and
H 289
H
N N
OP2O6(NH4)3
N OH N OH
O O
tert-geranyltransferase L txB,
Tris buffer, pH 8, 30 °C,4 h
N N
H H
1: (−)-indolactam-V 290: lyngbyatoxin
Scheme 55 C7-tert-geranylation of ()-indolactam-V (1) affording lyngbyatoxin (290) [28]

N3 CO 2Me CO2Me
O
PhMe, rf, 3 h
N3
O O
NaOMe, MeOH, 53%
-15 °C to rt, 6 h
86%
291 292
OH
CO2Me 1) MeI, K2CO3,

HO N acetone, rf, 14 h O N O
H H
2)
O NaOMe, dioxane,
110 °C, 45 h
O
293 294
3) NaOH, H 2O, dioxane, rf, 20 h
40%
1) PCC, O 2, Hg lamp (125 W), O

NaOAc, quartz tube, MeOH,
DCM, rt, 2.5 h 90 min
2) BF3-MeOH, O 13% N O
O N O
MeOH, rt, 17 h H H
39%
295 296: murrayaquinone B
Scheme 56 Synthesis of murrayaquinone B (296) by 7-prenylation via Claisen rearrangement by

Moody and co-workers [223]
regioselective Claisen rearrangement of azide 292, prepared by condensation of

benzaldehyde derivative 291 with methyl azidoacetate in refluxing toluene
affording 7-prenylindole 293 (Scheme 56) [223, 224]. If the tert-prenyl group
was replaced by allyl, boiling in bromobenzene was necessary to achieve the
analogous reaction. The endgame annulates the missing benzene ring, finishing
with a low yielding photochemical oxidation of 295.
Simple treatment of 6-hydroxyindole derivatives with tert-prenol in the presence
of BF3-Et2O does not appear to be selective, since mixtures of prenylated and
tert-prenylated products were obtained [225].
Xiong and Pirrung found that, when treating N-tert-prenylindoline (299) with
catalytic amounts of TFA under microwave conditions, 7-prenylindoline (300)
is formed by aza-Claisen rearrangement in 90% yield (Scheme 57) [226]. The
N-propargylated starting material 298 itself has been synthesised following a
protocol by Hennion and Hanzel [45]. Still, the synthesis of 7-prenylindole (103)
requires four steps from indoline (297).
Cl
(1.2 equiv.) H 2, Lindlar,
MeOH, rt, 30 min
N CuCl (0.1 equiv.), N 86%
H NEt3 (1.2 equiv.),
THF, 0 °C to rt, 12 h
297 91% 298
TFA (0.13 equiv.), activ. MnO 2

PhMe, μwave, (2 x 3 equiv.),
150 °C, 10 min N DCM, rf
N N
H H
90% 88%
299 300 103
Scheme 57 Synthesis of 7-prenylindole (103) by Xiong and Pirrung [226]
In 2003, Ganesan and co-workers reported the total synthesis of the fungal
natural product okaramine J (309, Scheme 58) from Penicillium simplicissimum
and Aspergillus aculeatus, which for the first time featured an N1 to C7 aza-Claisen
rearrangement of a tert-prenyl group with regioinversion [52]. Following a route
developed by Danishefsky and co-workers [227], treatment of the protected trypto-
phan derivative 301 with NBS afforded the unstable dihydropyrroloindole 302,
which was converted to the hydroxylated pyrroloindole 303 by DMDO oxidation
and subsequent NaBH4 reduction. The anthracene sulfonyl protecting group was
chosen because it was to be removed later under reductive conditions without
dehydrating the hydroxyindolenine 308.
Installation of the N-tert-prenyl group was accomplished via CuCl2-catalysed
propargylation of the indoline 303 in moderate yield (55%), followed by Lindlar
hydrogenation of 304. The key aza-Claisen rearrangement proceeded in the high
yield of 84% simply by treating the N-tert-prenylindoline 305 with TFA in DCM,
leading to the presumably charge-accelerated [3,3] sigmatropic rearrangement of
the tert-prenyl group affording 7-prenylindoline 306. Ganesan and co-workers
propose that the required conformation of the N–C bond is preferred only in the
case of 306 because of steric interaction with the bulky anthracenesulfonyl group
(Thorpe–Ingold effect).
The endgame of the synthesis features the intermolecular amide coupling
with 2-tert-prenyltryptophan methyl ester (307) employing PyBOP/NEt3 and the
cyclisation to the diketopiperazine 309 employing HBTU/iPr2NEt. Building block
307 was synthesised by Danishefsky and co-workers in course of their total
syntheses of gypsetin (94) and brevianamide E.
Other approaches. Treatment of an analogue of ()-indolactam V (1) with
prenyl bromide in HOAc/NaOAc afforded 7-prenylated, 7-tert-prenylated and
2-prenylated products [228]. It was also possible to build up the indole ring of
CO 2tBu O
1) DMDO, DCM,
NBS, OtBu -78 °C
O NEt3, DCM
HN O 2) NaBH 4, MeOH
S O N
S O 75% from 301
N N
H H Anth
301 302
O O
HO O tBu Br HO O tBu H 2 , Pd-Al2 O3 ,
O N O EtOAc
N
S O S O
N H CuCl2 (0.2 equiv.), N H 99%
H Anth iPr NEt, THF Anth
2
303 55% 304
O
O
HO O tBu
HO OtBu TFA (5 equiv.), O
DCM, rt, 16 h N
N O S O
S O N H
84% Anth
N H H
Anth
305 306
1) TMSOTf (20 equiv.), 2,6-

lutidine (50 equiv.), DCM O CO2 Me NH
HO N
H
2) N O
PyBOP (2 equiv.),
NEt3 (3 equiv), THF N H S O
CO2 Me H Anth
NH
H2 N 308
61%
307
1) Al-Hg, THF-H 2 O O
2) KOH, MeOH, dioxane HO
NH
3) HBTU, iPr 2NEt (3 equiv.), NH
DCM, 7 d N
N H
H O
36%
309: okaramine J
Scheme 58 Synthesis of the fungal natural product okaramine J (309) by aza-Claisen rearrange-
ment by Ganesan and co-workers [52]
7-tert-prenylindole starting from suitably functionalised pyrroles, as employed in

the total syntheses of pendolmycin [229, 230].
We thought this chapter could finish with one of the earliest total syntheses
reported in the field, which made a threefold prenylated indole alkaloid available,
admittedly by building up the heterocycle. The key step of the Kishi synthesis of
echinulin (318) from Aspergillus echinulatus is the double prenyl migration starting
from N,N-diprenylaniline (310) affording 2,4-diprenylaniline (311, Scheme 59)
O O
NH 2 312
ZnCl2 (2 equiv.), Br
O
xylene, rf
N
23%
310 311
O
O OH
LiAlH4
N N
H H
313 314
1) Ac 2 O, DMSO N
2) Wittig
3) HNMe2 , H 2CO
N O
H
EtO2 C
NH
316
HN
315 O
O H O H
N N
EtO 2C H
N 1) 0.1 N NaOH, N
H O H2 O-dioxane H O
N 2) rf N
H H
317 318: echinulin + epi-echinulin (2:1)
Scheme 59 Kishi’s echinulin synthesis [231]

[231, 232]. The rearrangement is achieved in 23% yield in boiling xylene in the
presence of zinc chloride and probably proceeds by aza-Claisen–Cope sequences
for both prenyl groups. Tert-Prenylated intermediates have not been identified.
Prior to that work, only one publication on aromatic aza-Claisen rearrangements
starting from N-allylanilines had been published by Hurd and Jenkins [233]. The
synthesis of echinulin (318) continues with the assembly of the indole ring of
313 by condensation with bromoketone 312, followed by LiAlH4 reduction to
alcohol 314. Oxidation to the aldehyde was carried out by Ac2O-DMSO. Wittig
methylenation and Mannich reaction afforded the gramine 315, which was con-
densed with diketopiperazine 316. Decarboxylation became possible after saponi-
fication of 317 affording a mixture of epimeric echinulins with the correct absolute
configuration in the L-alanine-derived portion.
6 Conclusion
A major development in the past 5 years has been the identification and biotechno-
logical production of fungal enzymes catalysing prenylations and tert-prenylations
of tryptophan derivatives, including diketopiperazines, with ammonium prenylpyr-
ophosphate. Currently, conversions of milligram amounts of substrates are possible,
addressing all indole positions except C5, C6 and the bridgeheads. Substantial
progress has also been made in the field of transition-metal catalysed tert-
prenylation of indole N1 and C3. A third important sector is defined by prenyl or
tert-prenyl shifts around the indole nucleus. This field has been worked on for about
four decades, but still delivers most competitive, often biomimetic strategies.
Still, there remain many open problems. It would be efficient to be able to
prenylate or tert-prenylate indole regioselectively at the benzene positions 4, 5
and 6 without having to rely on pre-functionalisation such as halogenation or
hydroxylation. Here, deeper investigation of prenyl shifts and of CH functiona-
lisation on indole is required. Enantioselective catalysis has to be explored further
towards the synthesis of optically pure 3-prenylated or -tert-prenylated alkaloids.
A chiral version of NBS would be helpful. In the case of conformationally flexible
starting materials, the diastereoselectivity of oxidative cyclisations of tryptophan-
derived diketopiperazines is still not convincing. In the area of chemoenzymatic
synthesis, the number and availability of enzymes has to be enhanced and their
substrate tolerance has to be elucidated in more detail.
References
1. Li SM (2010) Nat Prod Rep 27:57–78

2. Williams RM, Sanz-Cervera JF, Stocking E (2000) Top Curr Chem 209:97–173
3. Scholz U, Winterfeldt E (2000) Nat Prod Rep 17:349–366
4. Baird KJ, Grundon MF, Harrison DM, Magee MG (1981) Heterocycles 15:713–717
5. Wei W, Cai C, Kota S, Takahashi V, Ni F, Strosberg AD, Snyder JK (2009) Bioorg Med
Chem Lett 19:6926–6930
6. Jain HD, Zhang C, Zhou S, Zhou H, Ma J, Liu X, Liao X, Devequ AM, Dieckhaus CM,
Johnson MA, Smith KS, Macdonald TL, Kakeya H, Osada H, Cook JM (2008) Bioorg Med
Chem 16:4626–4651
7. Kawashima Y, Amanuma F, Sato M, Okuyama S, Nakashima Y, Sota K, Moriguchi I (1986)
J Med Chem 29:2284–2290
8. Kodato S, Nakagawa M, Hongu M, Kawate T, Hino T (1988) Tetrahedron 44:359–377
9. Nakagawa M, Fukushima H, Kawate T, Hongu M, Une T, Kodato S, Taniguchi M, Hino T
(1989) Chem Pharm Bull 37:23–32
10. Sanz-Cervera JF, Stocking EM, Usui T, Osada H, Williams RM (2000) Bioorg Med Chem
8:2407–2415
11. Kim JS, Padnya A, Weltzin M, Edmonds BW, Schulte MK, Glennon RA (2007) Bioorg Med
Chem Lett 17:4855–4860
12. Manian RDRS, Jayashankaran J, Raghunathan R (2007) Tetrahedron Lett 48:1385–1389
13. Jones GB, Moody CJ (1989) J Chem Soc Perkin Trans 1:2449–2454
14. Jones GB, Moody CJ (1988) J Chem Soc Chem Commun 166–167
15. Issa S, Walchshofer N, Kassab I, Termoss H, Chamat S, Geahchan A, Bouaziz Z (2010) Eur J
Med Chem 45:2567–2577
16. Cardoso ASP, Marques MMB, Srinivasan N, Prabhakar S, Lobo AM, Rzepa HS (2006) Org
Biomol Chem 4:3966–3972
17. Go ML, Leow JL, Gorla SK, Sch€ uller AP, Wang M, Casey PJ (2010) J Med Chem
53:6838–6850
18. Endo Y, Shudo K, Itai A, Hasegawa M, Sakai S (1986) Tetrahedron 42:5905–5924
19. Chen J, Lou J, Liu T, Wu R, Dong X, He Q, Yang B, Hu Y (2009) Arch Pharm 342:165–172
20. Simon G, Couthon-Gourves H, Haelters JP, Corbel B, Kervarec N, Michaud F, Meijer L
(2007) J Heterocycl Chem 44:793–801
21. Nakagawa M, Kodato S, Hongu M, Kawate T, Hino T (1986) Tetrahedron Lett
27:6217–6220
22. Morales-Rı́os MS, Santos-Sánchez NF, Mora-Pérez Y, Joseph-Nathan P (2004) Heterocycles
63:1131–1142
23. Manian RDRS, Jayashankaran J, Raghunathan R (2007) Synlett 874–880
24. Somei M, Sayama S, Naka K, Shinmoto K, Yamada F (2007) Heterocycles 73:537–554
25. Nakatsuka S, Miyazaki H, Teranishi K, Goto T (1986) Tetrahedron Lett 27:2391–2394
26. Grundon MF, Hamblin MR, Harrison DM, Logue JND, Maguire M, McGrath JA (1980)
J Chem Soc Perkin Trans 1 1294–1298
27. Prajapati D, Gadhwal S (2004) Tetrahedron 60:4909–4913
28. Huynh MU, Elston MC, Hernandez NM, Ball DB, Kajiyama S, Irie K, Gerwick WH,
Edwards DJ (2010) J Nat Prod 73:71–74
29. López-Alvarado P, Caballero E, Avendaño C, Menéndez JC (2006) Org Lett 8:4303–4306
30. Cardoso AS, Srinivasan N, Lobo AM, Prabhakar S (2001) Tetrahedron Lett 42:6663–6666
31. Cardoso ASP, Marques MMB, Srinivasan N, Prabhakar AC, Lobo AM (2007) Tetrahedron
63:10211–10225
32. Plate R, Theunisse AWG, Ottenheijm HCJ (1987) J Org Chem 52:370–375
33. Takase S, Itoh Y, Uchida I (1985) Tetrahedron Lett 26:847–850
34. Takase S, Uchida I, Tanaka H, Aoki H (1986) Tetrahedron 42:5879–5886
35. Takase S, Itoh Y, Uchida I, Tanaka H, Aoki H (1986) Tetrahedron 42:5887–5894
36. Grundmann A, Kuznetsova T, Afiyatullov SS, Li SM (2008) ChemBioChem 9:2059–2063
37. Voûte N, Philp D, Slawin AMZ, Westwood NJ (2010) Org Biomol Chem 8:442–450
38. Curran DP, Suh YG (1984) J Am Chem Soc 106:5002–5004
39. McMichael KD, Korver GL (1979) J Am Chem Soc 101:2746–2747
40. Gajewski JJ, Conrad ND (1979) J Am Chem Soc 101:2747–2748
41. Zou H, Zheng X, Li SM (2009) J Nat Prod 72:44–52

42. Luzung MR, Lewis CA, Baran PS (2009) Angew Chem Int Ed 48:7025–7029
43. Zou HX, Xie XL, Linne U, Zheng XD, Li SM (2010) Org Biomol Chem 8:3037–3044
44. Schultz AW, Lewis CA, Luzung MR, Baran PS, Moore BS (2010) J Nat Prod 73:373–377
45. Hennion GF, Hanzel RS (1960) J Am Chem Soc 82:4908–4912
46. Imada Y, Yuasa M, Nakamura I, Murahashi SI (1994) J Org Chem 59:2282–2284
47. Sugiyama H, Yokokawa F, Aoyama T, Shioiri T (2001) Tetrahedron Lett 42:7277–7280
48. Yokokawa F, Hideyuki S, Aoyama T, Shioiri T (2004) Synthesis 1476–1480
49. Hayashi H, Fujiwara T, Murao S, Motoo A (1991) Agric Biol Chem 55:3143–3145
50. Hewitt PR, Cleator E, Ley SV (2004) Org Biomol Chem 2:2415–2417
51. Baran PS, Guerrero CA, Corey EJ (2003) J Am Chem Soc 125:5628–5629
52. Roe JM, Webster RAB, Ganesan A (2003) Org Lett 5:2825–2827
53. Sheu JH, Chen CA, Chen BH (1999) Chem Commun 203–204
54. Marsch N (2010) Master Thesis, TU Braunschweig
55. Hino T, Hasumi K, Yamaguchi H, Taniguchi M, Nakagawa M (1985) Chem Pharm Bull
33:5202–5206
56. Wenkert E, Angell EC, Ferreira VF, Michelotti EL, Piettre SR, Sheu JH, Swindell CS (1986)
J Org Chem 51:2343–2351
57. Pirrung MC, Li Z, Park K, Zhu J (2002) J Org Chem 67:7919–7926
58. Hansen DB, Lewis AS, Gavalas SJ, Joullié MM (2006) Tetrahedron Asymmetry 17:15–21
59. Wen SJ, Zhang HW, Yao ZJ (2002) Tetrahedron Lett 43:5291–5294
60. Wen SJ, Yao ZJ (2004) Org Lett 6:2721–2724
61. Della Sala G, Capozzo D, Izzo I, Giordano A, Iommazzo A, Spinella A (2002) Tetrahedron
Lett 43:8839–8841
62. Fletcher AJ, Bax MN, Willis MC (2007) Chem Commun 4764–4766
63. Ackermann L, Sandmann R, Kondrashov MV (2009) Synlett 1219–1222
64. Ackermann L, Sandmann R, Schinkel M, Kondrashov MV (2009) Tetrahedron
65:8930–8939
65. Melkonyan FS, Topolyan AP, Karchava AV, Yurovskaya MA (2008) Chem Heterocycl
Comp 44:1288–1290
66. Westermaier M, Mayr H (2006) Org Lett 8:4791–4794
67. Casnati G, Francioni M, Guareschi A, Pochini A (1969) Tetrahedron Lett 10:2485–2487
68. O’Malley GJ, Cava MP (1987) Tetrahedron Lett 28:1131–1134
69. Wang H, Ganesan A (1997) Tetrahedron Lett 38:4327–4328
70. Bailey PD, Cochrane PJ, Lorenz K, Collier ID, Pearson DPJ, Rosair GM (2001) Tetrahedron
Lett 42:113–115
71. Edmondson SD, Danishefsky SJ (1998) Angew Chem Int Ed 37:1138–1140
72. Edmondson SD, Danishefsky SJ, Sepp-Laurenzino L, Rosen N (1999) J Am Chem Soc
121:2147–2155
73. Wang H, Ganesan A (1999) Org Lett 1:1647–1649
74. Limbach M, Dalai S, Janssen A, Es-Sayed M, Magull J, de Meijere A (2005) Eur J Org Chem
610–617
75. Casnati G, Pochini A (1970) J Chem Soc Chem Commun 1328–1329
76. Casnati G, Pochini A (1974) J Chem Soc Perkin Trans 1 754–757
77. Inada S, Nagai K, Takayanagi Y, Okazaki M (1976) Bull Chem Soc Jpn 49:833–834
78. Cardoso ASP, Lobo AM, Prabhakar S (2000) Tetrahedron Lett 41:3611–3613
79. Nakagawa M, Matsuki K, Hino T (1983) Tetrahedron Lett 24:2171–2174
80. Plate R, Ottenheijm HCJ (1986) Tetrahedron Lett 27:3755–3758
81. Caballero E, Avendaño C, Menéndez JC (2003) J Org Chem 68:6944–6951
82. Mitchell MO, Le Quesne PW (1990) Tetrahedron Lett 31:2681–2684
83. Moody CJ, Ward JG (1984) J Chem Soc Perkin Trans 1 2903–2909
84. Laurent A, Mison P, Nafti A, Pellissier N (1982) Tetrahedron Lett 23:655–658
85. Padwa A, Kulkarni Y (1979) Tetrahedron Lett 20:107–110
86. Padwa A, Akiba M, Cohen LA, MacDonald JG (1983) J Org Chem 48:695–703
87. Depew KM, Danishefsky SJ, Rosen N, Sepp-Lorenzino L (1996) J Am Chem Soc 118:
12463–12464
88. Schkeryantz JM, Woo JCG, Siliphaivanh P, Depew KM, Danishefsky SJ (1999) J Am Chem
Soc 121:11964–11975
89. Yamada F, Fukui Y, Shinmyo D, Somei M (1993) Heterocycles 35:99–104
90. Korakas P, Chaffee S, Shotwell JB, Duque P, Wood JL (2004) Proc Natl Acad Sci USA
101:12054–12057
91. Shinohara C, Hasumi K, Takei Y, Endo A (1994) J Antibiot 47:163–167
92. Nuber B, Hansske F (1994) J Antibiot 47:168–172
93. Schkeryantz JM, Woo JCG, Danishefsky SJ (1995) J Am Chem Soc 117:7025–7026
94. Baran PS, Maimone TJ, Richter JM (2007) Nature 446:404–408
95. Zhun IV, Ignatenko AV (2004) Russ Chem Bull 53:2221–2223
96. Tatsuta K, Mukai H, Mitsumoto K (2001) J Antibiot 54:105–108
97. Miller KA, Welch TR, Greshock TJ, Ding Y, Sherman DH, Williams RM (2008) J Org Chem
73:3116–3119
98. Wagger J, Grošelj U, Svete J, Stanovnik B (2010) Synlett 1197–1200
99. Pirrung MC, Liu Y, Deng L, Halstead DK, Li Z, May JF, Wedel M, Austin DA, Webster NJG
(2005) J Am Chem Soc 127:4609–4624
100. Cox RJ, Williams RM (2002) Tetrahedron Lett 43:2149–2152
101. Liu K, Wood HB, Jones AB (1999) Tetrahedron Lett 40:5119–5122
102. Russell RA (1975) Aust J Chem 28:2535–2538
103. Baran PS, Corey EJ (2002) J Am Chem Soc 124:7904–7905
104. Plieninger H, Sirowej H, Raum D (1971) Chem Ber 104:1863–1868
105. Kawasaki T, Masuda K, Baba Y, Takada K, Sakamoto M (1994) Chem Pharm Bull
42:1974–1976
106. Dunkerton LV, Chen H, McKillican BP (1988) Tetrahedron Lett 29:2539–2542
107. Plieninger H, Kraemer HP, Sirowej H (1974) Chem Ber 107:3915–3921
108. Achenbach H, Franke D, Renner C (1985) Arch Pharm 318:1147–1150
109. Araki S, Manabe S, Butsugan Y (1984) Bull Chem Soc Jpn 57:1433–1444
110. Yadav JS, Reddy BVS, Reddy PM, Srinivas C (2002) Tetrahedron Lett 43:5185–5187
111. Zhu X, Ganesan A (2002) J Org Chem 67:2705–2708
112. Amat M, Hadida S, Sathyanarayana S, Bosch J (1994) J Org Chem 59:10–11
113. Achenbach H, Franke D (1987) Arch Pharm 320:91–92
114. Somei M, Funamoto T, Ohta T (1987) Heterocycles 26:1783–1784
115. Lindel T (2003) In: Schmalz HG, Wirth T (eds) Organic synthesis highlights V. Wiley VCH,
Weinheim, Germany, pp 360–367
116. von Nussbaum F, Danishefsky SJ (2000) Angew Chem Int Ed 39:2175–2178
117. Miyake FY, Yakushijin K, Horne DA (2004) Angew Chem Int Ed 43:5357–5360
118. Miyake FY, Yakushijin K, Horne DA (2004) Org Lett 6:4249–4251
119. Wang H, Ganesan A (2000) J Org Chem 65:4685–4693
120. Dieter JW, Li Z, Nicholas KM (1987) Tetrahedron Lett 28:5415–5418
121. Yang H, Fang L, Zhang M, Zhu C (2009) Eur J Org Chem 666–672
122. Trost BM, Quancard J (2006) J Am Chem Soc 128:6314–6315
123. Amijs CHM, López-Carrillo V, Echavarren AM (2007) Org Lett 9:4021–4024
124. Trost BM, Stiles DT (2007) Org Lett 9:2763–2766
125. Tsuda T, Chujo Y, Nishi SL, Tawara K, Saegusa T (1980) J Am Chem Soc 102:6381–6384
126. Tsuji J, Yamada T, Minami I, Yuhara M, Nisar M, Shimizu I (1987) J Org Chem
52:2988–2995
127. Williams JM (1996) Synlett 705–710
128. Helmchen G, Pfaltz A (2000) Acc Chem Res 33:336–345
129. Otera J (1993) Chem Rev 93:1449–1470
130. Meyers C, Carreira EM (2003) Angew Chem Int Ed 42:694–696
131. Marti C, Carreira EM (2005) J Am Chem Soc 127:11505–11515

132. Overman LE, Rosen MD (2000) Angew Chem Int Ed 39:4596–4599
133. Overman LE, Rosen MD (2010) Tetrahedron 66:6514–6525
134. Cacchi S, Fabrizi G, Pace P (1998) J Org Chem 63:1001–1011
135. Fuji K, Kawabata T, Ohmori T, Node M (1995) Synlett 367–368
136. Bagul TD, Lakshmaiah G, Kawabata T, Fuji K (2002) Org Lett 4:249–251
137. Austin JF, Kim SG, Sinz CJ, Xiao WJ, MacMillan DWC (2004) Proc Natl Acad Sci USA
101:5482–5487
138. Sebahar PR, Williams RM (2000) J Am Chem Soc 122:5666–5667
139. Onishi T, Sebahar PR, Williams RM (2003) Org Lett 5:3135–3137
140. Onishi T, Sebahar PR, Williams RM (2004) Tetrahedron 60:9503–9515
141. Kimura M, Futamata M, Mukai R, Tamaru Y (2005) J Am Chem Soc 127:4592–4593
142. Usui I, Schmidt S, Keller M, Breit B (2008) Org Lett 10:1207–1210
143. Gruber S, Zaitsev AB, W€ orle M, Pregosin PS (2008) Organometallics 27:3796–3805
144. Sundararaju B, Achard M, Demerseman B, Toupet L, Sharma GVM, Bruneau C (2010)
Angew Chem Int Ed 49:2782–2785
145. Yen WB, Xie XL, Matuschek M, Li SM (2010) Org Biomol Chem 8:1133–1141
146. Yen WB, Yu X, Xie XL, Li SM (2010) Org Biomol Chem 8:2430–2438
147. Yin WB, Cheng J, Li SM (2009) Org Biomol Chem 7:2202–2207
148. Marsden SP, Depew KM, Danishefsky SJ (1994) J Am Chem Soc 116:11143–11144
149. Depew KM, Marsden SP, Zatorska D, Zatorski A, Bornmann WG, Danishefsky SJ (1999)
J Am Chem Soc 121:11953–11963
150. Nicolaou KC, Claremon DA, Barnette WE, Seitz SP (1979) J Am Chem Soc 101:3704
151. Richard DJ, Schiavi B, Joullié MM (2004) Proc Natl Acad Sci USA 101:11971–11976
152. Shangguan N, Hehre WJ, Ohlinger WS, Beavers MP, Joullié MM (2008) J Am Chem Soc
130:6281–6287
153. Sunazuka T, Shirahata T, Tsuchiya S, Hirose T, Mori R, Harigaya Y, Kuwajima I, Omura S
(2005) Org Lett 7:941–943
154. Fuchs JR, Funk RL (2005) Org Lett 7:677–680
155. Morales-Rı́os MS, Suárez-Castillo OR, Joseph-Nathan P (2002) Tetrahedron 58:1479–1484
156. Morales-Rı́os MS, Suárez-Castillo OR, Joseph-Nathan P (1999) J Org Chem 64:1086–1087
157. Morales-Rı́os MS, Suárez-Castillo OR, Trujillo-Serrato JJ, Joseph-Nathan P (2001) J Org
Chem 66:1186–1192
158. Nair V, Ros S, Jayan CN, Viji S (2003) Synthesis 2542–2546
159. Alcaide B, Almendros P, Rodrı́guez-Acebes R (2005) J Org Chem 70:3198–3204
160. Alcaide B, Almendros P, Aragoncillo C (2010) Eur J Org Chem 2845–2848
161. Grant CD, Krische MJ (2009) Org Lett 11:4485–4487
162. Skucas E, Bower JF, Krische MJ (2007) J Am Chem Soc 129:12678–12679
163. Itoh J, Han SB, Krische MJ (2009) Angew Chem Int Ed 48:6313–6316
164. Stocking EM, Williams RM, Sanz-Cervera JF (2000) J Am Chem Soc 122:9089–9098
165. Williams RM, Cox RJ (2003) Acc Chem Res 36:127–139
166. Barrow KD, Colley PW, Tribe DE (1979) J Chem Soc Chem Commun 225–226
167. Gorst-Allman CP, Steyn PS, Vleggaar R (1982) J Chem Soc Chem Commun 652–653
168. Greshock TJ, Grubbs AW, Tsukamoto S, Williams RM (2007) Angew Chem Int Ed
46:2262–2265
169. Grubbs AW, Artman GD III, Tsukamoto S, Williams RM (2007) Angew Chem Int Ed
46:2257–2261
170. Kato H, Yoshida T, Tokue T, Nojiri Y, Hirota H, Ohta T, Williams RM, Tsukamoto S (2007)
Angew Chem Int Ed 46:2254–2256
171. Tsukamoto S, Kato H, Samizo M, Nojiri Y, Onuki H, Hirota H, Ohta T (2008) J Nat Prod
71:2064
172. Finefield JM, Williams RM (2010) J Org Chem 75:2785–2789
173. Greshock TJ, Williams RM (2007) Org Lett 9:4255–4258
174. Grubbs AW, Artman GD III, Williams RM (2005) Tetrahedron Lett 46:9013–9016
175. Elomri A, Michel S, Tillequin F, Koch M (1992) Heterocycles 34:799–806
176. Somei M, Karasawa Y, Kaneko C (1981) Heterocycles 16:941–949
177. Kametani T, Kanaya N, Ihara M (1981) J Chem Soc Perkin Trans 1 959–963
178. Furlán RLE, Mata EG, Mascaretti OA, Peña C, Coba MP (1998) Tetrahedron 54:
13023–13034
179. Nicolaou KC, Estrada AA, Zak M, Lee SH, Safina BS (2005) Angew Chem Int Ed 44:
1378–1382
180. Davis FA, Townson JC, Vashi DB, ThimmaReddy T, McCauley JP, Harakal ME, Gosciniak
D (1990) J Org Chem 55:1254–1261
181. Miller KA, Tsukamoto S, Williams RM (2009) Nat Chem 1:63–68
182. Lysek N, Rachor E, Lindel T (2002) Z Naturforsch C: Biosci 57c:1056–1061
183. Peters L, K€onig GM, Terlau H, Wright AD (2002) J Nat Prod 65:1633–1637
184. Peters L, Wright AD, Krick A, K€ onig GM (2004) J Chem Ecol 30:1165–1181
185. Lindel T, Br€auchle L, Golz G, B€
ohrer P (2007) Org Lett 9:283–286
186. Kramer GW, Brown HC (1977) J Organomet Chem 132:9–27
187. Miyake FY, Yakushijin K, Horne DA (2004) Org Lett 6:711–713
188. Adla SK, Golz G, Jones PG, Lindel T (2010) Synthesis 2161–2170
189. Kawasaki T, Terashima R, Sakaguchi K, Sekiguchi H, Sakamoto M (1996) Tetrahedron Lett
37:7525–7528
190. Kawasaki T, Ogawa A, Terashima R, Saheki T, Ban N, Sekiguchi H, Sakaguchi K, Sakamoto
M (2005) J Org Chem 70:2957–2966
191. Kawasaki T, Shinada M, Ohzono M, Ogawa A, Terashima R, Sakamoto M (2008) J Org
Chem 73:5959–5964
192. Kawasaki T, Nagaoka M, Satoh T, Okamoto A, Ukon R, Ogawa A (2004) Tetrahedron
60:3493–3503
193. Malapel-Andrieu B, Piroëlle S, Mérour JY (1998) J Chem Res 594–595
194. Booker-Milburn KI, Fedouloff M, Paknoham SJ, Strachan JB, Melville JL, Voyle M (2000)
Tetrahedron Lett 41:4657–4661
195. Bycroft BW, Landon W (1970) J Chem Soc D Chem Commun 967–968
196. Mukaiyama T, Hayashi M, Narasaka K (1973) Chem Lett 291–294
197. Kawasaki T, Shinada M, Kamimura D, Ohzono M, Ogawa A (2006) Chem Commun
420–422
198. Sabahi A, Rainier JD (2010) ARKIVOC 8:116–125
199. He B, Song H, Du Y, Qin Y (2009) J Org Chem 74:298–304
200. Ignatenko VA, Deligonul N, Viswanathan R (2010) Org Lett 12:3594–3597
201. Nyong AM, Rainier JD (2005) J Org Chem 70:746–748
202. Plieninger H, Sirowej H (1971) Chem Ber 104:2027–2029
203. Forke R, Krahl MP, Krause T, Schlechtingen G, Kn€ olker HJ (2007) Synlett 268–272
204. Kn€olker HJ, Fr€
ohner W, Wagner A (1998) Tetrahedron Lett 39:2947–2950
205. Kn€olker HJ, Reddy KR (2002) Chem Rev 102:4304–4428
206. Dai Y, Xie X, Xu S, Ma D, Tang S, She X (2011) Org Lett 13:2302–2305
207. Yokoyama Y, Hikawa H, Mitsuhashi M, Uyama A, Hiroki Y, Murakami Y (2004) Eur J Org
Chem 1244–1253
208. Yamada K, Namerikawa Y, Haruyama T, Miwa Y, Yanada R, Ishikura M (2009) Eur J Org
Chem 5752–5759
209. Yokoyama Y, Hikawa H, Mitsuhashi M, Uyama A, Murakami Y (1999) Tetrahedron Lett
40:7803–7806
210. Xu Z, Hu W, Liu Q, Zhang L, Jia Y (2010) J Org Chem 7626–7635
211. Steffan N, Uns€old IA, Li SM (2007) ChemBioChem 8:1298–1307
212. Kremer A, Li SM (2008) Appl Microbiol Biotechnol 79:951–961
213. Luk LYP, Tanner ME (2009) J Am Chem Soc 131:13932–13933
214. Lee SL, Floss HG, Heinstein P (1976) Arch Biochem Biophys 177:84–94
215. Tsai HF, Wang H, Gebler JC, Poulter CD, Schardl CL (1995) Biochem Biophys Res
Commun 216:119–125
216. Liu X, Walsh CT (2009) Biochemistry 48:11032–11044
217. Gallagher RT, Clardy J, Wilson BJ (1980) Tetrahedron Lett 21:239–242
218. Laakso JA, Gloer JB, Wicklow DT, Dowd PF (1992) J Org Chem 57:2066–2071
219. Ruan HL, Stec E, Li SM (2009) Arch Microbiol 191:791–795
220. Moody CJ (1983) J Chem Soc Chem Commun 1129–1131
221. Moody CJ (1984) J Chem Soc Perkin Trans 1 1333–1337
222. El-Araby ME, Bernacki RJ, Makara GM, Pera PJ, Anderson WK (2004) Bioorg Med Chem
12:2867–2879
223. Martin T, Moody CJ (1988) J Chem Soc Perkin Trans 1 241–245
224. Martin T, Moody CJ (1985) J Chem Soc Chem Commun 1391–1392
225. Ramesh K, Kapil RS (1986) Indian J Chem 25B:462–465
226. Xiong X, Pirrung MC (2007) J Org Chem 72:5832–5834
227. Kamenecka TM, Danishefsky SJ (2001) Chem Eur J 7:41–63
228. Irie K, Isaka T, Iwata Y, Yanai Y, Nakamura Y, Koizumi F, Ohigashi H, Wender PA,
Satomi Y, Nishino S (1996) J Am Chem Soc 118:10733–10743
229. Okabe K, Muratake H, Natsume M (1990) Tetrahedron 46:5113–5120
230. Okabe K, Natsume M (1991) Tetrahedron 47:7615–7624
231. Takamatsu N, Inoue S, Kishi Y (1971) Tetrahedron Lett 12:4665–4668
232. Takamatsu N, Inoue S, Kishi Y (1971) Tetrahedron Lett 12:4661–4664
233. Hurd CD, Jenkins WW (1957) J Org Chem 22:1418–1423
Top Curr Chem (2012) 309: 131–162
DOI: 10.1007/128_2011_134
Published online: 3 May 2011
Marine Pyrroloiminoquinone Alkaloids
Yasuyuki Kita and Hiromichi Fujioka
Abstract Recent reports on the synthetic studies of marine pyrroloiminoquinone

alakloids and their analogs are reviewed.
Keywords Bispyrroloiminoquinone Discorhabdin Isobatzelline Makaluvamine

Pyrroloiminoquinone alakloid Prianosin B
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
2 Construction of the Pyrroloiminoquinone Skeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
3 Synthetic Works by Other Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
3.1 Makaluvamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
3.2 Isobatzellines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
3.3 Bispyrroloiminoquinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
3.4 Discorhabdins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
4 Our Synthetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
4.1 Discorhabdin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
4.2 Development of Methods for the Synthesis of Complex
Pyrroloiminoquinone Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
4.3 Makaluvamine F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
4.4 Total Synthesis of Discorhabdin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
4.5 Prianosin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
4.6 Discorhabdin A Analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Y. Kita (*)
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga
525-8577, Japan
H. Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka
565-0871, Japan
132 Y. Kita and H. Fujioka
1 Introduction
Marine organisms contain various compounds which are useful for their life and
relation with other organisms, and are getting much attention because the natural
products isolated from them hopefully have potential as new medicinally valuable
agents, agricultural chemicals, cosmetics, and health foods [1–5]. Among them,
the marine sponges of the genera Latrunculia, Batzella, Prianos, and Zyzzya are
a rich source of alkaloid metabolites containing either the tetra-, hexa-, or octa-
hydrogenated variants of pyrrolo[4,3,2-de]quinoline 1, pyrrolo[4,3,2-de]pyrrolo
[2,3-h]quinoline 2, pyrido[2,3-h]pyrrolo[4,3,2-de]quinoline 3, and pyrroloimino-
quinone 4 skeletons.
N N N N
N N NH N N N
H
O
1 2 3 4
Among these alkaloid metabolites, the alkaloids containing the pyrroloimino-

quinone 4 core skeletons comprise about 60 metabolites including makaluvamines,
isobatzellines, discorhabdins, tsitsikammamines, and wakayin. There are several
reviews of the structures, biological activities, and synthesis of the pyrroloimino-
quinone alkaloids and their analogs [6–9].
R4 R3
R3 R5 Br
+ R3
N N N
R4 R4
S
R5HN N R2 N N R2 N N R2
R1 R H
O O R1 O R1
makaluvamines discorhabdins tsitsikammamines
isobatzellines (prianosins, epinardins) wakayin
The representative makaluvamine alkaloids having the pyrroloiminoquinone

skeleton are shown in Fig. 1. They were isolated from marine sponges collected
in Fiji, Micronesia, Australia’s Great Barrier Reef, Indonesia, the Philippines, and
the Vanuatu area [10–15]. The stereogenic center of makaluvamine F has not been
determined. N-1-b-D-Ribofuranosylmakaluvamine I, which has a sugar moiety,
was also isolated from a South African sponge [16].
Figure 2 shows the isobatzelline alkaloids. They were isolated from the sponge
Batzella sp. and an Indopacific collection of Zyzzya fuliginosa. Their structures
are very close to makaluvamines and they have the 7-aminopyrroloiminoquinone
skeleton [17, 18].
Marine Pyrroloiminoquinone Alkaloids 133
R4 + R1O R3 +
N 3 N
R1
10
R2 N N N
H
O R3 O R2
R1 R2 R3 R4 R1 R2 R3
makaluvamine A H NH2 Me H makaluvamine D H H H
makaluvamine B H H Me H, Δ3 makaluvamine E H Me H, Δ10
makaluvamine C H NH2 H Me makaluvamine G H Me Me, Δ10
makaluvamine H H H Me Me makaluvamine J H H Me
makaluvamine I H NH2 H H makaluvamine K H Me H
makaluvamine N Br NH2 H H makaluvamine L H H Me, Δ10
makaluvamine M H H H, Δ10
makaluvamine P H Me Me
makaluvamine V OMe H H
OH N
Br
N
HO
S N NH2
O
O
N N
H H
O HO OH
makaluvamine F N-1-β-D-ribofuranosylmakaluvamine I
Fig. 1 Representative makaluvamine alkaloids
R1 R2
N 3
isobatzelline A SMe Cl
R2
isobatzelline B SMe H
isobatzelline C H H
H2N N R1
isobatzelline D SMe Cl, Δ3
Fig. 2 Isobatzelline O Me isobatzelline E H Cl, Δ3
alkaloids
Figure 3 shows the alkaloids with the pyrrolo[4,3,2-de]pyrrolo[2,3-h]quinoline

skeleton, i.e., wakayin and tsitsikammamines. Wakayin was isolated from a Fijian
ascidian and is the first pyrroloiminoquinone alkaloid not isolated from a marine
sponge [19]. Tsitsikammamines A and B were isolated from a South African
latrunculid sponge Latrunculiidae in 1996 [20]. They are reported to exhibit
a cytotoxicity and topoisomerase I inhibition. Furthermore, reinvestigation of the
extracts of the same sponge led to isolation of minor pyrroloiminoquinone
H HO HO 18
N + HO +
N HN N
N N N N N N
H H H H
O O R1 O R
wakayin tsitsikammamine A R1 = H N -18 oxime analogue of
tsitsikammamine B R1 = Me tsitsikammamine A R = H
N -18 oxime analogue of
tsitsikammamine B R = Me
Fig. 3 Wakayin and tsitsikammamines
metabolites, i.e., the N-18 oxim analogs of tsitsikammamines A and B. These

compounds, however, exhibited a significantly reduced cytotoxicity against
human colon tumor (HCT-116) when compared to their parent alkaloids [21].
The discorhabdin alkaloids were isolated from marine sponges such as the New
Zealand sponges of the genus Latrunculia, the Okinawan sponge Prianos melanos,
the Fijian sponge Zyzzya cf. Marsailis, etc. Figure 4 shows some representative
discorhabdin alkaloids. Among the various isolated discorhabdins (A–X), discor-
habdins A [22, 23], B [22, 23], D [24], H [21], I [25], J [6], L [25], M [6], N [6],
Q [26], R [27], and X [28], and prianosins B and D [29] have a sulfur-containing
fused ring system. Discorhabdins S, T, and U [30] have a methyl sulfide moiety.
Discorhabdin W [31] is a dimeric structure with a disulfide bond, while the others
have no sulfur atom. Furthermore, discorhabdins F [32], Q, S, and T and prianosin
B contain the 16,17-dehydropyrroloiminoquinone moiety. The enantiomeric pairs
of discorhabdins B, G*/I, L, and W were also isolated from Latrunculia species
sponges [33]. A study on the absolute stereochemistry of several discorhabdins was
reported by Copp et al. [34]. Discorhabdin Z was isolated from the Korean marine
sponge Sceptrella sp. [35] and dihydrodiscorhabdin B and discorhabdin Y were
isolated from a deep-water Alaskan sponge of the genus Latrunculia [36].
In 1995, Munro et al. reported the putative biosynthetic sequence linking the
marine pyrroloiminoquinone and related metabolites (Scheme 1) [6, 37]. Thus, the
oxidation of tryptamine first introduces the hydroxyl functions at the 4 and 7
positions, and the successive oxidation affords a quinone, which produces the
iminoquinone by imine formation between the carbonyl group and the amine in
the side chain. Further oxidation gives makaluvamines, and isobatzellines (Path A).
On the other hand, the route in which thyrosine adds to the iminoquinone gives
makaluvamines D, E, G, J–M, and P (Path B). The tsitsikammamines can then be
biosynthesized. Furthermore, two routes are possible to give the discorhabdins. One
is the route via makaluvamine F by early sulfur introduction followed by phenol
coupling to give discorhabdins A, B, I, Q, D, and L with sulfur-containing fused
O
O
H
3 R 17 discorhabdin A R = Br +
4
2 16 prianosin B R = Br, Δ 16 R N
5
N
6
discorhabdin B R = Br, Δ4 S
S
15
discorhabdin I R = H, Δ 4
8
11 14 discorhabdin Q R = Br, Δ4, Δ16 H N N
H N N H H
H H debromodiscorhabdin A R = H O
O
discorhabdin D R = H
discorhabdin L R = OH
OH OH OH
H H
Br
+ 4 +
HO N N R N
S S S
H N N H N N H N N
H H H H H H
O O O
discorhabdin X dihydrodiscorhabdin A dihydrodiscorhabdin D R = H
dihydrodiscorhabdin B Δ4 dihydrodiscorhabdin L R = OH
O
O O
Br 17
16
Br Br
N
N N
MeS
7 S S
N N
H N N N N
O Me H H H H
O O
discorhabdin S Δ16
discorhabdin T Δ7, Δ16 discorhabdin W
discorhabdin U Δ7
O O OH
H
R1 Br 17 Br
+ +
16 HO
N HN N
O
R2 N N N N HO N N
H H H H H H
O O O
R1 R2
discorhabdin Y discorhabdin Z
discorhabdin C Br H
discorhabdin E H H
discorhabdin F H H, Δ16
discorhabdin O H OMe
Fig. 4 Discorhabdin alkaloids

+ + 3 3
NH3 R R +
NH3 N
O + N
4
HN R4 R4
[O] [O] [O]
7
N N Path A O N R2 H2N N R2
H H N
O H
O R1 O R1
tryptamine O
HO makaluvamines A-C, H, I, N
isobatzellines A-E
Path B NH2
then [O]
OH HO
7
R7 R +
+ N
N
N N R6
ox. phenol- N N R6 H
H H
coupling 5 O
O R
tsitsikammamines
O makaluvamines D, E, G, J-M, P
R8 Br OH
early sulfur Br
N introduction
N
late sulfur S
9 N introduction
R N
H H N N
O
H H
ox. phenol- O
discorhabdins C, E, F, O coupling makaluvamine F
O O O
Br R H
+
N N R N
MeS S S
N N H N N H N N
H H H H H H
O O O
discorhabdins S, T, U discorhabdins A, B, I, Q discorhabdins D, L
Scheme 1 Proposed biosynthesis of pyrroloiminoquinone alkaloids
ring system. The other is the route via discorhabdins C, E, F, and O, which were
obtained by the preliminary phenol coupling. Further sulfur introduction then gives
discorhabdins S, T, U, A, B, I, Q, D, and L.
Most of the pyrroloiminoquinone alkaloids described above exhibit a strong
cytotoxicity towards human tumor cell lines, they are recognized to be the lead
compounds for developing new anticancer drugs, and they have attracted the
synthetic interest of many groups.
Our group accomplished the total syntheses of discorhabdin C in 1992 [38],
makaluvamine F in 1999 [39, 40], and discorhabdin A in 2002 [41, 42]. We also
accomplished the first total synthesis of prianosin B in 2009 [43]. We now report the
progress towards the synthesis of pyrroloiminoquinone alkaloids, mainly since
2000 including our studies, in this chapter.
2 Construction of the Pyrroloiminoquinone Skeleton
Two routes are currently known to construct the pyrroloiminoquinone skeleton

(Scheme 2). One is route a, in which the indole ring is first synthesized followed by
imine formation. The other is route b, in which the dihydroquinoline ring is first
formed followed by the five-membered ring formation.
Route a is similar to biosynthesis shown in Scheme 1, and many total syntheses
have been described using this route. Route a is divided into three methods (Scheme 3):
1) first formation of the quinone moiety followed by imine formation, 2) first formation
of the cyclic amine followed by oxidation, and 3) the direct iminoquinone formation of
the substrates having an azide side chain developed by us (see Schemes 24 and 27).
On the other hand, in route b, the quinoline ring is first formed, then the pyrrole
ring is closed followed by oxidation of the cyclic amine to give the pyrroloimino-
quinone skeleton (Scheme 4).
Y a
X N HN
route a route b CHO
R3 R3 R3
N N NHR1
b
OR2 R1 O R1 OR2
Scheme 2 Two routes for constructing the pyrroloiminoquinone skeleton
NHPG NHPG
O
oxidation
1)
(KSO3)2NO
MeO N (Fremy′s salt) MeO N
HO CAN etc. deprotection
R1 O R1
N3
N
HN
cyclization oxidation
2)
(KSO3)2NO
(Fremy′s salt) MeO N
MeO N MeO N CAN etc.
1 1 O R1
(MeO) R (MeO) R
N3
N3
PhI(OCOCF3)2
3) +
TMSOTf
MeO N
MeO N (CF3)2CHOH
1 H2O MeO R1
MeO R
Scheme 3 General methods for the pyrroloiminoquinone skeleton by route a

N HN N
oxidation
CHO CAN
MeO NO2
MeO N MeO N
(OMe) (MeO) R1 O R1
Scheme 4 General methods for the formation of the pyrroloiminoquinone skeleton by route b
3 Synthetic Works by Other Groups
3.1 Makaluvamines
Makaluvamines A [44–48], B [44, 48], C [44, 48, 49], D [44, 47, 48, 50–52],
E [44, 46], I [47, 52], and K [47], and N-1-b-D-ribofuranosylmakaluvamine I [52]
have already been synthesized. Most of these syntheses were reported before 2000.
Since 2000, there have been few synthetic works of natural products, while the
studies of the synthesis of their analogs and their biological activity are receiving
much attention.
For the synthesis of the makaluvamine family, most of the synthetic studies have
been done through route a in Schemes 2 and 3 for the construction of the pyrroloi-
minoquinone skeleton. As an example of the synthesis of the makaluvamines by
route a, Yamamura and Nishiyama’s synthesis is shown in Scheme 5. Thus,
Yamamura et al. reported the total synthesis of makaluvamines A–E (Scheme 5).
They started from the indole 5, which was converted to the lactam 6. Makaluva-
mines A, B, and E were synthesized from pyrroloiminoquinone 7, obtained from 6
(R1¼Me, R2¼H) by reduction and oxidation, and by the attack of the proper amino
functions. Makaluvamine C was synthesized from 6 (R1¼H, R2¼Me). Makaluva-
mine D was synthesized from the iminoquinone 8, obtained from 5 (R¼Bn) [44].
The total synthesis of veiutamine [53], which has a carbon side chain and a
structure similar to makaluvamine D, has also been achieved via route a (Scheme 6).
The 6-methoxyindole derivative 9 was converted to the Boc compound 11. Regio-
selective ortholithiation at 6-position using the Boc group as a directing group and
coupling with an aldehyde followed by intramolecular cyclization afforded the
tetracyclic compound 12, which was converted to veiutamine [54].
On the other hand, the synthesis of the makaluvamine family by route b shown in
Schemes 2 and 4 has rarely been reported. Kraus et al. reported the total synthesis of
makaluvamine C (Scheme 7). In their synthesis, the 6,6-bicyclic compound 14 was
formed first. The reduction of 14 then gave the indole 15, which was converted to
makaluvamine C by demethylation and in situ oxidation with Fremy’s salt [49].
We have discovered the inter- and intramolecular nucleophilic addition of
aromatic compounds mediated by hypervalent iodine reagent in CF3CH2OH or
O
R2 +
N HN
TeocHN CO2Et N
1) BH3 • SMe2 NH4Cl
2) CAN / 60 % 90 %
aq.HClO4 MeO N H2N N
MeO N MeO N
60 % O Me O Me
OMe R OMe R1 7
6 makaluvamine A
5 (R = Me, Bn) OH
1) BH3 • SMe2 NH2
2) CAN 97 % 10 % Pd / C
3) NH4OH AcO Δ
HO +
Me + N HN
N N
OH
N N
MeO N H2N N
H2N N H Me
H H 26 % O O
O 8 Me
O
tyramine BF3 • OEt2
92 % makaluvamine C 60 % makaluvamine B
hydrochloride
OH OH
+ +
HN HN
N N N N
H H
O Me OMe
makaluvamine D makaluvamine E
Scheme 5 Total synthesis of makaluvamines A–E
Me2N H2N Boc

Cl N
i
1) Pr(c-Hex)NLi (70 %)
2) Boc2O (96 %)
MeO MeO N MeO N
N
TIPS TIPS TIPS
9 10 11
O 1) H2, Pd / C (93 %)
1) s-BuLi 2) TBAF (99 %)
p-MOMOC6H4CHO 3) Fremy’s salt +
O N HN
(72 %) (33 %)
MOMO HO
2) NaH (86 %) 4) NH4Cl then HCl
(89 %)
MeO N H2N N
H
TIPS O
12
veiutamine
Scheme 6 Total synthesis of veiutamine
(CF3)2CHOH in 1994 (For details, see Scheme 23). In 2006, Nishiyama et al. also
used the hypervalent iodine reagent prepared from iodobenzene under electrolytic
conditions and developed a new method for the synthesis of tetrahydroquinolines
(Scheme 8). Thus, the reaction of the methoxyamide 16 with the active species
Me
O N O N Me Me +
N N
CHO H2, Pd / C TMSCl, NaI
76 % Fremy′s salt
BocHN NO2
BocHN N 73 % H2N N
OMe OMe H H
OMe O
13 14 15 makaluvamine C
Scheme 7 Kraus’s synthesis of makaluvamine C
O O
O PhI
CCE, LiClO4 +
N N
HN CF3CH2OH OMe OMe
OMe
MeO MeO
MeO
16 17
(CCE: Constant Current Electrolysis)
Scheme 8 Synthesis of tetrahydroquinolines using hypervalent iodine reagent
derived from iodobenzene under electrolytic conditions afforded the quinolone-

type product 17 [55].
The reaction was applied to the syntheses of the pyrroloiminoquinones, maka-
luvamines D and I and N-1-b-D-ribofuranosylmakaluvamine I (Scheme 9). The
arylpropionamide 20 was prepared from 3-benzyloxy-2-nitrotoluene (18).
Compound 20 produced the quinolinone 21 when subjected to either the electro-
chemically generated hypervalent iodine or PIFA. Quinolinone 21 was converted to
the aldehyde 22, which gave 23 by the reaction with Zn/AcOH, followed by
treatment with TsCl–NaH and catalytic hydrogenolysis. The oxidation of 23 with
Fermy’s salt produced an a-diketone 24. Exhaustive deprotection of 24 afforded
damirone C. Furthermore, the amination of damirone C provided makaluvamine I.
The coupling of damirone C with tyramine hydrochloride yielded makaluvamine D.
The coupling of 25, which was obtained from 24, with a chloro sugar produced the
desired glycosides 26-b and 26-a in 50% yield as a 23:2 mixture. Removal of the
TBS-protecting group in 26-b afforded 27. N-1-b-D-ribofuranosylmakaluvamine
I was obtained by the ammonolysis of 27 [52].
In 2000, Besson et al. reported the biological activity of several makaluvamine
analogs, which were synthesized by the reaction of five amines and the 7-methoxy-
1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline core. Evaluation of the cytotoxic activ-
ity on the murine L1210 cells afforded IC50 values in the 0.25–5.3 mM range
(Scheme 10) [56].
Since the previously reported 6-acetamidopyrrolo[1,2-a]benzimidazole (APBI)
has a structure similar to the makaluvamines and showed a similar topoisomerase
activity. Skibo et al. prepared the imidazoquinoxaline analogs, which possess the
ethylene tether and an amidine moiety, and are similar to the makaluvamines
(Scheme 11). However, they showed a weaker activity than makaluvamine H [57, 58].
Recently, Velu et al. studied the biological activity of various makaluvamine
analogs with benzylamine- or phenethylamine-type side chains, and revealed that
NO2 1) (CO2Et)2, NaH NO2 CO2Me

1) TFA, Et3SiH
BnO Me 2) NaOH, H2O2 CO2tBu
BnO
2) NH2OMe • HCl
3) H2SO4, MeOH
EDCl, HOBt,
4) BrCH2CO2tBu 19 Et3N
18
NO2 CO2Me
NO2 CO2Me
BnO PhI BnO
CONHOMe
CCE at 10 mA
LiClO4, CF3CH2OH 62 % N O
20
21 OMe
Ts
NO2 CHO 1) Zn, AcOH 51 % N
BnO 2) TsCl, NaH 85 % HO Fremy′s salt
21 3) H2, Pd / C, EtOAc THF / pH 7 phosphate
N 99 % N buffer 99 %
Boc Boc
22 23
HN
O
Ts
N HN known
1) TFA +
O quant. O H2N N
H
2) KOH makaluvamine I
O N MeOH O N
Boc 83% H HN
24 damirone C HO O
+
N N
H H
makaluvamine D
TBSO
O NBoc TBSO
Cl O O
TBSO N O
HN O O
N O
O O O O
KOH O
24 +
68 % NaH, 18-crown-6,
NBoc
O N DMF 50 % (β : α = 23 : 2) O O 26-β 26-α
25 Boc
NBoc N
TFA, 40 °C HO NH3, MeOH HO

26-β
99 % O N O
48 % O
N NH2
O O
HO OH 27 HO OH
N-1–b-D-ribofuranosylmakaluvamine I
Scheme 9 Syntheses of the pyrroloiminoquinones, makaluvamines D and I and N-1-b-D-

ribofuranosylmakaluvamine I
CF3CO2– +
HN N HN
CAN 1) RNH2
2) TFA
MeO N MeO N RHN N
H H H
OMe O O
28 8 29
- IC50 (μM) IC50 (μM)

CF3CO2 +
HN makaluvamine D R=
(R = 4-HOC6H4CH2CH2) 2.1 5.3
N
H
makaluvamine I (R = H) 0.25 +
RHN N Me2HN 0.3
H
O H
+
N 0.38
Scheme 10 Makaluvamine analogs by Besson
H3C O
X N N
N N or N
O CH3 R2HN
H 3C N H2N N R1 N
O O O 32
30 O 31
1
R = H or CH2OCH3 R2 = PhCH2CH2, HOCH2CH2
X = NH2+, imino APBI
PhCH2, 4-HOC6H4CH2CH2
X = O, APBI OMs
MeO
HN
1) Fuming HNO3 HN 1) Fremy′s salt N
O2 N NO2 1) H2, Pd / C pH 7
2) ethanolamine 2) HCO2H or
N 2
N
3) MsCl, Py. (MeOCH2CO)2O 2) R NH3Cl
3) 4N HCl X N Y N R1
X R1 (X = OMe)
33 X 34 35 O 36
X = OMe X = OMe X = OMe
Y = NH2, NHR2
NAc2 NHAc NH2
Scheme 11 Imidazoquinoxaline analogs by Skibo
compounds having small side chains with an electron-withdrawing group showed a

high anticancer activity against various cancer cell lines (Fig. 5) [59–62]. In 2008,
Passarella et al. carried out a similar study using N1–Me analogs [63].
3.2 Isobatzellines
Isobatzellines A [64], B [64], and C [48, 65] have already been synthesized. Most of
the syntheses of the isobatzellines were reported before 2000. After 2000, few
synthetic studies of the natural products have been carried out.
CF3CO2- CF3CO2-
+ +
HN HN
R = 4-CH3, 4-OCH3, 3,4-Di-OCH3
R R 3,4,5-Tris-OCH3, 3,4-OCH2O
N N 4-Cl, 4-F etc.
N N
H H H H
O O
37 38
Fig. 5 Makaluvamine analogs by Velu
OHC OHC
N N N
1) MeI, NaH (99 %)
2) (MeS)2, SO2Cl2 (98 %)
CHO
MeO NO2 MeO N MeO N SMe

H
OMe OMe OMe Me
39 40 41
N N
1) NaOH aq.
2) CAN Cl
3) NHCl4
H2N N SMe H2N N SMe
93 %
O Me O Me
isobatzelline B isobatzelline A
Scheme 12 Synthesis of isobatzellines B and A
Scheme 12 shows the synthesis of isobatzellines A and B, having a sulfur

function, by Alvarez and Joule et al. in 1999. After N-1-methylation of the tricyclic
indole 40, the crucial electrophilic substitution by dimethyl disulfide afforded 41.
The hydrolysis of 41 followed by CAN oxidation, then replacement of the
7-methoxy group with an amino group, gave isobatzelline B. By a similar proce-
dure, they also synthesized isobatzelline A [64].
3.3 Bispyrroloiminoquinones
There have been few synthetic studies of the wakayin and tsitsikammamine alka-
loids. Model synthetic studies of them were reported by Cave [66] and Barret [67]
more than 10 years ago and, recently, several new synthetic studies have appeared.
Velu et al. reported the regioselective synthesis of the bispyrroloquinone and
bispyrroloiminoquinone ring system found in the wakayin and tsitsikammamine
alkaloids. First, they accomplished the synthetic route to the bispyrroloquinone
system (Scheme 13). The treatment of N-tosyl-6-(benzylamino)-1H-indole-4,7-
dione 42 with ethyl acetoacetate or 1-phenylbutane-1,3-dione in the presence of
ceric ammonium nitrate (CAN) in MeOH/CH2Cl2 resulted in the formation of the
O O O O O
CH3COCH2COR R R
(R = OEt, Ph) NaOEt
Bn CAN EtOH
N N Me N N Me N N
H MeOH / CH2Cl2
O Ts Bn O Ts Bn O H
42 43 44
R = OEt (58 %) R = OEt (71 %)
R = Ph (67 %) R = Ph (86 %)
O O
Pd black R
R = OEt (75 %)
HCOONH4
Me R = Ph (74 %)
EtOH N N
H O H
45
Scheme 13 Synthesis of bispyrroloquinone ring system
N O N
EtO
CH3COCH2COOEt
Bn CAN Me
N N N N
H MeOH / CH2Cl2
O R Bn O R
Scheme 14 Synthesis of 46 47
bispyrroloiminoquinone ring R = Ts R = Ts (38 %)
system R=H R = H (41 %)
bispyrroloquinone derivative 43. This cyclization reaction proceeded via an

oxidative free radical mechanism. Removal of the tosyl group in 43 and deben-
zylation then afforded the bispyrroloquinone 45. The same synthetic methodology
afforded the bispyrroloquinone ring system present in wakayin and the tsitsikam-
mamines (Scheme 14) [68].
In 2006, Delfourne et al. reported the syntheses of two aza-analogs of wakayin
and tsitsikammamines A and B based on a 1,3-dipolar cycloaddition reaction
between the indole-4,7-dione 48 and a diazo-aminopropane derivative 49
(Scheme 15). One of the two analogs partially inhibits human topoisomerase I,
whereas the synthetic intermediates inhibit the enzyme DNA cleavage activity at a
concentration comparable to that of the control drug camptothecin [69, 70].
In 2009, Delfourne et al. reported the first total synthesis of tsitsikammamine
A [71]. The reaction of 54 with a quinone 55 gave two regioisomers 56 and 57.
The treatment of 56 with trifluoroacetic acid caused the formation of the second
five-membered nitrogen ring and the cleavage of the Boc protective group, then
oxidation with MnO2 gave the bispyrroloquinone derivative, and the subsequent
cyclization gave the corresponding iminoquinone 58. The tosyl group of 58 was
NHCO2C6H4-4-OMe NH2 NH2

O
O Ts O
1) THF, rt
2) pTsCl , KOH N
+
+ N+
N 3) TFA , m-cresol N N
N– N N N
Ts O
Ts O Ts O Ts
48 49 50 51
1) EtOH,NaHCO3, H N
N
4 A°molecular
N
sieve, reflux +
2) 1 N NaOH, N N
dioxane, rt N N N
H O H O H
52 (70 : 30) 53
Scheme 15 Synthesis of aza-analogs of wakayin and tsitsikammamines A and B
OMe
NHBoc MeO NHBoc NHBoc
O
O O
H
OH N
+ +
OH N
N N OH N
NH2 O Ts H
O Ts O Ts
54 55 MeO
56 (19 %) 57 (57 %)
MeO HO
N N
1) TFA 1) 1 N NaOH
56
2) MnO2 2) BBr3
3) abs . EtOH N N N N
4 A° molecular H H H
O Ts O
sieve, reflux 29 %, 2 steps
22 %, 3 steps 58 tsitsikammamine A
N N
H H
N N
1) TFA 1) 1N NaOH
57
2) MnO2 N 2) BBr3 N
3) abs . EtOH H
O Ts O
4 A° molecular 28 %, 2 steps
sieve, reflux 59 HO
MeO isomer of tsitsikammamine A
16 %, 3 steps
Scheme 16 Synthesis of tsitsikammamines A
removed by 1 N NaOH treatment, and demethylation using BBr3 afforded the free
base of tsitsikammamine A. A similar procedure gave the nonnatural regioisomer
from compound 57 (Scheme 16).
3.4 Discorhabdins
Discorhabdin alkaloids have the richest structure-diversity among the marine

pyrroloiminoquinone alkaloids, and new discorhabdins are still being discovered.
Although many synthetic studies have been carried out, only a few total syntheses
of the natural discorhabdins have been reported. The total synthesis of discorhabdin
C was accomplished by our group and Yamamura’s group at almost the same time,
and later by the Heathcock group. Heathcock et al. also synthesized discorhabdin E
at the same time. Those discorhabdins are rather simple. The more complex
discorhabdins, discorhabdin A and prianosin B, were synthesized only by us.
Scheme 17 shows the final steps of each synthesis of ()-discorhabdin C. For the
details of our synthesis, see Sect. 4. In Yamamura’s synthesis, discorhabdin C was
obtained in 24% yield upon anodic oxidation of the bromophenol derivative 60
(R¼H) [72, 73]. In Heathcock’s synthesis, discorhabdin C was obtained by a
phenolic coupling reaction of 60 (R¼Ts) with CuCl2 and Et3N under bubbling O2
followed by detosylation [74].
Scheme 18 shows Heathcock’s total synthesis of ()-discorhabdin E by the
same procedure as discorhabdin C [74]. The reaction of the imine 62, derived from
61, and o-bromotyramine furnished 63. The treatment of 63 with three equivalents of
CuCl2 and four equivalents of Et3N under bubbling O2 gave the N-tosyldiscorhabdin
E 64, the detosylation of which with NaOMe resulted in the formation of ()-
discorhabdin E.
In 2005, Munro et al. discovered discorhabdin W, the dimer of discorhabdin B.
At the time, they correlated discorhabdin W with discorhabdin B. Thus, reduction
of discorhabdin W with dithiothreitol gave the expected thiol 65, which was
OTMS
Kita et al. Br Br
1) MeCH=C(OMe)OTMS,CH2Cl2 N
2) PIFA, CF3CH2OH (42 %)
R=H N N
(PIFA: PhI(OCOCF3)2) H H
I O
Ph
OH OCOCF3 O
Br Br Br Br
Yamamura et al.
N N
LiClO4, CCE at 3 mA (24 %)
R=H
N N N N
H R H H
O O
60 Heathcock et al. discorhabdin C

1) CuCl2, Et3N, O2, CH3CN (81 %)
2) MeONa, MeOH (77 %)
R = Ts
Scheme 17 Final steps of the synthesis of ()-discorhabdin C

NHBoc OH
Br
O N
NaHCO3, EtOH N
TFA o -bromotyramine . HCl
CH2Cl2 2 steps 46 %
MeO N MeO N N N
O Ts O Ts H
O Ts
61 62 63
O O
Br Br
CuCl2, Et3N, O2 N N
NaOMe, MeOH
CH3CN 67 %
84 %
N N N N
H H H
O Ts O
64 (±)-discorhabdin E
Scheme 18 Total synthesis of ()-discorhabdin E
O O O
Br Br Br
HS
N N reduction N
S S N S
H 65
N N N N N N
H H H H sun light H
O O H
O
uncharacterized
discorhabdin W discorhabdin B
degradation
products
Scheme 19 Correlation of discorhabdin W and discorhabdin B
spontaneously converted to discorhabdin B. Conversely, irradiation of discorhabdin

B with sunlight afforded discorhabdin W (Scheme 19) [31].
In 2006, Copp et al. reported the semi-synthesis of discorhabdins P and U from
the natural discorhabdins C and B (Scheme 20). Discorhabdin C was reacted with
CH3I in dry acetone to yield discorhabdin P in 54% yield. Discorhabdin B was
reacted with CH3I in dry acetone to yield two products, discorhabdin U and 66. The
order of the methylation of discorhabdin B preferentially favors the thio group, and
a large excess of CH3I enables the methylation at the N-13 pyrrole position [75].
4 Our Synthetic Studies
4.1 Discorhabdin C
We synthesized discorhabdin C in 1992 [38]. For the total synthesis of discorhabdin

C, two approaches were studied (Scheme 21). One approach involves the imine
O – O
CF3CO2
Br Br Br Br
+
HN N
MeI, K2CO3
acetone
N N 90 °C, 4 h
N N
H H 54 % H
O O Me
discorhabdin C
discorhabdin P
O O O
–
Br CF3CO2 Br Br
+ +
HN HN HN
MeI, K2CO3 MeS
S MeS
acetone
80 °C, 3 h +
N N N N N N
H H H
H H H
O O Me O
discorhabdin B discorhabdin U (39 %) 66 (22 %)
Scheme 20 Semi-synthesis of discorhabdin P and U
O O OH
NHR
Br Br Br Br Br Br
O N N
route a route b
N N N N N N
H H H H H H
O O O
67 discorhabdin C 68
Scheme 21 Two retrosynthetic analysis for discorhabdin C
formation as the final step of the synthesis (route a). Another approach involves the
oxidative coupling of the indoloquinone imine as the final step (route b).
Unfortunately, all attempts to effect the final imine formation between the trypt-
amine nitrogen and the indoloquinone carbonyl in these types of intermediates failed
(route a in Scheme 21). We then studied an alternative approach (route b), in which
the phenolic coupling of the previously produced aminoindoloquinone imine is
employed in the final step, to accomplish the first total synthesis of discorhabdin C.
The benzaldehyde derivative 69 was converted to the indoloquinone 70. The direct
imine formation from the indoloquinone was achieved by protection of the indolo-
quinone nitrogen of 70 with the tosyl group followed by an acidic dehydrative
treatment to yield an unstable indoloquinone imine 72, which was subjected to the
following one-pot transformation without further purification.
The reaction of the indoloquinone imine 72 with 3,5-dibromotyramine hydro-
bromide caused a facile substitution reaction and subsequent detosylation to give the
O NHTEOC
OH O NHTEOC
CHO p-TsOH
TsCl
MeO N t-BuOK CH3CN
H MeO N
MeO O 92 % Ts
69 O
70 (TEOC = CO2 (CH2)2SiMe3) 71
OH
O
Br Br
N Br Br
3, 5-dibromo- N N
tyramine 1) silylation
Et3N, EtOH 2) PIFA
MeO N 51 % CF3CH2OH
N N
Ts H N N
O H 42 % H
O H
72 68 O
discorhabdin C
Scheme 22 Total synthesis of discorhabdin C via route b
OH O
Br Br
N N
S S
N N H N N
H H H H
Fig. 6 Makaluvamine F and O O
discorhabdin A makaluvamine F discorhabdin A
phenolic aminoindoloquinone imine 68. The conversion of 68 into its corresponding

silyl ether and the subsequent oxidative coupling reaction using PIFA gave rise to
discorhabdin C (Scheme 22) [38].
4.2 Development of Methods for the Synthesis of Complex

Pyrroloiminoquinone Alkaloids
Among the makaluvamines, makaluvamine F exhibits the most potent biological

activity (e.g., cytotoxicity towards the human colon tumor cell line HCT-116
(IC50 ¼ 0.17 mM) and inhibition of topoisomerase II). It has a labile N, S-acetal
moiety for oxidation, etc. Synthetic efforts by several groups then resulted in only
diverse preparations of the pyrroloiminoquinone unit. For the synthesis of more
complex pyrroloiminoquinone alkaloids such as makaluvamine F and discorhabdin
A (Fig. 6), we intended to develop several mild reactions.
The new methods (Schemes 23–25) valuable for the synthesis of complex
pyrroloiminoquinone alkaloids are based on the hypervalent iodine-induced nucle-
ophilic substitution of p-substituted phenol ethers via reactive cation radical inter-
mediates. Thus, we found a novel hypervalent iodine induced nucleophilic
substitution of p-substituted phenol ethers in the presence of a variety of nucleo-
philes, such as TMSN3, TMSOAc, and b-diketones, etc., in 1994. For this reaction
the reaction solvent was quite important, and CF3CH2OH and (CF3)2CHOH worked
very well (Scheme 23) [76].
–
OCOCF3
OMe OMe
Ph OCOCF3
PhI(OCOCF3)2 I
Nu
(PIFA) SET Nu–
MeO R MeO + R
(CF3)2CHOH
R CT-complex cation radical PhI R
74
73
Nu = N3, OAc, O O
etc.
Scheme 23 Hypervalent iodine-induced nucleophilic substitution of p-substituted phenol ethers
R1
RO
RO
R2
(MeO)n N
76 R3
R1 R1
OR = OMe, OEt, Oi-Pr
MeO PIFA, TMSOTf MeO O(CH2)2O (51-94 %)
R2 + R2
CF3CH2OH / ROH – R1
N3 R3 N R3
(MeO)n (MeO)n O
75 N2+
R2
(MeO)n N
R3
77
(57-89 %)
Scheme 24 Synthesis of quinone imine dimethylacetals and quinone imines
MeO PIFA MeO

( )n BF3.Et2O ( )n aq. MeNH2 MeO ( )n
+
R1 S R 3 CH2Cl2 R1 S R3 R 1 S R3
R2 -78 °C R2
Bn Bn R2
78 n = 1-3
79 (53-98 %)
Scheme 25 Intramolecular cyclization of phenyl ethers bearing an alkyl sulfide side chain
R1 PhI = O R1 R1 R1
TMSN3
+ +
R2 S MeCN R2 S H R2 N3
S R2 S
R3 3
R I R3 –
R3
Ph N3
80 OTMS 81 82
R1 = OMe, Br, H OTMS N3

R2 = OMe, OAc, H
R3 = OMe, H
PhI=O + 2TMSN3 Ph I Ph Ι
N3 N3
Scheme 26 Synthesis of a-azidodihydrobenzothiophene derivatives
The treatment of phenyl ethers 75 with an alkylazido group in the presence of

PIFA–TMSOTf in (CF3)2CHOH/ROH or CF3CH2OH/ROH gave the corresponding
quinone imine dimethylacetals 76, which in (CF3)2CHOH/H2O or CF3CH2OH/H2O
gave the corresponding quinine imines 77 (Scheme 24) [77, 78].
We next attempted to synthesize the a-azidodihydrobenzothiophenes, which can
serve as an N,S-acetal equivalent, by the introduction of an azido group to the
dihydrobenzothiophene derivatives. We first developed the new intramolecular
cyclization of phenyl ethers 78 bearing an alkylsulfide group using PIFA in
(CF3)2CHOH and PIFA–BF3·Et2O in CH2Cl2 that specifically proceeded to give
the corresponding sulfur-containing heterocycles 79 via the radical cation
(Scheme 25) [79].
After considerable effort, the sulfonium cation initially formed by the reaction of
the sulfide 80 with PhI¼O/Me3SiN3 is then deprotonated to give a cation interme-
diate 81. The azide anion attacks the a-position of 81 to produce the a-azide sulfide
82 (Scheme 26) [80].
4.3 Makaluvamine F
Having new mild reactions for synthesizing makaluvamine F in hand, we tried to

synthesize makaluvamine F (Scheme 27). The reactions of the N-protected indoles
83 with PIFA–TMSOTf in the presence of H2O afforded the corresponding N-
deprotected pyrroloiminoquinones 8. The treatment of the phenol ether 84 bearing
an alkyl sulfide side chain with PIFA–BF3·Et2O followed by the treatment with aq.
MeNH2 provided 5-bromo-6-benzyloxydihydrobenzothiophene 85. Although azi-
dation of 85 gave only a trace amount of the expected a-azido compound, treatment
of the acetylated compound with PhI¼O and Me3SiN3 followed by hydrolytic
deprotection provided the 2-azido-5-bromo-6-hydroxydihydrobenzothiophene 86.
Catalytic hydrogenation of 86 using 10% Pd-C in the presence of four equivalents
of trifluoroacetic acid (TFA) resulted in complete reduction leading to a TFA salt 87
in quantitative yield. The final coupling reaction in MeOH between both synthetic
N3 N
PIFA
TMSOTf
(±)-makaluvamine F
(CF3)2CHOH / 86 %
MeO N MeO N
H2O (50:1) H
MeO O Br
Ac
51% 8
83
+
HO
(quant.) S NH3
87 CF3CO2–
10 % Pd / C,
EtOH / CF3CO2H
Br 1) PIFA 1) BF3 • Et2O, EtSH
BF3•Et2O 2) Ac2O Br
BnO S 2) aq. MeNH2 3) PhI = O, TMSN3

66 % S HO
4) NaOH / MeOH S N3
84 Bn 85
34 % 86
Scheme 27 Total synthesis of ()-makaluvamine F
precursors, 87 and 8, proceeded to give the TFA salt of makaluvamine F

(Scheme 27) [39, 40].
4.4 Total Synthesis of Discorhabdin A
In 1987, prianosin A [22] was isolated from the Okinawan sponge Prianos melanos
by Kobayashi et al. and, in 1988, discorhabdin A [23] was isolated from New
Zealand sponges of the genus Latrunculia by Munro et al. Some years later, it was
found that prianosin A and discorhabdin A were the same compound. Discorhabdin
A (prianosin A) has a strong cytotoxicity (IC50 values of 37, 14, 40, and 13 ng/mL
against L1210, L5178Y, P388, and xrs-6 in vitro, respectively, and ED50 values of
50 ng/mL against P388) and shows antimicrobial activity. Discorhabdin A has a
unique sulfur-containing fused ring system incorporating azacarbocyclic spirocy-
clohexanone and pyrroloiminoquinone systems, and shows the most powerful
cytotoxic activity among the isolated discorhabdins.
First, on the basis of the hypothesis by Munro and co-workers shown in
Scheme 1, we examined the biosynthetically plausible route from makaluvamine
F using our previously developed oxidative spirocyclization reaction with PIFA. As
a result, the oxidative cyclization of makaluvamine F as well as the trimethylsily-
lated makaluvamine F using PIFA under various conditions yielded a complex
mixture, probably due to the high reactivity of the iodine(III) reagent toward the
sulfide (Scheme 28).
We then altered the synthetic strategy. The new strategy included the precon-
struction of the spirodienone system using the hypervalent iodine(III) reagent and
the final introduction of the sulfur group to the cross-linked system. Scheme 29
shows the synthesis of the spirodienone in discorhabdin A. The tritylation of the
OH O
Br Br
N N
spiro-
S S
cyclization
N N H N N
H H H H
O O
makaluvamine F discorhabdin A
Scheme 28 Synthetic approach to discorhabdin A from makaluvamine F
OH OTBS
OH
Br 1) DIBAH Br
1) TrCl, Et3N 1) 0.1 N HCl / MeOH
2) TBSCl, DBU
2) NBS, DMF 2 steps 84 % N
2)
NHTr NHTr
NH2 . HCl 2 steps 65 %
CO2Me MeO N
89 67 %
88 CO2Me OTBS O
90 Ts
91
OH O O
Br Br Br
N PIFA N N
MK10 +
CF3CH2OH 6S
49 %
N N N N N N
H H H
TBSO O Ts TBSO O Ts TBSO O Ts
92 93 94
4.8 : 1
Scheme 29 Synthesis of spirodienone
L-tyrosine methyl ester hydrochloride 88 with TrCl and Et3N followed by mono-
bromination with NBS yielded 89 (two steps, 65% yield). The reduction of 89
with DIBAH followed by silylation of the resulting alcohol with TBSCl gave the
bis-silylated compound 90, and a coupling reaction with pyrroloiminoquinone 91,
which was prepared by our previously developed PIFA-induced pyrroloiminoqui-
none formation (see Scheme 27), yielded 92. The spirodienone formation of 92
using PIFA effectively proceeded in the presence of montmorillonite K10 (MK10)
to give a diastereomeric mixture of 93 and 94. Both diastereomers were readily
separated by column chromatography on silica gel. The major isomer 93 has the
same absolute stereochemistry (S configuration) of the spirocenter (C-6) as that of
the natural discorhabdin A (Scheme 29).
In our total synthesis of discorhabdin A, the N,O-acetal compound 96 acted as a
key compound for the construction of the N,S-acetal compound (see Scheme 31),
and was prepared by the oxidative fragmentation reaction of an a-amino alcohol 95
initially using the highly toxic lead tetraacetate. We then developed a new method
using the low toxic hypervalent iodine(III) reagent. Thus, the reaction of the
a-amino alcohol 95, obtained from 93 by desilylation (see Scheme 31) and bis-
(trifluoroacetoxy)iodo(III) pentafluorobenzene (C6F5I(OCOCF3)2) in the presence
of NaHCO3, afforded the N,O-acetal compound 96 in 79% yield, maybe through the
five-membered ring intermediate (Scheme 30) [81].
Desilylation of 93 followed by an oxidative fragmentation reaction with C6F5I
(OCOCF3)2 and MeOH gave the N,O-acetal intermediate 96. The p-methoxyben-
zylthio group was efficiently introduced in the presence of BF3·Et2O to give the
unstable N,S-acetal 97 as a diastereomeric mixture. The treatment of 97 with 30%
HBr–AcOH followed by aqueous work up with MeNH2 produced the N-tosylated
discorhabdin A 98. Ultimately, we developed an efficient one-pot transformation
procedure yielding 98 from 96. Finally, removal of the tosyl group of 98 with
NaOMe in THF gave discorhabdin A in the optically pure form. The synthetic
product as its HCl salt was identical in all respects with the natural discorhabdin A
including its optical rotation (Scheme 31).
O O
Br C6F5I(OCOCF3)2 Br
N NaHCO3 N
CH3CN/MeOH
N
N N O I MeO N N
H C6F5 H
HO O Ts O Ts
95 79 %
96
Scheme 30 Facial formation of N,O-acetal 68
O O
Br Br
N 1) BF3 • Et2O N p-MeOBnSH
6S 2) C6F5I (OCOCF3)2 CH2Cl2
NaH CO3, MS3A –78 ~ 4 °C
8S N N CH3CN/MeOH MeO N N
H 2 steps 70% H
TBSO O Ts O Ts
93
96
O O
O
Br Br
Br
N N
HBr / AcOH NaOMe
S S
then THF / MeOH
aq. MeNH2 61 %
p-MeOBnS H N N H N N
N 22 % H H
H H O
O Ts
97 98 (+)-discorhabdin A
Scheme 31 Total synthesis of (+)-discorhabdin A

OTBS O O
Br PIFA Br Br
N MK10 N
(D)-88 • HCl R
CF3CH2OH S
N N N N N
H
H H H H
TBSO O Ts TBSO O
ent-93
ent-92 diastereomeric mixture (–)-discorhabdin A
(R : S = 4.8 : 1) [α]D-390
Scheme 32 Total synthesis of ()-discorhabdin A
We also completed the total synthesis of the unnatural discorhabdin A, ()-

discorhabdin A, starting from the D-tyrosine methyl ester by the same route as
described for (+)-discorhabdin A (Scheme 32).
4.5 Prianosin B
Prianosin B is the oxidized discorhabdin A, whose C16–17 bond is double bond. We

found that the detosylation and dehydrogenation reaction of the pyrroloiminoquinone
unit proceeded using a catalytic amount of NaN3 in good yield. We then applied the
reactions to the total synthesis of prianosin B (Scheme 33). Thus, the treatment of 98
O
Br N N
N + –
NaN3 (cat.) 15 N N N Ts
S
DMF
N
70 °C, 1 h TsN3 N
N –
H N 48 % O Ts
H O
–
O Ts I
N3
98
H
H O
N – N
16 NTs Br
N N * N
S
N N
-N3–
O O N N
II III H
H H
O
prianosin B
*
H O O
– +
N N N Ts –
N N N S C6H4CH3 N3– + S
H OH
–O A
Scheme 33 Total synthesis of (+)-prianosin B

(see Scheme 31) with NaN3 in DMF at 70 C caused detosylation and dehydrogena-
tion to produce prianosin B in 48% yield. The reaction mechanism for the dehydro-
genation reaction of pyrroloiminoquinone using NaN3 may be as follows. The
nucleophilic attack of N3 on the tosyl residue followed by the addition of metallated
enamine to TsN3 produces the intermediate II. Dehydrogenation would proceed by
the intramolecular elimination via a six-membered transition state to produce the
intermediate III and isomerization to produce prianosin B. Regeneration of the
azide anion during the reaction makes possible the use of catalytic amount of
NaN3. The reproduction of the azide anion was deduced from the presence of the
toluenesulfinic acid observed in the 1H-NMR spectrum [43].
However, Velu et al. reported that treatment of the pyrroloiminoquinone under
the same reaction conditions except for the reaction temperature gave only the
detosylated product. This shows that the reaction temperature is very important for
the dehydrogenation (Scheme 34) [82].
N N
NaN3 (1.2 eq.)
DMF or MeOH
R N 25 °C, 4 h R N
53-84 % H
O Ts O
99 100
R = OMe or
NH(CH2)1–2Ar
Scheme 34 Detosylation by N3
4.6 Discorhabdin A Analogs
We recently prepared several discorhabdin A analogs aiming at more stable com-

pounds, because discorhabdin A exhibits a strong cytotoxic activity in vitro, but it
shows no activity in vivo due to the instability of its highly strained N, S-acetal
structure. We then designed analogs of discorhabdin A which have a strong
cytotoxic activity and stability. We prepared various stable discorhabdin A oxa
analogs 101 with the oxygen cross-linked spiro fused ring system, and examined
their antitumor activities in vitro against five kinds of tumor model cells, WiDr,
HCT-116, DU-145, P388, and L1210. As a result, all the oxa analogs exhibited
good IC50 values. Especially 102a and its regioisomer 103a gave the best results.
Their IC50 values against HCT-116 (0.04 mM, 0.05 mM) are almost the same as
those of discorhabdin A (0.03 mM). To our surprise, their IC50 values against
L1210 (0.01 mM, 0.02 mM) are stronger than that of discorhabdin A (0.06 mM)
(Scheme 35) [83].
Concept of analogue synthesis

O O
Br R1 R2
N N
S O *
*
N N N N
H * H
H H R3
O O
Oxa analogues of
Discrhabdin A discorhabdin A
S atom O atom
5-membered ring 6-membered ring
O O O
X X
N N N
O O O
N N N N N N
H H H
O Ts O Ts O Ts
101 102a-c 103a-c
(a X = Br; b X = Cl; c X = I)
Scheme 35 Discorhabdin A oxa analogs
5 Conclusion
Marine organisms produce many types of biologically active compounds. As shown

here, sponges give us pyrroloiminoquinone and related metabolites, most of which
exhibit strong cytotoxicity towards tumor human cell lines. Furthermore, they have
unique structures different from the biological compounds isolated from land-
dwelling creatures. Then they are recognized as lead compounds for developing
new anticancer drugs. Although synthetic studies of rather simple pyrroloimino-
quinones such as makaluvamines, isobatzellines, and their analogs have already
been carried out by many groups, only a few total syntheses of more complex ones
such as discorhabdins, tsitsikammamines, and wakayin have appeared over the past
decade. However, many synthetic studies of such alkaloids have also been reported.
We hope that the studies of the structure–activity relationship and the mode of
action of alkaloids here and their analogs would reach good anticancer drugs.
References
1. Carté BK (1996) Biomedical potential of marine natural products. BioScience 46:271–285

2. Faulkner DJ (1992) Biomedical uses for natural marine chemicals. Oceanus 35:29–35
3. Faulkner DJ (1984) Marine natural products: metabolites of marine algae and herbivorous
marine mollusks. Nat Prod Rep 1:251–280
4. Barasch D (1990) Fishing for drugs. Am Health 9:20–21
5. Cohen T (1993) Pharmaceuticals from the sea. Technol Rev 96:15–16
6. Urban S, Hickford SJH, Blunt JW, Munro MHG (2000) Bioactive marine alkaloids. Curr Org
Chem 4:765–805
7. Harayama Y, Kita Y (2005) Pyrroloiminoquinone alkaloids. Discorhabdins and makaluvamines.
Curr Org Chem 9:1567–1588
8. Antunes EM, Copp BR, Davies-Coleman MT, Samaai T (2005) Pyrroloiminoquinone and
related metabolites from marine sponges. Nat Prod Rep 22:62–72
9. Delfoune E (2008) Analogues of marine pyrroloiminoquinone alkaloids: synthesis and
antitumor properties. Anticancer Agents Med Chem 8:910–916
10. Monks A, Scuderio DA, Skehan P, Shoemaker RH, Paull KD, Hose VC, Langley J, Cronise P,
Vaigro-Wolff A, Grey-Goodrich M, Campball H, Boyd MR (1991) Feasibility of a high-flux
anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer
Inst 83:757–766
11. Carney JR, Scheuer PJ, Kelly-Borges M (1993) Makaluvamine G, a cytotoxic pigment from
an Indonesian sponge Histodermella sp. Tetrahedron 49:8483–8486
12. Schmidt EW, Harper MK, Faulkner DJ (1995) Makaluvamines H-M and damirone C from the
Pohnpeian Sponge Zyzzya fuliginosa. J Nat Prod 58:1861–1867
13. Venables DA, Concepción GP, Matsumoto S, Barrows LR, Ireland CM (1997) Makaluvamine
N: a new pyrroloiminoquinone from Zyzzya fuliginosa. J Nat Prod 60:408–410
14. Radisky DC, Radisky ES, Barrows LR, Copp BR, Kramer RA, Ireland CM (1993) Novel
cytotoxic topoisomerase II inhibiting pyrroloiminoquinones from Fijian sponges of the genus
Zyzzya. J Am Chem Soc 115:1632–1638
15. Casapullo A, Cutignano A, Bruno I, Bifulco G, Debitus C, Gomez-Paloma L, Riccio R (2001)
Makaluvamine P, a new cytotoxic pyrroloiminoquinone from Zyzzya cf. fuliginosa. J Nat Prod
64:1354–1356
16. Keyzers RA, Samaai T, Davies-Coleman MT (2004) Novel pyrroloquinoline ribosides from
the South African latrunculid sponge Strongylodesma aliwaliensis. Tetrahedron Lett 45:
9415–9418
17. Sun HH, Sakemi S, Burres N, McCarthy P (1990) Isobatzellines A, B, C, and D. Cytotoxic and
antifungal pyrroloquinoline alkaloids from the marine sponge Batzella sp. J Org Chem
55:4964–4966
18. Chang LC, Otero-Quintero S, Hooper JNA, Bewley CA (2002) Batzelline D and isobatzelline
E from the Indopacific sponge Zyzzya fuliginosa. J Nat Prod 65:776–778
19. Copp BR, Ireland CM (1991) Wakayin: a novel cytotoxic pyrroloiminoquinone alkaloid
from the Ascidian Clavelina species. J Org Chem 56:4596–4597
20. Hooper GJ, Davies-Coleman MT, Kelly-Borges M, Coetzee PS (1996) New alkaloids from
a South African latrunculid sponge. Tetrahedron Lett 37:7135–7138
21. Antunes EM, Beukes DR, Kelly M, Samaai T, Barrows LR, Marshall KM, Sincich C,
Davies-Coleman MT (2004) Cytotoxic pyrroloiminoquinones from four new species of
South African latrunculid sponges. J Nat Prod 67:1268–1276
22. Kobayashi J, Cheng JF, Ishibashi M, Nakamura H, Ohizumi Y, Hirata Y, Sasaki T, Lu H,
Clardy J (1987) Prianosin A, a novel antileukemic alkaloid from the okinawan marine sponge
Prianos melanos. Tetrahedron Lett 28:4939–4942
23. Perry NB, Blunt JW, Munro MHG (1988) Cytotoxic pigments from New Zealand sponges of
the genus Latrunculia: discorhabdins A, B and C. Tetrahedron 44:1727–1734
24. Perry NB, Blunt JW, Munro MHG (1988) Discorhabdin D, an antitumor alkaloid from the
sponges Latrunculia brevis and Prianos sp. J Org Chem 53:4127–4128
25. Reyes F, Martin R, Rueda A, Fernandez R, Montalvo D, Gomez C, Sanchez-Puelles JM
(2004) Discorhabdins I and L, cytotoxic alkaloids from the sponge Latrunculia brevis. J Nat
Prod 67:463–465
26. Dijoux MG, Gamble WR, Hallock YF, Cardellina JH II, Soest R, Boyd MRA (1999)
New discorhabdin from two sponge Genera. J Nat Prod 62:636–637
27. Ford J, Capon RJ (2000) Discorhabdin R: a new antibacterial pyrroloiminoquinone from two
Latrunculiid marine sponges, Latrunculia sp. and Negombata sp. J Nat Prod 63:1527–1528
28. El-Naggar M, Capon RJ (2009) Discorhabdins revisited: cytotoxic alkaloids from Southern
Australian marine sponges of the genera Higginsia and Spongosorites. J Nat Prod 72:
460–464
29. Cheng J, Ohizumi Y, W€alchli MR, Nakamura H, Hirata Y, Sasaki T, Kobayashi J (1988)
Prianosins B, C, and D, novel sulfur-containing alkaloids with potent antineoplastic activity
from the Okinawan marine sponge Prianos melanos. J Org Chem 53:4621–4624
30. Gunasekera SP, Zuleta IA, Longley RE, Wright AE, Pomponi SA (2003) Discorhabdins S, T,
and U, new cytotoxic pyrroloiminoquinones from a deep-water caribbean sponge of the genus
Batzella. J Nat Prod 66:1615–1617
31. Lang G, Pinkert A, Blunt JW, Munro MHG (2005) Discorhabdin W, the first dimeric
discorhabdin. J Nat Prod 68:1796–1798
32. Blunt JW, Munro MHG, Battershill CN, Copp BR, McCombs JD, Perry NB, Prinsep M,
Thompson AM (1990) From the Antarctic to the antipodes: 45 of marine chemistry. New J
Chem 14:761–775
33. Grkovic T, Ding Y, Li X-C, Webb VL, Ferreira D, Copp BR (2008) Enantiomeric discorhab-
din alkaloids and establishment of their absolute configurations using theoretical calculations
of electronic circular dichroism spectra. J Org Chem 73:9133–9136
34. Grkovic T, Pearce AN, Munro MH, Blunt JW, Davies-Coleman MT, Copp BR (2010)
Isolation and characterization of diastereomers of discorhabdins H and K and assignment of
absolute configuration to discorhabdins D, N, Q, S, T, and U. J Nat Prod 73:1686–1693
35. Jeon J, Na Z, Jung M, Lee H-S, Sim CJ, Nahm K, Oh K-B, Shin J (2010) Discorhabdins from
the Korean marine sponge Sceptrella sp. J Nat Prod 73:258–262
36. Na M, Ding Y, Wang B, Tekwani BL, Schinazi RF, Franzblau S, Kelly M, Stone R, Li X-C,
Ferreira D, Hamann MT (2010) Anti-infective discorhabdins from a deep-water Alaskan
sponge of the genus Latrunculia. J Nat Prod 73:383–387
37. Lill RE, Major DA, Blunt JW, Munro MHG, Battershill CN, Mclean MG, Baxter RL (1995)
Studies on the biosynthesis of discorhabdin B in the New Zealand sponge Latrunculia sp.
J Nat Prod 58:306–311
38. Kita Y, Tohma H, Inagaki M, Hatanaka K, Yakura T (1992) Total synthesis of discorhabdin C:
a general aza spiro dienone formation from O-silylated phenol derivatives using a hypervalent
iodine reagent. J Am Chem Soc 114:2175–2180
39. Kita Y, Egi M, Tohma (1999) Total synthesis of sulfur-containing pyrroloiminoquinone
marine product, ()-makaluvamine F using hypervalent iodine(III)-induced reactions.
Chem Commun 143–144
40. Kita Y, Egi M, Takada T, Tohma H (1999) Development of novel reactions using hypervalent
iodine(III) reagents. Total synthesis of sulfur-containing pyrroloiminoquinone marine
product, ()-makaluvamine F. Synthesis 885–897
41. Tohma H, Harayama Y, Hashizume M, Iwata M, Egi M, Kita Y (2002) Synthetic studies on
the sulfur-cross-linked core of antitumor marine alkaloid, discorhabdins: total synthesis of
discorhabdin A. Angew Chem Int Ed 41:348–350
42. Tohma H, Harayama Y, Hashizume M, Iwata M, Kiyono Y, Egi M, Kita Y (2003) The first
total synthesis of discorhabdin A. J Am Chem Soc 125:11235–11240
43. Wada Y, Otani K, Endo N, Harayama Y, Kamimura D, Yoshida M, Fujioka H, Kita Y (2009)
The first total synthesis of prianosin B. Tetrahedron 65:1059–1062
44. Izawa T, Nishiyama S, Yamamura S (1994) Total syntheses of makaluvamines A, B, C, D and

E, cytotoxic pyrroloiminoquinone alkaloids isolated from marine sponge bearing inhibitory
activities against topoisomerase II. Tetrahedron 50:13593–13600
45. Yamada F, Hamabuchi S, Shimizu A, Somei M (1995) The chemistry of indoles. 74. Simple
total syntheses of marine alkaloids, betzelline C, isobetzelline C, damirone A, and makalu-
vamine A1. Heterocycles 41:1905–1908
46. Zhao R, Lown JW (1997) A concise synthesis of the pyrroloquinoline nucleus of the
makaluvamine alkaloids. Synth Commun 27:2103–2110
47. Wao M, Motoi O, Fukuda T, Ishibashi F (1998) New synthetic approach to pyrroloiminoqui-
none marine alkaloids. Total synthesis of makaluvamines A, D, I, and K. Tetrahedron 54:
8999–9010
48. Roberts D, Joule JA, Bros MA, Alvarez M (1997) Synthesis of pyrrolo[4,3,2-de]quinolines
from 6,7-dimethoxy-4-methylquinoline. Formal total syntheses of damirones A and B,
batzelline C, isobatzelline C, discorhabdin C, and makaluvamines A-D. J Org Chem 62:
568–577
49. Kraus GA, Selvakumar N (1998) Synthetic routes to pyrroloiminoquinone alkaloids. A direct
synthesis of makaluvamine C. J Org Chem 63:9846–9849
50. White JD, Yager KM, Yakura T (1994) Synthetic studies of the pyrroloquinoline nucleus
of the makaluvamine alkaloids. Synthesis of the topoisomerase I1 Inhibitor makaluvamine
D. J Am Chem Soc 116:1831–1838
51. Sadanandan EV, Pillai SK, Lakshmikantham MV, Billimoria AD, Culpepper JS, Cava MP
(1995) Efficient syntheses of the marine alkaloids makaluvamine D and discorhabdin C:
the 4,6,7-trimethoxyindole approach. J Org Chem 60:1800–1805
52. Inoue K, Ishikawa Y, Nishiyama S (2010) Synthesis of tetrahydropyrroloiminoquinone
alkaloids based on electrochemically generated hypervalent iodine oxidative cyclization.
Org Lett 12:436–439
53. Venables DA, Barrowa LR, Lassota P, Ireland CM (1997) Veiutamine. A new alkaloid from
the Fijian sponge Zyzzya fuliginose. Tetrahedron Lett 38:721–722
54. Moro-oka Y, Fukuda T, Iwao M (1999) The first total synthesis of veiutamine, a new type of
pyrroloiminoquinone marine alkaloid. Tetrahedron Lett 40:1713–1716
55. Amano Y, Nishiyama S (2006) Oxidative synthesis of azacyclic derivatives through the
nitrenium ion: application of a hypervalent iodine species electrochemically generated from
iodobenzene. Tetrahedron Lett 47:6505–6507
56. Beneteau V, Pierre A, Pfeiffer B, Renard P, Besson T (2000) Synthesis and antiproliferative
evaluation of 7-aminosubstituted pyrroloiminoquinone derivatives. Bioorg Med Chem Lett
10:2231–2234
57. LaBarbera DV, Skibo EB (2005) Synthesis of imidazo[1,5,4-de]quinoxalin-9-ones, benz-
imidazole analogues of pyrroloiminoquinone marine natural products. Bioorg Med Chem
13:387–395
58. Hoang H, LaBarbera DV, Mohammed KA, Ireland CM, Skibo EB (2007) Synthesis and
biological evaluation of imidazoquinoxalinones, imidazole analogues of pyrroloiminoquinone
marine natural products. J Med Chem 50:4561–4571
59. Shinkre BA, Raisch KP, Fan L, Velu SE (2007) Analogs of the marine alkaloid makaluva-
mines: synthesis, topoisomerase II inhibition, and anticancer activity. Bioorg Med Chem Lett
17:2890–2893
60. Shinkre BA, Raisch KP, Fan L, Velu SE (2008) Synthesis and antiproliferative activity of
benzyl and phenethyl analogs of makaluvamines. Bioorg Med Chem 16:2541–2549
61. Wang W, Rayburn ER, Velu SE, Nadkarni DH, Murugesan S, Zhang R (2009) In vitro and
in vivo anticancer activity of novel synthetic makaluvamine analogues. Clin Cancer Res 15:
3511–3518
62. Wang F, Ezell SJ, Zhang Y, Wang W, Rayburn ER, Nadkarn DH, Murugesan S, Velu SE,
Zhang R (2010) FBA-TPQ, a novel marine-derived compound as experimental therapy for
prostate cancer. Invest New Drugs 28:234–241
63. Passarella D, Belinghieri F, Scarpellini M, Pratesi G, Zunino F, Gia OM, Via LD, Santoroa G,
Danielia B (2008) Synthesis and biological evaluation of pyrroloiminoquinone derivatives.
Bioorg Med Chem 16:2431–2438
64. Alvarez M, Bros MA, Gras G, Ajana W, Joule JA (1999) Syntheses of batzelline A, batzeline
B, isobatzelline A, and isobatzelline B. Eur J Org Chem 1173–1183
65. Tao XL, Nishiyama S, Yamamura S (1991) Total syntheses of batzelline C and isobatzelline
C, the novel pyrroloquinoline alkaloids isolated from the marine sponge Batzella sp. Chem
Lett 1785–1786
66. Zhang L, Cava MP, Rogers RD, Rogers LM (1998) Synthesis of a wakayin model compound:
oxidative formation of a new pyrrole ring in the indol-3-ylindoloquinone system. Tetrahedron
Lett 39:7677–7678
67. Barret R, Roue N (1999) Synthesis of a bispyrroloquinone structure analogue to wakayin.
68. Murugesan S, Nadkarni DH, Velu SE (2009) A facile synthesis of bispyrroloquinone and
bispyrroloiminoquinone ring system of marine alkaloids. Tetrahedron Lett 50:3074–3076
69. Legentil L, Lesur B, Delfourne E (2006) Aza-analogues of the marine pyrroloquinoline
alkaloids wakayin and tsitsikammamines: synthesis and topoisomerase inhibition. Bioorg
Med Chem Lett 16:427–429
70. Legentil L, Benel L, Bertrand V, Lesur B, Delfourne E (2006) Synthesis and antitumor
characterization of pyrazolic analogues of the marine pyrroloquinoline alkaloids: wakayin
and tsitsikammamines. J Med Chem 49:2979–2988
71. Rives A, Delaine T, Legentil L, Delfourne E (2009) Total synthesis of the marine pyrroloi-
minoquinone alkaloid tsitsikammamine A. Tetrahedron Lett 50:1128–1130
72. Nishiyama S, Cheng JF, Tao XL, Yamamura S (1991) Synthetic studies on novel sulfur-
containing alkaloids, prianosins and discorhabdins: total synthesis of discorhabdin C.
73. Tao XL, Cheng JF, Nishiyama S, Yamamura S (1994) Synthetic studies on tetrahydropyr-
roloquinoline-containing natural products: syntheses of discorhabdin C, batzelline C and
isobatzelline C. Tetrahedron 50:2017–2028
74. Aubart KM, Heathcock CH (1999) A biomimetic approach to the discorhabdin alkaloids: total
syntheses of discorhabdins C and E and dethiadiscorhabdin D. J Org Chem 64:16–22
75. Grkovic T, Kaur B, Webbb VL, Copp BR (2006) Semi-synthetic preparation of the rare,
cytotoxic, deep-sea sourced sponge metabolites discorhabdins P and U. Bioorg Med Chem
Lett 16:1944–1946
76. Kita Y, Tohma H, Hatanaka K, Takada T, Fujita S, Mitoh S, Sakurai H, Oka S (1994)
Hypervalent iodine-induced nucleophilic substitution of para-substituted phenol ethers.
Generation of cation radicals as reactive intermediates. J Am Chem Soc 116:3684–3691
77. Kita Y, Egi M, Ohtsubo M, Saiki T, Okajima A, Takada T, Tohma H (1999) Hypervalent
iodine(III)-induced intramolecular cyclization reaction of substituted phenol ethers with an
alkyl azido side-chain: a novel and efficient synthesis of quinone imine derivatives. Chem
Pharm Bull 47:241–245
78. Kita Y, Egi M, Okajima A, Ohtsubo M, Takada T, Tohma H (1996) Hypervalent iodine(III)
induced intramolecular cyclization of substituted phenol ethers bearing an alkyl azido side-
chain – a novel synthesis of quinone imine ketals. Chem Commun 1491–1492
79. Kita Y, Egi M, Ohtsubo M, Saiki T, Takada T, Tohma H (1996) Novel and efficient synthesis
of sulfur-containing heterocycles using a hypervalent iodine(III) reagent. Chem Commun
2225–2226
80. Tohma H, Egi M, Ohtsubo M, Watanabe H, Takizawa S, Kita Y (1998) A novel and direct
a-azidation of cyclic sulfides using a hypervalent iodine(III) reagent. Chem Commun
173–174
81. Harayama Y, Yoshida M, Kamimura D, Kita Y (2005) The novel and efficient direct synthesis
of N,O-acetal compounds using a hypervalent iodine(III) reagent: an improved synthetic
method for a key intermediate of discorhabdins, Chem Commun 1764–1766
82. Patel SP, Nadkarni DH, Murugesan S, King JR, Velu SE (2008) Azide-mediated detosylation
of N-tosylpyrroloiminoquinones and N-tosylindole-4,7-quinones. Synlett 2864–2868
83. Wada Y, Otani K, Endo N, Harayama Y, Kamimura D, Yoshida M, Fujioka H, Kita Y (2009)
Synthesis of antitumor marine alkaloid discorhabdin A oxa analogues. Org Lett 11:
4048–4050
Top Curr Chem (2012) 309: 163–202
DOI: 10.1007/128_2011_217
Published online: 5 October 2011
Synthetic Studies on Amaryllidaceae and Other

Terrestrially Derived Alkaloids
Martin G. Banwell, Nadia (Yuqian) Gao, Brett D. Schwartz,

and Lorenzo V. White
Abstract The total syntheses of a wide range of terrestrially derived alkaloids,

especially ones isolated from members of the Amaryllidaceae family, are
described. Two recurring themes associated with these syntheses are the use of
two types of building blocks, namely ring-fused cyclopropanes, especially gemi-
nally-dihalogenated ones, and enzymatically derived cis-1,2-dihydrocatechols.
These have often served as precursors to 2- or 3-halogenated 2-cyclohexen-1-ols
that are themselves engaged in cross-coupling reactions, radical addition-elimina-
tion processes and/or Claisen- or Overman-type rearrangements so as to construct
the highly functionalized six-membered rings associated with the target alkaloids.
Keywords Alkaloids Amabiline Amaryllidaceae Aspidospermidine

Brunsvigine Colchicine Corey-Winter reaction Cross-coupling Cyclopro-
pane Erythramine Eschenmoser-Claisen rearrangement epi-Maritinamine
Galanthamine Grandirubrine Haemultine Imerubrine Ireland-Claisen
rearrangement g-Lycorane Lycoricidine Maritinamine Mitsunobu reaction
Nangustine Narciclasine Overman rearrangement Pancracine Pictet-
Spengler reaction Radical cyclisation Rhazinal Rhazinilam Suzuki-Miyaura
reaction Ullmann reaction Wittig reaction
M.G. Banwell (*), N.(Y.) Gao, B.D. Schwartz, and L.V. White
Research School of Chemistry, Institute of Advanced Studies, The Australian National University,
Canberra, ACT 0200, Australia
164 M.G. Banwell et al.
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
2 Colchicine, Imerubrine, Grandirubrine, Salimine and Jerusalemine . . . . . . . . . . . . . . . . . . . . . 165
2.1 Colchicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.2 Imerubrine and Grandirubrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
2.3 Salimine and Jerusalemine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
3 The Amaryllidaceae Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
3.1 Rhazinilam and Rhazinal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
3.2 Lycorane and Lycorinine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
3.3 The Montanine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
3.4 The Crinine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
3.5 Galanthamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
3.6 The Narcissus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
4 The Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
5 Aspidospermidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
7 Notes Added in Proof . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
1 Introduction
In 1819 the German chemist Carl F.W. Meissner introduced the term alkaloid (or
“alkali-like”) but its widespread application as a descriptor of natural products
containing a basic nitrogen only occurred in the 1880s and after the publication of a
review article by O. Jacobsen in Albert Ladenburg’s Chemical Dictionary (see [1]).
Alkaloids, many of which are heterocyclic in nature and the by-products of amino
acid metabolism, occur most commonly in the peripheral parts of plants such as the
leaves, roots, bark and/or fruit and less so in the wood. Interestingly, significantly
reduced concentrations of alkaloids are encountered in terpene- and resin-rich
plants. In addition, because many alkaloids are neurotoxic they are not normally
encountered in large quantities in the terrestrially based animal kingdom [2]. In
contrast, the marine environment appears to contain many alkaloid-producing
animals including sponges, tunicates and nudibranchs (for useful points-of-entry
into the literature on marine alkaloids see [3, 4]).
Alkaloids and their derivatives, especially those of the morphinan class, have a
long history of therapeutic use and remain some of the most heavily prescribed
drugs on the market today. Such features, together with issues of supply and the
broad range of remarkable structural variations encountered amongst the more than
15,000 alkaloids described thus far, have made them attractive targets for synthesis
[5]. Indeed, the development of the discipline of chemical synthesis has been
profoundly influenced by the manifold challenges that these natural products have
presented (and continue to present) to the practitioners in the field. There are some
key milestones in the area worth highlighting to the reader. In 1886 Landenburg
reported the first complete synthesis of an alkaloid, namely coniine [(R)-2-propylpi-
peridine] (see [6]). This involved condensing 2-methylpyridine with acetaldehyde
Synthetic Studies on Amaryllidaceae and Other Terrestrially Derived Alkaloids 165
followed by reduction of the ensuing 2-propenylpyridine with sodium to give the

racemic modification of the natural product. Robinson’s one-step synthesis of the
alkaloid tropinone under near-physiological conditions was reported in 1917 [7]
and is regarded as one of the most important developments in the discipline, not
least because it served to inspire many other biogenetically patterned syntheses.
The Woodward–Doering synthesis of quinine, reported in 1944 [8] and at a time
when there was a severe shortage of this anti-malarial agent, served to highlight the
emerging power of rational synthetic design and the increasing array of chemical
methodologies available for the purposes of constructing some of Nature’s most
challenging and important compounds. Gates’ synthesis of morphine followed in
the 1950s [9] and emphasised these points, as did reports on, inter alia, the assembly
of lysergic acid (Woodward 1954) [10], reserpine (Woodward 1958) [11], colchi-
cine (Eschenmoser 1959; van Tamelen 1961; Scott 1963; Woodward 1963) [12–18]
and strychnine (Woodward 1963) [19]. The development, in the mid- to late-1970s,
of biomimetic protocols for the synthesis of the dimeric and clinically significant
indole alkaloids such as vinblastine and vincristine represents another major devel-
opment in the field (see [20]). Of course, many beautiful syntheses of alkaloids have
emerged since this time and the current state-of-play is emphasised by, for example,
Overman’s preparation actinophyllic acid [21] as well as Reissig’s and
Vanderwal’s exceptionally concise syntheses of ()-strychnine [22, 23].
The present chapter is focussed on the contributions of the lead author’s group to
the synthesis of terrestrially derived alkaloids. The chapter is idiosyncratic in nature
insofar as the emphasis has been placed on work (both published and unpublished)
carried out by the group.
2 Colchicine, Imerubrine, Grandirubrine, Salimine

and Jerusalemine
2.1 Colchicine
Colchicine (1, see Scheme 1 – associated axis of chirality not shown), which
embodies a tropolone ring system, is a phenethyltetrahydroisoquinoline-derived
alkaloid that was originally isolated from the meadow saffron Colchicum
autumnale [24]. It is a highly potent anti-mitotic agent that is used in the treatment
of liver cirrhosis and gout while its N-deacetyl congener, demecolcine, is a clini-
cally effective antineoplastic agent [25]. Its novel structural features and potent
biological activities have prompted numerous synthetic studies. However, a fully
regiocontrolled synthesis remained elusive for some time. The first synthesis of the
alkaloid, described by Eschenmoser and Schreiber in 1959 [12], highlighted two
key problems that were not solved simultaneously within the one reaction sequence
until our report in 1992. Site-selective introduction of the C-7 acetamido group
associated with target 1 had proven somewhat problematic although Nakamura,
O O OH OMe
MeO HO O O
NHAc NHAc NHAc NHAc
C C
7 methylating methylating
agent agent
MeO MeO MeO MeO
MeO MeO MeO MeO

OMe OMe OMe OMe
1 2a 2b 3
Scheme 1 Formation of colchicine (1) and isocolchicine (3) via O-methylation of colchiceine (2)
Woodward and Evans [14, 17, 18] advanced solutions to this matter during the
course of their studies. The second difficulty stemmed from the rapid equilibrium
between the two tautomeric forms, 2a and 2b, of colchiceine (10-demethyl-
colchicine), the free tropolone that is the final intermediate in all pre-1992 syntheses
(Scheme 1). As a result of this equilibrium, O-methylation of colchiceine affords a
ca. 1:1 mixture of colchicine and isocolchicine (3), the latter product differing from
1 in that the positions of the methoxy and carbonyl moieties (as well as the
associated double-bonds) in ring-C are reversed.
Our solution to these longstanding problems involved implementing a synthetic
sequence ([26, 27]; for a summary of more recent syntheses of colchicine see [28])
that mimicked the proposed biogenesis [29] of the troponoid C-ring of colchicine
(Scheme 2). Thus, the aryl bromide 4 was converted into the corresponding lithio-
species 5 under standard conditions and this was then treated with the aldehyde 6 to
give the alcohol 7. Deprotection of this last compound with tetra-n-butylammonium
fluoride (TBAF) and subjection of the resulting phenol (61% yield from 4) to
a Wessely-type oxidation with lead(IV) acetate afforded a diastereoisomeric
mixture of the expected o-benzoquinone monoketals that upon treatment with
trifluoroacetic acid (TFA) engaged in a cyclization reaction to form the dibenzocy-
cloheptane 8 (42% overall yield from 7). Treatment of compound 8 with thallium
(III) nitrate in the presence of methanol afforded the o-benzoquinone monoketal 9
(97%) that was subjected to nucleophilic cyclopropanation using the
Corey–Chaykovsky ylide and thus affording, in a completely regioselective man-
ner, the ring-fused cyclopropane 10 (75%). In the pivotal and presumably biomi-
metic step of the reaction sequence, compound 10, a s-homo-o-benzoquinone
monoketal, was treated with TFA in dichloromethane at room temperature. This
induced fragmentation of the three-membered ring and accompanying loss of the
elements of methanol so as to generate the troponoid 11 in 89% yield (at 53%
conversion). Clearly compound 11 embodies the required regiochemical arrange-
ment of the methoxy and carbonyl moieties within the C-ring and all that remained
was to convert the C-7 alcohol into the corresponding acetamido group. This was
readily effected by the illustrated sequence wherein the alcohol was transformed
into the corresponding mesylate 12 (100%) which was displaced with sodium azide
to give the azide 13 (85%). Reduction of the latter with dihydrogen in the presence
of palladium on carbon then gave the corresponding amine 14 that was immediately
subjected to reaction with acetic anhydride and so affording the racemic modifica-
tion of colchicine (1) in 73% overall yield from the precursor azide.
OTBS
MeO
4 X = Br OTBS OH
n-BuLi
5 X = Li MeO MeO
(i) TBAF;
OH (ii) Pb(OAc)4; OH
+
MeO (iii) TFA MeO
O
MeO MeO MeO
MeO MeO
MeO
7 8
MeO
6
Tl(NO3)3,
MeOH
MeO O O O
MeO MeO
MeO MeO
X OH OH
TFA H2CSOMe2
MeO MeO MeO
MeO MeO MeO
MeO MeO MeO
11 X = OH 10 9
MsCl, Et3N
12 X = OMs
NaN3
13 X = N3
H2, Pd on C
14 X = NH2
Ac2O
1 X = NHAc
Scheme 2 First fully regiocontrolled total synthesis of colchicine (1)
A relatively straightforward modification to the latter parts of this sequence

allowed for the synthesis of enantiomerically enriched colchicine [28]. Specifically,
a ketone arising from oxidation of a derivative of alcohol 8 could be reduced in an
enantioselective manner using the CBS reagent and the resulting enantiomerically
enriched form of compound 8 was then carried forward in the same manner as
described above and thus providing colchicine (1) in >81% ee.
2.2 Imerubrine and Grandirubrine
The protocols detailed above have proven effective in the regiospecific construction
of other natural products incorporating a tropolone O-methyl ether unit. For exam-
ple, treatment of the s-homo-o-benzoquinone monoketal 15 with TFA gave the
tropoloisoquinoline natural product imerubrine (16) in 70% yield ([27, 30, 31]; for
more recent syntheses of these alkaloids see [32]). Furthermore, the a-diketone, 17,
arising from hydrolysis of compound 15 underwent thermal rearrangement to afford
the related natural product grandirubrine (18) (87% from 15). Interestingly, when
compounds 16 and 18 were tested as tubulin binding agents only the former showed
any activity and this was much weaker than that observed for colchicine [30–32].
OMe OH
OMe O O O
MeO O O
MeO MeO MeO MeO
N N N N
MeO MeO MeO MeO
OMe OMe OMe OMe
15 16 17 18
2.3 Salimine and Jerusalemine
In 1991 Abu Zarga et al. described the isolation of the alkaloids salimine,
jerusalemine and suhailamine from the Middle Eastern species Colchicum
decaisnei Boiss. (Liliaceae) [33]. On the basis of various spectroscopic studies
structures 19–21, respectively,1,2 were assigned to these compounds. Given the
resemblance of these structures to the intermediate 8 associated with our biomi-
metic synthesis of colchicine (Scheme 2) we sought to adapt this work so as to
prepare compounds 19 and 20, on the basis that these might display the same types
of anti-mitotic properties shown by allocolchicine (22) (see footnote 2), a com-
pound that is readily obtained by the methoxide ion-induced ring-contraction of the
C-ring of colchicine and which is also encountered in nature.
OMe OMe CO2Me
HO2C HO
NHAc NHMe NHAc
MeO MeO MeO
MeO HO MeO
MeO MeO MeO
19 20 21 / 22
The route we employed in obtaining the racemic modification of the structure

assigned to salimine (19) is shown in Scheme 3 and started with the Claisen–Schmidt
condensation of acetophenone 23 with aldehyde 24 [34]. The resulting chalcone
(92%) was subjected to simultaneous reduction of the carbon–carbon double bond
1
Each of these compounds presumably possesses an axis of chirality but the configurations of
these were not reported.
2
Abu Zarga et al. [33] assigned structure 21 to the alkaloid suhailamine without recognising that
this is also the structure of the well known colchicine derivative allocolchicine. Since the spectral
data derived from suhailamine do not match those recorded for allocolchicine, the structure
proposed for the former compound is presumed to be incorrect.
OBn
MeO
O OH OMe
(i) NaOH; MeO MeO
23 (ii) H2, OH (i) Pb(OAc)4; OH
5 % Pd on C; (ii) TFA;
+ MeO MeO
(iii) NaBH4 (iii) (MeO)2SO2
CHO
MeO MeO
MeO MeO MeO
MeO OMe 25 26
24
(i) TPAP, NMO;

(ii) EtSNa
OMe OMe OMe

HO2C MeO2C R
LiOH then (i) NH4OAc,
NHAc + NHAc O
H3O NaBH3CN;
MeO MeO MeO
(ii) Ac2O
MeO MeO MeO
MeO MeO MeO
(±)-19 30 27 R=OH
Tf2O
28 R=OTf CO, MeOH,
29 R=CO2Me Pd[0]
Scheme 3 Total synthesis of the structure, 19, assigned to the alkaloid salimine
and hydrogenolysis of the benzyl ether using dihydrogen in the presence of Pd on C

and this was followed by reduction of the carbonyl unit with sodium borohydride. The
ensuing alcohol 25 (96% from the chalcone) was subjected to an oxidative coupling
sequence using Pb(OAc)4 and then TFA as described earlier and after O-methylation
of the free phenol the dibenzocycloheptane 26 was obtained in 96% yield. Oxidation
of the benzylic hydroxyl group within this last compound using the Ley–Griffith
reagent was followed by selective demethylation of the required methoxy group
within the resulting ketone using the ethanethiolate anion. The phenol 27 (17%) so
formed was converted into the corresponding triflate 28 (46%) under standard
conditions and this was subjected to Pd[0]-catalysed carbomethoxylation and, thereby
affording keto-ester 29 in 43% yield. The structure of this last compound was
confirmed by single-crystal X-ray analysis. Reductive amination of the keto group
within compound 29 followed by acetylation of the resulting primary amine and
saponification of the ester unit within product 30 (45%) gave, after acid work-up,
the racemic form of the target 19 in 75% yield. A related sequence of reactions was
used to prepare, in racemic form, the structure 20 assigned to jerusalemine. However,
the spectral data recorded on both of these synthetically-derived materials did not
match those reported for the natural products thus suggesting that their structures have
been assigned incorrectly.
Interestingly, when the synthetically-derived “allocolchicinoids” ()-19 and

()-20 were subjected to the relevant binding assay they did not show inhibitory
effects on tubulin polymerisation. Furthermore, they were not cytotoxic to L1210
(murine lymphocytic leukaemia) cells [34].
3 The Amaryllidaceae Alkaloids
The title alkaloids are a structurally diverse class of natural products that display a
remarkable range of biological properties. As a consequence, enormous effort
has been devoted to the synthesis of such compounds and the work reported in
this area over the last three to four decades has served as something of an indicator
of the state-of-the-art of synthesis at any given time.
3.1 Rhazinilam and Rhazinal
Our own interest in the synthesis of the Amaryllidaceae alkaloids arose when
we recognised that, in common with colchicine (1), ()-rhazinilam (31) and
()-rhazinal (32) are both spindle toxins although their mode of action is different
in that, like Taxol™, they exert their biological effects by inhibiting the
depolymerisation of microtubules. This prompted us to develop syntheses
of these compounds and certain biogenetically related ones such as
(+)-epi-leuconolam (33) and ()-leuconolam (34) ([35, 36]; for an excellent and
very recent review on all of the reported syntheses of rhazinilam see [37]).
O O
NH NH
C
R O
D N X
N
31 R=H 33 X=α-OH
32 R=CHO 34 R=β-OH
The pivotal step associated with our approach to compounds 31–34 was an
organocatalysed, enantioselective and intramolecular Michael addition reaction of
the nucleophilic C-2 carbon of a pyrrole to an N-tethered a,b-unsaturated
aldehyde residue and thereby establishing the required CD-ring system. Full details
of the reaction sequence are shown in Scheme 4 and this involves initial reaction of
the potassium salt, 35, of pyrrole with butyrolactone (36) to give, after acidic work-
up, compound 37 (60–90%). Conversion of this last species into the corresponding
Weinreb amide 38 (87%) followed by its reaction with ethylmagnesium
bromide then afforded the ethyl ketone 39 (95%) that was subjected to standard
Horner–Wadsworth–Emmons (HWE) conditions and thereby generating the
N
K
HWE
N N
35 heat then reaction
+ O
H3O
+
X
R
O
Weinreb amide 37 X=OH 40 R=CO2Me
38 X=N(OMe)Me DIBAl-H
formation
EtMgBr 41 R=CH2OH
O 39 X=Et BaMnO4
42 R=CHO
36
MacMillan's
1st gen. catalyst
Y
(i) KOH then HCl;
MeO2C (ii) DCC, MeOH NaBH4
X X O
N N N
DMF, 47 X=Y=H 44 X=OH 43

POCl3 48 X=CHO,Y=H I2, MsCl 45 X=OMs
49 X=CHO,Y=I NaCN
AgOCOCF3 46 X=CN
2-(4,4,5,5-tetramethyl-1,3-2-
dioxaborolan-2-yl)benzenamine, Pd[0],
Na2CO3
NH2
(i) KOH then HCl;
(ii) EDCI, DMAP O PCC O
NH NH
MeO2C CHO
N R O
N N
X
50 32 R=CHO
(Ph3P)3RhCl 33 X=α-OH
31 R=H 34 X=β-OH
Scheme 4 Total syntheses of ()-rhazinal (32), ()-rhazinilam (31), (þ)-epi-leuconolam (33)

and ()-leuconolam (34)
a,b-unsaturated ester 40 which was obtained as a 1:1 mixture of diastereoisomers in

77% yield. Reduction of these esters with DIBAl-H gave the corresponding mixture
of allylic alcohols 41 (91%) which were immediately oxidised to the aldehydes 42
(76%) with barium permanganate. Treatment of this mixture with MacMillan’s first
generation organocatalyst [38] effected the anticipated intramolecular Michael
addition reaction and gave the required cyclisation product 43 in 81% chemical
yield and ca. 74% ee. A standard homologation sequence was then applied to
this aldehyde. Thus, it was reduced with NaBH4 to the corresponding alcohol
44 (84%) that was immediately converted into the corresponding mesylate 45
(95%) under standard conditions. Reaction of the latter compound with sodium
cyanide followed by hydrolysis of the resulting nitrile 46 (91%) and esterification
of the ensuing acid with methanol in the presence of DCC afforded compound
47 (63%). Vilsmeier–Haack formylation of pyrrole 47 gave the aldehyde 48 (78%)
that reacted, in an entirely regioselective manner, with molecular iodine in the

presence of silver trifluoroacetate to give the iodinated pyrrole 49 (quant.).
Suzuki–Miyaura cross-coupling of this last compound with the commercially
available 2-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine provided
the expected compound 50 (64%) that was engaged in a two-step macrolacta-
misation sequence and thereby affording ()-rhazinal (32) in 68% yield and ca.
74% ee as judged by chiral HPLC analysis.
Treatment of compound 32 with stoichiometric quantities of Wilkinson’s
“catalyst” effected decarbonylation of the substrate and thus gave, without any
erosion in optical purity, ()-rhazinilam (31) in 89% yield. Following protocols
established earlier within the group, compound 31 was treated with an excess of
PCC in the presence of 4 Å molecular sieves to give a chromatographically separable
mixture of (+)-epi-leuconolam (33) (46%) and ()-leuconolam (34) (28%).
We have employed a related reaction sequence to prepare a lower homologue
of rhazinal and then shown that this retains many of the potent anti-mitotic
properties of the natural product [39].
3.2 Lycorane and Lycorinine-Type Alkaloids
The lycorine alkaloids, of which lycorine (51) is the parent member [40], as well as
the biogenetically related lycorinine alkaloids, as represented by clividine (52) [41]
and narseronine (53) [42], constitute two further types of Amaryllidaceae alkaloids
that have attracted our attention. They display an extraordinary range of biological
effects including a pronounced capacity to selectively inhibit the growth of various
cancer cells, DNA binding properties, anti-viral activity, anti-fungal behaviour and
insect anti-feedant activity [42]. Despite this, there has been remarkably little effort
to develop syntheses of members of either of these two classes or analogues thereof.
Accordingly, we sought to establish practical routes to these systems and two
distinct approaches emerged from our studies in the area. The first of these is
highlighted in our syntheses of the ()-, ()-, and (+)-forms of the g-lycorane
[54 – representing (+)-form] [43], the latter two having been obtained
through degradation of lycorine as part of the work associated with establishing
its structure.
The details of our syntheses of these three forms of g-lycorane are presented in
Scheme 5. Thus, the known allylic acetate 55 was reacted with bromoform and sodium
hydroxide in the presence of a phase-transfer catalyst to give the ring-fused

gem-dibromocyclopropane 56. This was, in turn, converted, via a standard reaction
sequence, into the ketone 57. Subjection of this last species to an HWE reaction with
the anion derived from diethyl cyanomethylphosphonate then gave a ca. 2:1 mixture of
the E- and Z-isomeric forms of the a,b-unsaturated nitrile 58. Treatment of this mixture
with dihydrogen in the presence of PtO2 and chloroform resulted in the stereoselective
formation of the hydrochloride salt of the expected amine that was immediately
converted into the corresponding methyl carbamate 59 (32% overall yield from 55)
under standard conditions. In the pivotal step of the reaction sequence, this last
compound was treated with silver perchlorate in the weakly nucleophilic solvent
trifluoroethanol, resulting in the electrocyclic ring opening of the three-membered
Scheme 5 Total synthesis of ()-g-lycorane [()54]

ring and intramolecular trapping of the ensuing p-allyl cation by the nitrogen of the
pendant carbamate. In this way the hexahydroindole 60 was obtained in 95% yield.
Compound 60 readily engaged in a Suzuki–Miyaura cross-coupling reaction with
arylboronic acid 61 and thereby affording the expected product 62 in 87% yield.
Catalytic hydrogenation of alkene 62 proceeded in a completely facially selective
manner to give the C7-arylated perhydroindole 63 (quant.) that was then subjected to
treatment with phosphorus oxytrichloride and so effecting a Bischler–Napieralski
cyclisation reaction to give the lactam 64 (81%). Upon reduction with lithium
aluminium hydride this lactam provided ()-g-lycorane [()-54] in 84% yield.
This reaction sequence was readily modified so as to allow for the synthesis of
the (+)- and ()-forms of g-lycorane. Thus, by reacting the amine arising from the
reduction of the a,b-unsaturated nitriles 58 with ()-menthyl chloroformate,
treating the resulting diastereoisomeric carbamates with silver acetate and cross-
coupling the ensuing mixture of hexahydroindoles with aryl boronic acid 61, the
chromatographically separable C7-arylated hexahydroindoles 65 and 66 could be
obtained. These were then readily elaborated, using the same protocols as specified
in Scheme 5, to the (+)- and ()-enantiomeric forms, respectively, of the target
compound 54.
A chemoenzymatic approach to the lycorine framework is shown in Scheme 6

[44]. This involved using the enzymatically-derived and enantiomerically pure
cis-1,2-dihydrocatechol 67 as starting material. Thus, this diol was converted into
the corresponding acetonide 68 (93%) under standard conditions and the latter
compound subjected to a completely regio- and stereo-controlled epoxidation
reaction with m-CPBA to give the epoxide 69 in 95% yield. Treatment of oxirane
69 with the acetonitrile anion resulted in a completely regio-selective ring-opening
reaction and formation of the g-hydroxynitrile 70 (96%) that was subjected to a
Barton–McCombie deoxygenation reaction and thereby affording compound 71 in
77% yield over the two steps involved. Suzuki-Miyaura cross-coupling of
bromoalkene 71 the readily prepared aryl boronate ester 72 gave the expected
arylated cyclohexene 73 (75%) that, upon treatment with acetic acid in water at
80 C, underwent cleavage of the acetonide group and subsequent lactonisation to
give the tetracyclic compound 74 (89%). Subjection of nitrile 74 to reaction with
dihydrogen in the presence of Raney-cobalt in ammoniacal methanol resulted in
formation of the lactam 77 (65%), presumably via a pathway in which the initially
generated primary amine 75 engages in an SN0 reaction to give the amino acid 76
that, in turn, undergoes lactamisation to give product 77. The structure of the last
compound was secured by single-crystal X-ray analysis. Treatment of lactam 77
with trimethyloxonium tetrafluoroborate in the presence of Proton-sponge™
Scheme 6 Synthesis of compound 79, a degradation product of ()-lycorine (51)

effected O-methylation and reduction of compound 78 so formed (95%) using

lithium aluminium hydride then gave target compound 79 (89%) which had been
obtained previously by degradation of ()-lycorine (51).
A related strategy has been employed in developing a synthesis of the non-
natural enantiomeric form, ent-52, of the lycorinine alkaloid clividine in which a
nitrogen-centred radical cyclisation reaction is used in the key step (Scheme 7)
(White et al., unpublished work) (for a summary of the limited number of other
synthetic endeavours in this area see [45]). Thus, starting with the same cis-1,2-
dihydrocatechol (67) as used previously but now treating it with NBS in wet THF
and then converting the ensuing bromohydrin 80 into the corresponding acetonide
81 (92%) provided a material that upon successive treatment with sodium hydride
and LiCH2CN afforded the g-hydroxynitrile 82 (87%). Subjection of this last
compound to a Barton–McCombie deoxygenation reaction then gave nitrile 83
(81%) that is epimeric with that involved as an intermediate in the synthesis of the
lycorine degradation product 79 as detailed immediately above. Suzuki–Miyaura
cross-coupling of compound 83 with aryl boronate 72 gave the arylated
cyclohexene 84 (95%) that upon treatment with acetic acid/water afforded
hydroxy-lactone 85 (84%), the OH group of which was protected, under standard
conditions, as the corresponding TBDPS ether 86 (80% yield). Treatment of
compound 86 with dihydrogen in the presence of Raney-cobalt, protection of the
resulting amine as the Alloc-carbamate, N-methylation of this using LiHMDS and
methyl iodide followed by removal of the Alloc group using Pd[0] in the presence
of an excess of dimedone then gave the secondary amine 87 (62% over four steps)
that was immediately N-chlorinated using NCS to give compound 88, the substrate
required for the foreshadowed and pivotal radical cyclisation process. In the event,
treatment of the N-chloroamine 88 with tri-n-butyltin hydride in the presence of
AIBN gave, presumably via the intermediate benzylic radical 89 that accepts a
hydrogen atom at the b-face, the pentacyclic lactone 90 (82% yield). Treatment of
this last compound with HF•pyridine then afforded ent-clividine (ent-52) in 99%
yield. The structure of this last compound was confirmed through a single-crystal
X-ray analysis of the corresponding picrate salt. Since the enantiomer of the starting
material 67 is known, the route shown also provides access to the natural enantio-
meric form, 52, of clividine.
The stereochemical outcome of the nitrogen-centred radical cyclisation
88 ! 90 is strongly influenced by steric effects and the manipulation of these
offers considerable potential in the preparation of diastereoisomeric forms of the
lycorinine alkaloids. Thus, for example, cyclisation of the non-TBDPS-protected
form, 91, of compound 88 results in the generation of C11b-epi-ent-clividine (92)
(67%) (Scheme 8) (White et al., unpublished work) [45].
A synthesis of the alkaloid narseronine 53 that highlights yet another novel mode
of cyclisation of arylated cyclohexenes derived from compound 67 is shown
Scheme 9 (White et al., unpublished work; [45]). Thus, nitrile 73 (generated from
precursor 67 during the course of our synthesis of the lycorine degradation product
79 as shown in Scheme 6) was reduced with dihydrogen in the presence of Raney-
cobalt and the resulting primary amine was then protected as the corresponding
Scheme 7 Total synthesis of ent-clividine [ent-52]
Alloc-carbamate which was, in turn, N-methylated using methyl iodide in the

presence of LiHMDS, thus affording compound 93 in 86% yield. Successive
treatment of carbamate 93 with acetic acid/water (to effect cleavage of the acetonide
ring) and LiHMDS (to lactonise the initially formed diol) and Ag2O/MeI (to effect a
Scheme 8 Final step

associated with the synthesis
of C11b-epi-ent-clividine
(92)
Scheme 9 Total synthesis of narseronine (53)
Purdie–Irvine methylation of the residual hydroxyl group) afforded compound 94

(59%) that was treated with sodium hydroxide and then mineral acid to give the
hydroxyacid 95. This last compound was prone to relactonisation and, thereby,
regeneration of precursor 94. Nevertheless, when compound 95 was subjected to
Swern oxidation conditions, using an excess of DMSO and oxalyl chloride, the
keto-ester 96 was obtained in 48% yield. The formation of the methylthiomethyl
ester moiety in this reaction is presumably the result of the intervention of a
Pummerer-type rearrangement reaction. Treatment of compound 96 with Pd
(PPh3)4 and an excess of dimedone resulted in the removal of the Alloc protecting
group and formation of the secondary amine 97 which underwent a spontaneous
intramolecular hetero-Michael addition to the pendant enone moiety with the
ensuing enolate attacking the adjacent ester carbonyl and, after the usual addi-
tion/elimination reaction, delivering the unsaturated lactone 53 in 67% yield. The
spectral data obtained on compound 53 were in full accord with the assigned
structure that was eventually confirmed by a single-crystal X-ray analysis. Further-
more, there was excellent agreement between the spectral data recorded for com-
pound 53 and those reported for naturally-derived narseronine.
3.3 The Montanine Alkaloids
The use of enzymatically-derived cis-1,2-dihydrocatechols in conjunction with

radical cyclisation processes has also provided useful new routes to certain
members of the montanine alkaloid class, members of which have been isolated
from various Amaryllidaceae species and incorporate the 5,11-methanomorphan-
thridine framework bearing hydroxy or methoxy groups in varying configurations at
C2 and C3 [46]. ()-Brunsvigine (98) and ()-nangustine (99) are representative
members of the class and the non-natural enantiomeric forms of both have
been prepared by us from the chloro-analogue of cis-1,2-dihydrocatechol 67
([47]; for a summary of the limited number of other synthetic endeavours in this
area see [48]; [49]).
The route used in the conversion 100 ! ent-98 is shown in Scheme 10 and
begins with the conversion of the former compound into the acetal 101 under
standard conditions. Dihydroxylation of the non-chlorinated double-bond within
the latter compound using the Upjohn conditions [50] provided the diol 102
(66%) in a completely diastereoselective fashion and this was protected as the
corresponding di-MOM ether 103 (88%) using MOM chloride in the presence of
sodium hydride. Reductive cleavage of the acetal unit within compound 103 was
readily effected in a regioselective manner with DIBAl-H and the ensuing alcohol
Scheme 10 Total synthesis of ent-brunsvigine (ent-98)
104 (60%) was then converted into the corresponding (inverted) iodide 105 (66%)
using triiodoimidazole in the presence of triphenylphosphine. Reductive
deiodination of this last compound with tri-n-butyltin hydride (to give tris-ether
106) followed by selective cleavage of the PMB ether with DDQ then gave alcohol
107 (83% from 105) that was converted into the epimeric azide 108 (75%) under
Mitsunobu conditions. Subjection of compound 108 to a Staudinger reaction
then gave the corresponding amine 109 (98%) which participated in a reductive
amination reaction with p-methoxybenzaldehyde in the presence of sodium
cyanoborohydride. The resulting secondary amine 110 (56%) was coupled with
the racemic modification of the readily prepared acid 111 and the diastereoisomeric
forms of amide 112 (74%) so produced were subjected to reaction with tri-n-
butyltin hydride. This resulted in homolytic cleavage of the PhS group and the
ensuing benzylic radical then added, in an intramolecular fashion, to the nearer
terminus of the chlorinated double bond, thereby generating a new radical that
“collapses” with ejection of a chlorine radical, so as to produce the annulated and
b,g-unsaturated lactam 113 in 60% yield. Compound 113 was accompanied by
smaller amounts (7%) of its C3-epimer. Treatment of lactam 113 with a combina-
tion of LiAlH4 and AlCl3 resulted in the reductive removal of the carbonyl group
and formation of tertiary amine 114 (94%), the MOM groups within which were
removed on treatment with acidic methanol. The ensuing diol 115 (73%) was
treated with triphosgene, resulting in the simultaneous generation of a cyclic
carbonate unit and cleavage of the PMB group, thus leading to the carbamoyl
chloride 116. Exposure of this last compound to aqueous acid then afforded the
secondary amine 117 (42% from 115) that readily engaged in a Pictet–Spengler
reaction on treatment with paraformaldehyde in formic acid, thereby generating
compound 118 (65%) that embodies the polycyclic framework associated with the
target alkaloid. Indeed, simply treating this cyclic carbonate with potassium
hydroxide in methanol gave ent-brunsvigine (ent-98) in 87% yield that, save for
the sign of the specific rotation, was spectroscopically identical, in all respects, with
the natural product.
We have extended the chemistry shown in Scheme 10 to the preparation of
ent-nangustine (ent-99) and to the synthesis of compound 119 that corresponds
to the structure assigned to montabuphine [51]. Montabuphine has attracted con-
siderable attention because its isolation suggested that both enantiomeric forms of
the montanine alkaloid framework occur in nature. In the event, and by employing a
reaction sequence similar to that shown above, we were able to prepare target 119
from cis-1,2-dihydrocatechol 100. However, a comparison of the physical and
spectral data recorded on the synthesised form of amine 119 with those reported
for (+)-montabuphine suggests that they are different compounds.
An alternate approach to the basic pentacyclic framework of the montanine

alkaloids is shown in Scheme 11 [52] and involves an initial base-promoted
Michael addition reaction between the b-nitrostyrene 120 and cyclohexane-1,
3-dione (121). The resulting adduct, b-hydroxyenone 122 (quant.), was O-acylated
and the ensuing b-acetoxyenone 123 (74%) subjected to Luche reduction followed
by a basic work-up and, thereby affording enone 124 (67%). Subjection of the last
compound to a second Luche reduction followed by reduction of the nitro group to
the corresponding amine (using NiB2 in the presence of hydrazine) and conversion
of this into the corresponding p-toluenesulfonamide gave a ca. 1:1 and chromato-
graphically separable mixture of the two diastereoisomeric forms of allylic alcohol
126 (78% from 125). Independent treatment of each of these with diisopropyl
azodicarboxylate (DIAD) in the presence of triphenylphosphine resulted in an
Scheme 11 Synthesis of the basic pentacyclic framework, 103, associated with the montanine
alkaloids
intramolecular Mitsunobu reaction and formation of the corresponding 3-arylhexa-

hydroindole, 127 or 128, as the major product (70–85% yield) of reaction. Reduc-
tive cleavage of the sulfonamide residue within the former product using sodium
naphthalenide followed by immediate subjection of the product amine to a
Pictet–Spengler reaction then gave compound 129 (56%), the structure of which
was established by single-crystal X-ray analysis. Subjection of diastereoisomer 128
to an analogous reaction sequence afforded congener 130 (59%), the acquisition of
which constitutes a formal total synthesis of the racemic modification of the
montanine alkaloid pancracine (131).
3.4 The Crinine Alkaloids
The crinine alkaloids, which can embody either enantiomeric form of the 2,3,
4,4a-tetrahydro-1H-6H-5,10b-ethanophenanthridine framework, represent an
important sub-class within the Amaryllidaceae alkaloid family [53]. Many
members of this subclass display interesting biological properties including
immuno-stimulatory, cytotoxic and anti-malarial activities. As a consequence,
they have been the subject of numerous synthetic studies [53].
The key substructure associated with such systems is a C3a-arylpolyhydroindole
residue and, as shown in the three examples presented below, upon subjection of
such species to a Pictet–Spengler reaction the full tetracyclic framework of the
crinine alkaloids is established. Accordingly, this approach has been widely
adopted in establishing total syntheses of such natural products. Our syntheses of
the racemic modifications of maritinamine (132), epi-maritinamine (133) and
haemultine (134) as well as ent-amabiline (135) (Gao et al., unpublished work;
[54], [55]) serve to highlight three quite distinct approaches to the C3a-arylpolyhy-
droindole substructure. Two of these approaches exploit ring-fused gem-dihalogen-
ocyclopropanes as early or mid-stage intermediates.
The synthetic route used to access the alkaloids 132 and 133 is shown in
Scheme 12 [54] and begins with conversion of the readily available b-arylated
cyclopentenone 136 into the corresponding allylic acetate 137 (98%) that was
subjected to an Ireland–Claisen rearrangement reaction, thereby affording
the propionic acid derivative 138 (83%). Conversion of this last compound, via
dehydration of the derived primary amine, into the corresponding nitrile 139
provided the substrate for a dichlorocarbene addition reaction that delivered a ca.
1:1 diastereoisomeric mixture of the ring-fused cyclopropane 140 (38%). Reduc-
tion of the nitrile group within the last compound, protection of the resulting
Scheme 12 Total syntheses of ()-maritinamine [()-132] and ()-epi-maritinamine [()-133]
primary amine as the corresponding tert-butyl carbamate 141 (75%) and treatment
of this with silver tetrafluoroborate resulted in electrocyclic ring-opening of the three-
membered ring followed by intramolecular trapping of the ensuing p-allyl cation by
the pendant nitrogen and thus generating the desired C3a-arylated hexahydroindole
142 (65–75%). Treatment of compound 142 under Bouveault–Blanc-type reduction
conditions and subjection of the ensuing dechlorinated olefin 143 (98%) to a regio- but
non-stereocontrolled oxymercuration/demercuration protocol provided a chromato-
graphically separable mixture of alcohols 144 (25%) and 145 (71%). Independent
subjection of each of compounds 144 and 145 to reaction with paraformaldehyde in
the presence of formic acid resulted in cleavage of the carbamate residues and a
subsequent Pictet–Spengler reaction gave, after work-up with potassium carbonate
(of the resulting secondary amine), the required pentacyclic species 146 (72%) and
147 (58%), respectively. Treatment of each of these with boron trichloride resulted
in selective cleavage of the isopropyl ether residues and the formation of the target
crinines 132 (70%) and 133 (70%), respectively.
We have employed another cyclopropane-based approach to the synthesis of

the crinine alkaloids in seeking to prepare the natural product haemultine that,
somewhat controversially, has been assigned structure 134. Haemultine has not
been the subject of any total synthesis studies and this is probably because
the preparation of systems containing oxygenation in the C-ring has been rather
challenging. The reaction sequence used in accessing the racemic form of
compound 134 is shown in Scheme 13 (Gao et al., unpublished work) and involves,
as the first step, treatment of the readily available, ring-fused cyclopropane 148 with
silver cyanate and thereby affording and after cleavage of the three-membered ring
and trapping of the resulting p-allyl cation, the isocyanate 149. This was not
isolated but intercepted with added tert-butanol to give the carbamate 150 (79%).
Acid-catalysed cleavage of the Boc group followed by reaction of the resulting
primary amine with nosyl chloride afforded the sulfonamide 151 (87%) that was
subjected to a Suzuki–Miyaura cross-coupling reaction with the aryl boronic acid
61 and so affording the cyclohexene 152 (77%). Sequential treatment of the last
compound with sodium hydride and then 1-bromobut-2-yne afforded the secondary
amine-based sulfonamide 153 (86%) that readily participated in an intramolecular
Alder-ene reaction on treatment with 5 mol% Pd(OAc)2 in refluxing benzene and in
the presence of the strong s-donating ligand N,N0 -bis(benzylidene)ethylenediamine
(BBEDA) [56]. As a result the C3a-arylhexahydroindole derivative 154 was
obtained in 94% yield. Brief exposure of this compound to ozonolysis followed
by a work-up with dimethylsulfide (DMS) then gave the ketone 155 (33%), the
structure of which was confirmed by single-crystal X-ray analysis. Treatment of the
latter compound with thiophenolate anion resulted in cleavage of the nosyl group
and formation of the rather unstable amino-ketone 156. As a consequence it was
immediately subjected to reduction with sodium borohydride and this gave the
amino-alcohol 157 in 56% yield and as a single diastereoisomer. Treatment of
compound 157 with formaldehyde in the presence of hydrochloric acid then
delivered, via a Pictet–Spengler reaction, the target compound ()-134 (70%) the
structure of which was confirmed by single-crystal X-ray analysis. Efforts are now
underway to resolve this material into its constituent enantiomers and once this is
achieved and the specific rotations of these are determined it should be possible to
establish whether one of them matches the natural product haemultine.
A quite distinct approach to C3a-arylhexahydroindoles, and thence crinanes,
is highlighted in a synthesis of (+)-amabiline (135), the non-natural form of
the alkaloid, that we reported in 2009 [55]. Thus, as shown in Scheme 14, the
enantiomerically pure cis-1,2-dihydrocatechol 67 was converted, over two standard
steps, into the known diol 158 (85%) that was, in turn, subjected to selective
mono-O-silylation with TBS-Cl to give the homoallylic alcohol 159 (95%). Treat-
ment of compound 159 with p-methoxybenzyl trichloroacetimidate (p-MBTCA) in
conjunction with trityl tetrafluoroborate effected protection of the remaining
hydroxyl group without inducing loss of the TBS group and thereby affording
the cyclohexenyl bromide 160 (98%). This last compound engaged in a
Suzuki–Miyaura cross-coupling reaction with boronic acid 61 to give the arylated
cyclohexene 161 (90%) that upon treatment with tetra-n-butylammonium fluoride
Scheme 13 Total synthesis of the racemic form of the structure assigned to haemultine (134)
(TBAF) gave the allylic alcohol 162 (94%). Subjection of compound 162 to an
Eschenmoser–Claisen rearrangement using N,N-dimethylacetamide dimethylacetal
in toluene afforded the expected amide 163 (95%) that upon treatment with lithium
triethylborohydride gave the primary alcohol 164 (94%) which was transformed, by
standard methods, into the corresponding azide 165 (85%). Conversion of the PMB
ether moiety within compound 165 into the corresponding mesylate 166 followed
by Staudinger reduction of the azide residue within this last compound presumably
Scheme 14 Total synthesis of (þ)-amabiline (135)
gave the corresponding primary amine but this immediately engaged in an intra-
molecular SN0 reaction and thereby affording the C3a-arylhexahydroindole 167
(64%). Treatment of the last compound treatment with paraformaldehyde in the
presence of formic acid effected a Pictet–Spengler reaction and thus forming the
(bis)-formate ester 168. The target 135 was finally generated, in 65% overall yield
from 167, by treating compound 168 with dihydrogen in the presence of palladium
on carbon and potassium carbonate, thereby effecting both ester hydrolysis and
hydrogenation of the D-ring double bond.
3.5 Galanthamine
The alkaloid galanthamine (169) has been obtained from various Amaryllidaceae
species including daffodils, the red spider lily (Lycoris radiata) and the Caucasian
snowdrop (Galanthus woronowii). Its effectiveness as a centrally acting, selective,
reversible and competitive inhibitor of acetylcholinesterase has resulted in
galanthamine being introduced into the clinic in both the USA and Europe for the
symptomatic treatment of mild to moderate forms of Alzheimer’s disease [57].
These and various other intriguing features of this alkaloid have prompted exten-
sive synthetic studies of it [57].
The outcomes of our own efforts in the area [58], which have led to a synthesis of
the non-natural enantiomeric form of galanthamine (i.e. ent-169), are shown in
Schemes 15 and 16. Once again, the reaction sequence starts with the versatile cis-
1,2-dihydrocatechol 67 which is converted, using the well-established two-step
protocol shown in the first part of Scheme 6, into epoxide 69. Treatment of the latter
compound with acetic acid in the presence of phosphoric acid gave a trans-diol
mono-acetate that upon treatment with MOM-Cl afforded the anticipated and fully
protected compound 170 (74% from 69). Suzuki–Miyaura cross-coupling of the
product of acetate hydrolysis, namely cyclohexenyl bromide 171, with the readily
prepared arylboronic acid 172 afforded the expected cross-coupling product 173
(94%) that was subjected to a Mitsunobu inversion process, thus delivering, after
hydrolysis of the intermediate a-chloroacetate, the epimeric alcohol 174 (93%).
The latter compound readily participated in the same type of Eschenmoser–Claisen
rearrangement reaction used in the conversion 162 ! 163 (Scheme 14), thereby
affording amide 175 (89%) incorporating the critical quaternary carbon-centre
associated with the target natural product. Treatment of compound 175 with
molecular bromine in a mixture of toluene and acetone afforded, via a bromonium
ion-mediated cyclisation, the furannulated compound 176 (93%) that was readily
debrominated upon exposure to dihydrogen in the presence of palladium on
carbon and potassium carbonate. Acetylation of the ensuing alcohol 177 (68%)
Scheme 15 Synthesis of the ABC-ring system associated with ent-galanthamine (ent-169)
under standard conditions afforded ester 178 (90%) that was subjected to acetonide
hydrolysis using aqueous acetic acid. The ensuing diol was converted into the
corresponding thiocarbonate 179 (94%) that was, in turn, subjected to a Corey–Winter
reaction using trimethylphosphite and thereby delivering the cyclohexene 180

(72%). In anticipation of the manipulation of the amide unit within this last system,
the acetate was converted into the corresponding TBDPS ether 181 (81%) by
standard methods.
The completion of the synthesis of (+)-galanthamine from ether 181 clearly
requires construction of the D-ring of the target. To that end, compound 181
(Scheme 16) was treated with lithium triethylborohydride and thus providing the
1 -alcohol 182 (95%). Successive treatment of this last compound with
Dess–Martin periodinane (DMP) and N-bromosuccinimide (NBS) in the presence
of AIBN gave an intermediate acyl bromide that was intercepted with added
methylamine and thus affording amide 183 (78%). Removal of the TBDPS group
within this last compound and subjection of the resulting alcohol 184 to a
Pictet–Spengler reaction conditions gave, after work-up under basic conditions,
the lactam 185 (75%). Subjecting this compound to reaction with a-chloroacetic
acid under Mitsunobu conditions gave the expected ester 186 (93%) that upon
treatment with lithium aluminium hydride afforded the final target (+)-
galanthamine (ent-169) in 85% yield.
Scheme 16 Completion of a total synthesis of ent-galanthamine (ent-169)
This first generation synthesis of (+)-galanthamine should be capable of consid-

erable refinement, especially in regards to the protecting group regimes employed
and the manner in which the heterocyclic D-ring is constructed. Furthermore, since
the enantiomer of the starting material 67 is available, the illustrated chemistry also
allows access to ()-galanthamine (169). As such, a plethora of galanthamine
analogues is available in either enantiomeric form and these will be subjected to
evaluation as inhibitors of acetylcholinesterase. In addition, the application of this
chemistry to the synthesis of the structurally related morphine alkaloids is now
under investigation.
3.6 The Narcissus Alkaloids
The Narcissus “alkaloids” lycoricidine (187), narciclasine (188) and pancratistatin

(189) have attracted considerable attention because of their intriguing range of
properties including a capacity to inhibit protein synthesis and, thence, serve as
anti-viral as well as selective cytotoxic agents [59, 60]. These compounds also
display potent growth regulating and/or insect antifeedant activities. Such features,
coupled with the limited availability of these compounds from their natural sources,
have prompted extensive studies concerned with their synthesis. We have devel-
oped two distinct approaches to lycoricidine, narciclasine and various analogues
and these are now described [61–63]. Once again, one of these relies on cyclopropane
chemistry while the other exploits enantiomerically pure cis-1,2-dihydrocatechols
as starting materials.
The cyclopropane-based route [61] to various lycorine and pancratistatin

analogues is shown in Scheme 17 and starts with the conversion of cyclopentadiene
(190) into the ketal 191 (70%) via sequential treatment of the former compound
with lead tetraacetate in acetic acid, methanolic potassium carbonate and then
cyclohexanone in the presence of p-TsOH. Addition of dibromocarbene to
cyclopentene 191 afforded the gem-dibromocyclopropane 192 (84%) that upon
treatment with silver cyanate and then methanol gave a chromatographically
separable mixture of the allylic carbamates 193 (28%) and 194 (40%).
Suzuki–Miyaura cross-coupling of the latter product with aryl boronic acid 61
afforded the expected arylated cyclohexene 195 (82%) that was subjected to acid-
catalysed ketal group hydrolysis and the ensuing diol 196 was then reprotected as
the corresponding diacetate 197 (89%). Treatment of this last compound with a
combination of triflic anhydride and DMAP in dichloromethane at 0–15 C effected
a Bischler–Napieralski cyclisation reaction under remarkably mild conditions, thus
affording, after acid-catalysed hydrolysis of resulting imidates, lactam 198 (85%),
the structure of which was established by single-crystal X-ray analysis. Treatment
of compound 198 with sodium methoxide in THF/methanol then gave the racemic
modification of 2-deoxylycoricidine (199) (96%).
The allylic carbamate 193 formed as shown in Scheme 17 can be exploited in the
synthesis of a pancratistatin analogue. Thus, Suzuki–Miyaura cross-coupling of this
carbamate with aryl boronic acid 61 (Scheme 18) afforded the expected arylated
cyclohexene 200 (87%) that upon sequential treatment with diborane, alkaline
hydrogen peroxide, aqueous acid then acetic anhydride gave the triacetate 201
(42%). Subjecting this last compound to the Bischler–Napieralski reaction
Scheme 17 Synthesis of the racemic modification of 2-deoxylycoricidine (199)
conditions used for the conversion 197 ! 198 then afforded the second targeted
analogue, namely the triacetate 202 (59%).
A distinctly different approach to the Narcissus alkaloids is shown in Scheme 19
[62, 63] and started with the ever-useful cis-1,2-dihydrocatechol 67 that was first
converted into the PMP-acetal 203 (85%) under standard conditions.
Dihydroxylation of diene 203 under the Upjohn [50] conditions afforded diol 204
that was then converted into the (bis)-MOM ether 205 (59% from 203). Reductive
cleavage of the acetal moiety within the last compound could be accomplished
using DIBAl-H and the alcohol 206 (84%) so formed was protected as the
corresponding MOM ether 207 (90%). DDQ-mediated cleavage of the PMB ether
unit within this last compound then gave the mono-ol 208 (95%) that was subjected
to an Overman rearrangement reaction and thereby giving the corresponding
acetamide (65%). This was then cleaved to the corresponding amine 209 (89%)
by treatment with DIBAl-H. Suzuki–Miyaura cross-coupling of this last compound
with the readily available arylboronic acid 210 afforded, after spontaneous
lactamisation of the intermediate amino-ester, the (tris)-MOM ether 211 (83%)
of the non-natural enantiomer of lycoricidine. Treatment of compound 211 with
Scheme 18 Synthesis of the lycoricidine analogue 202
TMS-Br effected exhaustive cleavage of MOM ethers and thus afforded ent-
lycoricidine (ent-187) (62%) the structure of which was confirmed through a
single-crystal X-ray analysis of the derived triacetate.
A simple modification of the reaction sequence shown above has allowed
for the synthesis of ent-narciclasine (ent-188). Thus, as shown in Scheme 20,
Suzuki–Miyaura cross-coupling of the previously prepared 2-bromocyclohex-
2-enamine 209 with the readily synthesised aryl boronic acid 212 afforded the
expected lactam 213 (63%). Once again, treatment of the last compound with TMS-
Br resulted in exhaustive cleavage of the MOM ether residues and, this time, the
formation of the target compound ent-188 (48%).
Compounds ent-187 and ent-188, as well as several analogues available using
chemistry similar to that shown in Schemes 19 and 20, have been evaluated for their
cytotoxic effects in a 13-member human cancer cell-line panel and found to be only
weakly active [64]. In contrast, an authentic sample of the natural enantiomeric
form of narciclasine (188) was found to be highly active in the same screens.
4 The Erythrina Alkaloids
The Erythrina alkaloids represent a group of natural products isolated from various
species of plants of the same name and found in tropical and sub-tropical regions of
the world. They are all spirocyclic isoquinoline alkaloids and found in all parts of
Scheme 19 Total synthesis of ent-lycoricidine (ent-187)
Scheme 20 Total synthesis of ent-narciclasine (ent-188)

the source plants. Various substructural types are encountered within the class, the
most common of which are represented by erysodine (214) (an erythrinadiene) and
erythratine (215) (an erythrinene) that differ, inter alia, in the degrees and
arrangements of unsaturation within the five-membered and cyclohexane rings
[65]. These types of alkaloids exhibit a range of fascinating properties including
curare-like activities, as well as hypotensive, diuretic, laxative, sedative and CNS-
depressive properties. Not surprisingly, then, they have been the subjects of numer-
ous synthetic studies. Our own efforts in the area have focussed on the synthesis of
the non-natural enantiomer of erythramine (216) ([66]; for a summary of other
synthetic endeavours in this area see [67]). As with a number of the studies
described above, the underpinning technology used in obtaining ent-erythramine
is the electrocyclic ring-opening of a ring-fused gem-dihalocyclopropane and
trapping of the ensuing p-allyl cation by a pendant nucleophile.
The reaction sequence used in obtaining ent-erythramine (ent-216) is shown in

Scheme 21 and begins with the Suzuki–Miyaura cross-coupling of the readily
available aryl boronic acid 217 with the enantiomerically pure cyclopentene 218
that is generated, using chemoenzymatic techniques, from cyclopentadiene.
Selective cleavage of the TBDMS ether within the coupling product 219 (92%)
could be accomplished using pyridinium p-toluenesulfonate (PPTS) in ethanol
and the ensuing alcohol 220 (71%) was O-methylated with methyl iodide in the
presence of potassium hydride to give ether 221 (quant.). Subjection of this last
compound to reaction with dichlorocarbene gave ca. 2:1 mixture of
diastereoisomeric forms of the gem-dichlorocyclopropane 222 (91%). A five-
step reaction sequence was used to convert the side-chain TBDPS ether within
this last compound into the corresponding Alloc-protected primary amine. Thus,
compound 222 was desilylated using TBAF and the ensuing alcohol converted
into the corresponding mesylate that was treated with sodium azide, thereby
affording the expected azido-compound. Staudinger reduction of this last species
and reaction of the ensuing primary amine with allyl chloroformate afforded the
key sub-target 223 (87% overall yield from 222). In the first of two key reactions
associated with the synthesis, compound 223 was first treated with LiHMDS
and then silver tetrafluoroborate. By such means the required ring-cleavage/
spirocyclisation process took place and after treatment of the resulting
product mixture with Pd[0] in the presence of dimedone (to effect cleavage of
the Alloc-protecting group) a chromatographically separable mixture of the
diasteroisomeric spirocycles 224 (30%) and 225 (26%) was obtained. For the
purpose of installing the B-ring of the target alkaloid, compound 225 was treated
Scheme 21 Total synthesis of ent-erythramine (ent-216)
with ethylene oxide and the resulting amino-alcohol, the structure of which was
confirmed by X-ray analysis, was treated with molecular iodine triphenyl-
phosphine and imidazole. The iodide 226 (44%) so formed was reacted with tri-
n-butyltin hydride and AIBN and thereby inducing a radical addition/elimination
sequence analogous to that involved during the conversion 112 ! 113
(Scheme 10) with the result that ent-erythramine (ent-216) was generated in
89% yield. The biological evaluation of this compound and related ones is
currently underway.
5 Aspidospermidine
The Aspidosperma alkaloids are a group of more than 100 monomeric and dimeric
monoterpene indole alkaloids with aspidospermidine (228) representing a key
member of the class and sometimes considered to be the parent [68]. Numerous
total syntheses of this pentacyclic compound have been reported. Our own
contributions in the area were prompted by the discovery of a new method for
preparing indoles via a palladium-catalysed Ullmann cross-coupling reaction that
proceeds especially efficiently at close to room temperature [69] and which we felt
could serve as the centrepiece in developing a new synthesis of compound 228 and,
in the longer term, syntheses of dimeric members of the indole alkaloid class such
as the clinically significant alkaloids vinblastine and vincristine.
The early to middle stages of the route that we have used in synthesising target
228 are shown in Scheme 22 ([70]; for a summary of other synthetic endeavours
in this area see [71]) and involve the initial conversion of commercially available
3-ethoxycyclohexenone (229) into 3-ethylcyclohexenone (230) (89%) by standard
methods. Sodium borohydride-mediated reduction of the latter compound and
acetylation of the resulting allylic alcohol gave the allylic acetate 231 (96%) that
readily engaged in an Ireland–Claisen rearrangement to give the carboxylic acid 232
(62%) incorporating the quaternary carbon centre required in the final target. Chain
extension of compound 232 was achieved by first reducing the carboxylic acid
residue to the corresponding alcohol 233 (96%), oxidising this to the aldehyde
followed by engaging that in a Wittig reaction with (methoxymethylene)triphenyl-
phosphorane to give the enol ether 234 (92%). Compound 234 was then converted,
over two simple steps, into the alcohol 235 (84%) representing the higher homo-
logue of compound 233. Acetylation of compound 235 followed by an allylic
oxidation using a mixture of Cr(CO)6 and t-BuOOH gave the corresponding enone
(65%) that, in anticipation of the foreshadowed Pd[0]-catalysed Ullmann reaction,
was subjected to a Johnson-type a-iodination reaction using molecular iodine in
the presence of pyridine. The a-iodoenone 236 (quant.) so formed was subjected
to reaction with o-nitroiodobenzene (237) in the presence of copper powder and
Pd[0]. This afforded the cross-coupled product 238 (75%). The acetate residue
within compound 238 was converted, over three very conventional and reliable
steps, into the corresponding azide 239 (87%) and heating of this in refluxing
benzene resulted in the intramolecular 1,3-dipolar cycloaddition of the azide residue
onto the pendant enone followed by extrusion of dinitrogen from the resulting
triazoline to give the ring-fused aziridine 240 (72%). Treatment of this last
Scheme 22 Synthesis of the ABCD-ring system associated with aspidospermidine (228)
compound with HCl then afforded the a-chloroenone 241 (as its hydrochloride salt).
Reaction of compound 241 with titanium trichloride (in the form of its THF solvate)
resulted in reductive dechlorination and reductive cyclisation reactions and thereby
generating indole 242 (46% from 240).
The completion of the synthesis of aspidospermidine relied on a protocol

introduced by Heathcock [72] for annulating the E-ring to the ABCD-framework
of 228. Thus, as shown in Scheme 23, acylation of target compound 242 with
a-chloroacetyl chloride followed by a Finkelstein reaction afforded the
a-iodoacetamide 243 that upon treatment with silver triflate effected an intramo-
lecular alkylation reaction and the formation of the isoindole-based lactam 244.
Finally, reduction of this last compound with lithium aluminium hydride gave the
racemic modification of aspidospermidine (228) (32%).
Scheme 23 Completion of a total synthesis of ()-aspidospermidine [()-228]
Given that the S-enantiomer of compound 233 is readily available in essentially

enantiomerically pure form the work shown above constitutes a formal total
synthesis of the unnatural or ()-enantiomer of the title alkaloid. Since the alcohol
R-233 will almost certainly be available by closely related means, the chemistry
presented here should also allow access to the naturally occurring enantiomeric
forms of various Aspidosperma alkaloids.
6 Conclusion
An underpinning feature associated with many of the reaction sequences described

above is the generation of a 2- or 3-halogenated 2-cyclohexen-1-ol moiety from a
ring-fused gem-dihalocyclopropane or a cis-1,2-dihydrocatechol. This emphasis
arises because of the exceptional synthetic utility of this moiety. In particular, the
capacity to engage it (or its derivatives) in cross-coupling reactions, radical addition-
elimination processes and/or Claisen- or Overman-type rearrangements means
that it can be exploited in an extraordinarily diverse range of settings and thus
serve as a precursor to a remarkable range of structures. In this context the
a-iodocyclohexenone 236 (Scheme 22), a pivotal precursor to aspidospermidine,

can be viewed as a 2-halogeno-2-cyclohexen-1-ol derivative and one that readily
engages in cross-coupling reactions. It is also worth noting that the double bond
embedded within such cross-coupling products (e.g. 238, Scheme 22) has, by virtue
of the attachment of the strongly electron-withdrawing carbonyl and nitrophenyl
groups at the same end of it, some potentially very useful electrophilic properties
that should be capable of exploitation in various contexts.
On the face of it, the utilisation of cyclohexane-1,3-dione (121) as shown in
Scheme 11 does not appear to fit the analysis presented immediately above.
However, by virtue of its participation in the illustrated Michael addition reaction
(120 + 121 ! 122) and the subsequent manipulation of adduct 122 (equivalent to
a cross-coupling product) compound 121 could legitimately be viewed as a syn-
thetic equivalent for a 2-halogeno-2-cyclohexen-1-ol. The chemical efficiency of
the Michael addition reaction is notable and suggests a greater utility for this
process than has been realised so far.
The availability of the cis-1,2-dihydrocatechols in enantiomerically pure form
has meant that, thus far, they have proven somewhat more useful as precursors to
alkaloids than the gem-dihalocyclopropanes. However, that situation could well
change if such systems were also available in scalemic form. Addressing this matter
is the subject of ongoing work in our laboratories.
7 Notes Added in Proof
1. MacMillan has recently described concise and enantioselective syntheses of

strychnine and several related alkaloids (S. B. Jones, B. Simmons, A. Mastracchio
and D. W. C. MacMillan, Nature, 2011, 475, 183);
2. Details of the synthesis of ent-clividine [ent-52] shown in Scheme 7 have now
been published (L. V. White, B. D. Schwartz, M. G. Banwell and A. C. Willis,
J. Org. Chem., 2011, 76, 6250)
3. Details of the synthesis of narseronine (53) shown in Scheme 9 have now been
published (B. D. Schwartz, M. G. Banwell and I. A. Cade, Tetrahedron Lett., 2011,
52, 4526)
References
1. Hesse M (2002) Alkaloids: nature’s curse or blessing? Wiley-VCH, Weinheim, pp 1–3

2. Blum MS (1995) Chemistry and toxicology of diverse classes of alkaloids. Alaken Inc.,
Ft. Collins, Colorado
3. Urban S, Hickford SJH, Blunt JW, Munro MHG (2000) Curr Org Chem 4:765
4. Hughes CC, Fenical W (2010) Chem Eur J 16:12512
5. ApSimon J (1977) The total synthesis of natural products, vol 3. Wiley, New York
6. Enders D, Tiebes J (1993) Liebigs Ann Chem 173 and references cited therein
7. Robinson R (1917) J Chem Soc 762

8. Woodward RB, Doering WE (1944) J Am Chem Soc 66:849
9. Gates M, Tschudi G (1956) J Am Chem Soc 78:1380
10. Kornfeld EC, Fornefeld EJ, Kline GB, Mann MJ, Morrison DE, Jones RG, Woodward RB
(1956) J Am Chem Soc 78:3087
11. Woodward RB, Bader FE, Bickel H, Frey AJ, Kierstead RW (1958) Tetrahedron 2:1
12. Schreiber J, Leimgruber W, Pesaro M, Schudel P, Threlfall T, Eschenmoser A (1961) Helv
Chim Acta 44:540
13. van Tamelen EE, Spencer TA, Allen DS, Orvis RL (1961) Tetrahedron 14:8
14. Nakamura T (1962) Chem Pharm Bull 10:299
15. Scott AI, McCapra F, Buchanan RL, Day AC, Young DW (1965) Tetrahedron 21:3605
16. Scott AI, McCapra F, Nabney J, Young DW, Day AC, Baker AJ, Davidson TA (1963) J Am
Chem Soc 85:3040
17. Woodward RB (1963) (with G. Volpp and J. Z. Gougoutas), The Harvey Lectures 31
18. Evans DA, Tanis SP, Hart DJ (1981) J Am Chem Soc 103:5813
19. Woodward RB, Cava MP, Ollis WD, Hunger A, Daeniker HU, Schenker K (1954) J Am Chem
Soc 76:4749
20. Magnus P, Ladlow M, Elliot J, Kim CS (1989) J Chem Soc Chem Commun 518 and references
cited therein
21. Martin CL, Overman LE, Rodhe JM (2010) J Am Chem Soc 132:4894
22. Beemelmanns C, Reissig H-U (2010) Angew Chem Int Ed 49:8021
23. Martin DBC, Vanderwal CD (2011) Chem Sci 2:649
24. Chemnitius F (1928) J Prakt Chem 118:29
25. Brossi A (1990) J Med Chem 33:2311
26. Banwell MG, Lambert JN, Mackay MF, Greenwood RJ (1992) J Chem Soc Chem Commun
974
27. Banwell MG (1996) Pure Appl Chem 68:539
28. Graening T, Bette V, Neud€orfl J, Lex J, Schmalz H-G (2005) Org Lett 7:4317
29. Battersby AR, MacDonald E, Stachulski AV (1983) J Chem Soc Perkin Trans 1 3053
30. Banwell MG, Ireland NK (1994) J Chem Soc Chem Commun 591
31. Banwell MG, Hamel E, Ireland NK, Mackay MF (1994) Heterocycles 39:205
32. Lee JC, Cha JK (2001) J Am Chem Soc 123:3243
33. Abu Zarga MH, Sabri SS, Al-Tel TH, Atta-ur-Rahman, Shah Z, Feroz M (1991) J Nat Prod
54:936
34. Banwell MG, Fam M-A, Gable RW, Hamel E (1994) J Chem Soc Chem Commun 2647
35. Banwell MG, Edwards AJ, Jolliffe KA, Smith JA, Hamel E, Verdier-Pinard P (2003) Org
Biomol Chem 1:296
36. Banwell MG, Beck DAS, Willis AC (2006) Arkivoc (iii):163
37. Kholod I, Vallat O, Buciumas A-M, Neier R (2011) Heterocycles 82:917
38. Paras NA, MacMillan DWC (2001) J Am Chem Soc 123:4370
39. Banwell M, Edwards A, Smith J, Hamel E, Verdier-Pinard P (2000) J Chem Soc Perkin Trans 1
1497
40. Cook JW, Loudon JD (1952) In: Manske RHF, Holmes HL (eds) The alkaloids, vol 2.
Academic Press, New York, p 331
41. D€opke W, Bienert M (1970) Tetrahedron Lett 11:3245
42. Pigni NB, Berkov S, Elamrani A, Benaissa M, Viladomat F, Codina C, Bastida J (2010)
Molecules 15:7083
43. Banwell MG, Harvey JE, Hockless DCR (2000) J Org Chem 65:4241
44. Jones MT, Schwartz BD, Willis AC, Banwell MG (2009) Org Lett 11:3506
45. Haning H, Giro-Manas C, Paddock VL, Bochet CG, White AJP, Bernardinelli G, Mann I,
Oppolzer W, Spivey AC (2011) Org Biomol Chem 9:2809
46. Martin SF (1988) In: Brossi A (ed) The alkaloids, vol 30. Academic Press, San Diego, p 251
47. Banwell MG, Kokas OJ, Willis AC (2007) Org Lett 9:3503
48. Anada M, Tanaka M, Shimada N, Nambu H, Yamawaki M, Hashimoto S (2009) Tetrahedron

65:3069
49. Kokas OJ, Banwell MG, Willis AC (2008) Tetrahedron 64:6444
50. VanRheenen V, Kelly RC, Cha DY (1976) Tetrahedron Lett 1973
51. Matveenko M, Banwell MG, Willis AC (2008) Org Lett 10:4693
52. Banwell MG, Edwards AJ, Jolliffe KA, Kemmler M (2001) J Chem Soc Perkin Trans 1 1345
53. Lewis JR (1998) Nat Prod Rep 15:107
54. Banwell MG, Harvey JE, Jolliffe KA (2001) J Chem Soc Perkin Trans 1 2002
55. Findlay AD, Banwell MG (2009) Org Lett 11:3160
56. Lehmann AL, Willis AC, Banwell MG (2010) Aust J Chem 63:1665
57. Magnus P, Sane N, Fauber BP, Lynch V (2009) J Am Chem Soc 131:16045
58. Banwell MG, Ma X, Karunaratne OP, Willis AC (2010) Aust J Chem 63:1437
59. Lewis JR (1994) Nat Prod Rep 11:329
60. Rinner U, Hudlicky T (2005) Synlett 365
61. Banwell MG, Cowden CJ, Gable RW (1994) J Chem Soc Perkin Trans 1 3515
62. Matveenko M, Kokas OJ, Banwell MG, Willis AC (2007) Org Lett 9:3683
63. Matveenko M, Banwell MG, Willis AC (2008) Tetrahedron 64:4817
64. Matveenko M, Banwell MG, Joffe M, Wan S, Fantino E (2009) Chem Biodivers 6:685
65. Parsons AF, Palframan MJ (2010) In: Cordell GA (ed) The alkaloids, chemistry and biology,
vol 68. Elsevier, Oxford, p 39
66. Stanislawski PC, Willis AC, Banwell MG (2007) Chem Asian J 2:1127
67. Chuang KV, Navarro R, Reisman SE (2011) Chem Sci. 2:1086
68. Pereira J, Barlier M, Guillou C (2007) Org Lett 9:3101, and references cited therein
69. Banwell MG, Kelly BD, Kokas OJ, Lupton DW (2003) Org Lett 5:2497
70. Banwell MG, Lupton DW, Willis AC (2005) Aust J Chem 58:722
71. De Simone F, Gertsch J, Waser J (2010) Angew Chem Int Ed 49:5767
72. Toczko MA, Heathcock CH (2000) J Org Chem 65:2642
Top Curr Chem (2012) 309: 203–254
DOI: 10.1007/128_2011_192
Published online: 5 July 2011
Synthesis of Pyrrole and Carbazole Alkaloids
Ingmar Bauer and Hans-Joachim Kn€

olker
Abstract An overview of recent transition metal-catalyzed syntheses of pyrroles

and carbazoles is presented. The focus is on methods which have been applied to
the preparation of biologically active naturally occurring pyrrole and carbazole
alkaloids. For pyrroles, special attention is paid to silver(I)-catalyzed cyclization
reactions. For carbazoles, iron(0)-mediated and palladium(0/II)-catalyzed cycliza-
tion reactions are highlighted and their broad range of applications is discussed.
Keywords Carbazoles Iron Oxidative cyclization Palladium Pyrroles Silver
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
2 Synthesis of Pyrrole Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
2.1 Silver-Catalyzed Cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
2.2 Gold-Catalyzed Cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
2.3 Copper-Catalyzed Cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
2.4 Cyclizations Catalyzed by Other Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
3 Synthesis of Carbazole Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
3.1 Iron-Mediated Synthesis of Carbazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
3.2 Palladium-Catalyzed Synthesis of Carbazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Abbreviations
ADP Adenosine diphosphate

ATP Adenosine triphosphate
BINAP 2,20 -Bis(diphenylphosphino)-1,10 -binaphthyl
I. Bauer and H.-J. Kn€olker (*)

Department Chemie, Technische Universit€at Dresden, Bergstraße 66, 01069 Dresden, Germany
204 I. Bauer and H.-J. Kn€
olker
CDK5 Cyclin-dependent kinase 5

DIBAL-H Diisobutylaluminum hydride
DMDO Dimethyldioxirane
dppp 1,3-Bis(diphenylphosphino)propane
ent Enantiomeric
HIV Human immunodeficiency virus
MTPA-Cl a-Methoxy-a-trifluoromethylphenylacetyl chloride
NHC N-Heterocyclic carbene
rac Racemic
S-Phos 2-Dicyclohexylphosphino-20 ,60 -dimethoxybiphenyl
TB Tuberculosis
TBAF Tetrabutylammonium fluoride
TON Turnover number
TPS tert-Butyldiphenylsilyl
X-Phos 2-Dicyclohexylphosphino-20 ,40 ,60 -triisopropylbiphenyl
1 Introduction
Pyrroles represent an important class of biologically active heterocyclic compounds

which are also of pharmacological interest. A large number of structurally diverse
pyrrole, pyrroline, and pyrrolidine alkaloids is known [1–7]. As a subunit of the
porphyrin framework, pyrroles are abundant in all aerobic organisms. Classical
approaches to pyrroles include the Hantzsch, Knorr, and Paal–Knorr synthesis [8].
The biological importance of pyrroles prompted many research groups to develop
new methods for their construction. In recent years, metal-mediated routes to
pyrroles have been covered in several reviews [9–16]. Even though many elegant
new pyrrole syntheses have been described, only a few have found broader appli-
cation to the synthesis of naturally occurring pyrrole, pyrroline, and pyrrolidine
alkaloids. Section 2 of the present review provides an outline of recent progress in
metal-mediated pyrrole synthesis.
The pyrrole ring is also the central core of the carbazole framework. During the
last four decades an increasing number of naturally occurring carbazole alkaloids
has been described [17–20]. The majority of carbazoles originates from higher
plants of the genera Murraya, Glycosmis, Clausena, and Micromelum, all from the
family Rutaceae. Other sources are bacteria (e.g., Streptomyces), algae (e.g., Hyella
caespitosa), and fungi (e.g., Aspergillus species). Due to their versatile biological
activity, carbazoles have been the subject of extensive biological and chemical
investigations during recent years. The range of their pharmacological effects
includes anti-HIV, anti-TB, anti-malarial, anti-tumor, and neuronal cell protective
activity. Our study of the anti-TB activity of carbazoles revealed that some com-
pounds may be considered to be new lead structures for anti-TB agents [21–23].
Beyond classical approaches (for example the Fischer–Borsche, Graebe–Ullmann,
and Cadogan syntheses), a variety of transition metal-catalyzed routes to carbazoles
Synthesis of Pyrrole and Carbazole Alkaloids 205
has been developed. The present chapter also summarizes recent progress and
applications from our laboratories as an update of previous reviews [19, 24, 25].
2 Synthesis of Pyrrole Alkaloids
2.1 Silver-Catalyzed Cyclization
In 2004 we reported a novel silver-mediated oxidative cyclization of homopropar-

gylamines 2 to pyrroles 3 (Scheme 1) [26]. The substrates 2 are easily available by
addition of propargyl Grignard reagents to Schiff bases 1 (R2 ¼ aryl). If R1 is not
an acceptor group, silver(I) functions as an oxidant in the course of this reaction.
Thus, stoichiometric amounts of silver(I) salts are consumed in the aromatization
to the pyrroles 3. The reaction is presumably induced by coordination of the
alkyne to the silver(I) cation followed by an amino-argentation of the alkyne
moiety, protonation of a vinylsilver(I) complex, b-hydride elimination to gener-
ate metallic silver and hydrogen, and a final deprotonation of the intermediate
pyrrolium ion. For trimethylsilyl-substituted propargyl Grignard reagents (R3 ¼
SiMe3), the trimethylsilyl group is lost by protodesilylation in the course of the
cyclization process.
R2 H BF3 •OEt2 R2 Ag(I)

R2 N R3
N 1
R3 NH R3
R BrMg R 1
R1
1 2 3
AgOAc
–
– AcOH
OAc
[Ag]+
R2 –
OAc
R2
N 3
R N+ R3
R1 H
H R1
H+ – [AgH]
[Ag] [Ag]
H
–OAc
H
R2 N R3
R2 N+ R3 Ag + 0.5 H2
–
R1 OAc
R1
Scheme 1 Synthesis of pyrroles 3 from Schiff bases 1 by silver(I)-mediated oxidative cyclization

of the homopropargylamines 2
olker
Using this method, we have synthesized the indolizino[8,7-b]indole alkaloid ()-

harmicine [()-7] [27]. (R)-(+)-Harmicine (7) was isolated in 1998 from the ethanol
extract of the leaves of the Malaysian plant Kopsia griffithii, which shows anti-
leishmania activity [28]. Our synthesis started from 3,4-dihydro-b-carboline (4)
(Scheme 2). Addition of trimethylsilylpropargylmagnesium bromide afforded 1-(3-
trimethylsilylpropargyl)-1,2,3,4-tetrahydro-b-carboline (5). Silver(I)-mediated oxi-
dative cyclization of compound 5 afforded 5,6-dihydro-11H-indolizino[8,7-b]indole
(6) with concomitant loss of the trimethylsilyl group. Finally, rhodium-catalyzed
hydrogenation provided ()-harmicine [()-7] in three steps and 46% overall yield.
Zhang et al. isolated the pyrrolo[2,1-a]isoquinoline alkaloid crispine A (11) from
the extracts of the plant Carduus crispus [29]. Extracts of this plant have been used
in traditional Chinese folk medicine for the treatment of cold, stomach ache, and
rheumatism. In a screening assay, Zhang et al. found that the extracts of C. crispus
inhibit the growth of some human cancer cell lines and show cytotoxic activity
[29]. The silver(I)-promoted oxidative cyclization of homopropargylamines opened
up simple access to racemic crispine A [()-11] (Scheme 3) [30]. Addition of
BF3•OEt2 AgOAc
NH
N
SiMe3 N 77 %
N BrMg H
H SiMe3
68 %
4 5
N H2, Rh/C N
N 88 % N
H H
6 (±)-7 (±)-harmicine
Scheme 2 Silver(I)-mediated synthesis of ()-harmicine [()-7]
MeO BF3•OEt2 MeO NH AgOAc

N SiMe3 58 %
MeO MeO
BrMg SiMe3
8 61 % 9
MeO N H2, Rh/C MeO N

66 %
MeO MeO
10 (±)-11 (±)-crispine A
Scheme 3 Silver(I)-mediated synthesis of ()-crispine A [()-11]

trimethylsilylpropargylmagnesium bromide to 3,4-dihydro-6,7-dimethoxyisoqui-

noline (8) led to the homopropargylamine 9. Oxidative cyclization of 9 with
concomitant protodesilylation in the presence of silver(I) acetate afforded the
pyrrolo[2,1-a]isoquinoline 10. Subsequent catalytic hydrogenation using rhodium
on charcoal provided ()-crispine A [()-11] in three steps and 23% overall yield.
In extension of our silver(I)-mediated synthesis of pyrroles, we have developed a
catalytic version which could be realized by using a tosyl function as acceptor at the
nitrogen atom. Thus, cyclization of N-tosyl-substituted homopropargylamines 12 to
D2-pyrrolines 13 has been achieved with catalytic amounts of the silver(I) salt.
Aromatization by subsequent elimination of r-toluenesulfinic acid on treatment
with potassium tert-butoxide as base afforded the pyrroles 14 (Scheme 4) [31].
This procedure was applied to the syntheses of pentabromo- and pentachloro-
pseudilin. Pentabromopseudilin (20) was isolated from Pseudomonas bromoutilis
[32, 33] and a marine species of Chromobacterium [34]. Pentabromopseudilin (20)
is a highly active antibiotic and also shows anti-tumor and phytotoxic activity
[34, 35]. Pentachloropseudilin (23) was first isolated from an Actinoplanes strain
(ATCC 33002) [36]. Pentachloropseudilin (23) has a lower antibiotic potency than
pentabromopseudilin (20).
Our synthesis of pentabromopseudilin (20) started from 2-methoxybenzalde-
hyde (15) (Scheme 5) [31]. Treatment with p-toluenesulfonamide provided the
N-tosylimine 16. Reaction of compound 16 with trimethylsilylpropargylmagne-
sium bromide and subsequent protodesilylation with tetrabutylammonium fluoride
(TBAF) afforded the homopropargylamine 17. Catalytic amounts of silver(I)
R1 cat. Ag(I) KOt-Bu

R1 N R1 N
NH H
Ts Ts
12 13 14
Scheme 4 Pyrroles 14 by silver(I)-catalyzed cyclization of N-tosyl-homopropargylamines 12
1. BrMg
OMe OMe SiMe3
p-TsNH2 2. TBAF OMe cat. AgOAc
CHO
N
94 % 66 % NH 88 %
Ts
Ts
15 16 17
Br Br
HO
OMe 1. KOt-Bu OH Br
2. Na2S Py•HBr•Br2
N Br
N 73 % N 59 % H
H
Ts
Br
18 19 20 pentabromopseudilin
Scheme 5 Silver(I)-catalyzed synthesis of pentabromopseudilin (20)

olker
acetate induced a cyclization by intramolecular hydroamination of 17 to the

2,3-dihydropyrrole 18. Subsequent aromatization and cleavage of the methyl
ether provided pseudilin (19). Pentabromination of 19 with pyridinium tribromide
afforded pentabromopseudilin (20) in seven steps and 24% overall yield.
The analogous route to pentachloropseudilin (23) was not successful due to an
insufficient electrophilic pentachlorination of pseudilin (19). The problem was
solved by using 3,5-dichloro-2-methoxybenzaldehyde (21) as starting material
(Scheme 6). Thus, two of the five chlorine atoms are already present at an early
stage. For the synthesis of O-methyldichloropseudilin 22, compound 21 was sub-
jected to the same sequence of synthetic steps as described above for pentabro-
mopseudilin (20). Electrophilic chlorination using N-chlorosuccinimide (NCS)
followed by cleavage of the methyl ether provided pentachloropseudilin (23)
which was obtained in seven steps and 19% overall yield. Moreover, intermediate
22 opens up the access to non-natural pseudilin derivatives containing different
halogens in the phenolic and the pyrrole ring as shown by the synthesis of tribro-
modichloropseudilin. Using 3,5-difluoro-2-methoxybenzaldehyde as starting mate-
rial, the reaction sequence described above led to tribromodifluoropseudilin [31].
The pentahalogenated pseudilins have been studied in terms of their ability
to inhibit skeletal muscle myosin-2 ATPase. This property can be potentially
exploited for the treatment of a broad range of diseases such as cancer, malaria,
and muscle malfunctions. It turned out that pentabromopseudilin (20) was as
efficient as the known myosin-2 ATPase inhibitor ()-blebbistatin. An X-ray
crystallographic analysis of pentabromopseudilin (20) with the myosin-2 motor-
domain complex and Mg2+ADP-meta-vanadate led to the discovery of a new
allosteric binding site of this motor protein. Thus, halogenated pseudilins can be
regarded as a new class of myosin ATPase inhibitors [31].
In analogy to homopropargylamines, dihomopropargylamines can also be sub-
jected to a silver-catalyzed hydroamination. Messerle et al. evaluated a number
of different catalytic systems for the cyclization of 4-pentyn-1-amine to give
2-methyl-D1-pyrroline. As catalysts they used silver(I) complexes which were
generated from silver(I) salts and different P- and N-containing bidentate ligands.
The best catalyst was obtained from 1-[2-(diphenylphosphino)ethyl]pyrazole and
silver(I) triflate and achieved a turnover rate of 129 h1 [37]. Phenanthroline silver
complexes are efficient and recyclable catalysts for the intramolecular hydroamina-
tion of dihomopropargylamines to 2-substituted D1-pyrrolines [38].
OMe Cl
OMe
1. NCS HO Cl
Cl CHO Cl Cl
5 steps 2. BBr3
N N Cl
H 64 % H
29 %
Cl Cl Cl
21 22 23 pentachloropseudilin
Scheme 6 Silver(I)-catalyzed synthesis of ()-pentachloropseudilin (23)

• cat. Ag(I)
NH or N
PG
cat. Au(I) PG
24 25
Scheme 7 Cyclization of buta-2,3-dien-1-amines 24 to D3-pyrrolines 25
The cyclization of buta-2,3-dien-1-amines 24 to form D3-pyrrolines 25 can be

achieved with silver(I) salts as catalysts (Scheme 7) [39–41]. Reissig et al. utilized
this strategy for the synthesis of the pyrrolidine alkaloid ()-codonopsinine [42]
and to the azaspirane core of the fungal immunosuppressant FR 901483 [43].
Further silver(I)-catalyzed syntheses of pyrroles include the cycloisomerization
of N-allyl-N-propargylamines to afford 3-vinylidenepyrrolidines, which can be
isomerized to 3-vinyl-3-pyrrolines [44]. The reaction of b-alkynylketones with
primary amines in the presence of silver(I) or gold(I) catalysts provides functiona-
lized pyrroles in good yields [45].
2.2 Gold-Catalyzed Cyclization
Gold has become very popular as catalyst in organic synthesis in recent years (for
reviews, see [10, 12, 15, 46]). Gold catalysis has also been investigated for construc-
tion of the pyrrole ring system. In analogy to the silver(I)-catalyzed process described
above, the hydroamination of a-aminoallenes 24 to substituted D3-pyrrolines 25 has
also been catalyzed by gold(I) salts (Scheme 7). The active catalyst in this process is
probably a gold(I) species, even when gold(III) salts are employed as precatalysts
[47]. The cycloisomerization of N-allyl-N-propargylamines, which can be achieved
with silver(I) catalysts (see above) [44], has also been studied using gold(I) catalysis.
This gold-catalyzed process provided 3-alkylidene-4-vinylpyrrolidines which can
potentially be transformed to pyrroles [48]. The gold(I)-catalyzed ring expansion
of 2-alkynyl-3-aryl-1-tosylaziridines afforded 2,5-disubstituted 1-tosylpyrroles
[49, 50]. Pale et al. carried out this reaction with cyclohexane-fused aziridines to
furnish 4,5,6,7-tetrahydroindoles [51]. 1-Aminopent-4-en-2-ynes undergo a gold(I)-
catalyzed cyclization to give 2-substituted 4-methylpyrroles [52]. Cyclization of
1-amino-3-alkyn-2-ols using a combination of (triphenylphosphane)gold(I) chloride
with either silver(I) bis(trifluoromethanesulfonyl)imide or silver(I) triflate as catalytic
system provided substituted pyrroles [53]. Toste et al. reported a gold(I)-catalyzed
cyclization of homopropargyl azides 26 to substituted pyrroles 27 (Scheme 8) [54].
2.3 Copper-Catalyzed Cyclization
Buchwald et al. reported a Cu(I)-catalyzed domino amidation/hydroamidation

procedure of 1-halobut-1-en-3-ynes 28 with tert-butyl carbamate to form substi-
tuted N-Boc-protected pyrroles 29 (Scheme 9) [55].
olker
R
R
cat. Au[I] (or Zn[II] or Pt[IV])
N
N3 H
26 27
Scheme 8 Synthesis of pyrroles 27 by cyclization of homopropargyl azides 26
X cat. Cu(I) R
R
H2N–Boc N
Boc
28 29
Scheme 9 Synthesis of N-Boc-pyrroles 29 from 1-halobut-1-en-3-ynes 28 and tert-butyl carbamate
The same group has also developed an efficient Cu-catalyzed method for the
reaction of 1,4-dihalo-1,3-dienes with tert-butyl carbamate to afford N-Boc-pyrroles
[56]. A similar cyclizing amidation of 1,4-diiodo-1,3-dienes with primary amides
led to di- or trisubstituted N-acylpyrroles in good yields using copper(I) iodide as
catalyst [57]. A double copper(I)-catalyzed vinylation of N,N0 -bis-Boc-hydrazine
afforded N,N0 -bis-Boc-N,N0 -divinylhydrazines. Thermally induced [3,3] sigmatro-
pic rearrangement of these intermediates followed by cyclization provided unsym-
metrically substituted pyrroles [58]. 1,2,5-Triarylpyrroles have been obtained by
copper(I) chloride-catalyzed addition of arylamines to 1,4-diarylbuta-1,3-diynes
[59]. Oxidative cyclization of b-amino-a,b-enones or b-amino-a,b-enoates with
dialkyl acetylenedicarboxylates catalyzed by copper(I) iodide in the presence of
oxygen afforded a variety of persubstituted pyrroles [60]. Cu(II)-catalyzed 1,4-
addition of ethyl acetoacetate or acetylacetone to a-ethoxycarbonylvinyl azides
and subsequent cyclocondensation provided 2,3,4,5-tetrasubstituted pyrroles [61].
2.4 Cyclizations Catalyzed by Other Metals
This section covers cyclizations to the pyrrole nucleus catalyzed by other metals
(Ti, Mn, Ru, Pd, Pt, Zn, In). Dembinski and co-workers used zinc(II) chloride as
ligand-free catalyst for the microwave-assisted cyclization of homopropargyl
azides 26 to afford substituted pyrroles 27 (Scheme 8) [62]. A similar methodology
for the synthesis of 2,4,5-trisubstituted pyrroles was described by Driver et al.
employing substituted 1-azidobuta-1,3-dienes in a cyclization reaction using cata-
lytic amounts of zinc(II) iodide [63]. A three-component zinc-catalyzed one-pot
cyclization of aromatic and aliphatic propargylic acetates, silyl enol ethers,
and primary amines to substituted pyrroles has been described by Zhan et al.
The reaction sequence includes propargylation of the silyl enol ether, amination,
5-exo-dig-cyclization, and isomerization [64]. Hiroya and co-workers have shown
that platinum(IV) efficiently catalyzes the cyclization of homopropargyl azides 26

to give functionalized pyrroles 27 in good yields (Scheme 8) [65]. Platinum(II) has
been proven to be less effective in this process. The platinum-catalyzed ring
expansion of 2-alkynyl-1-benzylaziridines in aqueous media provided substituted
pyrroles in good yields [66]. This method corresponds to the similar gold-catalyzed
process employing 2-alkynyl-1-tosylaziridines (cf. Sect. 2.2, [49, 50]). Highly
substituted pyrroles have become accessible in a one-pot indium(III)-catalyzed
three-component reaction of propargylic alcohols, 1,3-dicarbonyl compounds,
and primary amines [67]. A variety of alkyne-1,4-diols has been subjected to a
ruthenium(II)-catalyzed isomerization leading to 1,4-diketones. In the presence of
primary amines, a spontaneous cyclization occurs to provide 1,2,5-trisubstituted
pyrroles [68]. Starting from a-haloalkynols, Ackermann et al. obtained mixtures of
diastereoisomeric 1-halobut-1-en-3-ynes. In the presence of a primary amine,
titanium tetrachloride-catalyzed intermolecular hydroamination of these com-
pounds led to di-, tri-, tetra-, and pentasubstituted pyrroles [69]. M€uller and
co-workers reported a one-pot three-component reaction of acid chlorides,
N-Boc-protected propargylamines, and sodium iodide to afford 2-substituted
N-Boc-4-iodopyrroles [70]. An initial palladium-catalyzed Sonogashira coupling
led to the intermediate ynones. Subsequent addition of iodide followed by cyclo-
condensation afforded the pyrroles. As the palladium catalyst was still active after
this reaction sequence, it could be exploited for another Sonogashira-coupling
at the N-Boc-4-iodopyrrole to generate 4-alkynyl-N-Boc-pyrroles [70]. Starting
from vinyl azides and 1,3-dicarbonyl compounds, Mn(III)-catalyzed cyclization
provided 2,3,5-trisubstituted and 2,3,4,5-tetrasubstituted pyrroles [71]. This reac-
tion is related to the corresponding Cu(II)-catalyzed process reported by the same
group (cf. Sect. 2.3, [61]). In contrast to the latter, a radical mechanism has been
proposed for the Mn(III)-catalyzed reaction [71].
3 Synthesis of Carbazole Alkaloids
3.1 Iron-Mediated Synthesis of Carbazoles
In 1989 we reported an iron-mediated route for the construction of the tricyclic

carbazole skeleton [72, 73]. This convergent method was applied to the total
synthesis of the naturally occurring alkaloid carbazomycin A [72]. Key steps of
our iron-mediated approach are the consecutive CC bond formation and oxidative
cyclization (formation of the CN bond) between an electrophilic tricarbonyl(Z5-
cyclohexadienylium)iron complex salt 30 and an arylamine 31 (Scheme 10).
Subsequent oxidation and demetalation provides the aromatized carbazole 32.
Starting material for this synthetic strategy is tricarbonyl(Z5-cyclohexadieny-
lium)iron tetrafluoroborate 30, which can be prepared from cyclohexa-1,3-diene
(33) and pentacarbonyliron in two steps [74, 75]. Using catalytic amounts of a
olker
R R′
R R′
+ +
(OC)3Fe
− H2N N
BF4
H
30 (R = H) 31 32
Scheme 10 General principle of the iron-mediated carbazole synthesis
Fe(CO)5 Ph3C+BF4–
+
(OC)3Fe (OC)3Fe
cat. 1-azadiene 98 %
99 % BF4–
33 34 30
Scheme 11 Preparation of tricarbonyl(Z5-cyclohexadienylium)iron tetrafluoroborate (30)
1-azabuta-1,3-diene, the complexation of 33 with pentacarbonyliron provided

tricarbonyl(Z4-cyclohexadiene)iron (34) in excellent yield (Scheme 11) [76–78].
The modified reactivity of the diene system in this complex has been exploited for
many applications [79–88]. Hydride abstraction at complex 34 using triphenylcar-
benium tetrafluoroborate afforded the iron complex salt 30 [89, 90].
Tricarbonyl(Z5-cyclohexadienylium)iron complex salts represent versatile elec-
trophiles which readily react with a broad range of nucleophiles [81–83, 85, 87, 88].
According to the Davies–Green–Mingos rules, attack of nucleophiles occurs at
the terminus of the tricarbonyliron-coordinated cyclohexadienylium system [91].
Electrophilic substitution of arylamines 35 by the iron complex salt 30 afforded 5-
aryl-substituted tricarbonyl(Z4-cyclohexadiene)iron complexes 36 (Scheme 12).
Oxidative cyclization of the iron complexes 36 generated the tricyclic carbazole
ring system. Depending on the oxidizing agent, three different reaction modes for
the oxidative cyclization leading to CN bond formation have been observed.
The iron-mediated arylamine cyclization (mode A in Scheme 12) proceeds via
the steps cyclodehydrogenation, aromatization, and concomitant demetalation, and
can be achieved with various oxidizing agents (e.g., very active manganese dioxide
[92, 93], iodine in pyridine [94–96], and ferrocenium hexafluorophosphate [92, 97,
98]). Applications of this procedure to the total synthesis of carbazole alkaloids
include for example hyellazole [97] and carazostatin [98]; for reviews, see
[18–20, 83]. More recent applications of this route to natural product synthesis
are described in Sect. 3.1.1.
Alternatively, a mild and efficient one-pot electrophilic aromatic substitution/
oxidative cyclization without isolation of the intermediate complexes 36 has
been achieved using air as oxidizing agent (mode B in Scheme 12). Thus, reaction
via mode B leads to tricarbonyl(Z4-4a,9a-dihydrocarbazole)iron complexes 37,
which on demetalation with trimethylamine N-oxide and subsequent catalytic
dehydrogenation provide the carbazoles 40. The naturally occurring carbazole
+ OR
(OC)3Fe
+
−
BF4 H2N
30 35
electrophilic (R = alkyl)
substitution
(OC)3Fe
OR
H2N
36
oxidative air oxidation to

mode A mode B mode C MnO2
cyclization quinone imine
H OR (OC)3Fe
(OC)3Fe O
oxidative oxidizing
cyclization agent, e.g.: H N HN
H 38
+ v.a. MnO2 oxidative
aromatization 37 v.a. MnO2
I2, pyridine cyclization
+ Cp2Fe+PF6–, Na2CO3
demetalation H O
oxidation 1. Me3NO (OC)3Fe
(aromatization) 2. Pd / C
+ or H N 39
demetalation NBS demetalation
+ Me3NO
aromatization
OR OR OH
N N N
H H H
40 40 41
Arylamine Oxidative Quinone imine

cyclization cyclization by air cyclization
Scheme 12 Cyclization modes of the iron-mediated carbazole synthesis
alkaloids carbazoquinocin C [99], carbazomycin A and B [100], (R)-carquinostatin

A [101–104], (R)-lavanduquinocin [105, 106], and (R)-()-neocarazostatin B [103,
107] have been synthesized using this procedure. A more recent example is
presented in Sect. 3.1.2.
A third pathway leads via the quinone imine intermediates 38 to 3-hydro-
xycarbazoles 41 (mode C in Scheme 12) [97, 98, 108, 109]. Oxidation of the
complexes 36 with manganese dioxide afforded the quinone imines 38, which on
treatment with very active manganese dioxide undergo oxidative cyclization to the
tricarbonyl(Z4-4b,8a-dihydrocarbazol-3-one)iron complexes 39. Demetalation of
39 with trimethylamine N-oxide and subsequent aromatization lead to the 3-hydro-
xycarbazoles 41. The isomerization providing the aromatic carbazole system is a
olker
consequence of enolization followed by a [1,5] hydride shift. The quinone imine

cyclization has been applied to the syntheses of carbazomycin C and D [108],
hyellazole (44) [97], and carazostatin [98].
3.1.1 Arylamine Cyclization
Hyellazole (44) and 6-chlorohyellazole (46) were isolated from the blue-green alga
Hyella caespitosa [110]. They represent the first carbazole alkaloids obtained from
marine sources. Hyellazole (44) and 6-chlorohyellazole (46) were both synthesized
starting from the iron complex salt 30 and arylamine 42 (Scheme 13) [111]. The
arylamine 42 is available from 2,6-dimethoxytoluene in five steps and 76% overall
yield. Complex salt 30 and arylamine 42 react in an electrophilic substitution to
complex 43. Three different reagents have been found to accomplish the oxidative
cyclization of complex 43. The quinone imine cyclization of 43 by sequential
application of manganese dioxide, very active manganese dioxide, and trimethyla-
mine N-oxide followed by O-methylation provided hyellazole (44) in five steps and
57% yield based on 30 [97]. A more efficient oxidative cyclization of complex 43
was achieved with ferrocenium hexafluorophosphate in the presence of sodium
carbonate to give hyellazole (44) in 59% yield along with 29% of the corresponding
tricarbonyliron-complexed dihydrocarbazol-3-one. The latter could be transformed
to hyellazole (44) on treatment with trimethylamine N-oxide and subsequent
methylation to contribute to an overall yield of 83% based on 30 [97]. More
recently, a third strategy has been reported for the oxidative cyclization of 43
using N-bromosuccinimide (NBS) to give hyellazole (44) in 69% yield [111].
Electrophilic bromination with the same reagent in the presence of catalytic
amounts of hydrobromic acid provides 6-bromohyellazole (45) in 92% yield.
1. Cp2FePF6, Na2CO3
2. a) Me3NO
-
BF4 OMe (OC)3Fe b) MeI
MeOH OMe 84 %
(OC)3Fe + + or
H2N Me 82 °C
98 % H2N Me NBS, Na2CO3
C6H5 69 %
30 42 43 C6H5
1. NBS, Na2CO3
2. NBS, cat. HBr
69 %
OMe Br OMe Cl OMe

NBS CuCl
Me Me Me
cat. HBr 96 %
N N N
H C6H5 92 % H C6H5 H C6H5
44 hyellazole 45 46 6-chlorohyellazole
Scheme 13 Synthesis of 6-chlorohyellazole (46)

OMe OMe OMe

Fe(CO)5 MeO
or (OC)3Fe + (OC)3Fe
N Ph
cat. Ar
47 48 Ar = 4-MeOC6H4 49 50
OMe O
Ph3C+BF4– BF4– MeO H2O, Δ
MeO
+
(OC)3Fe + (OC)3Fe+ (OC)3Fe +
BF4– BF4–
51 52 52 53 Fe(CO)3
Scheme 14 Synthesis of the 2-methoxycyclohexadienyliron complex salt 52
These two steps can be combined to a one-pot procedure affording 6-bromohyella-

zole (45) in 69% yield. Compound 45 can be readily transformed into 6-chloro-
hyellazole (46) in 96% yield using copper(I) chloride in dimethylformamide. Direct
chlorination of 44 with N-chlorosuccinimide (NCS) occurs at C-4 and, thus,
provides no access to the naturally occurring 6-chlorohyellazole (46) [111].
The synthesis of 7-oxygenated carbazoles via the iron-mediated route requires
the 2-methoxy-substituted iron complex salt 52 (Scheme 14). Complexation of the
methoxycyclohexadienes 47 and 48 with pentacarbonyliron in the presence of
catalytic amounts of 1-(p-anisyl)-4-phenyl-1-azabuta-1,3-diene affords a mixture
of the regioisomeric 1-methoxy- and 2-methoxy-Z4-cyclohexadieneiron complexes
49 and 50 [77, 78, 84]. Hydride abstraction by triphenylcarbenium tetrafluoroborate
provides a mixture of regioisomeric Z5-cyclohexadienyliron complexes 51 and
52. Separation of the 1-methoxy- and 2-methoxy-substituted complex salts 51
and 52 can be achieved by selective hydrolysis of 51 to the cyclohexadieno-
netricarbonyliron complex 53 [74].
Following our iron-mediated approach, 2,7-dioxygenated carbazole alkaloids
became readily available. Several members of this family of natural products
show promising pharmacological effects. 7-Methoxy-O-methylmukonal (57) was
isolated from the roots of Murraya siamensis [112]. Clausine H (59) and clausine K
(60) were obtained from the stem bark of Clausena excavata collected in Taiwan by
Wu et al. [113]. Ito and co-workers isolated clauszoline-C (59), identical to Wu’s
clausine H (59), from C. excavata collected in Singapore [114]. Clauszoline-J (60),
with the same structure as clausine K (60), was obtained from C. excavata Burm. f.
grown in a greenhouse in Shizuoka [115]. Clausine O (58) was isolated from the
root bark of C. excavata [116]. Clausine K (clauszoline-J) (60) was also obtained
from the roots of Clausena harmandiana by Kittakoop and co-workers [117].
Clausine H (clauszoline-C) (59) shows antiplasmodial activity [117]. Clausine K
(clauszoline-C) (60) exhibits activity against Mycobacterium tuberculosis [118].
Using iron complex salt 52 as starting material, the 2,7-dioxygenated carbazole
alkaloids 57–60 have been synthesized (Scheme 15) [119]. We used 7-methoxy-
O-methylmukonal (57) as relay compound which provides access to clausine H
olker
BF4– MeO
Me (OC)3Fe iodine, pyridine
(OC)3Fe +
+ MeCN, rt Me
H2N OMe 76 % 68 %
OMe H2N OMe
52 54 55
Me CHO CHO
DDQ BBr3
MeO OMe MeO OMe HO OH
N 67 % 68 % N
N
H H H
56 57 7-methoxy- 58 clausine O
MnO2, KCN, MeOH O-methylmukonal
100 %
COOMe COOH
KOH
MeO OMe MeO OMe
N EtOH N
H 53 % H
59 clausine H 60 clausine K
(clauszoline-C) (clauszoline-J)
Scheme 15 Iron-mediated synthesis of 2,7-dioxygenated carbazole alkaloids
(clauszoline-C) (59), clausine K (clauszoline-J) (60), and clausine O (58). Reaction

of complex salt 52 with 3-methoxy-4-methylaniline (54) afforded by an electro-
philic substitution the iron complex 55. Using iodine in pyridine, oxidative
cyclization of complex 55 with concomitant aromatization and demetalation led
to 2,7-dimethoxy-3-methylcarbazole (56). Compound 56 has the appropriate sub-
stitution pattern to provide access to the naturally occurring 2,7-dioxygenated
carbazole alkaloids mentioned above. Oxidation of the methyl group at C-3
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) afforded 7-methoxy-O-
methylmukonal (57). Double ether cleavage of 57 with boron tribromide leads to
clausine O (58) in 68% yield. Application of Corey’s methyl ester synthesis [120]
by oxidation of aldehydes with manganese dioxide in the presence of potassium
cyanide in methanol converted 7-methoxy-O-methylmukonal (57) quantitatively to
clausine H (clauszoline-C) (59). Saponification of 59 with potassium hydroxide in
methanol provides clausine K (clauszoline-J) (60) [119].
Furoannulated carbazole alkaloids represent a relatively new class of natural
products which have been isolated from terrestrial plants [121, 122]. The number of
members of this family known to date is rather limited. Furoclausine-A (61) along
with furoclausine-B was isolated first by Wu and co-workers from the root bark of
C. excavata [122]. We have developed an efficient and convergent access to furo
[3,2-a]carbazoles via our iron-mediated arylamine cyclization [123, 124]. Retro-
synthetic analysis of furoclausine-A (61) suggests 1-methoxycyclohexa-1,4-diene
(48) and the arylamine 62 as building blocks (Scheme 16). The latter was obtained
by alkylation of 2-methyl-5-nitrophenol (63) with 2-bromo-1,1-diethoxyethane
[Fe]
CHO
[Fe(CO)3] Me
HO O + OEt
H2N O
N MeO
H OEt
61 furoclausine-A 48 62
BrCH2CH(OEt)2
Me
O2N OH
63
Scheme 16 Retrosynthetic analysis of furoclausine-A (61)
Me OEt MeO
BF4–
O (OC)3Fe
OEt MeCN Me
(OC)3Fe+ +
25 °C OEt
H2N O
OMe 87 %
NH2 OEt
52 62 64
Me Me
iodine, pyridine, Δ amberlyst 15
OEt
MeO O MeO O
71 % N C6H5Cl, Δ N
OEt 82 %
H H
65 66
CHO CHO
DDQ BBr3
MeO O HO O
43 % 41 %
N N
H H
67 61 furoclausine-A
Scheme 17 Synthesis of furoclausine-A (61)
followed by catalytic hydrogenation (80% overall yield). Annulation of the furan

was carried out after construction of the carbazole framework.
Reaction of the arylamine 62 with the complex salt 52 in acetonitrile at room
temperature afforded complex 64 in 87% yield (Scheme 17) [125]. Subsequent
oxidative cyclization, aromatization and demetalation using iodine in pyridine
provided carbazole 65 in 71% yield. Heating of compound 65 in chlorobenzene
in the presence of the acidic cation exchange resin amberlyst 15 led to ring closure
with formation of the furo[3,2-a]carbazole 66. Oxidation of the methyl group at
C-3 to a formyl group using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
olker
O O
O
N
HN N H
OH HN H
OH
Me Me
N
H R N
H R
68a antiostatin A1 R = (CH2)4CH3 69a antiostatin B2 R = (CH2)5CH3

68b antiostatin A2 R = (CH2)2CH(CH3)CH2CH3 69b antiostatin B3 R = (CH2)4CH(CH3)2
68c antiostatin A3 R = (CH2)4CH(CH3)2 69c antiostatin B4 R = (CH2)6CH3
68d antiostatin A4 R = (CH2)6CH3 69d antiostatin B5 R = (CH2)5CH(CH3)2
Fig. 1 Antiostatins A1A4 (68a–d) and B2B5 (69a–d)
afforded O-methylfuroclausine-A (67). Finally, cleavage of the methyl ether with

boron tribromide led to furoclausine-A (61) which was obtained in seven steps and
7% overall yield based on 2-methyl-5-nitrophenol (63).
The antiostatins, a unique class of carbazole alkaloids, are characterized by a
3-hydroxy- and a 4-acylamino group. They have been isolated from Streptomyces
cyaneus 2007-SV1 [126]. Depending on the side chain at C-4, the antiostatins are
classified as antiostatins A (68a–d) with an acetamide and antiostatins B (69a–d)
with an isobutylbiuret moiety (Fig. 1). The antiostatins strongly inhibit the radical
induced lipid peroxidation by acting as scavengers of oxygen-derived free radicals.
These species are known to promote diseases such as cerebral and myocardial
ischemia [127–130], inflammation, autoimmune diseases, diabetes, rheumatism,
and cancer [131–133]. Therefore, radical scavengers are under extensive investiga-
tion as potential drugs for treatment of these diseases.
Our convergent approach to this class of natural products utilizes the iron-
mediated arylamine cyclization for construction of the carbazole framework. The
retrosynthetic analysis of the antiostatins B (69a–d) leads to cyclohexa-1,3-diene
(33) and the arylamines 70 as building blocks (Scheme 18) [134]. The different side
chains at C-1 are introduced by a palladium(0)-catalyzed Sonogashira–Hagihara
coupling. The amino group at C-4 is attached to the preformed carbazole skeleton.
For introduction of the biuret side chain, we have developed 5-isobutyl-1-nitro-
biuret (71) as reagent to access the antiostatins of the B-series.
The anilines 70 were obtained in five steps and 62–88% overall yield from
2,6-dimethoxytoluene (Scheme 19) [134]. The different alkyl side chains, charac-
terizing the antiostatins within each series, were introduced by Sonogashira–
Hagihara coupling with the appropriate terminal alkyne. Electrophilic substitution
using the iron complex salt 30 afforded the complexes 74. Subsequent oxidative
cyclization with concomitant aromatization and demetalation by treatment of 74
with an excess of ferrocenium hexafluorophosphate provided the carbazoles 75.
Initial protection of the carbazole nitrogen as tert-butyl carbamate followed by
regioselective nitration at C-4 using claycop led to the 4-nitrocarbazoles 77. These
O
O
N
N H
HN H OH
OMe
[Fe(CO)3] O O
Me + + O2N
H2N Me N N N
N H H H
H R
R 69 33 70 71
[Fe]
Sonogashira–Hagihara
cat. Pd(0) OMe
+ H R′
H2N Me
OTf
72 73
Scheme 18 Retrosynthetic analysis of the antiostatins B (69a–d); R = R’CH2CH2
OMe
BF4– (OC)3Fe
Me MeCN OMe Cp2FePF6, Na2CO3
+
(OC)3Fe +
R 82 °C H2N Me 63–96 %
89–100 %
NH2 R
30 70 74
OMe OMe O2N

OMe
Boc2O claycop
Me Me Me
93–100 % N 81–91 %
N N
H R R R
Boc Boc
75 76 77
Scheme 19 Synthesis of the antiostatin precursors 77
intermediates served as precursors for the antiostatins of the A (68a–d) and B

(69a–d) series [134].
Catalytic hydrogenation of 77 to the 4-aminocarbazoles 78 followed by acetyla-
tion of the amino group afforded the acetamides 79 (Scheme 20). Thermal removal
of the Boc protecting group and ether cleavage using boron tribromide led in
excellent overall yields to all four members of the antiostatin A series (68a–d)
[134].
The antiostatins B2B5 (69a–d) were also obtained from the advanced precursor
77 (Scheme 21). Thermal removal of the Boc group and subsequent catalytic
hydrogenation provided the 4-aminocarbazoles 82. The unusual biuret side chain
was attached by reaction with 5-isobutyl-1-nitrobiuret, which proved to be an effi-
cient reagent for this purpose. Finally, the methyl ether was cleaved by reaction with
boron tribromide to afford the four antiostatins of the B series (69a–d) [134].
olker
H2N AcHN
OMe OMe
H2, Pd / C AcCl 180 °C
77 Me Me
92–100 % N 81–97 % 100 %
N
R R
Boc Boc
78 79
AcHN AcHN
OMe OH
BBr3
Me Me 68a antiostatin A1 R = (CH2)4CH3
N 65–94 % N 68b antiostatin A2 R = (CH2)2CH(CH3)CH2CH3
H R H R
68c antiostatin A3 R = (CH2)4CH(CH3)2
80 68 68d antiostatin A4 R = (CH2)6CH3
Scheme 20 Synthesis of antiostatins A1 A4 (68ad)
O O
O2N H2N O2N
OMe OMe N N N
180 °C H2, Pd / C H H H
77
100 % Me Me 83–91 %
82–100 %
N N
H R H R
81 82
O O
O O
N N
N H N H
HN H BBr3 HN H
OMe OH
74–94 %
Me Me 69a antiostatin B2 R = (CH2)5CH3
N N 69b antiostatin B3 R = (CH2)4CH(CH3)2
H R H R 69c antiostatin B4 R = (CH2)6CH3
83 69 69d antiostatin B5 R = (CH2)5CH(CH3)2
Scheme 21 Synthesis of antiostatins B2B5 (69ad)
3.1.2 Oxidative Cyclization by Air
In analogy to the antiostatins, the 3,4-dioxygenated carbazole alkaloids neocara-

zostatin B (84) and carquinostatin A (93) also display a pronounced antioxidative
activity. Neocarazostatin B (84) was isolated first from the culture of Streptomyces
sp. strain GP 38 [135]. The related o-quinone derivative, carquinostatin A (93),
was obtained by Seto et al. from Streptomyces exfoliates 2419-SVT2 [136]. The
absolute stereochemistry of neocarazostatin B (84) was not reported. In analogy
to the known absolute configuration of carquinostatin A (93), we assumed an
(R)-configuration for the 2-hydroxypropyl side chain. We developed the first
enantioselective synthesis of neocarazostatin B (84), which can be further
HO AcO
OMe Br OMe
[Ni]
+
Me Me Br
[Ni] N OH N OAc
H H
[Fe] 85 86
84
(R)-(–)-neocarazostatin B
[Fe(CO)3]
OAc
OAc
OMe
OMe
+ O
+
H2N Me
H2 N Me OAc
Br
87 88 89 33
Scheme 22 Retrosynthetic analysis of neocarazostatin B (84)
transformed into carquinostatin A (93) [103]. Thus, we could prove our assumption
by comparison of the optical rotation value of our synthetic compound with that of
the natural product. The synthetic strategy is related to our previous syntheses
of carquinostatin A (93) [101, 102, 104] and lavanduquinocin [106]. We projected
to introduce the prenyl side chain at the carbazole framework by a nickel-mediated
prenylation (Scheme 22). The carbazole skeleton should derive from the arylamine
89 and cyclohexa-1,3-diene (33) by an iron-mediated oxidative coupling under air.
The 2-hydroxypropyl side chain should be attached to the aromatic amine 87 by
lithiation and subsequent reaction with (R)-propene oxide (88).
The arylamine 89 was obtained in eight steps and 65% overall yield starting from
guaiacol. This precursor enables one to differentiate between the oxy substituents at
C-3 and C-4 of the carbazole. The chiral side chain is introduced by regioselective
bromination, halogenmetal exchange, and subsequent reaction with (R)-propene
oxide (88). Reaction of the highly functionalized arylamine 89 with the iron
complex salt 30 in acetonitrile in air afforded complex 90 in 68% yield (Scheme 23)
[103]. This transformation combines electrophilic aromatic substitution and oxida-
tive cyclization (mode B in Scheme 12). The oxidative cyclization of similar
systems by air in acidic medium was reported by us previously for the synthesis
of the carbazole alkaloids mukonine and mukonidine [137, 138]. The one-pot
electrophilic substitution and oxidative cyclization was reported first in the course
of the synthesis of carbazoquinocin C [99]. In this case, the acidic conditions are
provided by tetrafluoroboric acid, which is released during the electrophilic substi-
tution. Aromatization and concomitant demetalation of 90 was achieved by treat-
ment with N-bromosuccinimide (NBS) under basic reaction conditions to furnish
olker
OAc
AcO
OMe OMe
BF4– MeCN (OC)3Fe NBS
+ + H2N Me
(OC)3Fe Me Na2CO3
air, 25 °C N OAc
OAc H 100 %
68 %
30 89 90
AcO AcO OMe AcO

OMe Br OMe
NBS prenyl-Br (86)
Me Me Me
N OAc cat. HBr N OAc Ni(CO)4
H 88 % H N OAc
66 % H
91 85 92
HO OMe O
O
LiAlH4 CAN
Me Me
92 % 92 %
N OH N OH
H H
84 (R)-(–)-neocarazostatin B 93 carquinostatin A
Scheme 23 Enantioselective synthesis of (R)-()-neocarazostatin B (84) and carquinostatin

A (93)
carbazole 91 quantitatively. NBS under acidic conditions is used for regioselective

aromatic bromination at C-6. Treatment of the 6-bromocarbazole 85 with an in situ
prepared dimeric p-prenylnickel complex afforded the 6-prenylcarbazole 92.
Removal of both acetyl protecting groups of 92 by treatment with lithium alumi-
num hydride provided (R)-()-neocarazostatin B (84). Based on comparison of the
values for the specific rotation, the absolute configuration proved to be identical
with that of natural neocarazostatin B. (R)-()-Neocarazostatin B (84) is air
sensitive and is slowly oxidized to carquinostatin A (93). Smooth oxidation was
achieved with ceric ammonium nitrate (CAN) to give carquinostatin A (93) in 92%
yield. The present route via neocarazostatin B (84) constitutes a new access to
carquinostatin A (93) which complements our previous syntheses [101, 102, 104].
3.2 Palladium-Catalyzed Synthesis of Carbazoles
Palladium appears to be the most versatile metal for catalytic reactions in

organic synthesis. Most prominent are cross-coupling reactions between com-
pounds with sp2 or sp3 C–X bonds and metal organyls. Moreover, a large number
of palladium-mediated reactions for C–H bond activation has been described.
In most cases, palladium(0) displays the catalytically active species. However,
palladium(II)-catalyzed reactions (e.g., the Wacker process) are also well-known.

Palladium also plays a major role in diverse approaches to the carbazole ring system
which are summarized below. Only a few of them have been widely used for the
synthesis of naturally occurring carbazole alkaloids.
3.2.1 Buchwald–Hartwig Amination Followed by Oxidative Cyclization

(Pd[0]/Pd[II])
One of the most versatile approaches to highly functionalized carbazoles is the

sequential palladium-catalyzed C–N/C–C coupling for assembly of the central
pyrrole moiety. Many total syntheses of naturally occurring carbazole alkaloids
are following this route. The initial C–N bond formation by a palladium(0)-cata-
lyzed Buchwald–Hartwig amination of aryl halides or triflates 94 with arylamines
31 affords the diarylamines 95 (Scheme 24) [139, 140]. Oxidative cyclization of the
diarylamines 95 to the carbazoles 32 proceeds via a double C–H bond activation
and is achieved in the presence of palladium(II) compounds.
The oxidative cyclization step has been improved over the years. The first report
on the palladium(II)-promoted cyclization of diarylamines to carbazoles dates back
to the year 1975. Åkermark required stoichiometric amounts of palladium to
achieve an oxidative C–C bond coupling by double sp2-C–H bond activation
[141]. We improved this reaction considerably by using for the first time only
catalytic amounts of palladium(II) as originally reported in 1994 [142–152]. Further
fine-tuning of the reaction conditions has led to a redox cascade that links three
redox systems resembling the Wacker process (Scheme 25). Electrons are trans-
ferred from the diarylamine 95 to palladium(II) to afford the carbazole 32
and palladium(0). The latter donates two electrons to copper(II) regenerating
palladium(II) under formation of copper(I). Finally, copper(I) transfers one electron
to oxygen. Copper(II) is regenerated and molecular oxygen is transformed to water.
Thus, palladium(II) and copper(II) can be employed in catalytic amounts and air
represents the effective oxidant.
The palladium(II)-catalyzed oxidative cyclization has been applied to the total
synthesis of a broad range of naturally occurring carbazole alkaloids. Earlier exam-
ples have been presented in our previous review in this series [19]. Herein, we
describe recent progress in this area from our laboratories and other research groups.
R R′
R R′
cat. Pd(0) R R′ Pd(II)
+
N N
X NH2 H H
94 31 95 32
Scheme 24 Synthesis of carbazoles 32 by Buchwald–Hartwig amination and subsequent oxida-

tive cyclization of the diarylamines 95
olker
R R′
N
H Pd(II) Cu(I) O2 (air)
95
+ 2 H+
Pd(0) Cu(II) 2 H2O

R R′
N
H
32
Scheme 25 Redox cascade of the palladium(II)-catalyzed oxidative cyclization of diarylamines

95 to carbazoles 32
Åkermark–Knölker
cat. Pd(II) Negishi
HO cat. Zr(IV)
OH COOMe
OMe
cat. Pd
Me + + R
H2 N Me Bu3Sn
N OTf
HO H Br 99
R OMe
97 98 cat. Zr(IV)
Buchwald–Hartwig Stille
cat. Pd(0) cat. Pd(0)
Me3Al
96a carbazomadurin A R = Me + + R
96b carbazomadurin B R = Et Bu3SnCl
100
Scheme 26 Retrosynthetic analysis of carbazomadurin A (96a) and B (96b)
Carbazomadurin A (96a) and B (96b) were isolated from the microorganism

Actinomadura madurae by Seto et al. in 1997. They display a strong neuronal
cell protecting activity against L-glutamate induced cell death which is ascribed to
their antioxidative effect [153]. We accomplished the first synthesis of carbazoma-
durin A (96a) using the sequential aryl amination and oxidative cyclization accord-
ing to Scheme 24 [154]. Carbazomadurin B (96b) can be synthesized following
the same route [154, 155]. Retrosynthetic analysis of the carbazomadurins dis-
plays the extensive use of palladium-catalyzed reactions following our approach
(Scheme 26). The carbazole framework is constructed by Buchwald–Hartwig
amination and subsequent oxidative cyclization of the diarylamine using catalytic
amounts of palladium(II). The side chain at C-1 is introduced by Stille coupling.
Key step for the synthesis of the vinylstannane 99 is the zirconium(IV)-catalyzed
carboalumination developed by Negishi.
The palladium-catalyzed approach to carbazomadurin A (96a) and B (96b)
requires the aryl triflate 97 and arylamine 98 as precursors. The former was
obtained from isovanillic acid in two steps and 91% overall yield. Arylamine 98 can
be prepared in five steps and 44% overall yield starting from commercially avail-
able 2-bromo-6-nitrotoluene. Buchwald–Hartwig coupling of the two components
using 5 mol% of palladium(II) acetate and 7.5 mol% of 2,20 -bis(diphenylpho-
sphino)-1,10 -binaphthyl (BINAP) in the presence of cesium carbonate afforded
the diarylamine 101 (Scheme 27). Subsequent oxidative cyclization provided the
COOMe COOMe
OMe
cat. Pd(OAc)2, cat. BINAP OMe Pd(OAc)2
+
H2N Me 43 %
OTf 62 % N Me
Br H
OMe OMe Br
97 98 101
COOMe COOMe
OMe 1. BBr3 OTPS
2. TPSCl cat. Pd(PPh3)4
Me Me
70 % 99a R = Me
N N
MeO H Br TPSO H Br Bu3Sn R 99b R = Et
102
103
COOMe HO HO
OTPS OTPS OH
DIBAL-H TBAF
Me
100 % Me Me
N
H N N
TPSO TPSO H HO H
R
R R
104a R = Me (95 %) 105a R = Me 96a R = Me (70 %) carbazomadurin A
104b R = Et (90 %) 105b R = Et 96b R = Et (88 %) carbazomadurin B
TPSCl
100 %
TPSO TPSO HO
OTPS OTPS OH
DMDO TBAF
Me
Me Me
53 % N
N N HO H
TPSO H TPSO H
O R
R O R
106a R = Me (±)-107a R = Me (±)-109a R = Me(24 %)
106b R = Et 107b / 108 R = Et (±)-epocarbazolin A
OO 109b / 110 R = Et (18 %)

R = Me
R
O epocarbazolin B
oxone O + diastereomer
cat. 111 O O
18 % 111
HO
TPSO
OH
OTPS
TBAF
Me Me
18 % N
N HO H
TPSO H
O
O
(–)-112 (–)-109a (–)-epocarbazolin A
Scheme 27 Palladium-catalyzed synthesis of the carbazomadurins A (96a) and B (96b), and the
epocarbazolins A (109a) and B (109b)
olker
carbazole 102. In the present case, stoichiometric amounts of palladium(II) acetate

have been employed for this step without further optimization. Ether cleavage and
protection of the two hydroxy groups provided the disilyl ether 103. This key
intermediate represents a relay compound for the syntheses of carbazomadurin A
(96a) and B (96b). Stille coupling with the vinylstannanes 99a and 99b introduces
the two different side chains of the natural products. The E-vinylstannane 99a is con-
veniently prepared from 5-methyl-1-hexyne (100a) via consecutive zirconium(IV)-
catalyzed carboalumination, iodation, halogen–metal exchange, and transmetalation
using tributyltin chloride. The E-vinylstannane 99b can be obtained in six
steps starting from commercially available (S)-()-2-methyl-1-butanol. The (S)-
configuration assumed for the stereogenic center of natural carbazomadurin B
(96b) was later on shown to be correct. The syntheses of carbazomadurin A (96a)
and B (96b) were completed by ester reduction using diisobutylaluminum hydride
(DIBAL-H) and removal of the silyl protecting groups. The nine-step synthesis
starting from isovanillic acid afforded carbazomadurin A (96a) in 11% and carbazo-
madurin B (96b) in 13% overall yield [154, 155].
The structurally related carbazole alkaloids epocarbazolin A (109a) and epo-
carbazolin B (109b) were isolated from Streptomyces anulatus T688-8. These
compounds show a potent rat 5-lipoxygenase inhibitory activity [156]. We
envisaged the synthesis of 109a and 109b from the carbazomadurin precursors
105a and 105b. Protection of the free hydroxy group provided quantitatively the
trisilylated carbazoles 106a and 106b (Scheme 27) [157]. Epoxidation of the
achiral derivative 106a with dimethyldioxirane (DMDO) and subsequent
removal of the silyl groups afforded rac-epocarbazolin A [()-109a]. The same
procedure using the chiral intermediate 106b provided a mixture of epocarbazo-
lin B (109b) and its diastereoisomer 110 [157]. An asymmetric approach using a
modified Shi epoxidation has been employed for the synthesis of the unnatural
()-epocarbazolin A [()-109a] (Scheme 27). The absolute configuration of this
product is still unknown. Epoxidation of the trisilyl-protected carbazomadurin A
106a using Shi catalyst 111 afforded the ()-tri-O-silylepocarbazolin A ()-112.
Removal of the protecting groups led to ()-epocarbazolin A [()-109a] with a
specific rotation of ½a26D ¼ 55. The natural product was reported to have
a specific rotation of ½a26D ¼ þ75. Thus, the non-natural enantiomer of epo-
carbazolin A [()-109a] was obtained with an enantiomeric excess of approxi-
mately 73% [157].
A series of 7-oxygenated carbazole alkaloids has been synthesized by us for the
first time, including clauszoline-K (117), 3-formyl-7-hydroxycarbazole (119), clau-
sine M (120), clausine N (121), and siamenol (124) [148]. Clauszoline-K (117)
and clauszoline-L (118) have been isolated by Ito et al. from the stem bark of
C. excavata [115]. Wu and co-workers had isolated the same compound 118
one year earlier from the same source and named it clausine C (118) [158]. 3-
Formyl-7-hydroxycarbazole (119) was obtained from the root bark of Murraya
euchrestifolia [159]. Clausine M (120) and clausine N (121) were isolated from the
root bark of C. excavata by Wu et al. [116]. Siamenol (124) was isolated from an
extract of M. siamensis and proved to have anti-HIV activity [160].
Our approach to the 7-oxygenated carbazoles starts with a Buchwald–Hartwig

amination of m-anisidine (113) and p-bromotoluene (114) to give the diarylamine
115 in quantitative yield (Scheme 28) [148]. For the oxidative cyclization of 115 we
investigated different conditions (Table 1). The best yield was obtained using
0.1 equiv. of palladium(II) acetate and 2.5 equiv. of copper(II) acetate as co-oxidant
in glacial acetic acid under air. Smaller amounts of palladium(II) acetate decrease
the yield slightly but lead to rather high turnover numbers up to 26.5. 7-Methoxy-3-
methylcarbazole (116) constitutes the crucial compound leading to six different
7-oxygenated carbazole alkaloids. Oxidation of the methyl group at C-3 in 116 to
a formyl group using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) affords
Me Pd(OAc)2
Me cat. Pd(OAc)2 Cu(OAc)2
+
MeO NH2 rac-BINAP MeO N Table 1
Br H
113 100 %
114 115
Me
CHO MnO2 COOMe
DDQ KCN
MeO MeO MeO
N 79 % N MeOH N
H H 100 % H clausine C
116 117 clauszoline-K 118 (clauszoline-L)
BBr3 BBr3
KOH, EtOH
34 % 52 % 99 %
CHO COOMe COOH
NBS HO MeO
HO
100 % N N
N
H H H
119 120 clausine M 121 clausine N
Br Me Me
Br Me Br
BBr3
86
MeO HO HO
N 100 % Ni(cod)2
N N
H H 47 % H
122 123 124 siamenol
Scheme 28 Palladium-catalyzed synthesis of 7-oxygenated carbazole alkaloids
Table 1 Optimization of the palladium(II)-catalyzed oxidative cyclization to 7-methoxy-

3-methylcarbazole (116)
Pd(OAc)2 (equiv.) Cu(OAc)2 (equiv.) Reaction conditions 116, Yield (%) TONa
1.2 – AcOH, reflux, argon, 2 h 36 –
0.1 2.5 AcOH, reflux, air, 23 h 64 6.4
0.1 2.5 AcOH, reflux, air, 2 days 72 7.2
0.05 2.5 AcOH, reflux, air, 40 h 61 12.2
0.02 2.5 AcOH, reflux, air, 6 days 53 26.5
a
TON ¼ turnover number
olker
clauszoline-K (117) in 79% yield. Ether cleavage of 117 with boron tribromide
provides the naturally occurring alkaloid 3-formyl-7-hydroxycarbazole (119).
Treatment of clauszoline-K (117) with manganese dioxide in the presence of
potassium cyanide in methanol converts the formyl group to a methyl ester function
and thus, affords clausine C (118). Clausine C (118) can be further transformed to
clausine M (120) or clausine N (121) by ether cleavage or saponification of the
methyl ester. Quantitative and regioselective electrophilic bromination of interme-
diate 116 at C-6 was achieved using N-bromosuccinimide (NBS). Ether cleavage
followed by coupling with a dimeric p-prenylnickel bromide complex, generated in
situ from prenyl bromide (86) and bis(1,5-cyclooctadiene)nickel(0), provided sia-
menol (124) [148].
A wide range of 6-oxygenated carbazole alkaloids has been isolated from natural
sources. Glycozoline (128) was originally isolated from the root bark of Glycosmis
pentaphylla [161, 162]. It shows antibiotic and antifungal properties [163]. The
related 3-methyl-6-hydroxycarbazole (131) was obtained first from G. pentaphylla
and named glycozolinine (131) [164]. Bhattacharyya isolated the same compound
one year later and named it glycozolinol (131) [165]. Glycomaurrol (135) was
found in the extract of the stem bark of Glycosmis mauritiana [166]. Franzblau
isolated 3-formyl-6-methoxycarbazole (129) and micromeline (130) from the stem
bark extract of Micromelum hirsutum [167]. Both compounds showed anti-TB
activity. The furo[2,3-c]carbazole alkaloid eustifoline-D (132) (Scheme 29) was
isolated from the root bark of M. euchrestifolia Hayata [168], a plant that has been
traditionally used in Chinese folk medicine.
Our palladium-catalyzed approach for the construction of the carbazole frame-
work led to the 6-oxygenated tricyclic carbazole alkaloids glycozoline (128),
methyl 6-methoxycarbazole-3-carboxylate (133), glycomaurrol (135) and micro-
meline (130), as well as to the furo[2,3-c]carbazole alkaloid eustifoline-D (132)
(Scheme 29) [149]. Palladium-catalyzed coupling of p-bromoanisole (125) and
p-toluidine (126) as the first step led almost quantitatively to the diarylamine 127.
Oxidative cyclization of intermediate 127 using 0.1 equiv. of palladium(II)
acetate in the presence of an excess of copper(II) acetate provided glycozoline
(128) in 60% yield, which corresponds to a turnover number of TON ¼ 6 for the
palladium(II) catalyst. Glycozoline (128) represents a central intermediate of this
approach. Oxidation of the 3-methyl group to a formyl moiety with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) provided 3-formyl-6-methoxycarbazole
(129). Further oxidation of the formyl group using Corey’s conditions by treat-
ment with manganese dioxide and potassium cyanide in methanol afforded
methyl 6-methoxycarbazole-3-carboxylate (133), which is a naturally occurring
carbazole alkaloid. Alternatively, compound 129 can be regioselectively bromi-
nated at the 5-position. Subsequent cleavage of the methyl ether and prenylation
at C-5 with the dimeric p-prenylnickel bromide complex afforded micromeline
(130). Ether cleavage of glycozoline (128) with boron tribromide provided the
6-hydroxycarbazole glycozolinine (131). Annulation of the furan ring by reaction
with 2-bromo-1,1-diethoxyethane and subsequent cyclization under acidic con-
ditions using catalytic amounts of amberlyst 15 led to eustifoline-D (132) and its
MeO Me MeO Me
cat. Pd(OAc)2 cat. Pd(OAc)2
+
cat. BINAP N Cu(OAc)2
Br H 2N
97% H 60%
125 126 127
1. NBS,
MeO Me MeO CHO
2. BBr3 HO CHO
DDQ 3. prenylBr (86), Ni(cod)2
76% 21%
N N
H H N
H
128 glycozoline 129 130 micromeline
MnO2, KCN, MeOH

BBr3
97% 97%
HO Me OEt COOMe
O Me MeO
Br
1. EtO
2. amberlyst 15
N 36% N N
H H H
glycozolinine
131 132 eustifoline-D 133
(glycozolinol)
NBS
45%
Br
HO Me HO Me
prenylBr (86)
Ni(cod)2
N 25% N
H H
134 135 glycomaurrol
Scheme 29 Palladium-catalyzed synthesis of 6-oxygenated carbazole alkaloids and the

furo[2,3-c]carbazole alkaloid eustifoline-D (132)
regioisomer in a ratio of 4.3:1. In analogy to 3-formyl-6-methoxycarbazole

(129), glycozolinine (131) was brominated at C-5. Coupling of the resulting
5-bromocarbazole 134 with the dimeric p-prenylnickel bromide complex provided
glycomaurrol (135) [149].
1,6-Dioxygenated carbazole alkaloids have been obtained from several species
of the genus Clausena. The first 1,6-dioxygenated carbazole alkaloid from natural
sources was 6-methoxymurrayanine which has been isolated from the roots of
Clausena lansium by El-Feraly et al. in 1991 [169]. This report was followed four
years later by the isolation of clausenine and clausenol (140) from the dried stem bark
of Clausena anisata by Chakraborty and co-workers [170]. Both compounds show
antibiotic activity. In 1996, Wu et al. isolated clausine I (142) and clausine G (143)
from C. excavata [113, 158]. Clausine I (142) inhibits blood platelet aggregation.
Clausine Z (144) was obtained from the stem and leaves of C. excavata by Potterat
et al. in 2005 [171]. It is active against cyclin-dependent kinase 5 (CDK5) and
protects cerebral granule neurons against free radical induced cell death.
olker
We achieved the first total synthesis of the 1,6-dioxygenated carbazole alkaloids

clausine G (143), clausine I (142), and clausine Z (144) using our palladium-
catalyzed approach (Scheme 30) [172]. Methyl 4-amino-3-benzyloxybenzoate
(136) was obtained in three steps from commercially available 3-hydroxy-4-
nitrobenzoic acid. Buchwald–Hartwig coupling of the arylamine 136 with
p-bromoanisole (125) using catalytic amounts of palladium(0) and S-Phos
(2-dicyclohexylphosphino-20 ,60 -dimethoxybiphenyl) as ligand afforded the diary-
lamine 137. For the oxidative cyclization to carbazole 138, application of over-
stoichiometric amounts of palladium(II) acetate provided the best results, which has
been ascribed to the presence of an electron-withdrawing group [141]. Clausine G
(143) is readily prepared by catalytic debenzylation of the central intermediate 138.
Reduction of 138 with lithium aluminum hydride converted the ester function into a
methyl group and gave compound 139. Subsequent removal of the benzyl protect-
ing group led to clausenol (140). Reduction of intermediate 138 with diisobutyla-
luminum hydride (DIBAL-H) and subsequent oxidation of the benzylic alcohol
with manganese dioxide afforded the 3-formylcarbazole 141. This product was
COOMe MeO COOMe

cat. Pd(OAc)2, cat. S-Phos 2 eq. Pd(OAc)2
H2N 4-bromoanisole (125) N 62 %
OBn 90 % H OBn
136 137
MeO COOMe MeO Me MeO Me

LiAlH4 H2, Pd / C
94 % 100 %
N N N
H OBn H OBn H OH
138 139 140 clausenol
1. DIBAL-H H2, Pd / C
2. MnO2 89 %
95 %
MeO CHO MeO CHO MeO COOMe

AlCl3
100 %
N N N
H OBn H OH H OH
141 142 clausine I 143 clausine G
BBr3
55 %
HO CHO
N
H OH
144 clausine Z
Scheme 30 Palladium-catalyzed synthesis of 1,6-dioxygenated carbazole alkaloids

either selectively debenzylated using aluminum trichloride to give clausine I (142),

or treated with boron tribromide to provide clausine Z (144) by cleavage of both
ether groups (Scheme 30) [172]. Moreover, the naturally occurring carbazole
alkaloids clausenine and 6-methoxymurrayanine have been synthesized via a simi-
lar reaction sequence starting from methyl 4-amino-3-methoxybenzoate [172].
A large number of 2-oxygenated carbazoles has been isolated from natural
sources [18, 20]. Mukonidine (149) and clausine L (O-methylmukonidine) (148)
have been isolated by Wu et al. from the Chinese medicinal plant C. excavata [173].
2-Methoxy-3-methylcarbazole (146) was obtained first from the seeds of the Indian
medicinal plant Murraya koenigii by Bhattacharyya and co-workers [174]. The
isolation of O-methylmukonal (147) was reported by Lange et al. from M. siamen-
sis [112]. Two years later, Bhattacharyya found the same compound in the roots
of G. pentaphylla and renamed it glycosinine (147) [175]. Clausine V (151),
a 2,7-dioxygenated carbazole alkaloid, was extracted from the root bark of
C. excavata by Wu and co-workers [116].
Naturally occurring 2-oxygenated carbazole alkaloids are easily accessible via
our palladium-catalyzed route. Thus, 2-methoxy-3-methylcarbazole (146), glyco-
sinine (147), clausine L (148), and mukonidine (149) became available via one
synthetic sequence (Scheme 31) [150]. Buchwald–Hartwig coupling of 3-methoxy-
4-methylaniline (54) with iodobenzene provided the diarylamine 145. The
subsequent oxidative cyclization of 145 has been investigated using different sets
of reaction conditions (Table 2). The best result was obtained using 0.3 equiv. of
Me
Me Me
cat. Pd(OAc)2, cat. BINAP Pd(OAc)2
iodobenzene Table 2 OMe
H2N OMe N OMe N
72 %
H H
54 145 146
CHO COOMe COOMe

MnO2
DDQ KCN BBr3
99 % OMe MeOH OMe OH
95 %
N 96 % N N
H H H
147 glycosinine 148 clausine L 149 mukonidine
Scheme 31 Palladium-catalyzed synthesis of 2-oxygenated carbazole alkaloids
Table 2 Optimization of the palladium(II)-catalyzed oxidative cyclization of the diarylamine 145

to 2-methoxy-3-methylcarbazole (146)
Pd(OAc)2 Cu(OAc)2 Reaction conditions 146, Yield (%) 145 (%)a TONb
(equiv.) (equiv.)
1.2 – AcOH, reflux, Ar, 1.5 h 48 9 –
0.3 2.5 AcOH, reflux, Ar, 15 h 58 – 1.9
0.3 2.5 AcOH, 90 C, Ar, 21 h 56 33 1.9
0.3 2.5 PivOH, 90 C, Ar, 3 h 63 26 2.1
a
Reisolated starting material
b
olker
palladium(II) acetate and 2.5 equiv. of copper(II) acetate in pivalic acid under argon
atmosphere. The use of pivalic acid instead of acetic acid proved to be advanta-
geous [176]. However, the turnover number of 2.1 for this reaction was rather poor.
The product, 2-methoxy-3-methylcarbazole (146), represents a naturally occurring
carbazole alkaloid. Oxidation of the methyl group at C-3 with 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) led to glycosinine (147). Further oxidation to the
methyl ester using manganese dioxide and potassium cyanide in methanol provided
clausine L (148). Finally, ether cleavage of 148 with boron tribromide afforded
mukonidine (149) [150].
Clausine V (151) was prepared in two steps (Scheme 32) [150]. Buchwald–
Hartwig coupling of m-anisidine (113) with 3-bromoanisole afforded the diaryla-
mine 150. Different reaction conditions have been tried for the subsequent
palladium(II)-catalyzed oxidative cyclization to clausine V (151) (Table 3). Appli-
cation of 0.1 equiv. of palladium(II) acetate and 0.1 equiv. of copper(II) acetate in
glacial acetic acid under an oxygen atmosphere gave the best result for the catalytic
process (49% yield). The turnover number of almost 5 confirmed that the system
works in a catalytic mode. However, in this case the best yield (67%) was obtained
using stoichiometric amounts of palladium(II) acetate in air without co-oxidant.
Pityriazole (152) represents an unusual example of a 2-oxygenated carbazole
alkaloid since it has an additional indol-3-yl substituent at C-1. This natural product
was isolated along with other tryptophan metabolites by Steglich and co-workers
from a culture of the human pathogenic yeast Malassezia furfur, which is believed
to be responsible for the skin disease pityriasis versicolor [177]. Due to the structural
similarity of pityriazole (152) to mukonidine (149) and clausine L (148), we
cat. Pd(OAc)2, cat. BINAP
H2N OMe 3-bromoanisole MeO N OMe

100% H
113 150
Pd(OAc)2
MeO OMe
Table 3 N
H
151 clausine V
Scheme 32 Synthesis of clausine V (151)

to clausine V (151)
Pd(OAc)2 Co-oxidant (equiv.) Reaction conditions 151, Yield (%) TONa
(equiv.)
1.2 – AcOH, reflux, air, 50 min 67 –
0.1 0.1 Cu(OAc)2 AcOH, reflux, air, 9 h 37 3.7
0.1 0.1 Cu(OAc)2 AcOH, reflux, O2, 9 h 49 4.9
0.1 0.1 Mn(OAc)3 · 2 H2O AcOH, reflux, O2, 6 h 47 4.7
a
envisaged a common synthetic strategy for all three natural products [178]. Our
synthetic strategy for pityriazole (152) involved construction of the central pyrrole
ring of the carbazole framework by palladium(0)-catalyzed Buchwald–Hartwig
amination and subsequent palladium(II)-catalyzed oxidative cyclization (Scheme 33).
The indol-3-yl group at C-1 should be introduced by palladium(0)-catalyzed
Suzuki–Miyaura coupling with the N-protected indol-3-ylboronic acid 155.
Palladium(0)-catalyzed coupling of iodobenzene (153) and the commercial
arylamine 154 afforded quantitatively the diarylamine 156 (Scheme 34) [178].
The oxidative cyclization of the diarylamine 156 to clausine L (148) is catalytic
in palladium(II) and copper(II) acetate (or manganese(III) acetate, respectively).
Thus, air is the actual oxidizing agent in this process. For example, employing only
0.05 equiv. of palladium(II) acetate and 0.1 equiv. of copper(II) acetate provided
Åkermark–Knölker Suzuki–Miyaura
cat. Pd(II) cat. Pd(0)
COOH (HO)2B
cat. Pd COOMe
OH + +
N I H2N OMe N
H PhO2S
152 153 154 155
N
H
Buchwald–Hartwig
cat. Pd(0)
Scheme 33 Retrosynthetic analysis of pityriazole (152)
cat. BINAP COOMe

COOMe
cat. Pd(OAc)2 cat. Pd(OAc)2
C6H5I (153) N OMe cat. Mn(OAc)3 or Cu(OAc)2
H2N OMe
100 % H Table 4
154 156
COOMe COOMe COOMe

BBr3 I2, Cu(OAc)2
OMe 95 % OH 85 % OH
N N N
H H H I
148 clausine L 149 mukonidine 157
COOMe COOH
(HO)2B cat. S-Phos OH OH
cat. Pd(OAc)2 KOH, EtOH
157 + N N
N 82 % H 86 % H
SO2Ph
N N
PhO2S H
155 158 152 pityriazole
Scheme 34 Synthesis of clausine L (148), mukonidine (149), and pityriazole (152)

olker

to clausine L (148)
Pd(OAc)2 Co-oxidant Reaction conditions 148, 156, (%)a TONb
(equiv.) (equiv.) Yield (%)
0.1 2.5 Cu(OAc)2 PivOH, 100 C, air, 1 day 44 55 4.4
0.1 0.1 Cu(OAc)2 PivOH, 100 C, air, 17 h 55 38 5.5
0.05 0.1 Cu(OAc)2 PivOH, 100 C, air, 3.5 days 61 24 12.2
0.12 0.1 Mn(OAc)3 PivOH, 100 C, air, 3 days 62 15 5.2
a
Reisolated starting material
b
TON ¼ turnover number for Pd(II)
Åkermark–Knölker alkylation and

cat. Pd(II) [3,3]-sigmatropic rearrangement
Me Me Me
O OH
cat. Pd
O + +
N OCOCF3
H Br
O NH2 NO2
159 160 161 162 163
Buchwald–Hartwig Wacker
cat. Pd(0) cat. Pd(II)
Scheme 35 Retrosynthetic analysis of euchrestifoline (159)
clausine L (148) in 61% yield which corresponds to a turnover number (TON) of

12.2 for this reaction (Table 4). It is interesting to note that in all cases remaining
starting material could be recovered. Ether cleavage of clausine L (148) using boron
tribromide afforded mukonidine (149) and opened up a highly efficient access
to this alkaloid (three steps and 59% overall yield). Electrophilic iodination
of mukonidine (149) at C-1 led to 1-iodomukonidine (157). The subsequent
Suzuki–Miyaura coupling with the indolylboronic acid 155 was carried out
with microwave heating using moist potassium phosphate as base and S-Phos
(2-dicyclohexylphosphino-20 ,60 -dimethoxybiphenyl) as ligand to give the 1-indo-
lylcarbazole 158 in 82% yield. Saponification of the methyl ester with concomitant
removal of the protecting group provided pityriazole (152). Using our route,
pityriazole is available in six steps and an overall yield of 35%. Moreover, this
approach provided the first synthetic access to clausine L (148) [178].
Euchrestifoline (159) was isolated from the leaves of the Chinese medicinal
plant M. euchrestifolia by Wu and co-workers [179]. The structurally related
compound girinimbine (168) was obtained and characterized first by Chakraborty
and co-workers from the stem bark of M. koenigii [180]. Retrosynthetic analysis of
the tetracyclic ring system leads to bromobenzene (160) and 2,2,8-trimethyl-2H-
chromen-5-amine (161) as appropriate starting materials for application of our
methodology (Scheme 35). The keto function was thought to be introduced via
a regioselective Wacker oxidation of the chromene moiety. Compound 161
should be obtained from 2-methyl-4-nitrophenol (162) and the propargyl trifluor-

oacetate 163.
The propargyl ether 164 was prepared by alkylation of 2-methyl-5-nitrophenol
(162) with the propargyl trifluoroacetate 163, which was prepared in situ from the
corresponding propargyl alcohol and trifluoroacetic anhydride (TFAA) (71% yield
over both steps) (Scheme 36) [181]. [3,3]-Sigmatropic rearrangement of 164 with
subsequent cyclization afforded the nitrochromene 165, which on reduction of
the nitro group with iron powder in acetic acid led to the aminochromene 161.
Buchwald–Hartwig coupling of 161 and bromobenzene (160) provided the diaryl-
amine 166. Using catalytic amounts of palladium(II) acetate in the presence of
copper(II) acetate in a 10:1 mixture of acetic acid and water initiates both, Wacker
oxidation of the double bond and oxidative cyclization by double aryl C–H bond
activation. A detailed study of this transformation revealed that the activation of the
vinylic C–H bond proceeds faster. Thus, after a reaction time of only 5 h, Wacker
oxidation of 166 led to the chromanone 167 (TON ¼ 5.7). Resubmission of
compound 167 to the conditions for palladium(II)-catalyzed oxidation for an
extended period of time (24 h) resulted in cyclization to euchrestifoline (159)
OH
TFAA, DBU
Me Me Me
163
OH O O
OCOCF3 o-xylene Fe, AcOH
71% (two steps) 140°C 100%
98%
NO2 NO2 NO2
162 164 165
Me 0.1 eq Pd (OAc)2
Me Me
cat. BINAP 2.5 eq Cu (OAc)2
O
cat. Pd(OAc)2 AcOH / H2O
N O N O
c6H5 (160) 90°C, 5 h H
93% H 57%
NH2 O
161 166 167
0.1 eq Pd(OAc)2
0.1 eq Cu(OAc)2
AcOH / H2O
90 °C, 48 h
40 %
Me Me 0.1 eq Pd(OAc)2
0.1 eq Cu(OAc)2
1. LiAlH4 AcOH
O
O 2.HCl 90 °C, 24 h
N N
70% H 44%
H
O
168 girinimbine 159 euchrestifoline
Scheme 36 Synthesis of euchrestifoline (159) and girinimbine (168)

olker
(TON ¼ 4.4). Under optimized conditions compound 166 can be directly con-
verted to euchrestifoline (159) by reaction with 0.1 equiv. of palladium(II) acetate
and 0.1 equiv. of copper(II) acetate for 2 days. The turnover number for the one-pot
triple C–H bond activation (TON of 4.0) is in the same order of magnitude as for the
individual reactions (Wacker oxidation and oxidative cyclization). Euchrestifoline
(159) was further transformed into girinimbine (168) by reduction of the ketone
using lithium aluminum hydride followed by elimination under acidic conditions.
The 2,6-dioxygenated carbazole alkaloid glycozolidine (170) was isolated first
by Chakraborty et al. from the root bark of G. pentaphylla in 1966 [182]. Glyco-
zolidal (171) and glycozolidol (175) were obtained from the same natural source by
Bhattacharyya et al. [183, 184]. Carbalexin C (179) represents a stress-induced
phytoalexin generated in the leaves of G. pentaphylla and Glycosmis parviflora
[185]. Lansine (181) was isolated by Kapil et al. from the leaves of C. lansium
[186]. Glycozolidal (171) and lansine (181) were also isolated by Wu and co-
workers from the stem bark of the Chinese medicinal plant C. excavata [113].
Glycozolidine (170) was synthesized via a straightforward two-step reaction
sequence. Buchwald–Hartwig coupling of 4-bromoanisol (125) with 3-methoxy-
4-methylaniline (54) afforded the diarylamine 169 (Scheme 37) [152]. Oxidative
cyclization of 169 using 0.1 equiv. of palladium(II) acetate and 2.5 equiv. of
copper(II) acetate under microwave irradiation provided glycozolidine (170)
(TON ¼ 6.8). Oxidation of the methyl group of 170 using 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) afforded glycozolidal (171).
The hydroxy-methoxycarbazoles glycozolidol (175), carbalexin C (179), and
lansine (181) were prepared using protecting groups for the hydroxy groups at the
2- or 6-position, respectively. Thus, the synthesis of glycozolidol (175) starts with
Buchwald–Hartwig amination of the benzyl-protected p-bromophenol 172 and
3-methoxy-4-methylaniline (54) (Scheme 38) [152]. The palladium(II)-catalyzed
oxidative cyclization provided the benzyl-protected glycozolidol 174 (TON ¼ 6.0)
under the same conditions as described above for the synthesis of glycozolidine
(170) (cf. Scheme 37). Finally, removal of the benzyl group led to glycozolidol
(175).
MeO Me MeO Me
+
75% N OMe
Br H2N OMe
H
125 54 169
0.1 eq Pd(OAc)2 MeO Me MeO CHO

2.5 eq Cu(OAc)2 DDQ
OMe 75% OMe
AcOH, air, MW
68% N N
H H
170 glycozolidine 171 glycozolidal
Scheme 37 Synthesis of glycozolidine (170) and glycozolidal (171)

BnO Me BnO Me
+
83% N OMe
Br H 2N OMe
H
172 54 173
0.1 eq Pd(OAc)2 BnO Me HO Me

2.5 eq Cu(OAc)2 H2, Pd / C
OMe OMe
AcOH, air, MW 91%
60% N N
H H
174 175 glycozolidol
Scheme 38 Synthesis of glycozolidol (175)
MeO Me MeO Me
+
86% N OTPS
Br H2N OTPS
H
125 176 177
0.1 eq Pd(OAc)2 MeO Me MeO Me

2.5 eq Cu(OAc)2 TBAF
AcOH, air, MW OTPS 90% OH
76 % N N
H H
178 179 carbalexin C
DDQ
77%
MeO CHO MeO CHO

TBAF
OTPS 65% OH
N N
H H
180 181 lansine
Scheme 39 Synthesis of carbalexin C (179) and lansine (181)
For the synthesis of carbalexin C (179) and lansine (181) the protecting group
strategy was reversed. The TPS-protected 2-methyl-5-aminophenol 176 had to be
employed to enable a release of the free hydroxy group at C-2 in the final step of the
synthesis. Buchwald–Hartwig coupling of compound 176 with p-bromoanisole
(125) afforded the diarylamine 177 (Scheme 39) [152]. The palladium(II)-catalyzed
oxidative cyclization in the presence of copper(II) acetate as co-oxidant under
microwave irradiation gave the carbazole 178 (TON ¼ 7.6). Desilylation of
compound 178 led to carbalexin C (179). This first total synthesis provided
the phytoalexin carbalexin C (179) in five steps and 59% overall yield based
olker
R R′
R R′
cat. Pd(OAc)2 R R′ O2 or air
+
P-ligand N AcOH N
OTf NH2 H H
182 31 95 32
Scheme 40 Synthesis of carbazoles 32 by a one-pot Buchwald–Hartwig amination/oxidative

cyclization
on 2-methyl-5-nitrophenol (162). Oxidation of the methyl group at C-3 of the

carbazole 178 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave com-
pound 180 and subsequent removal of the silyl protecting group afforded lansine
(181).
The palladium(II)-catalyzed oxidative cyclization of diarylamines in pivalic acid
as solvent has been applied to the synthesis of murrayafoline A (188), mukonine
(201) and clausenine [187]. Ohno et al. combined the palladium(0)-catalyzed
N-arylation of arylamines and the palladium(II)-catalyzed oxidative cyclization
of the resulting diarylamines to a one-pot procedure (Scheme 40) [188, 189].
Buchwald–Hartwig coupling of aryl triflates 182 with the arylamines 31 using
2-dicyclohexylphosphino-20 ,40 ,60 -triisopropylbiphenyl (X-Phos) as ligand led to
the intermediate diarylamines 95. Subsequent addition of acetic acid and exposure
to air or oxygen atmosphere initiated the oxidative cyclization to carbazoles 32.
This procedure has been applied to the synthesis of a variety of substituted non-
natural carbazoles. The alkaloid clausine L (148) which displays anti-platelet
aggregation activity could be prepared in 74% yield by direct coupling of methyl
4-amino-2-methoxybenzoate (154) with phenyl trifluoromethanesulfonate.
3.2.2 Copper-Catalyzed N-Arylation Followed by Oxidative Cyclization

(Cu[II]/Pd[II])
A construction of the carbazole framework involving copper(II)-catalyzed aryla-

mine arylation and palladium(II)-mediated oxidative cyclization has been
reported by Menéndez et al. (Scheme 41) [190, 191]. The diarylamines 95 were
obtained by copper(II) acetate-catalyzed N-arylation of arylamines 31 with phe-
nyllead triacetate (183) using Barton’s conditions [192]. Subsequent oxidative
cyclization using palladium(II) acetate under microwave irradiation afforded
the carbazoles 32. This procedure was applied to the synthesis of murrayafoline
A (188) [190].
Subsequently, these authors also used the palladium(II)-catalyzed version
with copper(II) acetate as co-oxidant, originally reported by Kn€olker et al.
[142–152], for the synthesis of murrayafoline A (188), 2-methoxy-3-methylcarba-
zole (146), and glycozolidine (170) (Scheme 42), as well as some non-natural
carbazoles [191].
R R'
R R'
R R'
cat. Cu(II) Pd(II)
+
N
H N
Pb(OAc)3 NH2 H
183 31 95 32
Scheme 41 Synthesis of carbazoles 32 by Cu(II)-catalyzed N-arylation of the arylamines 31 and

subsequent oxidative cyclization of the diarylamines 95
Me R1 Me
R1
cat. Cu(OAc)2
+
H2N R3 N R3
Pb(OAc)3 2 H
R R2
184 R1 = H 54 R2 = H, R3 = OMe 145 R1 = R2 = H, R3 = OMe (73 %)

185 R1 = OMe 186 R2 = OMe, R3 = H 169 R1 = R3 = OMe, R2 = H (77 %)
187 R1 = R3 = H, R2 = OMe (76 %)
0.4 eq Pd(OAc)2 R1 Me
2.0 eq Cu(OAc)2 146 R1 = R2 = H, R3 = OMe (89 %)
R3 170 R1 = R3 = OMe, R2 = H (80 %) glycozolidine
N 188 R1 = R3 = H, R2 = OMe (88 %) murrayafoline A
H R2
Scheme 42 Synthesis of 2-methoxy-3-methylcarbazole (146), glycozolidine (170), and murraya-

foline A (188)
3.2.3 Suzuki–Miyaura Coupling Followed by Oxidative C–H Bond

Amination or Amidation (Pd[0]/Pd[II])
In contrast to the synthetic approaches described in Sects. 3.2.1 and 3.2.2, the
N-arylation and C–C coupling steps can also be reversed. Suzuki–Miyaura coupling
of N-substituted 2-haloarylamines 189 with arylboronic acids 190 provides
N-substituted 2-aminobiaryls 191 (Scheme 43). A palladium(II)-catalyzed oxida-
tive cyclization of the latter forms the tricyclic carbazole framework. Different
from the first reaction step in Scheme 24, this is an oxidative C–N coupling which
requires N–H and C–H activation, whereas the C–C bond is formed in a cross-
coupling process.
Oxidative cyclization of 2-phenylacetanilides in the presence of catalytic
amounts of palladium(II) acetate and copper(II) acetate as co-oxidant in an oxygen
atmosphere affords N-acetylcarbazoles. Subsequent hydrolysis or reduction of
the N-acetylcarbazoles leads to the corresponding 9H-carbazoles [193]. For the
synthesis of mukonidine (149) and glycosinine (147) oxidative cyclization
of the N-acetylated 2-aminobiphenyl 193 afforded the N-acetylcarbazole 194
(Scheme 44) [194]. Demethylation of 194 and amide cleavage led to mukonidine
(149). Alternatively, reduction of compound 194 with lithium aluminum hydride
olker
R3
R1 R3
X R3
R1
cat. Pd(0) H cat. Pd(II)
+ R1
NH N oxidizing
B(OH)2 R2 N
R2 agent
R2
189 190 191 192
Scheme 43 Synthesis of carbazoles 192 by Suzuki–Miyaura coupling and subsequent oxidative

cyclization of the 2-aminobiaryl compounds 191
COOMe
COOMe
cat.Pd(OAc)2
OMe
Cu(OAc)2
OMe
HN O2 N
94 % Ac
Ac
193 194
1. BBr3 1. LiAlH4
2. H2SO4 / MeOH 2. MnO2
85 % 74 %
COOMe CHO
OH OMe
N N
H H
149 mukonidine 147 glycosinine
Scheme 44 Synthesis of mukonidine (149) and glycosinine (147)
followed by oxidation of the resulting benzylic alcohol with manganese dioxide

provided glycosinine (147). Analogously, mukonine (201) was obtained starting
from an appropriate 2-phenylacetanilide.
Using 0.2 equiv. of palladium(II) acetate and (diacetoxy)iodobenzene as co-
oxidant, Gaunt et al. achieved an oxidative cyclization of N-alkylbiphenyl-
2-amines including C–H activation at the 20 -position to give N-alkylcarbazoles
[195]. The potential of this method was demonstrated by the synthesis of an
N-glycosylcarbazole.
3.2.4 Buchwald–Hartwig Amination Followed by Heck-Type Coupling

(Pd[0]/Pd[0])
Carbazoles can be obtained by a sequence of Buchwald–Hartwig amination and

intramolecular Heck-type biaryl coupling. Depending on the distribution of
the functional groups in the substrates, two procedures can be distinguished

for this approach. The two leaving groups can be placed in one ring as given for
the 1,2-dihalo(triflyloxy)arenes 195. Buchwald–Hartwig coupling with a non-
halogenated arylamine 196 followed by Heck-type diaryl coupling of the interme-
diate monohalodiarylamines 197 provides the carbazoles 32. Alternatively, the
leaving groups can be located in different rings, one in the arene 195 and the
other ortho to the amino group of the arylamine 196 as shown first by Sakamoto
et al. [196]. On palladium(0)-catalyzed coupling the carbazoles 32 are formed via
an intermediate diarylamine 197 by the same reaction sequence (Scheme 45).
Buchwald–Hartwig coupling of 2-chloroaniline (199) and aryl bromides was
used as the first step by Bedford and co-workers [197]. Subsequent palladium(0)-
catalyzed cyclization by C–H bond activation afforded the carbazole ring system.
For a few examples the transformations could be carried out in one pot. Carbazole
natural products, including clausine P and glycozolidine (170) [197], and a
number of fluorocarbazoles [198] are available by this procedure. Starting from
simple o-substituted iodoarenes and N-sulfonated or N-acetylated o-bromoanilines,
Catellani et al. described a palladium(0)- and norbornene-catalyzed synthesis of
substituted carbazoles by sequential C–C and C–N cross coupling [199]. This
methodology has been used for the synthesis of carbazomycin A.
Fagnou et al. applied the intramolecular arylation to the synthesis of mukonine
(201) (Scheme 46) [200]. Buchwald–Hartwig coupling of 2-chloroaniline (199)
R R′ R R′
H(X) (H)Y R R′
cat. Pd(0) cat. Pd(0)
+
N
X H2N N
(X)H H Y(H) H
195 196 197 32
Scheme 45 Synthesis of carbazoles 32 by Buchwald–Hartwig amination and subsequent cycli-

zation by intramolecular Heck-type coupling of the intermediate diarylamines 197
cat. Pd2(dba)3 MeOOC

MeOOC OMe Cl
P-ligand, K3PO4
+
85 % N
OTf H2N H
OMe Cl
198 199 200
0.03 eq Pd(OAc)2 MeOOC

PCy3-HBF4, K2CO3
86 %
N
MeO H
201 mukonine
Scheme 46 Synthesis of mukonine (201)

olker
Me Me
Cl cat. Pd(OAc)2, PCy3
+ H2N K3PO4, NMP
Cl N
OMe 72 %
H OMe
202 203 188 murrayafoline A
Scheme 47 Synthesis of murrayafoline A (188)
with the aryl triflate 198 led to the diarylamine 200. Subsequent Heck-type cycli-
zation afforded mukonine (201).
Chlorinated diarylamines have also been successfully cyclized using N-hetero-
cyclic carbene (NHC) palladium catalysts. It has been demonstrated that the
turnover number of the catalytic system is substantially improved by using imida-
zolium salt additives along with a mono-NHC–palladium(II) pre-catalyst [201].
A potential homo-coupling of the halogenated arylamines is avoided by having
the halogen leaving groups attached to the same arene. Guided by this idea,
Ackermann et al. reported a palladium-catalyzed domino synthesis of substituted
carbazoles with readily available anilines and 1,2-dihaloarenes (Scheme 47) [202].
The procedure has been applied to the synthesis of murrayafoline A (188) by
coupling of 1,2-dichlorobenzene (202) with the arylamine 203.
3.2.5 Suzuki–Miyaura Coupling Followed by Double Buchwald–Hartwig

Amination (Pd[0]/Pd[0])
N-Substituted carbazoles 192 are available by double Buchwald–Hartwig amina-

tion of 2,20 -dihalobiaryl compounds or biaryl bistriflates 204 with primary amines
205 in the presence of catalytic amounts of palladium(0) (Scheme 48) [203–205].
Chida et al. used this strategy for the total synthesis of murrastifoline
A [204, 205]) and ()-murrayazoline [()-206] [206]. In addition to the double
Buchwald–Hartwig amination generating the carbazole framework, two further
palladium(0)-catalyzed couplings have been applied to construct the hexacyclic
skeleton of ()-murrayazoline [()-206], an O-arylation and a Suzuki–Miyaura
coupling. Retrosynthetic analysis of ()-murrayazoline [()-206] led to 2-bromo-
phenylboronic acid, the arylamine 211, and the monoprotected cyclohexane-1,4-
dione 212 as precursors (Scheme 49).
2,20 -Dibromobiphenyl 210 and the amine 209 were prepared in five and ten
steps, respectively. The double Buchwald–Hartwig coupling of 209 and 210 using
0.2 equiv. of tris(dibenzylideneacetone)dipalladium, 0.6 equiv. of 2-dicyclohexyl-
phosphino-20 ,40 ,60 -triisopropylbiphenyl (X-Phos), and 3 equiv. of sodium tert-but-
oxide in toluene at 130 C in a sealed tube afforded the carbazole 213 in 59% yield
(Scheme 50) [206]. Subsequent treatment with scandium(III) triflate resulted in
removal of the MOM group, cleavage of the ketal, and subsequent Friedel–Crafts-
R1 R3 R1 R3
cat. Pd(0)
+ H2N–R2
N
X X
R2
204 205 192
Scheme 48 Synthesis of carbazoles 192 by double Buchwald–Hartwig amination of biaryl

compounds 204
Pd(0)
Suzuki–Miyaura coupling
Me
Me
Pd(0)
OH
Pd(0) O O-Arylation
N N
double O
N-Arylation Me Me Me
Me Me
207
(±)-206 Friedel–Crafts-type
(±)-murrayazoline Michael Addition
Me
Br Br
H2N O OH
OMOM + N
Me O
Me Me
Me Me
210 209 208
O
Me
S
+ OMOM O
Br S
B(OH)2 H2N
211 212
Scheme 49 Retrosynthetic analysis of ()-murrayazoline [()-206]
type Michael addition to give the pentacyclic carbazole 207. Conversion of the
hydroxy group into the triflate and diastereoselective methylation of the ketone led
to the carbinol 215. Finally, cyclization by O-arylation using stoichiometric
amounts of palladium(II) acetate, 2-di-tert-butylphosphinobiphenyl, and cesium
carbonate provided ()-murrayazoline [()-206].
Further applications of the double N-arylation to the synthesis of carbazoles
include the natural products ellipticine [207] and mukonine (201) [208], and
various non-natural 11-phenylbenzofuro[3,2-b]carbazoles [209].
olker
Me
Me
cat. Pd2(dba)3 OMOM
H2N O
X-Phos, NaOt-Bu N
OMOM +
Me 59% Me
Me O
Br Br Me O
210 209 213 O
Me
Me
Sc(OTf)3 OH Tf2O
OH
N
73 % N O 94 %
Me
Me
Me
Me
O
208 207
Me Me Me
Pd(OAc)2
OTf MeMgBr OTf P-ligand
N O
N 77 % N OH Cs2CO3
O
Me Me 80 % Me
Me Me
Me Me Me
214 215 (±)-206 (±)-murrayazoline
Scheme 50 Synthesis of ()-murrayazoline [()-206]
3.2.6 Suzuki–Miyaura Coupling Followed by SNAr-Reaction (Pd[0])
A tandem Suzuki–Miyaura coupling/nucleophilic aromatic substitution to carba-

zoles was developed by St. Jean et al. (Scheme 51) [210]. Reaction of N-sulfonyl-
protected 2-aminophenylboronates 216 with 1-bromo-2-fluorobenzenes 217 under
palladium(0)-catalysis provides the N-sulfonyl-protected carbazoles 218. This
annulation is compatible with a variety of electron-withdrawing groups (e.g.,
aldehydes, esters, and sulfones) and has been applied to an efficient synthesis of
glycosinine (147) (four steps, 50% overall yield).
B(OR)2 EWG
EWG
X cat. Pd(0)
+
NH MW N
SO2R F SO2R
216 217 218
Scheme 51 Synthesis of carbazoles 218 by tandem Suzuki–Miyaura cross-coupling and SNAr-

reaction
3.2.7 Nucleophilic Addition to Arynes Followed by Heck-Type

Coupling (Pd[0])
In a one-pot procedure, the reaction of o-iodoanilines 219 with silylaryl triflates 220
in the presence of cesium fluoride affords via an aryne intermediate the o-iododiar-
ylamines 221 which are subsequently cyclized to carbazoles 32 by an in situ
generated palladium(0) catalyst (Scheme 52) [211, 212].
This procedure has been applied to the synthesis of mukonine (201) (Scheme 53)
[212]. The o-iodoaniline 222 was prepared in two steps from commercially avail-
able 4-amino-3-methoxybenzoic acid. Reaction of compound 222 with the silylaryl
triflate 220a in the presence of cesium fluoride leads to an intermediate diarylamine,
which is cyclized in situ by addition of catalytic amounts of palladium(II) acetate
and tricyclohexylphosphane to afford mukonine (201) (three steps and 76% overall
yield).
R R′ I R R′
I TMS
CsF R R′ cat. Pd(0)
+
NH2 TfO N N
H H
219 220 221 32
Scheme 52 Synthesis of carbazoles 32 by nucleophilic addition to arynes and subsequent

cyclization by intramolecular Heck-type coupling of the diarylamines 221
COOMe
TMS I COOMe
CsF
+
then cat. Pd(OAc)2
OTf H2N N
cat. PCy3
OMe H OMe
95 %
220a 222 201 mukonine
Scheme 53 Synthesis of mukonine (201)
3.2.8 Hydrolysis of Benzoxazol-2-ones Followed by Oxidative Cyclization

(Pd[II])
Tamariz et al. developed an access to 1-methoxycarbazoles 225 via hydrolysis of

3-arylbenzoxazol-2-ones 223 and subsequent palladium(II)-mediated oxidative
cyclization of the resulting diarylamines 224 (Scheme 54) [213, 214]. The required
benzoxazol-2-ones 223 are obtained by regioselective Lewis acid-catalyzed
Diels–Alder reaction of 4,5-dimethylene-3-aryl-1,3-oxazolidin-2-ones with alk-
enes followed by aromatization using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ).
olker
R R
O R R′
R′
O 1. NaOH, EtOH Pd(II)
N 2. MeI N N
H H OMe
Ar OMe
223 224 225
Scheme 54 Synthesis of 1-methoxycarbazoles 225 by hydrolysis of the benzoxazol-2-ones 223

and subsequent palladium(II)-mediated oxidative cyclization of the diarylamines 224
OMe
O CHO
O
O O NEt3 CHO DDQ
+ 4-MeOC6H4 N O
O
dioxane BF3•Et2O N 70 %
40 % 93 % 4-MeOC6H4
NCO
226 227 228 229
CHO 1.NaOH MeO CHO MeO CHO

O
O EtOH Pd(OAc)2
N 2.MeI N 80 %
77 % H N
4-MeOC6H4 OMe H OMe
230 231 232
6-methoxymurrayanine
Scheme 55 Synthesis of 6-methoxymurrayanine (232)
This sequence has been used for the synthesis of 6-methoxymurrayanine (232)
(Scheme 55) [214]. Reaction of butane-2,3-dione (226) with 4-methoxyphenyl
isocyanate (227) to 4,5-dimethylene-3-(4-methoxyphenyl)-1,3-oxazolidin-2-one
(228) followed by regioselective boron trifluoride-catalyzed Diels–Alder reaction
with acrolein afforded the oxazolone 229. Only minor amounts of the undesired
regioisomer were formed. Aromatization using 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) afforded the benzoxazol-2-one 230. Saponification of the
cyclic carbamate and subsequent O-methylation led to the diarylamine 231. Finally,
oxidative cyclization using stoichiometric amounts of palladium(II) acetate
provided 6-methoxymurrayanine (232).
This method has also been applied to the synthesis of murrayanine, murrayafo-
line A (188) [213], and clausenine [214] using stoichiometric amounts of palladium
(II) actetate for the oxidative cyclization of the intermediate diarylamines.
3.2.9 Hydrolysis of Benzoxazol-2-ones Followed by Heck-Type Coupling

(Pd[0])
More recently, a variation of the method described above (cf. Scheme 54) has
been reported (Scheme 56) [215]. Hydrolytic cleavage of the 3-(2-bromophenyl)
R
O
O Br R′ R
N 1. NaOH, EtOH R′ R cat. Pd(0)
2. MeI N
R′ Br N
H OMe H OMe
233 234 225
Scheme 56 Synthesis of 1-methoxycarbazoles 225 by hydrolysis of the benzoxazol-2-ones 233

and subsequent cyclization by intramolecular Heck-type coupling of the diarylamines 234
benzoxazol-2-ones 233 followed by methylation of the hydroxy group provides the

diarylamines 234. Subsequent cyclization by palladium(0)-catalyzed intramolecu-
lar Heck-type biaryl coupling leads to the 1-methoxycarbazoles 225. Following this
approach, murrayanine has been synthesized in four steps and 45% overall yield
[215].
3.2.10 Stille Coupling Followed by Reductive Annulation (Pd[0]/Pd[0])
S€oderberg et al. have developed a sequence of Stille coupling followed by palladium

(0)-catalyzed reductive N-heteroannulation for the synthesis of tetrahydrocarbazo-
lones 238 (Scheme 57) [216, 217]. Palladium(0)-catalyzed coupling of 2-nitroar-
ylstannanes 236 with 2-iodo-2-cyclohexenones 235 afforded the 2-(2-nitrophenyl)-
2-cyclohexenones 237. Cyclization with carbon monoxide in the presence of
catalytic amounts of bis(dibenzylideneacetone)palladium, 1,3-bis(diphenylphos-
phino)propane (dppp), and 1,10-phenanthroline led to the corresponding tetrahy-
drocarbazolones 238 which can be transformed to the carbazoles 32 by
Wolff–Kishner reduction and subsequent aromatization. This approach has been
applied to the formal synthesis of murrayaquinone A [216].
O O O
Bu3Sn R′ R′
I cat. Pd(0) R cat. Pd(0) R′
R
R + CO
O 2N N
O2N
H
235 236 237
238
R R′
1. Wolff–Kishner reduction
2. aromatization N
H
32
Scheme 57 Synthesis of carbazoles 32 by Stille coupling and subsequent reductive annulation

olker
4 Conclusion
Transition metal-mediated and -catalyzed coupling reactions can be exploited for

selective C–C and/or C–N bond formations. Thus, this chemistry opens up the way
to highly efficient routes for the synthesis of heterocyclic ring systems, like pyrroles
and carbazoles which are frequently found as frameworks of biologically active
naturally occurring alkaloids. The silver(I)-mediated oxidative cyclization of
homopropargylamines to pyrroles can be converted to a catalytic process by
using the corresponding N-tosylhomopropargylamines as substrates. Both versions
of this procedure have been applied successfully to natural product synthesis and
applications include ()-harmicine, ()-crispine A, pentabromopseudilin, and
pentachloropseudilin. A range of different methodologies has been developed for
the synthesis of carbazoles. The iron-mediated synthesis of carbazoles represents a
very useful procedure and has been applied to the total synthesis of hyellazole,
6-chlorohyellazole, 2,7-dioxygenated carbazole alkaloids, furoclausine A, the anti-
ostatin A and B series, (R)-()-neocarazostatin B, and (R)-carquinostatin A. Diverse
palladium-catalyzed routes have been developed for the synthesis of carbazole
alkaloids. Among these, the sequence of Buchwald–Hartwig amination followed
by palladium(II)-catalyzed oxidative cyclization of the intermediate diarylamine
has proven to be the most versatile method and superior to the alternative proce-
dures. Recent applications include the total syntheses of the carbazomadurins,
epocarbazolins, 7-oxygenated carbazole alkaloids, 6-oxygenated carbazole alka-
loids, 1,6-dioxygenated carbazole alkaloids, 2-oxygenated carbazole alkaloids,
2,6-dioxygenated carbazole alkaloids, clausine V, pityriazole, euchrestifoline, and
girinimbine.
References
1. Sundberg RJ (1984) In: Katritzky AR, Rees CW (eds) Comprehensive heterocyclic chemis-
try, vol 4. Pergamon Press, Oxford, pp 313–376
2. Bean GP (1990) In: Jones RA (ed) Chemistry of heterocyclic compounds, pyrroles. Wiley,
New York, pp 105–294
3. Jones RA (1992) Chemistry of heterocyclic compounds, Part II, vol 48. Wiley, New York
4. Sundberg RJ (1996) In: Katritzky AR, Rees CW, Scriven EFV (eds) Comprehensive
heterocyclic chemistry II, vol 2. Elsevier, Oxford, pp 119–206
5. Gribble GW (1996) In: Katritzky AR, Rees CW, Scriven EFV (eds) Comprehensive hetero-
cyclic chemistry II, vol 2. Elsevier, Oxford, pp 207–257
6. O’Hagan D (2000) Nat Prod Rep 17:435–446
7. Bellina F, Rossi R (2006) Tetrahedron 62:7213–7256
8. Joule JA, Mills K (2010) Heterocyclic chemistry. Wiley-Blackwell, New York
9. Patil NT, Yamamoto Y (2007) Arkivoc (x) 121–141
10. Hashmi ASK (2007) Chem Rev 107:3180–3211
11. F€urstner A, Davies P (2007) Angew Chem Int Ed 46:3410–3449
12. Arcadi A (2008) Chem Rev 108:3266–3325
13. Patil NT, Yamamoto Y (2008) Chem Rev 108:3395–3442
14. Kirsch SF (2008) Synthesis 3183–3204

15. Belmont P, Parker E (2009) Eur J Org Chem 6075–6089
16. Das A, Sohel SMA, Liu R-S (2010) Org Biomol Chem 8:960–979
17. Chakraborty DP, Roy S (1991) In: Herz W, Grisebach H, Kirby CW, Steglich W, Tamm C
(eds) Progress in the chemistry of organic natural products, vol 57. Springer, Wien,
pp 71–152
18. Kn€olker H-J, Reddy KR (2002) Chem Rev 102:4303–4428
19. Kn€olker H-J (2005) Top Curr Chem 244:115–148
20. Kn€olker H-J, Reddy KR (2008) In: Cordell GA (ed) The alkaloids, vol 65. Academic Press,
Amsterdam, pp 1–430
21. Choi TA, Czerwonka R, Fr€ ohner W, Krahl MP, Reddy KR, Franzblau SG, Kn€ olker H-J
(2006) ChemMedChem 1:812–815
22. Choi TA, Czerwonka R, Kn€ oll J, Krahl MP, Reddy KR, Franzblau SG, Kn€ olker H-J (2006)
Med Chem Res 15:28–30
23. Choi TA, Czerwonka R, Forke R, J€ager A, Kn€ oll J, Krahl MP, Krause T, Reddy KR,
Franzblau SG, Kn€ olker H-J (2008) Med Chem Res 17:374–385
24. Agarwal S, C€ammerer S, Filali S, Fr€ ohner W, Kn€ oll J, Krahl MP, Reddy KR, Kn€ olker H-J
(2005) Curr Org Chem 9:1601–1614
25. Agarwal S, Filali S, Fr€ ohner W, Kn€ oll J, Krahl MP, Reddy KR, Kn€ olker H-J (2006) In:
Kartsev VG (ed) The chemistry and biological activity of synthetic and natural compounds –
nitrogen-containing heterocycles, vol 1. ICSPF Press, Moscow, pp 176–186
26. Agarwal S, Kn€ olker H-J (2004) Org Biomol Chem 2:3060–3062
27. Kn€olker H-J, Agarwal S (2004) Synlett 1767–1768
28. Kam TS, Sim KM (1998) Phytochemistry 47:145–147
29. Zhang Q, Tu G, Zhao Y, Cheng T (2002) Tetrahedron 58:6795–6798
30. Kn€olker H-J, Agarwal S (2005) Tetrahedron Lett 46:1173–1175
31. Martin R, J€ager A, B€ohl M, Richter S, Fedorov R, Manstein DJ, Gutzeit HO, Kn€ olker H-J
(2009) Angew Chem Int Ed 48:8042–8046
32. Burkholder PR, Pfister RM, Leitz FH (1966) Appl Microbiol 14:649–653
33. Lovell FM (1966) J Am Chem Soc 88:4510–4511
34. Andersen RJ, Wolfe MS, Faulkner DJ (1974) Mar Biol 27:281–285
35. Laatsch H, Renneberg B, Hanefeld U, Kellner M, Pudleiner H, Hamprecht G, Kraemer H-P,
Anke H (1995) Chem Pharm Bull 43:537–546
36. Cavalleri B, Volpe G, Tuan G, Berti M, Parenti F (1978) Curr Microbiol 1:319–324
37. Beeren SR, Dabb SL, Messerle BA (2009) J Organomet Chem 694:309–312
38. Carney JM, Donoghue PJ, Wuest WM, Wiest O, Helquist P (2008) Org Lett 10:3903–3906
39. Fl€ogel O, Reissig H-U (2004) Synlett 895–897
40. Dieter RK, Chen NY, Yu HY, Nice LE, Gore VK (2005) J Org Chem 70:2109–2119
41. Mitasev B, Brummond KM (2006) Synlett 3100–3104
42. Chowdhury MA, Reissig H-U (2006) Synlett 2383–2386
43. Kaden S, Reissig H-U (2006) Org Lett 8:4763–4766
44. Ji K-G, Shu X-Z, Zhao S-C, Zhu H-T, Niu Y-N, Liu X-Y, Liang Y-M (2009) Org Lett
11:3206–3209
45. Harrison TJ, Kozak JA, Corbella-Pané M, Dake GR (2006) J Org Chem 71:4525–4529
46. Hashmi ASK, Rudolph M (2008) Chem Soc Rev 37:1766–1775
47. Morita N, Krause N (2006) Eur J Org Chem 4634–4641
48. Lee SI, Kim SM, Kim SY, Chung YK (2006) Synlett 2256–2260
49. Davies PW, Martin N (2009) Org Lett 11:2293–2296
50. Chen D-D, Hou X-L, Dai L-X (2009) Tetrahedron Lett 50:6944–6946
51. Blanc A, Alix A, Weibel JM, Pale P (2010) Eur J Org Chem 1644–1647
52. Peng HM, Zhao J, Li X (2009) Adv Synth Catal 351:1371–1377
53. Egi M, Azechi K, Akai S (2009) Org Lett 11:5002–5005
54. Gorin DJ, Davis NR, Toste FD (2005) J Am Chem Soc 127:11260–11261
olker
55. Martı́n R, Rodrı́guez Rivero MR, Buchwald SL (2006) Angew Chem Int Ed 45:7079–7082
56. Martı́n R, Larsen CH, Cuenca A, Buchwald SL (2007) Org Lett 9:3379–3382
57. Yuan X, Xu X, Zhou X, Yuan J, Mai L, Li Y (2007) J Org Chem 72:1510–1513
58. Rivero MR, Buchwald SL (2007) Org Lett 9:973–976
59. Zheng Q, Hua R (2010) Tetrahedron Lett 51:4512–4514
60. Yan R-L, Luo J, Wang C-X, Ma C-W, Huang G-S, Liang Y-M (2010) J Org Chem
75:5395–5397
61. Chiba S, Wang Y-F, Lapointe G, Narasaka K (2008) Org Lett 10:313–316
62. Wyrebek P, Sniady A, Bewick N, Li Y, Mikus A, Wheeler KA, Dembinski R (2009)
Tetrahedron 65:1268–1275
63. Dong H, Shen M, Redford JE, Stokes BJ, Pumphrey AL, Driver TG (2007) Org Lett
9:5191–5194
64. Liu X-t, Hao L, Lin M, Chen L, Zhan Z-p (2010) Org Biomol Chem 8:3064–3072
65. Hiroya K, Matsumoto S, Ashikawa M, Ogiwara K, Sakamoto T (2006) Org Lett
8:5349–5352
66. Yoshida M, Al-Amin M, Shishido K (2009) Synthesis 2454–2466
67. Liu X-t, Huang L, Zheng F-j, Zhan Z-p (2008) Adv Synth Catal 350:2778–2788
68. Pridmore SJ, Slatford PA, Taylor JE, Whittlesey MK, Williams JMJ (2009) Tetrahedron
65:8981–8986
69. Ackermann L, Sandmann R, Kaspar LT (2009) Org Lett 11:2031–2034
70. Merkul E, Boersch C, Frank W, M€ uller TJJ (2009) Org Lett 11:2269–2272
71. Wang Y-F, Toh KK, Chiba S, Narasaka K (2008) Org Lett 10:5019–5022
72. Kn€olker H-J, Bauermeister M, Bl€aser D, Boese R, Pannek J-B (1989) Angew Chem Int Ed
Engl 28:223–225
73. Kn€olker H-J (1992) Synlett 371–387
74. Birch AJ, Cross PE, Lewis J, White DA, Wild SB (1968) J Chem Soc A 332–340
75. Ireland RE, Brown GG, Stanford RH, McKenzie TC (1974) J Org Chem 39:51–59
76. Kn€olker H-J, Baum E, Gonser P, Rohde G, R€ ottele H (1998) Organometallics 17:3916–3925
77. Kn€olker H-J, Ahrens B, Gonser P, Heininger M, Jones PG (2000) Tetrahedron 56:2259–2271
78. Kn€olker H-J (2000) Chem Rev 100:2941–2962
79. Pearson AJ (1980) Acc Chem Res 13:463–469
80. Pearson AJ (1982) In: Wilkinson G, Stone FGA, Abel EW (eds) Comprehensive organome-
tallic chemistry, vol 8. Pergamon Press, Oxford, pp 939–1011
81. Pearson AJ (1985) Metallo-organic chemistry. Wiley, Chichester, pp 247–347
82. Kn€olker H-J (1998) In: Beller M, Bolm C (eds) Transition metals for organic synthesis:
building blocks and fine chemicals, vol 1. Wiley-VCH, Weinheim, pp 534–549
83. Kn€olker H-J (1999) Chem Soc Rev 28:151–157
84. Kn€olker H-J, Braier A, Br€ ocher DJ, C€ammerer S, Fr€ ohner W, Gonser P, Hermann H,
Herzberg D, Reddy KR, Rohde G (2001) Pure Appl Chem 73:1075–1086
85. Stephenson GR, Perseghini M, Togni A (2001) In: Lautens M (ed) Science of synthesis, vol
1. Thieme, Stuttgart, pp 745–796
86. Kn€olker H-J (2004) Curr Org Synth 1:309–331
87. Kn€olker H-J (2004) In: Beller M, Bolm C (eds) Transition metals for organic synthesis:
building blocks and fine chemicals, vol 1, 2nd edn. Wiley-VCH, Weinheim, pp 585–599
88. Bauer I, Kn€olker H-J (2009) In: Rawal VH, Kozmin SA (eds) Science of synthesis, vol 46.
Thieme, Stuttgart, pp 637–668
89. Fischer EO, Fischer RD (1960) Angew Chem 72:919
90. Kn€olker H-J, Baum G, Foitzik N, Goesmann H, Gonser P, Jones PG, R€ ottele H (1998) Eur J
Inorg Chem 993–1007
91. Davies SG, Green MLH, Mingos DMP (1978) Tetrahedron 34:3047–3077
92. Kn€olker H-J, Bauermeister M, Pannek J-B, Bl€aser D, Boese R (1993) Tetrahedron
49:841–862
93. Kn€olker H-J, Bauermeister M (1993) Tetrahedron 49:11221–11236
94. Kn€olker H-J, Reddy KR (1998) Tetrahedron Lett 39:4007–4008

95. Kn€olker H-J, Fr€ ohner W (2000) Synthesis 2131–2136
96. Kn€olker H-J, Reddy KR (2000) Tetrahedron 56:4733–4737
97. Kn€olker H-J, Baum E, Hopfmann T (1999) Tetrahedron 55:10391–10412
98. Kn€olker H-J, Hopfmann T (2002) Tetrahedron 58:8937–8945
99. Kn€olker H-J, Fr€ ohner W (1997) Tetrahedron Lett 38:1535–1538
101. Kn€olker H-J, Fr€ ohner W (1997) Synlett 1108–1110
102. Kn€olker H-J, Baum E, Reddy KR (2000) Tetrahedron Lett 41:1171–1174
103. Czerwonka R, Reddy KR, Baum E, Kn€ olker H-J (2006) Chem Commun 711–713
104. Fr€ohner W, Reddy KR, Kn€ olker H-J (2007) Heterocycles 74:895–912
106. Kn€olker H-J, Baum E, Reddy KR (2000) Chirality 12:526–528
107. Kn€olker H-J, Fr€ ohner W, Wagner A (1998) Tetrahedron Lett 39:2947–2950
108. Kn€olker H-J, Schlechtingen G (1997) J Chem Soc Perkin Trans 1 349–350
109. Kn€olker H-J, Bauermeister M, Pannek J-B, Wolpert M (1995) Synthesis 397–408
110. Cardellina JH, Kirkup MP, Moore RE, Mynderse JS, Seff K, Simmons CJ (1979) Tetrahe-
dron Lett 20:4915–4916
111. Kn€olker H-J, Fr€ ohner W, Heinrich R (2004) Synlett 2705–2708
112. Ruangrungsi N, Ariyaprayoon J, Lange GL, Organ MG (1990) J Nat Prod 53:946–952
113. Wu T-S, Huang S-C, Wu P-L, Teng C-M (1996) Phytochemistry 43:133–140
114. Ito C, Ohta H, Tan HT-W, Furukawa H (1996) Chem Pharm Bull 44:2231–2235
115. Ito C, Katsuno S, Ohta H, Omura M, Kajiura I, Furukawa H (1997) Chem Pharm Bull 45:
48–52
116. Wu T-S, Huang S-C, Wu P-L, Kuoh C-S (1999) Phytochemistry 52:523–527
117. Yenjai C, Sripontan S, Sriprajun P, Kittakoop P, Jintasirikul A, Tanticharoen M, Thebt-
aranonth Y (2000) Planta Med 66:277–279
118. Sunthitikawinsakul A, Kongkathip N, Kongkathip B, Phonnakhu S, Daly JW, Spande TF,
Nimit Y, Rochanaruangrai S (2003) Planta Med 69:155–157
119. Kataeva O, Krahl MP, Kn€ olker H-J (2005) Org Biomol Chem 3:3099–3101
120. Corey EJ, Gilman NW, Ganem BE (1968) J Am Chem Soc 90:5616–5617
121. Ito C, Furukawa H (1990) Chem Pharm Bull 38:1548–1550
122. Wu T-S, Huang S-C, Wu P-L (1997) Heterocycles 45:969–973
123. Fr€ohner W, Krahl MP, Reddy KR, Kn€ olker H-J (2004) Heterocycles 63:2393–2407
124. Kn€olker H-J, Reddy KR (2005) In: Kartsev VG (ed) Selected methods for synthesis and
modification of heterocycles – the chemistry and biological activity of natural indole systems
(Part 1), vol 4. ICSPF Press, Moscow, pp 166–181
125. Kn€olker H-J, Krahl MP (2004) Synlett 528–530
126. Mo C-J, Shin-ya K, Furihata K, Furihata K, Shimazu A, Hayakawa Y, Seto H (1990) J
Antibiot 43:1337–1340
127. Flamm E, Demopoulos H, Seligman M, Poser R, Ransohoff J (1978) Stroke 9:445–447
128. Hess ML, Rowe GT, Caplan M, Romson JL, Lucchesi B (1985) Adv Myocardiol 5:159–175
129. Hammond B, Kontos HA, Hess ML (1985) Can J Physiol Pharmacol 63:173–187
130. Bolli R, Jeroudi MO, Patel BS, DuBose CM, Lai EK, Roberts R, McCay PB (1989) Proc Natl
Acad Sci U S A 86:4695–4699
131. Cerutti PA (1985) Science 227:375–381
132. Cheeseman KH, Forni LG (1988) Biochem Pharmacol 37:4225–4233
133. Palinski W, Rosenfeld ME, Yl€a-Herttuala S, Gurtner GC, Socher SS, Butler SW, Parthasar-
athy S, Carew TE, Steinberg D, Witztum JL (1989) Proc Natl Acad Sci U S A 86:1372–1376
134. Knott KE, Auschill S, J€ager A, Kn€ olker H-J (2009) Chem Commun 1467–1469
135. Kato S, Shindo K, Kataoka Y, Yamagishi Y, Mochizuki J (1991) J Antibiot 44:903–907
136. Shin-ya K, Tanaka M, Furihata K, Hayakawa Y, Seto H (1993) Tetrahedron Lett
34:4943–4944
olker
137. Kn€olker H-J, Wolpert M (1997) Tetrahedron Lett 38:533–536

138. Kn€olker H-J, Wolpert M (2003) Tetrahedron 59:5317–5322
139. Hartwig JF (1998) Angew Chem Int Ed 37:2046–2067
140. Muci A, Buchwald S (2002) Top Curr Chem 219:131–209
141. Åkermark B, Eberson L, Jonsson E, Pettersson E (1975) J Org Chem 40:1365–1367
142. Kn€olker H-J, O’Sullivan N (1994) Tetrahedron 50:10893–10908
143. Kn€olker H-J (1995) In: Moody CJ (ed) Advances in nitrogen heterocycles, vol 1. JAI Press,
Greenwich (CT), pp 173–204
144. Kn€olker H-J, Fr€ ohner W (1998) J Chem Soc Perkin Trans 1 173–175
145. Kn€olker H-J, Reddy KR, Wagner A (1998) Tetrahedron Lett 39:8267–8270
146. Kn€olker H-J, Fr€ohner W, Reddy KR (2002) Synthesis 557–564
147. Kn€olker H-J, Reddy KR (2003) Heterocycles 60:1049–1052
148. Krahl MP, J€ager A, Krause T, Kn€ olker H-J (2006) Org Biomol Chem 4:3215–3219
149. Forke R, Krahl MP, Krause T, Schlechtingen G, Kn€ olker H-J (2007) Synlett 268–272
150. Forke R, Krahl MP, D€abritz F, J€ager A, Kn€ olker H-J (2008) Synlett 1870–1876
151. Kn€olker H-J (2008) In: Fattorusso E, Taglialatela-Scafati O (eds) Modern alkaloids –
structure, isolation, synthesis and biology. Wiley-VCH, Weinheim, pp 475–501
152. Schmidt M, Kn€olker H-J (2009) Synlett 2421–2424
153. Kotoda N, Shin-ya K, Furihata K, Hayakawa Y, Seto H (1997) J Antibiot 50:770–772
154. Kn€olker H-J, Kn€ oll J (2003) Chem Commun 1170–1171
155. Kn€oll J, Kn€olker H-J (2006) Synlett 651–653
156. Nihei Y, Yamamoto H, Hasegawa M, Hanada M, Fukagawa Y, Oki T (1993) J Antibiot
46:25–33
157. Kn€oll J, Kn€olker H-J (2006) Tetrahedron Lett 47:6079–6082
158. Wu T-S, Huang S-C, Wu P-L (1996) Phytochemistry 43:1427–1429
159. Ito C, Okahana N, Wu T-S, Wang M-L, Lai J-S, Kuoh C-S, Furukawa H (1992) Chem Pharm
Bull 40:230–232
160. Meragelman KM, McKee TC, Boyd MR (2000) J Nat Prod 63:427–428
161. Chakraborty DP (1966) Tetrahedron Lett 7:661–664
162. Chakraborty DP (1969) Phytochemistry 8:769–772
163. Chowdhury DN, Basak SK, Das BP (1978) Curr Sci 47:490–491
164. Mukherjee S, Mukherjee M, Ganguly SN (1983) Phytochemistry 22:1064–1065
165. Bhattacharyya P, Sarkar T, Chakraborty A, Chowdhury BK (1984) Indian J Chem
23B:49–51
166. Kumar V, Reisch J, Wickramasinghe A (1989) Aust J Chem 42:1375–1379
167. Ma C, Case RJ, Wang Y, Zhang H-J, Tan GT, Hung NV, Cuong NM, Franzblau SG, Soejarto
DD, Fong HHS, Pauli GF (2005) Planta Med 71:261–267
168. Ito C, Furukawa H (1990) Chem Pharm Bull 38:1548–1550
169. Li W-S, McChesney JD, El-Feraly FS (1991) Phytochemistry 30:343–346
170. Chakraborty A, Chowdhury BK, Bhattacharyya P (1995) Phytochemistry 40:295–298
171. Potterat O, Puder C, Bolek W, Wagner K, Ke C, Ye Y, Gillardon F (2005) Pharmazie
60:637–639
172. B€orger C, Kn€olker H-J (2008) Synlett 1698–1702
173. Wu T-S, Huang S-C, Lai J-S, Teng C-M, Ko F-N, Kuoh C-S (1993) Phytochemistry
32:449–451
174. Bhattacharyya P, Chowdhury BK (1985) Indian J Chem 24B:452–452
175. Jash SS, Biswas GK, Bhattacharyya SK, Bhattacharyya P, Chakraborty A, Chowdhury BK
(1992) Phytochemistry 31:2503–2505
176. Lafrance M, Fagnou K (2006) J Am Chem Soc 128:16496–16497
177. Irlinger B, Bartsch A, Kr€amer H-J, Mayser P, Steglich W (2005) Helv Chim Acta
88:1472–1484
178. Forke R, J€ager A, Kn€ olker H-J (2008) Org Biomol Chem 6:2481–2483
179. Wu T-S, Wang M-L, Wu P-L (1996) Phytochemistry 43:785–789
180. Chakraborty DP, Barman BK, Bose PK (1964) Sci Cult 30:445
181. Gruner KK, Kn€olker H-J (2008) Org Biomol Chem 6:3902–3904
182. Chakraborty DP, Das BP (1966) Sci Cult 32:181–182
183. Bhattacharyya P, Chowdhury BK (1985) J Nat Prod 48:465–466
184. Bhattacharyya P, Chakrabartty PK, Chowdhury BK (1985) Phytochemistry 24:882–883
185. Pacher T, Bacher M, Hofer O, Greger H (2001) Phytochemistry 58:129–135
186. Prakash D, Raj K, Kapil RS, Popli SP (1980) Indian J Chem 19B:1075–1076
187. Liegault B, Lee D, Huestis MP, Stuart DR, Fagnou K (2008) J Org Chem 73:5022–5028
188. Watanabe T, Ueda S, Inuki S, Oishi S, Fujii N, Ohno H (2007) Chem Commun 4516–4518
189. Watanabe T, Oishi S, Fujii N, Ohno H (2009) J Org Chem 74:4720–4726
190. Sridharan V, Martı́n MA, Menéndez JC (2006) Synlett 2375–2378
191. Sridharan V, Martı́n MA, Menéndez JC (2009) Eur J Org Chem 4614–4621
192. Barton DHR, Donnelly DMX, Finet J-P, Guiry PJ (1991) J Chem Soc Perkin Trans 1
2095–2102
193. Tsang WCP, Zheng N, Buchwald SL (2005) J Am Chem Soc 127:14560–14561
194. Tsang WCP, Munday RH, Brasche G, Zheng N, Buchwald SL (2008) J Org Chem
73:7603–7610
195. Jordan-Hore JA, Johansson CCC, Gulias M, Beck EM, Gaunt MJ (2008) J Am Chem Soc
130:16184–16186
196. Iwaki T, Yasuhara A, Sakamoto T (1999) J Chem Soc Perkin Trans 1 1505–1510
197. Bedford RB, Betham M (2006) J Org Chem 71:9403–9410
198. Bedford RB, Betham M, Charmant JPH, Weeks AL (2008) Tetrahedron 64:6038–6050
199. Ca ND, Sassi G, Catellani M (2008) Adv Synth Catal 350:2179–2182
200. Campeau L-C, Parisien M, Jean A, Fagnou K (2006) J Am Chem Soc 128:581–590
201. Campeau L-C, Thansandote P, Fagnou K (2005) Org Lett 7:1857–1860
202. Ackermann L, Althammer A (2007) Angew Chem Int Ed 46:1627–1629
203. Nozaki K, Takahashi K, Nakano K, Hiyama T, Tang H-Z, Fujiki M, Yamaguchi S, Tamo K
(2003) Angew Chem Int Ed 42:2051–2053
204. Kitawaki T, Hayashi Y, Chida N (2005) Heterocycles 65:1561–1567
205. Kitawaki T, Hayashi Y, Ueno A, Chida N (2006) Tetrahedron 62:6792–6801
206. Ueno A, Kitawaki T, Chida N (2008) Org Lett 10:1999–2002
207. Konakahara T, Kiran YB, Okuno Y, Ikeda R, Sakai N (2010) Tetrahedron Lett 51:
2335–2338
208. Kuwahara A, Nakano K, Nozaki K (2005) J Org Chem 70:413–419
209. Kawaguchi K, Nakano K, Nozaki K (2008) Org Lett 10:1199–1202
210. St.Jean DJ, Poon SF, Schwarzbach JL (2007) Org Lett 9:4893–4896
211. Liu Z, Larock RC (2004) Org Lett 6:3739–3741
212. Liu Z, Larock RC (2007) Tetrahedron 63:347–355
213. Benavides A, Peralta J, Delgado F, Tamariz J (2004) Synthesis 2499–2504
214. Bernal P, Benavides A, Bautista R, Tamariz J (2007) Synthesis 1943–1948
215. Bernal P, Tamariz J (2007) Helv Chim Acta 90:1449–1454
216. Scott TL, S€oderberg BCG (2003) Tetrahedron 59:6323–6332
217. Scott TL, Yu X, Gorugantula SP, Carrero-Martı́nez G, S€
oderberg BCG (2006) Tetrahedron
62:10835–10842
Index
A 3-Bromoindole, 75
Acetylcholine esterase (AChE), 2 6-Bromoindolin-3-one, 110
Actinomadura madurae, 224 Bromoisovanillin, 52
Actinophyllic acid, 165 Brunsvigine, 163, 179
Actinoplanes (ATCC 33002), 207 Buprenorphine, 35, 59
Alkaloids, cernuane-type, 24
fawcettimine-type, 4
lycoposerramines, 1 C
phlegmarine-type, 11 Cadaverine, 2
quinolizidine-type, 23 Carbalexins, 236, 237
spirocyclic isoquinoline, 193 Carbazoles, 203
2-Alkylmercaptoindoles, thia-Claisen iron(0)-mediated/palladium(0/II)-catalyzed
rearrangements, 112 cyclizations, 203
Allocolchicine, 168 iron-mediated synthesis, 211
Allyldiisopinocampheylborane, 14 palladium-catalyzed synthesis, 222
Alzheimer’s disease, 2, 188 Carbazomadurins, 224, 248
Amabiline, 163, 183, 185, 187 Carbazomycins, 211, 241
Amaryllidaceae, 52, 163 Carbazoquinocin C, 213
Amauromine, 70, 112 Carduus crispus, 206
Ambiguine H, 85 Carquinostatin, 213, 220
Analgesia, 33 Cermizines, 20, 24
Annonidine A, 90 Cernuine, 20, 24
Annonidinium manni, 90 Chlorodiisopinocampheylborane, 15
Antiostatins, 217 6-Chlorohyellazole, 214
Ardeemin, 100 Citronellal, 21, 27
Aspidosperma alkaloids, 197 Citronellic acid, 7
Aspidospermidine, 163, 197 Clausena excavata, 215, 226
Asterriquinone B1, 86 Clausena lansium, 229
Asymmetric synthesis, 1 Clausenine, 231, 238, 246
Aszonalenin, 99 Clausenol, 229
Azepinoindole, 117 Clausines, 215, 226, 229
Azidodihydrobenzothiophene, 151 Clauszoline, 216, 226
Clavicipitic acids, 116
Clividine, 172
B Codeine, 33, 55
Bispyrroloiminoquinones, 131, 143 Codeinone, 56
Blebbistatin, 208 Codonopsinine, 209
Brevianamides, 77, 120 Colchiceine, 166
255
256 Index
Colchicine, 163, 165 FR 901483, 209

Colchicum autumnale, 165 Fumitremorgin B, 70, 77
Coniine, 164 Furoannulated carbazole alkaloids, 216
Corey-Winter reaction, 163 Furoclausine, 216
Crinine alkaloids, 183
Crispine A, 206
Cross-coupling, 163 G
Cyclin-dependent kinase 5 (CDK5), 229 Galanthamine, 52, 163, 188
Cyclohexadiene-cis-diol, 51 Galanthus woronowii, 188
Cyclopropane, 163 Girinimbine, 234
Glycomaurrol, 228
Glycosinine, 232, 240
D Glycosmis pentaphylla, 228
Debromoflustrabromine, 85 Glycozolidal, 236
Deformylflustrabromine, 70, 108 Glycozolidine, 236, 238
6-Demethoxyfumitremorgin C, 77 Glycozolidol, 236
Demethylation, 33 Glycozoline, 228
2-Deoxylycoricidine, 192 Glycozolinine, 228
Diels–Alder cycloaddition, 54 Grandirubrine, 163, 167
Dihomopropargylamines, 208 Grewe cyclization, 42
Dihydrocodeinone, 43 Gypsetin, 84, 120
Dihydrodiscorhabdin, 134
Dihydroindolo azocine, 86
Dihydroisocodeine, 49 H
Dihydroisocodeinone, 49 Haemultine, 163, 183, 185
Dihydrothebaine, 59 Hapalindole U, 85
2,6-Dihydroxynaphthalene, 40 Harmicine, 206
Diisopropyl azodicarboxylate Heck reaction, 44
(DIAD), 10 Heroin, 35
Dimethylallyl (prenyl) substituents, 68 Homoallylamine, 24
Dimethylallyltryptophan synthase, 117 Homopropargylamines, silver-mediated
Discorhabdins, 131, 134, 146, 152 oxidative cyclization, 205
Huperzine A, 2
Hydrocodone, 35, 59
E Hyella caespitosa, 214
Echinulins, 122 Hyellazole, 214
Ellipticine, 243
Epocarbazolins, 225
Ergot alkaloids, 118 I
Erysodine, 195 Imerubrine, 163, 167
Erythramine, 163, 195 Indolactam V, 70
Erythratine, 195 Indole prenylation, 67
Erythrina alkaloids, 193 Indoline, propargylation, 74
Eschenmoser–Claisen rearrangement, Iodoisovanillin, 54
48, 163 Ireland-Claisen rearrangement, 163
Euchrestifoline, 234 Iron, 203
Eustifoline, 228 Isatin, 101
Isobatzellines, 131, 142
Isocolchicine, 166
F Isoechinulin, 115
Fawcettimine, 4 Isoquinoline alkaloids, spirocyclic, 193
Flustramines, 95, 99, 101, 110, 113 Isovanillin, 45
Index 257
J Murrayazoline, 242, 243

Jerusalemine, 168 Mycobacterium tuberculosis, 215
Myosin-2 ATPase inhibitor, 208
K
Kopsia griffithii, 206 N
Nalbuphine, 35, 59
Naloxone, 35, 59
L Naltrexone, 35, 59
Lansine, 236 Nangustine, 163, 179
Latrunculiida, 133 Narciclasine, 163, 191, 194
Lavanduquinocin, 213, 221 Narseronine, 172, 176, 178
Leuconolam, 170 Narwedine, 52
Lycodine, 12 Neocarazostatin, 115, 213, 220
Lycopodine, 2 Neopinone, 56
Lycopodium alkaloids, 1 Nerve growth factor (NFG), 2
Lycoposerramines, 1 Noroxymorphone, 60
γ-Lycorane, 163 Notoamides, 103
Lycoricidine, 163, 191, 194
Lycorine, 172
Lycoris radiata, 188 O
Lyngbyatoxin, 118 Okaramine C, 74, 86, 120
Lysergic acid, 165 Opiate alkaloids, 33
Oripavine, 34, 59
Overman rearrangement, 163
M Oxidative cyclization, 203
Makaluvamines, 131, 138, 149 Oxofuro[2,3-b]indoles, 101
Malassezia furfur, 232 Oxycodone, 35
Maritinamine, 163, 183
3-Mercaptoindoles, 89
7-Methoxy-3-methylcarbazole, 227 P
2-Methoxy-3-methylcarbazole, 238 Palladium, 203
1-Methoxycarbazoles, 247 Pancratistatin, 191
6-Methoxymurrayanine, 229, 246 Paraherquamide A, 102
7-Methoxy-O-methylmukonal, 215 Pelletierine, 2
Micromeline, 228 Pentabromopseudilin, 207
Micromelum euchrestifolia, 228, 234 Pentachloropseudilin, 207
Micromelum hirsutum, 228 Phenanthroline silver complexes, 208
Mitsunobu reaction, 163 2-Phenylacetanilides, 239
Montabuphine, 181 11-Phenylbenzofuro[3,2-b]carbazoles, 243
Montanine alkaloids, 179 Phenyloxazolidinone, 7
Morphinans, 43 Phlegmariurine, 11
Morphine, 165 Phytoalexins, 237
total synthesis, 33 Pictet-Spengler reaction, 163
Mukonidine, 221, 231, 232, 240 4-(2-Piperidyl)acetoacetic acid, 2
Mukonine, 221, 238, 245 Pityriasis versicolor, 232
Murraya euchrestifolia, 118 Pityriazole, 232
Murraya siamensis, 215, 226 Prenylation, indoles, 67
Murrayafoline, 238, 242, 246 3-tert-Prenylindol-2-one, 111
Murrayanine, 246 3-Prenyloxyindoles, 89
Murrayaquinone, 118, 247 Prenylstannane, 84
258 Index
N-Prenyltryprostatin B, 82 T
Prianosins, 131, 134, 155 Tardioxopiperazine, 115
Propargylic halides, indole, 75 Tetrahydro-1H-6H-5,10b-
Pseudilin, 208 ethanophenanthridine, 183
Pseudomonas bromoutilis, 207 Thebaine, 34, 55, 59
Pyrroles, 203, 205 Topoisomerase I, inhibition, 133, 144
silver(I)-catalyzed cyclization, 203 Tricarbonyl(η5-cyclohexadienylium)iron, 212
Pyrrolo[2,3-b]indole, 83 Tris(dimethylamino)sulfonium
Pyrroloiminoquinones, marine, 131 difluorotrimethylsilicate
(TASF), 19
Tropinone, 165
Q Tryprostatin B, 77, 79
Quinone imine dimethylacetals, 150 Tryptophan, N-tert-prenylation, 73
Tsitsikammamines, 132, 144
Tsuji–Trost coupling, 44
R
Radical cyclisation, 163
Regioselectivity, 67 U
Reserpine, 165 Ullmann reaction, 163
Rhazinal, 163, 170
Rhazinilam, 163, 170
Roquefortine, 102 V
Variecolorin, 115
Versicolamide, 107
S Vinblastine/vincristine, 165
Salimine, 168 3-Vinyl-3-pyrrolines, 209
Senepodine G, 23
Serratinine, tricyclic compounds, 5
Siamenol, 226 W
Silver, 203 Wakayin, 132, 144
Spirotryprostatins, 91, 97 Weinreb amide, 8
Stephacidins, 103, 104 Wittig reaction, 163
Strychnine, 165
Suhailamine, 168
Sulpinines, 118 Z
Suzuki-Miyaura reaction, 163 Zyzzya fuliginosa, 132

Alkaloid Synthesis

Uploaded by

Copyright:

Available Formats

Alkaloid Synthesis

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Alkaloid Synthesis

Uploaded by

Copyright:

Available Formats

309

Topics in Current Chemistry

S.V. Ley M. Olivucci J. Thiem M. Venturi P. Vogel

C.-H. Wong H. Wong H. Yamamoto

Alkaloid Synthesis Luminescence Applied in Sensor Science

Computational Mechanisms of Au and Pt Functional Metal-Organic Frameworks: Gas

Volume Editor: Hans-Joachim Knölker

S.K. Adla M.G. Banwell I. Bauer H. Fujioka N.(Y.) Gao

ISSN 0340-1022 e-ISSN 1436-5049

# Springer-Verlag Berlin Heidelberg 2012

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Prof. Dr. Christopher A. Hunter Prof. Dr. Massimo Olivucci

Prof. Dr. Jean-Marie Lehn Prof. Dr. Margherita Venturi

Prof. Dr. Pierre Vogel Prof. Dr. Henry Wong

Topics in Current Chemistry is included in Springer’s eBook package Chemistry

Aims and Scope

in Germany outlines recent developments in the synthesis of pyrrole and carbazole

Dresden Hans-Joachim Knölker

Lycopodium Alkaloids: Isolation and Asymmetric Synthesis . . . . . . . . . . . . . . . 1

Synthesis of Morphine Alkaloids and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Indole Prenylation in Alkaloid Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Marine Pyrroloiminoquinone Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Synthetic Studies on Amaryllidaceae and Other Terrestrially

Synthesis of Pyrrole and Carbazole Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Lycopodium Alkaloids: Isolation

Mariko Kitajima and Hiromitsu Takayama

Abstract Lycopodium alkaloids have attracted the attention of many natural

Keywords Alkaloid Asymmetric synthesis Isolation Lycopodium Structure

M. Kitajima and H. Takayama (*)

AChE Acetylcholine esterase

Plants belonging to the genus Lycopodium, Family Lycopodiaceae, are widely

NH2 NH2 3-Oxoglutaric acid (6)

Tandem cyclization Tetracyclic

Scheme 1 Hypothetical biogetetic route of Lycopodium alkaloids

Fawcettimine-type alkaloids possess a C16N1 skeleton and are considered to be

Scheme 2 Hypothetical biogenesis of fawcettimine

Fig. 1 Structures of lycoposerramines-A and -B

EtOH, reflux, 80%

Scheme 3 Conversion of serratinine to tricyclic compounds

(R) configuration on C-4 (H-4b) by X-ray crystallographic analysis. On the other

H Ac O 1) KOH, MeOH H O 1) MeOTf

Scheme 4 Synthesis of lycoposerramine-B

Fig. 2 Structure of lycoposerramine-C

Scheme 5 Preparation of Weinreb amide 31

1) NaBH4, EtOH, rt, 78% O Me

Scheme 6 Alternative synthesis of Weinreb amide 31

The coupling reaction of Weinreb amide 31 with alkyne 34 using i-PrMgCl as a

Scheme 7 Synthesis of bicyclic compound 37 by Pauson-Khand reaction

Fig. 3 Mechanistic consideration of Pauson-Khand reaction of 36

of 36 with Co2(CO)8 in CH2Cl2 at room temperature under Ar atmosphere, fol-

Scheme 8 Synthesis of tricyclic compound 44

The stereochemistry of the resulting secondary alcohol was demonstrated by the

Lycoposerramine-C (27) Phlegmariurine-A (48)

Scheme 9 Completion of the total synthesis of lycoporerramine-C and phlegmariurine-A

oxidation, 45 was regioselectively converted into a,b-unsaturated ketone 46.

Phlegmarine-type alkaloids possess a C16N2 skeleton that consists of a piperidine

Scheme 10 Hypothetical biogenesis of lycodine and phlegmarine-type alkalooids

New compound 50, named lycoposerramine-V [36], had a phlegmarine skeleton

Fig. 4 Structures of lycoposerramine-V and its C-5 epimer