Frter1998 PDF

TETRAHEDRON
Tetrahedron 54 (1998) 7633-7703

Pergamo-
Tetrahedron report number 456
FragranceChemistry
Georg Fritter,* Jerzy A. Bajgrowicz, and Philip Kraft
Givaudan Roure Research Ltd.,
CH-8600 DObendorf,Switzerland
Received 26 February 1998
Absm~t."ThisTetrahedronReporton frasrancechemistrysummarizesthe recentprogressin the chemistry

of importantambe~sandalwood,wood,musk,and floraledonmts.Somedetailsof the olfactorymechanism,
current models for structore-odourrelationships, and the parameters of olfactory performanceare also
discussed. 1998Elsevier ScienceLtd. All fightsreserved.
Contents
1. Introduction 7633
2. Rational Design of Odorants 7635
2.1 Olfactory mechanismnmolecular complementarity 7635
2.20Ifactophore searchmmolecular similarity 7637
3. Synthesis of Odorants 7642
3.1 Amber odorants 7642
3.2 Woody odorants 7651
3.3 Sandalwood odorants 7658
3.4 Musk odorants 7664
3.5 Floral odorants 7675
4. Concluding Remarks 7688
1 INTRODUCTION
Fragrance chemistry is a fascinating blend of natural product, synthetic, analytical, and physical chemistry
with a certain amount of creative fantasy for odours, and molecular structures. Besides the rigor and logic of
isolation, analysis and synthesis, one is and should be carded away by serendipitous, artistic, intuitive moods.
In the broadest sense all compounds with a smell belong to the category of fragrance chemistry. In English
the term aroma chemicals is used for both fragrance and flavour compounds, although there is no strict separation
in practice. Thus, compounds with a sufficiently high vapour pressure will have an odour and this is normally the
case up to a molecular weight of around 300, a relatively low polarity granted.
0040-4020/98/$19.00 1998 Elsevier Science Ltd. All rights reserved.

PII: S0040-4020(98)00199-9
7634 G. Frdter et aL / Tetrahedron 54 (1998) 7633-7703
It is often incorrectly assumed that only compounds with apleasant smell belong to the realm of fragrance
chemistry.1 Not only is pleasant odour a very subjective notion, but fragrance compositions often include single
compounds which in higher concentrations or in pure form have an animal, faecal, sulfurous or sweaty obnoxious
odour. Also, fragrance chemistry deals with malodour, in order to counteract it; therefore, the analysis and
chemistry of e.g. sweat is also a topic of concern.
Fragrance chemistry 2,3 emerged from the very old tradition in virtually all civilizations of making fragrances
from naturally occurring materials, mostly of plants but also of animal origin, as there are essential oils, exudates,
balsams, and resins. In the second half of the 19th century, synthetic fragrance chemicals started to appear in the
chemical literature and on the market: coumarin (1, 1866), salicylaldehyde (2, 1876), vanillin (3, 1876),
phenylacetaldehyde (4, 1883), piperonal (5, 1890), the nitro musk Musk xylol (6, 1891), and ~-ionone (7, 1893).
yyc.o ( c.o <o c.o

HO" "F" 0"~ ~ " ' ~
1 2 OMe 3 4 5
NO2
Over the last 100 years, synthetic fragrance chemistry has been a continuous success story. Organic chemists
were able to offer the perfumers their nature identical raw materials in high and constant quality, and at low
price, e.g. linalool (8), citral (9), tz- and [3-ionone (10 and 7). Moreover previously unknown synthetic molecules
with new odour characteristics have become available and fantastic new possibilities for creation have
revolutionized perfumery. Methyl ionone (11), an unnatural homologue of 7/10, was first described in 1893 as
being stronger than et- and 13-ionone (10 and 7). Ethyl vanillin (12, 1894) is also stronger than its natural counterpart
3. Both have been successfully used in the creation of the perfume ,>Shalimar<< (Guerlain, 1925).
o
HO" ~
.,CHO
OEt
12
~ 0
13
Today, most of the synthetic fragrance chemicals are in the price range of US$10-100 per kg, perhaps
10% in the range of US$100-250 per kg, and only a few above this. The natural fragrance ingredients, like
essential oils, absolutes, and resins are, with a few exceptions, in the upper price range, and far above it: patchouli
oil costs about US$ 20 per kg, lavender oil US$ 60 per kg, jasmin concrete US$ 600 per kg, and Turkish rose oil
about US$ 2500 per kg. This is the reason, why in the last 25 years -since the analytical methods made it
possible- perfumers were provided with many reeonstitutions of expensive natural oils. In the so-called functional
perfumery, that is the perfumery of soaps, detergents, and household goods, where prices must be kept very low,
the compositions consist almost completely of synthetic materials. Today, only in fine fragrances the perfumer
can afford to use some natural products.
G. Frdter et al. / Tetrahedron 54 (1998) 7633-7703 7635
In this review we were not aiming at a comprehensive coverage of fragrance chemistry. In our opinion this
would neither be possible in the limited space, nor desirable for the reader. Rather we tried to show the beauty,
difficulty and the multidisciplinary character of the topic. Some excellent publications cover a part of our theme
up to ca. 1990. 3-7 A very special publication should also be mentioned here: Fragrance and Flavour Chemistry
published in Helvetica Chimica Acta during its first 75 years, s
This review is intended to have a more practical character, giving preference to processes and compounds
with technical and industrial relevance. This means, that the synthesis of a known fragrance chemical is included
only if it is of some exceptional originality and elegance. It is a legitimate question, why new fragrance compounds
are considered to be necessary, when there are some 2500 ingredients the perfumer can choose from. Yet, to be
really unique, and to allow the creation of something outstanding, new compounds are indispensable. New
odour tonalities give new possibilities for the creation. For instance, Moxalone (13) 9 has a musky-fruity tonality,
which is something new in this combination.
Besides the odour characteristics, other performance criteria like odour threshold, substantivity, toxicity,
transparency, stability, and biodegradability, are also important parameters of odorants. The lower the threshold
of a molecule, the more powerful it is, the higher impact it has in a composition. A higher impact means obviously
also a relative price reduction because of possible lower dosage, and an advantage in respect to a possible
environmental encumbrance.
The non-toxicity, of course, is a conditio sine qua non, and as such it must not be discussed here.
Substantiv/ty i0 means the behaviour of the fragrance in the application on skin, or hair, or fabric, e.g. the distribution
and residuality of a perfume in its use in a laundry-washing process. High residuality on laundry can be achieved
by high lipophilicity, which again can become problematic when biodegradability is addressed. To circumvent
this problem relatively lipophilic precursors of relatively hydrophilic fragrance molecules have been proposed,
which are cleaved in the washing process to ensure the desired residuality of the fragrance, n Transparency is a
difficult to describe characteristic of a fragrance ingredient, meaning how it performs in mixtures; whether it is
dominating or it lends itself to a harmonious accord. Stability in this context means the behaviour towards high
pH of 9-10 as it prevails during the washing process, towards oxidants in bleach, and in special applications also
towards low pH of 4-5. Last but not least, the biodegradability should be high. With all these requirements 12 it
is clearly a demanding task to find and introduce new fragrance chemicals.
2 RATIONAL DESIGN OF ODORANTS
2.1 Olfactory Mechanism--Molecular Complementarity

The knowledge of the mechanism of olfaction, and particularly of its primary event involving odoriferous
ligands and their receptors, would obviously facilitate the search for new and more efficient perfumery raw
materials. It would help to optimise the structures of the known lead molecules, and make possible a de novo
design of better performing compounds. Unfortunately, and despite all the recent research effort, the information
on the molecular interactions between olfactory receptors and their ligands is almost non-existent.
In 1991, Buck and Axel reported their discovery of a large family of genes encoding putative odorant
receptors, 13 possibly more than 1000 different proteins. They seem to belong to the largest group of receptors for
neurotransmitters and hormones--the seven-transmembrane-domain (7TM), G-protein-coupled receptors
(GPCRs). This super-family of proteins mediates numerous physiological phenomena, including vision. Studies
of any GPCR represent a challenge because of the instability outside the membrane and crystallization difficulties.
Even in the cases where functionally well defined specific receptors of endogenous ligands like retinal, histamine,
serotonine, dopamine, tachykinin, thrombin, endothelin, or substance P (of enormous importance for the
pharmaceutical research) are known, 14 little data on the tertiary structure of the receptor-ligand complex are
available. Some information on the amino acids crucial for the recognition of such ligands has been provided by
point mutation experiments and studies with chimeric analogues and labelled ligands. However, the large majority
of the models generated thusfar, 14-16 of contested practical value, have been based on the only available 7TM
7636 G. Frdter etal. / Tetrahedron 54 (1998) 7633-7703
template, a model of bacteriorhodopsin obtained by using electron diffraction data of its 2D crystals. 17 While
analysing such models one should never forget that bactefiorhodopsin, although functionally related to GPCRs,
does not belong to this super-family of receptors and has only little sequence homology with them.
Buck and Axers discovery triggered big expectations in the fragrance microcosm, but six years later the
confmrned experimental data on specific odorunt-receptor couples in vertebrates are still insufficient for any
exploitable molecular complementarity search. The most relevant experimental facts in this direction have been
provided by the groups of Breer, zs.19 Bargmann,2Oand most recently Firestein. 21The first one expressed the new
putative odorant receptor OR5 from rat in Sf9 insect cells, and observed a significant dose dependent increase in
the cytosolic level of IP3 -one of the second messengers involved in the olfactory signal transduction- upon
extracellular stimulation with the odorants Lilial [3-(4-tert-Butylphenyl)-2-methylpropanal, 14] and Lyral [4-
(4-Hydroxy-4-methylpent-1-yl)-cyclohex-3-ene-l-carboxaldehyde,369]. The second elegant study, based on
the chemotaxis of mutants of C. elegans, a worm with a very simple chemosensory system composed of 32
neurones, provided functional evidence for a specific interaction between the ODR-10 olfactory receptor protein
and diacetyl in this species. 2oThe OR-I7 gone,13 expressed in vivo through adenovirus-mediated gone transfer in
the olfactory epithelium of rat, responded selectively to n-octanal in an electro-olfactogram expedmenL 21
Another still unanswered question concerning the primary event in olfaction is how lipophilic odorant
ligands make their way through the aqueous mucus layer covering the olfactory epithelium to the receptor? In
other words, what are theperireceptor events?22b So called odorant binding proteins (OBP), soluble proteins of
low molecular weight with affinity to several structurally different odorants, were found abundantly in the nasal
mucus. They belong to the family of ligand carder lipocalins, and were historically the first proteins supposed to
be involved in the molecular recognition of odorants. ~ Their role is still unclear and several hypotheses have
been advanced: ~ They could influence odorant transport, its concentration near the receptor, the odorant signal
termination, or even stabilise an active conformation of odorant receptors through interactions with their exterior
portions. Recently, a bovine OBP membrane receptor, which seems not to be restricted to the olfactory tissues,
was discovered. ~ Therefore, OBPs could play a broader role within the body. Some other proteins found in the
nasal mucus of vertebrates such as olfactomedin~ and vomeromodulin do not have proven functions either.
Cytochrome P-450 is the most often mentioned among the degrading and detoxifying enzymes that seem also to
influence the odour perception. 22b'27
It should be noted here that odorants can interact with other parts of the nasal cavity. The trigeminal nerve
responds to some alrborn chemicals by triggering the sensation of piquancy, pungency, burning, astringency,
tingling, and cooling. 2s The speculations concerning human pheromones, 29a-cpotentially important for the creation
and marketing of perfumes, have been recently amplified by the work on the vomeronasal organ (VNO). 29 It
appears to have a distinct mechanism of signal transduction, 29c-~ resembling that of odorants, but there is no
clear evidence even for the presence of this organ, let alone its function in adult humans. 29a
After the period of completing the catalogue of genes encoding for proteins specifically located in the
olfactory epithelium, the main research activity is now focused on the signal transduction and the genetics of
olfaction. Papers reporting the expression and isolation of putative odorant recoptors have begun to appear, 19.30
but their functional relevance has not yet been proven. Both research and recent opinions on the olfactory
mechanism have been extensively reviewed. 22,29b,31-33
Based mainly on the results of Breer's group, is some speculative models of odorant receptor interactions
have been generated. Singer and Shepherd ~a tested docking of Lyral to a model of the putative rat olfactory
receptor encoded by the OR5 gone. They found a possible binding pocket composed of 6 amino acids of TM3
through TM7, not surprisingly situated close to the position of the binding site of retinal in bacteriorhodopsin
used as template. The same authors obtained similar results with the I9 receptorl3-benzaldehyde couple,34b and
proposed a general determinant-based model for ligand-receptor interactions in olfactory receptors. 3s They
suggested that odorant receptors contain an average of 2-4 subsites. Ligands contain a similar number of
determinants, and the set of them in the active geometry is called olfactophore. Singer etal. 36 performed a
correlated mutation analysis of putative odorant receptor sequences from rat, and proposed several substructures
G. Frdteret aL / Tetrahedron 54 (1998) 7633-7703 7637
involved in the ligand binding. The calculation of positive selection moments of the 6th TM of human olfactory
receptors allowed similar conclusions. 37
Top view of Lilial (14) docked at a possible binding site

of a model of the putative OR5 odorant receptor3s
These studies prompted us to present our modeP 8 of the OR5 receptor interacting with Lilial (14). The
hydrogen bond between a hydroxyl hearing amino acid (Tyr or Thr) and the carbonyl group is the common
receptor-ligand interaction in these models. Histidine residues of TM4, versatile in their binding interactions,
appear to be of prime importance. Despite these very exciting speculations, indispensable for the progress of any
science, the factual knowledge of the mechanism of olfaction does not yet allow the application of molecular
complementarity search techniques to the design of optimal olfactory agonists and antagonists.
7,2 O(factopbor $earcb---Molecular $imtlafay

The approach based on molecular similarity among compounds of the same odour note is of more practical
and immediate use in the search for more efficient odorants. Looking for the minimum structural requirement for
a given type of odour is not new. It paralleled the search for primary odours, and has progressively been adopting
the methods pioneered in medicinal chemistry. By analogy with the widely used termpharmacophore, olfactophore
has been coined35~9.4 for a set of structural features responsible for a defined odour-type sensation. We will use
it rather than osmophore which has historically (since its introduction by Rupe in 190041 for interchangeable
functional groups of odorants) served to design the (most) polar part of odoriferous compounds, probably
responsible for the strongest interactions with their receptors. 42
The acquisition of reliable stmcture-odour relationship (SOR) data constitutes the first and indispensable
step in any olfactophore search. The selection of useful information from the chemical and perfumery fiterature
is not easy because of the lack of unity in perfumers language, insufficient statistical significance of most of the
published d at~ and scarcity of results obtained with olfactorily pure single stereoisomers or their mixtures of
known ratio and configuration. The complex problem of the efficient measurement of the odour quantity 43 and
quality~ makes the task even more difficult.
7638 G. Frdter et aL /Tetrahedron 54 (1998) 7633-7703
Taking into account only the lowest energy conformers of the often very flexible odorants constitutes
another common reason for the lack of precision of the majority of olfactophore-search studies. The active shape
of odorants can be dramatically different from their preferred conformers due to a possible gain of energy provided
by the receptors and their environment in order to stabilize the ligand-receptor-G-protein complex.
Since this report focuses on the last decade of Fragrance Chemistry, we refer to the excellent reviews on
slructure-odour relationship 45 for older empirical rules, and models such as the triaxial rule, 46 and ambergris
triang/e 47 for amber odorants, or musk4s and sanda/wood rules.49,50 The history and current state of the SOR
research has been exhaustively reviewed in a recent paper. 51 Here, only the three most thoroughly studied
olfactophores, corresponding to the edour notes described in the following synthetic part, i. e. amber, sandalwood,
and mus/~ are considered.
D-
F r a g m . II g
A
1-1-15 m. I
(-)-Ambrox O
O
The two (accessibie) molecularfragments Ambrox (15) mapping the best
oonsidered responsible for the amber odour~ CATALYST hypothesis of the
amber o/factophore~
Fragment I O bond to a quM. C-atom
+ 4 carbons A-D hydrophobic
Fragment II 2 methyl groups attached to a e ~ f oriented H-bond acceptor
quaternaly C-atom small spheres = e0(cludedvolumes
Amber:. The domain of amber-like smelling compounds is particularly well suited for the olfactophore
search. The available SOR data obtained with structurally rigid compounds of known absolute configuration
allow to take into consideration a relatively small number of representative conformations. The difficult problem
of how to define the mul~acet amber type odour can be overcome by taking (-)-Ambrox [(-)-15] 52 as the
reference.
The steric accessibility (SA) of the osmophoric oxygen of the analogues of this odorant was calculated
using a probe radius of 1.4A. 53 The lower limit of the measured van der Waals surface, critical for the amber
edour, was found to be 5-6A 2. This structural feature was used as a supplementary criterion in another studys4
based on the so-called electron-topological (ET) approach.55 The two molecular fragments found indispensable
for the amber odour -highlighted in the depicted (-)-Ambrox molecule [(-)-15]- correspond to two electron-
topological matrices of contiguity (ETMC). These are built using effective charges as diagonal elements, and
Wiberg indices for bonded as well as optimized distances for unbonded atoms. The authors ~ report an
astonishingly high degree of prediction, about 95%. The ET method was also applied to other odour classes,
comprising sandalwood 56 and musk. 57
A differentapproach,3s taking into account the flexibilityof the ligands,is based on a broad coverage of
an energeticallyreasonable conformadonal space,s8 with a A E arbitrarilyfixed at 15 kcal/mol. An automated
analysiss9 of the generated conformationa/mode/s, which contained 2-79 conformers for each of the 23 carefully
selected compounds of the training set, led to hypotheses---setsof abstract chemical features~ displayed as
spheres positionedin space,that contributeto the analysed physiologicalactivity,/,e.amber odour. The following
G. Frdter et aL /Tetrahedron 54 (1998) 7633-7703 7639
selection of the best hypothesis and its fine-tuning by placing excluded volumes resulted in a model for the
amberolfactophore, which proved useful in the rationalization oftbe SOR d aJa and in the design ofuew molecules
with this smell.
The triaxial ru/e, 46 notwithstanding many exceptions,6! continues to be applied in the SOR studies of
amber odorants. It was applied in an analysis of the importance of the axial methyl groups of (-)-Ambrox
[(-)- 15] and its analogues for their interactions with a hypothetical odorant receptor via an axial hydrogen bond. 62
P2
Naipawer et al. so Ce-~O(H) ca. 4 A

(1981) (in a reasonab/econformer)
Chastrette et al. 71 Ce._>O(H) 6.5-7.1 A

(1990) (in the most stab/e conformer)
P3
(2)-(-)-1 6 P1
(z)-(-)-p-SartaU
Buchbauer et aL 73 PI~P2 2.9-3.0 A
P2
(1994) P/-.-)P3 6.3-6.4 A
P2-~P3 5.9.--6.0 A
Dimoglo et aL ss Ce-)C d 5.15 + 0.15 A

(1995) Co->O(H) 6.60 0.20 A
Cf--~O(H) 7.60 0.20 A
17 Pl
Ebanol
Sandalwood: Despite the quite abundant SOR literature on sandalwood odorants,63 only few data for
unequivocally def'med, i. e. optically pure, structures are available. The optically pure (Z)-[~-santalol, main odour
vector of natural sandalwood oil,('4 5z-androst-16-en-3a-ol,65 and (1S,3R,6R,SR)-tert-butylbicyclo[4.4.0]decan-
3-ol66,67 have been until recently the only pure substances for which the sandalwood odour was reported. The
first information on the single stereoisomers derived from campholenic aldehyde, which constitute the main
class of synthetic sandalwood-type odorants, was only released in 1995. 6s The majority of sandalwood smelling
compounds are fairly flexible except the steroid and the tert-butyldecalinol cited above. However, it should be
mentioned that the latter is not always rated among the most active compounds of the natural sandalwood odour,69
and that the odour of 5z-androst-16-en-3ct-ol is quite often perceived as different from that of sandalwood. 65
The classical sandalwood ru/es, 49~ and results of more recent studies underline the importance of the
distance between the hydroxy group and a bulky moiety, that preferably contains an electron-rich fragment, i. e.
a double bond, an ether function or a cyclopropane ring. The often flexible spacer linking these fragments should
be branched next to the hydroxyl bearing carbon. Different values for this distance, obtained in several studies,
are not always easy to compare because of different locations of the center of the bulky group. The initially
proposed approximately 4 A, distance between the hydroxyl oxygen and "a highly substituted or quaternary
carbon atom" in at least one reasonable conformation5 was sometimes found too short. 563.71 One should
always keep in mind that most of the fiterature studies consider only the lowest energy conformers, which are
certainly not the active conformers for all the ligands. The necessary structural features of the bulky part of a
sandalwood smelting substance are also difficult to define. For some they are limited to a quaternary carbon
atom, while others consider two adjacent tertiary or quaternary carbon atoms or a part of the molecular surface.
7640 G. Frdter et al. / Tetrahedron 54 (1998) 7633-7703
Other parameters have been used to augment the predictive power of such olfactophore models. Buch-
bauer, Wolscharm et al. studied the conformations and molecular surfaces of sandalwood odorants. 72 In one of
their recent works they applied the active-analogue approach73,74which takes into account the flexibility of the
ligands. The analysis of sets of energetically allowed conformers of twelve active compounds, of which only two
were single stereoisomers, together with six odourless analogues gave an olfactophore assumed by the authors to
consist of three osmophoric points. They correspond to the hydroxy osmophore, a lipophilic substiment, and a
bulky, rigid group, represented as a dummy atom in the middle of an alicyclic system. The sandalwood odour of
(Z)-dehydro-homo-~-santalol 7sa and (Z)-bis-homo-~-santalo175b seems to confirm their findings, hut the 7-0xa
analogue of the natural ~-santalol turned out to be odourless, 76despite the fulfilment of all the steric requirements.
This was rationalized by the difference in the electrostatic potential at the third point of their postulated sandalwood
olfactophore.
In addition to the distances between two fragments -atoms a+b+c+d, and atoms e+f, highlighted in the
depicted sandalwood odorants- the sandalwood olfactophore generated by the already mentioned ET method55
involves also some electronic interactions of the hydrophohic parts with the protein receptor. Frontier orbital
calculations carded out by Dimoglo et al. 56 led to the proposal that atoms ~ and Cf act as electron donors, while
atoms Cb, Cd and O(H), the latter with an electron density of-0.26.4:0.05 e, act as electron acceptors.
Two different santalophore patterns were obtained via a statistical evaluation of the empirical sandalwood
rules, 49-s for a set of 57 active and 82 inactive molecules, followed by comparison of four optimized structures
(lowest-energy conformers) of intensively sandalwood smelling, and relatively rigid compounds.71 They consist
of a "'tert-butyl group or an equivalent, and a hydroxyl group". A superpattern, defined as the envelope of the
superimposed structures, possibly interacting with different parts of the sandalwood receptor, was proposed. The
authors reported 100% correct predictions for a set of 17 active and inactive molecules, using this superpattern,
and some angles and distances within the ligands.
Musk: The SOR work in the domain of musks has a long tradition. It started with the serendipitous finding
of nitro musks at the end of the last century, and has been carried out since, most of the time separately within the
main three classes of these important perfumery raw materials: macrocyclic, nitro, and non-nitro benzenoid,
mainly polycylic musks. The slight differences between the typical musk odour of these chemical series brought
about hypotheses of the existence of more than one musk receptor-or a set of receptors- and consequently not
a unique musk olfactophore. 77 Another aspect of the musk SOR studies is the relation between this odour and
that of the often considered as sandalwood-like 5c~-androst-16-en-3a-ol and androstenone, so-called steroidal
musks,6s and suspected of having a pheromone function. As a result, the whole musk SOR domain appears
rather confusing.
The work of Bersuker et al. s7 is one of the most documented recent studies aiming at a unique musk
olfactophore. Using their ET approach,ss they analysed 362 compounds belonging to all classes of musks as well
as inactive analogues, and found two independent, stericatly accessible, molecular fragments indispensable for
the musk scent. The first one is a polar group (C=O, N--O, CmN) of which the most electronegative atom is
situated symmetrically from two methyl groups or methylene units at a distance of 6.7i-0.5A. The latter are
separated by 2.5x~0.5,~. The distance between two other methyl or methylene groups that constitute the second
fragment should be 5.5:k0.5A. Additional considerations, based mainly on the necessary steric accessibility of
these two fragments, allowed a very good predictability (97% for active, 94% for inactive compounds), which
would be even higher if one applied their hypothesis, that some aromatic musks interact with the receptor in
form of dimers.
These results were evaluated by Kansy et aL4 using a single (as in the original study57 ) and a mniticonformer
approach, with the help of the MOLOC7s and CATALYST~ software, respectively. The results were deceiving:
The overall predictability ratio was 54% for the fhst approach, in which the steric acce~hility was not considered,
and 59% in the second one. It was better, though still not satisfactory (65% overall, 84% for active, and only 30%
for inactive compounds), when the Bersuker database was screened with a CATALYSThypothesis, generated
automaticallywith a set of 40 selectedcompounds.
:"r
i0 I
I
L--'A
'~ f
Fragm./ C B
II
6 ~o 13
Musk Xylol Exaltolide, Thibotolide Moxalone
mapping the model of the
Two fragments musk o / f a c ~ r e generated Tentative positioning
indispensable for the musk scent ~' using CATALYST4o of the Compass model
features a2
Fragment I 0 (or N) symmetrically flanked A-C hydrophobic f ~ on Moxalone (13)
by 2 Me or methylene groups
Fragment II 2 Me or methylene groups d H-bond acceptor A--C appropriate
O-~Cc = O~Cd = 6.7+0.5 A A-~B = 3.6 A B->C = 4.0 A sudace shapee
C--+Cd = 2.5 :t: 0.5 A C--H:I = 5.5 A d ~ A =6.7 A d H-bond
Ce-~Cf = 5.5 +0.5 A d-~B = 8.0 A acceptor
Chastrette et al. also studied a large chemical domain of musks.79After having investigated single families
of mugk.~--nitrobenzenoids 79a and polycyclic carbonyl compounds79b- they used a neural network to analyse a
sample of 105 niuobenzenes, carbonyl tetralins, and carbonyl indanes. 79c Their strucuaes were described by a
simple common underlying skeleton, comprising a benzene ring with a tert-butyl orpseudo tert-butyl group, and
a nitro or carbonyl group in meta position, and eight descriptors. They consisted of six steric descriptors
--corresponding to five benzene-ring substituents and one of the heteroatoms- and two electronegativity descriptors
related to the hydrogen-bond acceptor. After training, the musk odour predictability attained 80%--mueh better
than the 66% of correct classification obtained using the discriminant method.
More frequent are studies of chemically restricted groups of relatively rigid musk compounds. Klopman
and Ptchelintsev s used 23 structural descriptors (15 activating and 8 desactivating) and clog P in a QSAR
equation of the musk odour of non-nitro aromatic mn~k%obtained using the CASE (computer automated structure
evaluation) technology with 152 compounds. The subsequent Multi-CASE analysis identified nine structural
determinants favourable for the musky scent as well as seven thwarting fragments. The system was able to
predict the odour of 18 compounds out of a subset of 20 randomly selected compounds. An analysis showed
some overlap between the structural requirements for musky odour in nitro and non-nitro musks. Similar QSAR
studies with reported high-predictive power of the elaborated models, in which the lipophilicity of the compounds
plays an important role, were recently carded out by Yoshii et aL,sl and Jdm et a/. s2
The flexible macrocyclic ketones and lactones, for which minor structural changes trigger dramatic changes
in odour are conspicuously absent in these investigations. Another feature that a fragrance chemist would like to
find in the musk QSAR studies is an evaluation of the predictive power of the generated olfactophore models,
based on a large and diverse enough set of compounds not used in the generation of these models.
7642 G. Frdteret al. / Tetrahedron 54 (1998) 7633-7703
3 SYNTHESIS OF ODORANTS
As certain chemical classes, certain skeletons or olfactophores, and certain functional groups or osmophores
are key for an odour, we are going to discuss chemistry by odour types. And since there are odour transitions
from ambery to woody, from woody to sandalwood-like, from sandalwood-like to musky, as well as from musky
tofloral, we will also proceed this way.
3.1. Amber Odorants

The commercially most important amber chemical is the tricyclic ether (-)-Ambrox [(-)-15]. 52 The
history of this material, which is central to fragrance creation, is a fascinating chapter of natural product and
synthetic chemistry with a commercial background. 83 Today (-)-15 costs around US$1000 per kg, and its world
consumption is 15-25 tons per year.
(-)-15 was first prepared from (-)-sclareol (19) 84 by oxidation of the side chain and formation of the T-
lactones (+)-selareolide (20) and (-)-iso-sclareolide (21), which have been reduced to the diols 22. Cyclization
of the diols then leads to the desired ether (-)-15 and the 8-epi-isomer (+)-iso-Ambrox [(+)-23].
This synthesis is still the commercial one, as the diterpene sclareol is a relatively cheap (US$150-200 per
kg) and abundant constituent of clary sage oil (Salvia sclarea L.). Besides technical improvements of the oxidation,
reduction, and cyclization steps, it is difficult to compete with this old synthesis.
=- 0 0
OH CrCka .,,O O LAH

AcOH ~ .jr. .....e
/~1~ - 19 0 1
OH
2 -)-15 //~1~ - 23
(-)-Ambrox
An impressive approach to (-)-15 is the microbiological conversion of 19 to 20, and to the (8R)-22
diastereomeric diols by Hyphozyma roseonigera5 or Cryptococcus albidus, 86demonslrating an environmentally
friendly oxidation.
The ruthenium tetroxide oxidation of sclareol (19) to sclareolide (20) is strongly dependent on the reoxidation
agent used. Sodium periodate gives only 18% yield of 20, whereas calcium hypoehlofite gives about 54%. 87
Mechanistically, the double-bond of (-)-sclareol is first cleaved to the corresponding a-hydroxy acid, which is
further oxidized -under decarboxylation- to give a methyl ketone, that cyclizes in the course of the reaction to
enol ether 24. Ruthenium-tetroxide oxidation of 24 then provides the aldehyde 25, that is converted via sclareolide
(20) into the target molecule (-)-Ambrox [(-)-15].
Another ingenious oxidation of 19 has been described with the system OsO4-NalO4 (1:70). ss The final
product of this oxidation 27 is isolated in high yield. The envisaged synthesis of (-)-15 has been completed in
high yield through a Baeyer-Villiger oxidation to the acetate 28 with subsequent reduction with lithium aluminium
hydride in the presence of BF3Et20.
The above transformation 19-,27 has been improved, and made more attractive for industrial application
by the use of O3-NaIO4 (77% yield) instead of the toxic and expensive OsO4. s9
OH
"Ru04'> ~ "Ru04"
AI4 - 19 AA - =4
AC 1. LAH
2. [0]
3. Nail,
AI~ - 25 T~l 2 AI~ - (-)-15
(-)-Ambrox
Apart from the well-established route to Ambrox [(-)-15] starting from 19, different other natural products
have been used as starting materials. Some of these syntheses have no industrial practical value for now, but they
certainly have their educational and aesthetic merits showing the lively imagination of organic chemists.
OH Nal04
plus "Os04"
03~"
//~ - 19 OsO,(cat.) A~ - 24 A~ - =s
~ O ~.,,~Ac
AA - ~7
MCPBA
AA - 28
LAH
BF~rEt20 ~-)-ls (-)-Ambrox
The communic acid methyl ester (E/Z-29), a close relative of sclareol (19), has been ozonized and reduced,
and then cyclized under BUchi-conditions. In three more steps, necessary for the transformation CO2Me -*Me,
(-)-15 was synthesizedP
7644 G. Frdter et al. /Tetrahedron 54 (1998) 7633-7703
H
1. 03, CH2CI2 ~ ' ~
2. Me,zS
3. LAH
4. pTsOH,
MEN02
5. LAH
Me02C ." (E/Z) 29 7. Huang-
Minion
The monoterpene thujone (30), a waste material of the Canadian forest industry, is a less obvious starting
material for the synthesis of (-)-15. Nevertheless it has been converted 91 to (-)-Ambrox in 15 steps through the
intermediates 31 and 32, culminating in a beautiful ring closure of the 1,5-diol moiety of 32 to the tetrahydrofuran
ring of (-)- 15.
31
0
HOH 32
OH
II
Drimenol (33) has been transformed to (-)-15 in six steps, 92 whereas (S)-(+)-carvone (34) needed some 13
steps 93 to reach the target. The enantiomerically pure tosylate 35, which can be prepared from geranylacetone,
furnished (-)-15 after 15 steps. ~
d t
33 34 35
For the study of structure-odour relationship of ambery compounds the diasteromers, 95a enantiomers. ~a
nor-compounds, 9sb ring-opened analogues 53b and 5~-isomers 95bof (-)-15 have been prepared. While (-)-15 has
an odour threshold of 0.3 ppb, the 9-epi isomer (-)-36 is even slightly more powerful with a threshold of 0.15
ppb. Yet, the enantiomer [(+)-lb'] is about 10 times weaker (2.4 ppb), and the 8-epi isomer (+)-23 even 100 times
weaker (34 ppb). The racemate (+)-15 is only slightly weaker than (-)-15 with a threshold of 0.5 ppb, and its
odour is very similar to that of (-)-15.
G. Frdter et aL /Tetrahedron 54 (! 998) 7633-7703 7645
0 ~ " o
"oe#S o,aS
A H -,_).(m)t~oSx )-23
(8.epa)
AH - (-)-36
(9-epi) ....
(+)-15
(+)-Ambmx
0.3 ppb 34 ppb 0.15 ppb 2.4
Sclareol (2) constitutes the only practical starting material for (-)-15. Therefore, the available quantity of
(-)-15 is limited, and its price accordingly high. The increasing demand for this valuable amber odorant on the
one hand, and the fact that raceraic Ambrox [()-1~ is olfactorily very similar to (-)-15 on the other hand,
prompted different laboratories to design new syntheses of ()-15.
As long ago as the fifties the acid-catalyzed cyclizations of homofameseic acid (37) and monocyclo
o2H o2H
homofamesoic acid (38) to racemic sclareolide [()-20] and its diastereomers were reported. 96,97,9s
7 ()-20 38 39
Hon'mofamesoicacid Monocyclo
homo~rnusoicacid
The cyclization of (E)-37 has been studied in detail,99 and it was found that at -78C in dichloromethane,
catalyzed with SnCL,, ()-20 can be obtained in 82% yield. Similarly, treatment of (E)-38 with trifluoroacetic
acid at 0C for 2 h provided ()-20 in 64% yield, whereas (Z)-~ under the same conditions gave ()-9-epi-20 in
similar yield,t In the cyclization of both 37 and 38 the stereochemistry of the double bonds (E vs Z) is Iranslated
to the stereochemistry of the products via the preferred chairlike transition state. Thus, the feasibility of this route
to ()-20, which subsequently is processed to (-)-15 in two steps, depends on the availability of (E,E)-37 and
(E)-38, respectively. For the preparation of (E,Z)-37 famesyl bromide was treated with potassium cyanide and
the resulting nitrile was hydrolyzed.1ol Another route to (E,Z)-37 comprises the treatment of nerolidol with
carbon monoxide in the presence of palladium dichloride.102 (E,Z)-38 Can, for instance, be prepared from the
dihydro Ct4-aldehyde 39 via a Knoevenagel condensation with malonic acid, 13aor with methyl cyanoacetate
and subsequent hydrolysis.l3b Wittig C3-elongation of dihydro ~-ionone (40) also furnishes 38.to3c
The readily available ~-keto ester 41 [from dihydro ~-ionone (40)] has been converted to ()-15 in six
steps. 1o4 The introduction of the side chain had to be carried out by the detour through the O-ailyl group
(41--~42-,43-o44), because C-alkylatiun of 41 failed. Grignard reaction with 44 furnished in high yield and
stereoselectivity the tertiary alcohol 45 with the wrong stereochemistry on C-8. This has been very elegantly
corrected in the cyclization step of the diol 46. Kinetically controlled cyclization with a sterically favoured
equatorial approach of the intramolecular nucleophile to the tertiary carbonium ion yielded ()-15 in good yield
and high selectivity.
A couple of variations to this approach have been published, 15 but the breakthrough in the synthesis of
rac-Ambrox [()-15] came about by the biomimetic, acid-catalyzed cyclization of the polyene alcohol
homofamesol (48).
7646 G. Frdter et al. I Tetrahedron 54 (1998) 7633-7703
~
C 02Et C 02Et
o 0 ~
0 41 42
~DO2 Et
NMP ~
CaCl2
~~i )
43 91% 4
(14:86)
OH
"a*e
1. 03
~
OH
"'**t
pTsOH
2. NaBH4 MEN02
5 6 75% /v~ I:1 (+)-15
OH
FSOsH
nPrNO2
-80 *C
71%
~" FSO~ --
nPrNO~
73%
/V~I~ (+)-15
ONMe2
xy~ae I"~
79~
G. Frtiter et a t / Tetrahedron 54 (1998) 7633-7703 7647
ONMe2
OH
DMF-DMA
xylene 1",1,
81%
FSO3H _
nPrN02
m*/. (+)-lS
()-3s
The lower homologue, (E,E)-farnesol [(E,E)-47] was first successfully cyclized to drimenol (33). ]o6 This
low-temperature cyclization with fluorosulfonic acid was then used for the one step synthesis of (+)-15 from
(E,E)-homofamesol [(E,E)-48] in 73% yield. 17
A detailed study has been undertaken to understand and optimize this industrially important process. I~
All four stereoisomers of homofarnesol (48) were separately treated with fluorosulfonic acid, and the product
mixtures analyzed. The most important result was, that under these conditions the isomerisation of (E,E)-48 to
(3Z,7E)-48 is fast enough to compete with the cyelization. Thus, pure (E,E)-48 furnishes a mixture of 40% (:t:)-
15 and 35 % (+)-36 (9-epi-l$). This isomerisation diminishes slightly the synthetic elegance, but since (-)-36 is
even more powerful than (-)-15, it is no problem from the olfactory point of view.
As with the corresponding homofamesoic acid (37), the feasibility of the process depends on the accessibility
of (E,E)-48, or the corresponding monoeyclo homofarnesol (E)-54. (E)-Nerolidol [(E)-49] can be transformed to
the separable 2:1 mixture of the amides 50. (E,E)-50 was reduced to (E,E)-48, and then cyclized with chlorosulfonic
acid at -78C in nitropropane to afford a mixture of (+)-15 and (+)-36 in 75 % yield. 19 (E)-Configurated
monocyclo homofarnesol [(E)-54] has been prepared from dihydro-~ionone (51) through the intermediates 52
and 53. Cyclization of (E)-fl under the same conditions prodded the mixture of (+)-15 and (+)-36 in 86%
yield. Io9
O O
[o]
AA - s7
~ C O2H
-I-
9
~ 57a
0
)
HOTs
S9
Zn
S8
b'Tb CI/cI
Next to Ambrox(15), Amberketal (58) is one of the best known amber odorants. It also has already a long
history, and its most straightforward preparation is that from manool ($$),n-113 which is a commercialized
constituent of Halocarpus biformis (Podocarpaceae) from New Zealand.114This synthesis proceeds through the
intermediate methylene ketone 56, and each synthetic variant is judged on how it solves the problem of preparing
56 and by the ratio of 58 vs. 59. The epi-8-isomer 59 is virtually odoudess; m thus, the more selective the
transformation to the powerful epimer 58, the better.
Besides manool ($$) also anticopalic acid (60) can be used as a starting material for 58 by oxidation of the
corresponding ester. 115 The epoxidation of 56 with m-chloroperbenzoic acid is highly diastereoseiective, and
yields 57. Treatment of 57 with p-toluenesulfonic acid in toluene furnishes selectively the odourless isomer $9,
whereas zinc chloride in dichloromethane at 18C yields only 58. This demonstrates the subtility of the ring
closure. 115 It has been shown, that clays, e. g. vermiculite, also catalyze the ring closure of 57--->58
stereoselectively.]]s,116 The striking difference in the ring-closure reaction catalyzed with p-toluene sulfonic
acid and zinc chloride, respectively, has been rationalized with 57a for the case of protonation of the epoxide $7,
and subsequent attack of the carbonyl oxygen on the developing tertiary centre. In the case of the Lewis acid
catalysis a complexation as in 571) has been assumed, which would ensure an attack of the carbonyl group from
the ix-face, providing 58. Communic ester (E/Z)-29 was used as a natural tfiterpenic starting material for 58.117
The handicap of this approach is the necessary three-step sequence to convert the carbalkoxy group into the
methyl group.
Sclareol (19) is better suited for the preparation of Amberketal (58), and has consequently been used for
this purpose, us-12 The monoacetate of sclareol (61) could be oxidized very efficiently to the ketoacetate 62
with a catalytic amount of ruthenium trichloride and a stoichiometric amount of sodium periodate. Pyrolysis of
62 led in high yield to the T-isomer 63 as the main product, which finally was transformed into Amberketal (58)
with a catalytic amount of osmium tetroxide and trimethylamine oxide.
The commercial importance of (-)-Ambrox [(-)-15] and later that of (+)-Ambrox [(t")-15] prompted
different, but mostly indnstrial laboratories to search for new analogues with the aim of being either cheaper or
possessing additional odour aspects.
One of such attempts was the synthesis of dehydro-nor-Ambrox 68.121Dihydro-ct-ionone (64) was alkylated
to give 65, which by treatment with sodium hypochlorite was transformed into 66. Ozonization, followed by ring
closure and reduction, led to 67, which after three additional steps gave the target 68. This compound displays an
ambersris aspect with a warm, wood-tobacco tonality. Dehydro-Ambrox (69), which has a woody-ambery character
was prepared by using the [3-isomeric starting material $1.122
OH NaHCO3
RuCI3 ,~- ~ " J OAC in DMSO
Qo.
150<'O
A~ - 61 84%
OsO4
Me3NO
5o-~Yo
Cl r "c02~u
::~0 LDA
BrCH2CO21Bu 70%
86*/.
64 65 66
.C 021Bu
1. 03 0 2. LAH
2. zn (Cu) 3. MeS02Cl
PyH
67 68
51 69
As already mentioned, the stereoisomer (-)-9-epi-Ambrox [(-)-36] is more powerful than Ambrox
[(-)-15] itself, although only by a factor of two. In spite of this fact, this compound hardly earned any synthetic
interest. One exception is a demonstration of the synthetic potential of the oxy-Cope rearmngementJ ~ J ~ The
enantiopure bicyclic ketone [(-)-70] was transformed to the oxy-Cope starting material 71 with lithium
dihydrofuran. Under usual rearrangement conditions 71 yielded the corresponding enolate, which in situ reacted
with phenylselenyl chloride to provide 72. Introduction of the double bond by eliminiation and subsequent
alkylation furnished 73, which finally, after four more steps, gave the target molecule (-)-36.
7650 G. Frdter et al. /Tetrahedron 54 (1998) 7633-7703
PhSe\
(-).7o
THF
-78oc H 71
1. KH, THF
2. PhSeCI
-78oc
72
1. Nal04
. LDA
0 Mel
72 73
(-)-ss
Calculations of the steric accessibility of the functional group led to the syntheses of three analogues 74,
75, and 76, all of which possess a typical ambergris odour, s3
74 75 76 77
Karan~
Two interesting cases in the context of amber odorants are 77125 and 80,126 because they are structurally
new in this field. 77 is derived from the commercial, green, floral smelling aldehyde, Cyclal C, and has been
commercialized as Karanal (Quest). It has an intense and persistent amber-like odour with woody, floral and
lily-like tonalities.
H H~;O ~ HO
KOH
EtOH
8O%
78 79 80
Spimmbrene
More interesting is the spiroketal 80126 known as Spirambrene (Givaudan Route). It is synthesized from
2-formyl carane (78) in only two steps. Spirambren~ (80) displays a powerful ambery, woody, slightly aldehydic
odour, and contributes significantly to ,,Kenzo pour homme~ (Kenzo, 1991), and the beautiful creation ,,Oui-
Non~ (Kooka~; 1993).
G. Frtiteret aL / Tetrahedron54 (1998) 7633-7703 7651
81
.(3
PPA
100C
82
H2 o
._O__~ ....._~
(-)-83
The ambery-woody compounds of the general formula 81 constitute another class of interesting new amber
odorants. 127 They were found with the help of one of the amber olfactophore models presented in chapter 2.2. 38
Surprisingly, the propeUane (-)-83 has also an intense ambery-woody note. 128 The formation of dehydro-83
from sclareolide (20) was completely unexpected, and can be rationalized through a series of (1,2)-shifts with 82
as plausible intermediate.128
3.2 WoodyOdorants
Perfumes like ~Tr6sor<< (Lancome, 1990), ,Casmir<< (Chopard, 1991), and ~Dune<~ (Dior, 1991) marked a
new style of perfumery technique--massive constructions around a comparatively small number of long-lasting
synthetic materials, that could be used at very high levels, of up to 25%. The woody odorant Iso E supe r (88) is
perhaps the most important building block for this new type of formulation. Almost equal amounts of Hedione ,
Galaxolide, methyl ionone, and Iso E super~ (88) make up some 80% of the formula of Tr6sor. 129
84 88 86
_ H~
87 88
Iso E super
th 500 ng/L
Iso E super ~ (88), that possesses a rich, warm-woody odour with a shade of amber was claimed in 1973 by
IFF. 13 Its industrial synthesis starts with the Diels-Alder reaction of myrcene (84) with 3-methylpent-2-en-2-
one (85), followed by an acid-catalyzed cyclization, which leads to 88. Surprisingly, an analysis carded out at
Givaudan Roure showed that the compound responsible for the intense woody odour of this product is not 88, but
a small impurity (<5%) with an odour threshold of 5 pg/L, and the structure 93.
The formation of 93 in the industrial synthesis of 88 is not obvious at first sight. However, protonation of
86 does not lead only to 87 but also to 89, which can give 90 due to a protonation-deprotonation equilibrium. Its
cyclization provides 92, and finally, after deprotonation, the active compound 93.
"',,,,~ 90
_ H e
91 93
H (<5%)
th 5 pg/L
A synthesis of 93 was carried out in order to prove unequivocally its structure. 131,132 c~-Ionone (94) was
diastereoselectively I~-methylated by cuprate addition, oxidized, and transformed into 97 by the action of sodium
hypochlorite. An ozonolysis, and subsequent zinc reduction gave 98, that after addition of ethynylmagnesium
bromide, and hydrogenation furnished 99. This was then methylated and transformed by [3,3]-sigmatropic Ire-
land-Claisen rearrangemend 33 to provide after reaction with methyl lithium selectively the powerful impurity of
Iso E super 93.
Me2CuLi H[~~OMe NaOCI

94 95 96
OMe 1. 03,-70 OMe 1. i - M g B r

2. Zn, H20 2. H2
, 97 98 "~JO" "0
CI v "0
1. LDA, THF
2. Mel 1. MePh, $,J,
3. LDA, TMSCI ~TMS 2. MeLi, Et20

93
G. Frtiter et al. / Tetrahedron 54 (1998) 7633-7703 7653
Apparently, this synthesis was far too complicated to be carried out on industrial scale. Therefore, numerous
derivatives of 93 were synthesized, of which 104 turned out to be one of the best. The synthesis by Diels-Alder
reaction of 101 with 102, and subsequent cyclization is well suited for industrial production. The odour threshold
of 104 is about the same as that of 93, and its elegantwarm-woody, sweet-powderysmell is even more attractive.
101 102 103 104
Another interesting commercial product of woody tonality is Timberol (107-109) from Dragoco. It has a
powdery-woody odour with animal undertones, and has been used, for example, in ,~Marbert Man,< (Marbert,
1977) and ,~Basara~, (Shiseido, 1993) in up to 4% and 6%, respectively. Its commercial synthesis 134 commences
with a classical aldol condensation of citral (105) and 2-pentanone. Subsequent cyclization and complete
hydrogenation provides a mixture of mainly 107, 108, and 109.
o
H ~ 1. H3P04
2. H2
105 106
OH OH OH
Timberol
OH
O ~ 0 1. H2
2. (Pd/C)
KO~u LAH
3. OU
11 111 ~ ""
U
OH
~ OH
112 ~ ""'
113
Limbanol steroid-type
conformation
Because of the good performance of this mixture a Firmenich group 135 did an in-depth study around
Timberol (107-109), and found the (E)-derivative 108, which makes up only 13% of the commercial product,
to be mainly responsible for the odour characteristics. They attributed its steroid-type sweaty-animal undertones,
to a steroid-type folding. 135 By transition from the ionone- to the irone-series they planned to accentuate the
steroid-type shape; thus, intensifying the woody odour character. The resulting neo-tetrahydroirone analogue
(113) is registered as Limbanol.
The first synthesis of Limbanol (113) started from 2,5,6,6-tetramethylcyclohex-2-en- 1-one (110),136which
was hydrogenated, isomerized, and alkylated to provide 111. Reaction with lithium aluminium hydride furnished
112, that was then transformed to the target molecule 113. As predicted, Limbanol (113) possesses a woody-
animal, steroid-type odour of higher intensity than that of'fimberol (107-109).
OH
~O LAH
~ 4~)H
) 1"Nail
~
2" Ok>',,,,"~ 11= ~15
110 11 1
Yet, the dehydro-oxa-analog 115 turned out to be more accessible than Limbanol (113), while being very
similar in odour and almost equal in strength. 135Reduction of 110 by lithium aluminium hydride, and nucleophilic
opening of 1,2-epoxypentane constitutes a two-step sequence to a Limbanol-type odorant.
o
1.NaOH
H202
2.H
A2cO
NNHH
/ Ts pt(PPh43)
116 CH2C 2I 117
Mel, K3PO4
~ 0 0
~(~n~
119 " ~ ~
steroid-typeconformation
With the idea to mimic the B-C-D part of the steroid-type conformation of Limbanol (113) by a medium-
sized ring, compound 119 and its corresponding alcohol were designed by molecular modelling. 137The Eschen-
moser-Ohloff fragmentation of 116 furnished cyelododec-5-yn-l-one (117), that was (Z)-dimethylated via
diboration with dipinacolyl hypodiborate, and subsequent Suzuki coupling. While the corresponding alcohol
turned out to be very weak, at least ketone 119 had an animal woody odour--in contrast to cyclododecanone,
which has only a camphoraceous odour profile. 137
G. Fr~iteret al. /Tetrahedron 54 (1998) 7633-7703 7655
~ O 1. NaC=CH
2. [(Ph~SiO~V(O)]
3. Me2NH NMe2
Polywood 121 122
O 1. KOH
MeO~ ~CO2Me 2. SOC12 _
3. NAN3,A, HCI
4. NaBH4
/ \ 123 5. / ~ , PyH /\H 124
Polywood (128), an old, warm, dry-woody smelling perfumery synthetic, was also object to some more
research. 138,139 The dehydro derivative 124 of Polywood (120) was prepared by a regioselective [4+2]
dieneamine cycloaddition of methyl acrylate to 122, using 121 as starting material. A five-step sequence led
from the Diels-Alder adduct to the target compound 124 that possesses an accentuated woody odour note. 138
125
~ tBuLi 0 ~,,,,,~
127 128 129

126
A simple addition of tert-butyl lithium to the related starting material 2,6,6-trimethylcyclohex-2-en- 1-one
(125) 14 led the Firmenich group to the highly hindered tertiary alcohol 126, TM which showed a pronounced
patchouli-type, woody-earthy odour. Similar in odour, though at first glance quite different in structure, is the
captive material 129 of 11;I;.142 An ene reaction transforms the dipentene derivative 127 via the intermediate 128
into the fragrant adamantane derivative 129 with a patchouli-like, woody, piney-camphoraceous odour.
1. Nail 1. A (800)
2. Br/ 2. Red-AI
130 131 132
In 1971, an efficient synthetic sequence of C-alkylation to the dienone of 1311,Claisen rearrangement, and
intramolecular Diels-Alder cycloaddition was developed, 143 that led from phenols to tricyclic ketones. Most
interesting from the olfactory point of view was compound 132, prepared from the corresponding unsaturated
tricyclic ketone by reduction with sodium bis(2-methoxyethoxy)aluminium hydride. It possesses a camphoraceous,
patchouli, earthy-woody odour, and its structure is related to that of the the odour vector of patchouli oil (-)-135.
Li 2. Pd/H2 OH
133 134 (-)-135

(-)-patchoulol
Patchouli (Pogostemon cablin Benth.) is a small shrub cultivated in India, the Philippines, Java, Sumatra,
and Singapore. Its essential oil has a powerful woody-balsamic odour with herbaceous, earthy, camphoraceous,
andfloral nuances in a well balanced manner. The tricyclic alcohol, patchoulol (135), the structure elucidation
of which took almost 100 years (from 1869-1967), 144is most important for the characteristic odour of this essen-
tial oil. An elegant stereocontrolled synthesis of (-)-135 was carded out by N~f et al. 145in 1981.2,6,6-Trimethyl-
2,4-cyclohexadien-l-one (133) was alkylated with enantiopure (+)-3-methylpent-4-enyl bromide. An
intramolecular Diels-Alder reaction in the next step, and subsequent hydrogenation furnished (-)-135 in three
steps. However, this as many other approaches to (-)-135 or racemic (+)-135 so far could not compete with the
price of the natural product.
OH OH
135 136 137
patchoulol
Therefore, work on the structural features responsible for the odour characteristics of 135 was carried out.
Removal of the 8-methyl group increases the woody, and decreases the camphoraceous character. 146Cutting out
the C-6--C-7 bond gives compound 136, that again had an intense woody odour, while the earthy and
camphoraceous aspects of 135 were missing. 147 Removing also C-l-C-11 and C - 7 ~ - 8 , however, results in a
strong camphoraceous, earthy odour with woody-powdery undertones. 148 Other monocyclic analogs of 136
prepared by Weyerstahl et al. 148by addition of alkyl lithium reagents to 125 also have at least one of the patchouli
descriptors, woody, earthy or camphoraceous. As ill luck would have it, they missed 126, though they prepared
its n-butyl- and iso-butyl-analogues.148
2. Naa,.q, 1. BuLl
+ KOH 0 Mel
3. H2, 2. Nail, OH
138 139 Pd/C 140 Mel 141
3. LAH
Looking at 129, 132, 135, and some camphor derivatives, 149 it seems that patchoufi odorants should be
rigid, sterically hindered CI2--C15 secondary or tertiary alcohols. Compound 141 turned out to be the best of a
series of bicyclo[2.2.2]octanes, that were synthesized by the Diels-Alder reaction of cyclohexa- 1,3-dienes with
the ketene equivalent 139.15 Hydrolysis, hydrogenation, and dimethylation of the resulting ketone furnished
after lithium aluminium hydride reduction the odoriferous bicycloalcohol 141 with a strong patchouli odour
accompanied by woody-camphoraceous nuances. Compared to patchouli oil, which because of its attractive
price was for example used in an overdose of 40% in >>Gentleman<<(Givenchy, 1974), the compounds 126, 129,
132, and also 141 are already competitive in terms of synthetic accessibility and production costs.
For vetiver oil, used in 20% in >>Vetiver, (Guerlain, 1961), there are no such synthetics. Vetiver oil is the
steam distillate from the roots of Vetiveria zizanoides Stapf.--a wild, tufted grass cultivated in Java, India,
REunion, and Haiti. The content of three sesquiterpenes, tx- and ~-vetivone and khusimol, always present in the
oil, can attain 35%. They became fairly popular synthetic targets, 151 but there is no consensus 152 on their
contribution to the persistent, heavy, woody-earthy, somewhat sweet-sour and balsamic scent of the vetiver oils.
According to Btichi et al.153a this odour is mainly due to the spiroketone 142, and (-)-khusimone [(-)-143].153a
1. 03 EtO OEt
"-,. 2. pTsOH 2. HCI, Me2CO
0 """'" Me02C/ 3. ~0)~..
142 0 (-)-143 Me02C
khusimone 144 145 pTsOH
O
He
~ 1. Methylenation H H
2. LAH O
NaOH
3. POCI3
4. N2CHC02Et Et
~O H MeO2C O CI-- O ""','"
146 147 (-)-143
khusimone
Several syntheses of 142153b and (+)-143 have been reported, 153anone of which could be carded out on an
industrial scale at tolerable cost. Of these, the most inexpensive way to (+)-143 was reported by Biichi et al. 153a
in 1976. The first stereoselective approach to natural (-)-khusimone [(-)-143] was reported by Liu and Chan, 154
who used (-)-ct-campholenic ester 144 as starting material. Ozonization followed by aldol condensation provided
145, which was further transformed by [2+2] cycloaddition of a ketene equivalent, methylenation, reduction of
the ester moiety, halogenation of the resulting alcohol, and homologation of the cyclobutanone ring. Cyclization
of 147--->(-)-143 was accomplished in 70% yield by treatment with aqueous sodium hydroxide in refluxing
methanol. 153 Needless to say, this synthesis is also far too complicated for an industrial production.
7658 G. Frtter et al. / Tetrahedron 54 (1998) 7633-7703
> C 02M e >

""C H 0
148 149 150 151 O
Mahagonate
"' - H AoOI
AIOI3
152 153 155
thujopsene Vertofix (+)-cedrol
Even if there is no real synthetic vetiver odorant, some compounds in one way or another are reminiscent
of vetiver oil, the most important being 149, 151 and 154. Mahagonate (149), produced by Dragoco by Diels-
Alder reaction of ct-terpinene (148) and methyl acrylate under thermal or Lewis acid conditions, has a woody,
spicy, vetiver odour. The ct,13-unsaturated spiroketone 151 with some structural resemblance to 142 is easily
accessible from (-)-3-formylpinane (150) by simple Robinson anellation with methyl vinyl ketone.lS5 It possesses
a leathery-woody, vetiver-cedarwood type odour, similar in many respects to that of Vertofix (154).
Vertofix (154) is manufactured by Friedel-Crafts acylation of the hydrocarbon fraction of cedarwood oil
with acetyl chloride or acetic anhydride and catalysts such as zinc chloride or aluminium chloride. Thujopsene
(152), which constitutes some 40-50% of the hydrocarbon fraction, thereby undergoes acid-catalyzed
rearrangement to the tricyclic olef'm 153, which then is acylated to 154, the primary odorant of VertofLx (154). 156
The odour of Vertofix (154) is described as warm, woody, reminiscent of vetiver and cedar, with leathery
aspects. With 12%, Vertofix dominates the woody aspects of ,>Chanel No. 19<<(Chanel, 1970), and ,Cacharel
pour 1' Homme<< (Cacharel,1981) even contains an "overdose" of some 20% of it.
As cedarwood oil (Juniperus virginiana L.) is a by-product of the American timber industry, it is one of the
most economical and abundant sources of sesquiterpenes. This makes it an attractive starting material for the
synthesis of other odorants like Vertofix. On the other hand, any attempt to introduce a new cedarwood odorant
is a lost cause, simply because cedarwood oil is so inexpensive. (+)-Cedrol (155) is responsible for its soft,
woody odour, typical of cedarwood, and it is isolated from the oil by fractional distillation followed by
crystallization. The syntheses of 155 by Stork and Clarke, 157 and Corey eta/. 158 can already be considered
classics in total synthesis.
3.3 Sandalwood Odorants

The sandalwood oil constitutes one of the oldest and most expensive perfumery raw materials. Among
different sandalwood oils, that of the heartwood and roots of Santalum album L. trees from the East Indian state
of Karnataka (Mysore before 1973) is the most appreciated by perfumers.159 Besides its unique olfactory properties,
which make it play an important religious and social role in India, it also appears to have an important therapeutic
value. 16o
The multifaceted, persistent, natural and inimitable scent of sandalwood oil is due not only to its main
constituents of more or less sandalwood odour, but also to the minor impact chemicals and possibly to synergistic
effects of other, weak and odoufless compounds. New, trace constituents (e. 8. 158, 163, 165,161 166) are still
being isolated and identified, and numerous papers have reviewed the rich domain of sandalwood scent, including
the analytical studies. 63,162
~ O H ~ O H
16 156
(Z)-(-)-I~-santalol (2)-(+)-ct-santalol
typical sandalwood, woody, woody, cedarwood sweet, sandalwood
milky,urinous
~ O H
158 159
OH ~ 160
0
(2)-et-trans-be
rgamotol ~-photosantaloAl (EF~taLal
sandalwood,citrus sanda/wood, anima//cmusky
, sweaty, sandalwood
161
~ 162
0
~ 163
0
nor-ct-santalenone (E)-ct-santalal woody, ambergris,sandalwood

woody, sandalwood,ionone-like woody, cedarwood
164
~ 165
0
~ 0
166
nor-13-santalenone nor-ct4rans-bergamot
enone acetyldihydroalbene
sweaty, woody,green, fatty, nutty,milky,sandalwood woody, amber, ionone
sandalwood
167 168
N-furfurylpyrrole dendrolasine c-santalene
roasty,pyrazine-like,herbaceous green,fatty, nitrile4ike,agmmenoils woody, cedarwood
It is difficult to evaluate the contribution of the different constituents of sandalwood oil to the overall
odour profile, 163 but (Z)-(-)-I~-santalol (16) is unanimously considered as the main sandalwood, i.e. lactonic,
floral, woody, milky, musky (urinous, animal), odour vector. It accounts for approximately 25% of the oils weight.
The importance of the most abundant (Z)-(+)-o~-santalol (156, approx. 45--47%), bringing more woody, cedarwood
character, is more controversial. (x-Santalene (169), the main sesquiterpene hydrocarbon was ranked third among
the most odour-intensive molecules in the oil by Nikiforov et al.,164 but others grant it little sensory importance.
The most recently identified nor-(x-trans-bergamotenone (165), 161 despite its low concentration of <0.01%, is
said to be of great importance to the overall odour of the oil. The depicted compounds 16, and 156-169 are
considered as the main contributors to the scent of the East Indian sandalwood oil.
1. LiOH
O 2. H2, Pd/C
3. LDA, DMPU / ~ ,
02, P(OEt)3 ._
"13CI4 4. LAH
170 dr >99:1
171 CO2R* 5. NalO 4
172 O
1. NaN(TMS)2 ~ 1. O O
I'~0,~ ~ 0 (EtO)2P~I(OEt
2. H30e 0 2. Zn,
3. LAHCHL~r2,TiCI4
or DIBAH ~ O H
173 (Z)-(-)-16
, ~ ,~Br
E3uOK,
BuLi
174 0
175 169
1. FB(OMe)2 .~ ~ ; ~
2. H202 156 OH
L exo-176 endo-176
~0 Br~~~.. H~04
OH IBuOK,
BuLi
174 177 178 Br
1. LICKOR
2. FB(OMe)2~ 157
3. H202
179 __ OH
G. Frdter et aL / Tetrahedron 54 (1998) 7633-7703 7661
As with many other natural products, the components of sandalwood oil inspired total syntheses. These
have been reviewed,49b,63a and recently focus has shifted to the constituents and isomers of minor olfactory
importance, such as santalenes and epi-santalols. Therefore, we will mention only the most recent enantioselective
syntheses of the three main santalols (16, 156, and 157).
In 1990, Krotz and Helmchen64 reported the first synthesis of optically pure (Z)-(-)-~-santalol (16). It is
based on the preferred exo-alkylation of 3-methyl-2-norbornanone (172), obtained through the asymmetric Diels-
Alder cycloaddition of cyclopentadiene to trans-crotonate 170 with (R)-pantolactone used as auxiliary. Another
crucial step of the synthesis is the oxidation of the dianion generated from the hydrolysed and hydrogenated 171,
and in situ reduction of the s-peroxide to the t~-hydroxycarboxylic acid. In a similar way, they prepared ~l-
santalene, (E)-l$-santalol, and the corresponding enantiomers. Their olfactory evaluation consolidated the structure-
odour relationship data: only natural (-)-~-santalols (Z >> E) smelled sandalwood-like.
Schlosser and Zhong applied their findings on the conformational mobility and the conformational
preferences of allylpotassium type intermediates in the elegant syntheses of both (Z)-(+)-ct-santalol (156) 165
and (Z)-(+)-epi-~-santalol (157). 166 They proceeded through the formal hydration of the corresponding santalenes,
realised via regioselective metallation with the superbasic LICKOR reagent, followed by trapping with
fluorodimethoxyboron and subsequent oxidation of the termodynamically favoured endo-conformer of the
allylpotassium species 176. This site selective functionalization of isoprene units should, in principle, also work
with other santalenes for which numerous other stereoselective syntheses have been published. 167 Despite all
the synthetic attempts aimed at (-)- or rac-~-santalol no industrially viable process has yet been found.
" 1O-OH
BF~,B20
100o(3 181 182
180 2. H2, Ra-Ni in Sandela, Sandel H&R, Sandiff, Santalydol, etc.
sandalwood.like
The natural sandalwood oil always constituted a valuable ingredient of perfume compositions, but it has
become scarce and even more expensive since 1974, when its price quintupled; it is now at about US$ 250-400
per kg depending on the origin and quality. The perfumers have therefore to rely on cheaper synthetic substitutes.
Among them, two classes of compounds have been commercially successful. Both originated from the fortuitous
findings of German chemists. The first class of compounds, terpenyl cyclohexanols, are obtained by acid-catalysed
condensation of phenols (e. g. phenol, guaiacol) with cheap terpenes [camphene (180), pinenes], followed by
hydrogenation to provide complex mixtures of secondary alcohols. The first paper reporting such products appeared
in 1947,168 but the relative configuration of the odoriferous minor isomers (181, 182) were revealed only in
1954.169 The interest in these products culminated in 1970s, and has since then focused on a better chemically
defined class of compounds, that of derivatives of ct-campholenic aldehyde (185), of which the compounds 17
and 189-199 represent the most important commercialized, and recently patented compounds.
Both enantiomers of campholenal (185) are readily available from the corresponding ct-pinenes (183) via
acid catalysed transposition of their epoxides (184). The next steps towards f'mal products are stralghtforward--
aldol condensation and reduction of the enones to saturated or allylic alcohols, alternatively preceded by
deconjugation (17; Ebanol) or deconjugative ct-methylation (194; Polysantol). The synthesis of substituted 4-
(2,2,3-trimethylcyclopent-3-enyl)pent-4-en-l-ols (e. g. 195-197) 17, 171,172begins by a cheap (x-methylenation
of 185. The enal 187 is then reacted in the classical way via Wittig-Horner reaction, and Clalsen or Carrol
rearrangements. The cyclohexeno1198 was obtained via Robinson type cyclisation of dione 188.173 The synthesis
of 199, which differs from 189 (Sandalore ) by one oxygen atom inserted into the spacer is also simple: an
opening of epoxybutane with reduced 185, or LAH/AICI3 reduction of the corresponding dioxolane.174
As usual, process modifications lowering the production costs follow the original patents, e. g. an improved
process for producing alkyl-substituted butenols in which new catalysts are used for the two last steps has been
7662 G. Fr6ter et al. / Tetrahedron 54 (1998) 7633-7703
acid
> 0
183 184 185
R1 0
186 187 188
I I I
17 189 190
Ebanol Sandalore Bmhmanol
'~ OH
192 Bao:lanol, 193

Bangalol, Radjanol, Sandacore,Sandelice,
Sandranol, Sandolene Santalaire, Madml
~ OH
3LJvO. VU.3o.
Polysantol 195170,172 196171
OH
OH
198173
claimed. 176 Piperidinium acetate catalysed the formation of enone 186 (85% yield, azeotropic distillation of
water), which was then hydrogenated in the presence of a Cu-Zn catalyst to give 193 with 81% yield and better
purity.
The average market price of synthetic substitutes of sandalwood oil varies from US$ 20 per kg for
terpenylcyclohexanols to about US$ 50-200 per kg for the campholenal derivatives 17 and 189-194. This broad
price range is justified by the difference in their performances: odour threshold compared to the vapour pressure
of the product, substantivity, naturalness, etc. The most expensive, and the most appreciated by perfumers, seem
to be the pent-4-en-2-ols 17 and 194. However, there is still room for improvement. Recently, a new class of
G. Frtiter et al. I Tetrahedron 54 (1998) 7633-7703 7663
polycyclic derivatives of campholenal, containing one or two bioisosteric cyclopropane rings instead of the
double bonds, e. g. 200, has been claimed. 177 Some of these compounds are performing much better than the
existing benchmark products in terms of any of the above-mentioned parameters, but would this outweigh the
evident handicap consisting in the industrially difficult cyclopropanation step?
~ OH
200
Until very recently little has been known on the structure-odour relationship of the enantiopure isomers of
the commercial products. This information is now becoming available, often through the patent literature, and
the manufacturers of these products begin to apply some degree of stereoselection in order to provide more
intense odorants of higher quality for the same weight of raw material.
Four stereoisomers of Polysantol were obtained 68 via stereoselective reduction of acetals 202, followed by
chromatographic separation of the diastereomeric hydroxyethers 2031204, PCC oxydation, and reduction of the
corresponding oxoethers. The stereoisomers of 194 were also prepared by enzymatic hydrolysis of the
corresponding chloroacetates. The typical sandalwood scent is most pronounced in the two (2S)-isomers, of
which perfumers prefer the (1'S,2S)-194.
o
183 185 201
202 "-., 203 (25%) |

+
~ _ ~ .....~ , ~ ~ 0 H
1'S 2S 1. PCC
2. Flashchrom.
"""
~'~''" OH
(1'S,2S)-194 3. Na, Et20 204 frS*/.) O ~ ......
The known 17s relative-configuration-odour-relationship data of the four diastereomeric pairs constituting
Ebanol (17) have recently been completed by the olfactory description of all eight stereoisomers of this product. 179
Similarly, the four isomers of 195 were prepared and evaluated.17 The two sandalwood-smelling diastereomers
of (2R)-190, prepared by asymmetric hydrogenation of 193 using the Ru2CI4[(R)-ToI-BINAP]2NEt3catalyst, are
described in a recent patent. 18
. .....
1'S
~'-~~
3R j 2S
OH ~ OH
17 190 195
(1'S,2S,3R)>(1'R,2S,3FI) Intensityofthesandalwood-likescent (I'R,2R)>(I'R,2S)
>>other6stereoisomers (l'S,2R)~-(l'FI,2R)>>other
2 >other2
This, and certainly soon more knowledge of the exact configuration of the best odour vectors should allow
fine-tuning of the sandalwood olfactophore model, and enable a more rational design of still better sandalwood
odorants. This olfactophore consists of a bulky moiety separated by a spacer from the hydroxyl group. After
analysis of the above-detailed SOR data it is tempting to postulate, that the geometry of the immediate proximity
of the osmophoric hydroxy group tolerates less variations than the orientation of the more distant lipophilic
bulky group.
The bulky moiety of the norbornane in [~-santalol (16), 1811182, and analogues (e. g. 205181) as well as
that of the trimethylcyclopentenyl group in campholenal derivatives (17,189-199) can be replaced by structures
of similar steric bulk (cf 206,182207,183 208,70209,184210,185 and 211186 ). Even 2-methoxyisopropyl (cf 212187),
and tert-butyl substituents (e. g. in 21367) are apparently able to mimic this feature.
92
205 | ~,ln 206 207

n=1,2 OH RI=Me,Et; R2=_H,Me
208 209
epoxybrahmanol
OH
~ O H ~ O ~ OH
211 212 R
3.4 Musk Odorants

The musks are of central importance for the fragrance industry. They form the bottom note (the dry out) of
a perfume composition, i. e. the musky undertone stays the longest on the skin or on the fabric (substantivity, vide
infra). The musk odour is difficult to describe, it is often called warm, sweet, powdery, animal, etc., it is longlasting,
tenacious, and substantive. The use of musks goes back to antiquity, and is itself a chapter of human cultural
history.
The chemistry of the natural musk odorants started with the discovery of the macrocyclic musks, ketones
and lactones, during the first half of this century, when their isolation from animal and plant sources and subse-
quent structure elucidation took place.
Muscone (214), civetone (215), and Exaltone (216) are the main odorous principles from the animal
kingdom, whereas the lactones Exaltolide (18), and (Z)-AT-ambrettolide (217) have been isolated from plants.
The chemistry of macrocyclic musks has been reviewedJ 88
The class of nitro-musks was discovered by serendipity during the search for new explosives some hundred
years ago, is9 when the structure of the above natural musks was not yet known, and the latter had an exorbitant
price. Musk xylol (6), Musk ketone (218), Musk Tibetene (219), Musk Ambrette (220), and Moskene (221) are
the most prominent representatives of this class. It is a fascinating coincidence, that these penta- and hexa-
substituted polynitro benzene derivatives display a musky odour, with an ambery, sweet vanilla,powdery character,
and a touch of a highly esteemed animal tonality. Because of these odour chracteristics, and their very favourable
price, especially compared to the natural and later the synthetic macrocyclic musks, the nitro musks became
high-volume industrial chemicalsJ 9 During the 1980s their use began to decline. The reason is partly
toxicological, 191-193partly practical, 194but mainly the introduction of a third class of high-performing musks to
the market.
o 0
214 215 216

Muscone Civetone Exaltone
18 Exaltolide 217
Thibetolide Ambretlolide
This third class of synthetic musks consists of polycyclic, aromatic compounds. Phantolide (222), 195
Celestolide (223), 196 Traseolide (224), 197Fixolide or Tonalide (225), 19s and Galaxolide (226) 199 are the
main representatives, the last two being the most important today. Their chemistry is text-book aromatic
chemistry, 19 their odours are musky with fruity and woody effects, and an animal undertone. The polycyclic
musks are today in the same price class as the nitro musks or even cheaper, i.e. US$15-20 per kg, and several
thousands of tons are manufactured per year. Because of their low biodegradability, and their tendency to bio-
accumulate, they are causing some concern today.2-2o2
As can be imagined, to put up a unifying theory of the structure-odour relationship of these chemically
very different classes of musk compounds remains a very demanding task, to say the least (cfchapter 2.2).
NNNO
O2 ../,~ Oa Oa Oa 02 02
6 218 219
Muskxylol Muskketone MuskTibetene
O2N'~NO2
~.~O~ O 2 N ~
220 221
MuskAmbrette Moskene
222 223 224

Phantolide Celestolide Traseolide
225 226
Fixolide,Tonalide Galaxolide
G. Fr6ter et aL /Tetrahedron 54 (1998) 7633-7703 7667
02, cat. H2SO4 H~:~SO4
/ \ 231 232
The chemistry of the nitro musks can be considered today as a closed chapter, and that of the nitro-free
aromatic, polycyclic musks is also approaching an end. The aromatic hydrocarbons 227, 228, and 229, which
are the intermediates for the above polycyclic musks, have been oxidized to the carbonyl compounds 230, 231,
and 232, which are powerful musks, compound 231 possessing in addition a woody, camphoraceous note. 23
Interestingly, acetals and ketals of this series display a more woody odour (Okoumal). 2o3,204
C p2"ncl2 AICI3
233 234 O cat,, 61% 235 O-lO C
880
1. L~H [o]
0 >
2. MeSOn, 80*/,
P20s cat.
236 trans- 237
o.c
f V "~ '",,,
trans- 238 cis- 238
The aldehyde analogue of Fixolide , trans-238, has been claimed to be stronger than Fixolide (225)
itself. 25 trans-238 has been prepared by reacting isoprene (233) with pivaloyl chloride (234) to give 235, which
underwent a Friedel--Crafts reaction with ortho-xylene to provide 236. The latter compound was then reduced,
7668 G. Frdter et aL / Tetrahedron 54 (1998) 7633-7703
and transformed via methyl-migration to the hydrocarbon trans-237 as the main product (15% cis-isomer).
Oxidation with ammonium cerium(IV) nitrate furnished trans-23& The diastereomeric cis-238 is described as a
strong musk, but weaker than trans-23& 2~6 Besides this recent example of diastereoselectivity of odour and/or
odour strength there are a few cases of enantioselectivity of odour sensation known in the polycyclic musk field.
(S)-225 (R)-225
(S)-225 (Fixolide , Tonalide ) has the characteristic, strong, musk odour, whereas the enantiomer (R)-
225 displays a light and sweet aromatic odour. 207 The nitrile 240 has been prepared in both enantiomeric forms
from (R)- and (S)-235, respectively, which have been prepared by enantioselective protonation of the enolate
derived from 239 with (-)- and (+)-N-isopropylephedrin. 28,29 The further synthesis follows the route described
before, with a slight loss of chirality. Of the two enantiomers, the (6S,7S)-238 is the more powerful musk.
~ 0 1. LDA ~ O ~
2. AICI3 O
i~4~ - 800/0
239 (R)-235 (~%ee) (R)-236
1. LAH
2. H2S04 ..o
3. [0]
(6S,TS)- 238 (6S,7S)- 240
(77%ee)
Galaxolide (226) is a ca. l: 1:1:1 mixture of the four stereoisomers, i.e. two racemic, diastereomeric pairs.
All the four isomers have been prepared, and evaluated olfactorily. 21 Pentamethylindan (241) was reacted with
propylenoxides, (S)- and (R)-242, to give the diastereomeric mixtures (S)- and (R)-243, respectively. Ring closure
to the isochromanes with formaldehyde under acid catalysis furnished the enantiomerically pure diastereomeric
pairs cis-(4S,7 R )-226 and trans-( 4S, 7 S)-22a~, and cis-(4R,T S)-22~ together with trans-( 4R,7 R )-226. The two
main problems, the structure elucidation, i. e. the differentiation between the cis- and the trans-isomers of 226,
and the separation of the isomers, were solved as follows.
The chromecarbonyl complexes of 226 were prepared, separated by chromatography on silica gel, and
further purified by crystallization. The pure Cr(CO)3 complexes were then oxidized to provide the pure isomers
of 22~. The structure assignment was performed by X-ray crystallography of the pure rac-trans-22~ (mp 67 C),
and the Cr(CO)3 complex of (4S,7R)-226.
G. Frtiter et al. /Tetrahedron 54 (1998) 7633-7703 7669
II1=.,~
+ (4S,7R)-226
,,..~..~ (CH20)x.._
H (S)-242 H H2ScatO~4 0
~ O (CH~)x
H,~(R).242 H H2S04
60"/o cat.
(R)-243 + (4R,7S)-226
II1'"~*~0
(4R,7R)-226
CO2
v
244
v
Me 1. [Na]
-CO2Me 2. H3O~
~
245a
O H ~ ~
245b
O
Ay ~[Zn]
()-214 246 216

rac-Muscone Exaltone
The stereocbemistry of odour sensation in this case is particularly striking: The (4S)-isomers, i.e. cis-
(4S,7R)-226, and trans-(4S,7S)-226 are the powerful musky isomers, the trans-isomer [(4S,7S)-226] being slightly
weaker by a factor of ca. 2, and slightly more dry than (4S,7R)-226. The (4R)-isomers, cis-(4R,7S)- and trans-
(4R,7R)-226 arc weak to very weak, ca. 250 and 900 times weaker than (4S,7R)-22,6. This was in agreement with
the original hypothesis based on the matching of androstenone and the stcreoisomers of Galaxolide, 21o the two
products being related by a specific anosmia association.
Today the importance of the macrocyclic musks is increasing again, because of their ready biodegradability.
The stumbling-block for their really large-scale use has up to now been their relatively high price compared to
the other classes of musks, the nitro- and nitro-free polycyclic musks. Any synthesis of both macrocyclic ketones,
or macrocyclic lactones has its key step in the formation of the large ring (14-17 membered in the case of
macrocyclic musks). The first approaches as well as the first industrial syntheses all used the technique of
macrocyclization. 6 In connection with the synthesis of antibiotic macrolides new macrocyclization strategies
have been developed during the last 20 years. 211,212 However, only a few of these methods are applicable in
industry.
A major step forward in macrocyclization was the acyloin condensation of ct,o)-diesters. Application of
this reaction to dimethyl 1,15-pcntadecanedioate(244) furnished 245a / 245b, 213,214 which was either treated
with zinc in acidic media to provide Exahone (216) or dehydrated over alumina to the et,~-unsaturated ketone
246. This ketone can be converted to muscone(214) by means of a Michael reaction with methyl magnesium
bromide. 215 It is very important to realize, that the main difficulty in macrocyclization, namely dimedzation and
polymerization, normally makes high dilution (_<1 raM) necessary. The acyloin condensation, as a surface reaction
on the sodium metal, circumvents this problem, and the reaction can be carried out under very practical conditions
of around 1 M solutions.
0.1%solutiony ~ 0 0
H @, 85%
15
247 18 Exaltolide. Thibetolide
l 1. depolym.
2. cont. dist.
248 \ o/o
Using very high dilution (o-hydroxy pcntadecanoic acid was cyclized directly to Exaltolide (15), 216 but
only the polymerisation-depolymerization process 217 allowed a large-scale preparation. In a further development
glycerol esters of (~-hydroxy acids are prepared in situ, and the monomeric macrocyclic lactone formed in a
reversible transcstedfication process is continuously distilled off. 2i8
(E)- 16-Hexadec-9-cnolidc (251, Ambrettolide , Isoambrettolide) is an industrially used, valuable fragrance
ingredient. It is prepared from aleuritic acid (2,49), the main acidic constituent of shellac, by the dimethylamino-
dioxolane mediated double-bond formation, followed by ring closure. 219,220 A one-pot variant has also been
described, using two equivalents of dimethylformamide dimethyl acetal. 221
1. ie2NCH(OMe)~'
HO HO"~'O
9 250 251 Ambrettolide,
Isoambrettolide
1. HB(CsH11)2
O 1%X/ (-)-2ss~
2. 2 eq. Et2Zn
, ~Ao N M e2 H O'"
Et2Zn
CH212
91%
3. NH4CIaq
252 75% 254
1. Swem
2. LAH
-78 C
H O"" 82*/. O
255 (R)-(-)-214
(R)-(-)-Muscone
As an example of the muscone (214) chemistry the synthesis of the natural (R)-(-)-214 is presented here.
Oppolzer's route 222 follows a ring-closure strategy starting with 14-pentadecynal (252), which is hydroborated,
and the resulting (E)-alkenylborane is transmetallated in a 0.05 M (!) solution with diethyl zinc in the presence of
1% of the chiral catalyst (-)-253, in order to make the ring closure to 254 highly enantioselective (92 %ee). The
allylic alcohol 254 is then transformed to 255 by a stereoselective Simmons-Smith cyclopropanation, and the
synthesis is finished with an oxidation and a reduction step.
4OO
~N 256~ 2. ~
CI
O 257
2. H2, Pd/C
IPCY3 /~
cl,,. I
c,..3u_-,
PCY3 258
Olefmmetathesis is an established technique for ring-closure of macrocycles,223,224but recently new catalytic

systems have emerged 225 to give new impetus to this field. By a ring-closing methathesis employing the Grubbs
catalyst 258, 225 methyl diene 257 was transformed in 68% yield to (+)-(12R)-12-methyl-13-
tridecanolide(259)226--the stereogenic centre was created via Oppolzer's bornane 10,2-sultame 256. While the
enantiomers of muscone (214) smell very similar, the enantiomers of 12-methyl-13-tridecanolide(259), which is
a natural constituent of angelica root oil (Archangelica officinalis Hoffm.),227 differ significantly in their odour
characteristics: (+)-(12R)-259 possesses a musk note with a sandalwood tonality, while (-)-(12S)-259 has an
animal musk odour with camphoraceous aspects. 228
2X SnMe4cat.
260 261 262
In contrast to the synthesis of 259, ring-opening metathesis was used in the preparation of 1,9-cyclohexadiene
(261), en route to the macrocyclic ketone 262. 229 Cyclooctene (2611)is dimerized under the catalytic influence of
Re207 to 261, which after monoepoxidation and rearrangement was transformed to the macrocyclic musk ketone
(8E/Z)-cyclohexadec- 8-enone(262). 23
TMSI EtO Me2N

II 2
EIOH O 2.
HO ~ ONa
263 264 , , 3
3. KOH
1. A, KOH
" " "2 S ' "3

o OMe, [!!
265 0 266
Very recently, powerful thia-macrolides have been described. 231 Starting with e-caprolactone (263) the
thia-lactone 266 has been prepared through the intermediates 264 and 265. Compound 266 displays a tenacious
musk odour with a green-massy tonality, and with 0.2 ng/L an exceptionally low threshold value.
The other successful strategy to macrocyclic rings, besides the direct ring closure, is ring enlargement
which is a standard synthetic strategy. 232 For the musk specialities this route became important when
cyclododecanone (267) came to the market, at a reasonable price, as one of the downstream products of
G. Fr6ter et al. / Tetrahedron 54 (1998) 7633-7703 7673
OOH
~:~0 1. ~",,~0 H ~-~ H202
(~uO)2 AcOH
2. H~
267 268 269
Na o3,
NariS03
A
270 18 Exaltolide 271 Habanolide
Thibetolide
the butadiene oligomerization in the early sixties. A few examples shall demonstrate here the utility of
cyclododecanone (26/) as a starting material.233 267 can be transformed in two steps into the bicyclic enolether
268, which upon treatment with hydrogen peroxide (70%) yields the hydroperoxide 269. The labile 269 then
undergoes a fragmentation reaction to a mixture of Exaltolide (18), and the dehydro-Exaltolides 271. 234--236
This fragmentation has been studied in more detail under iron-copper catalysis. 237 The mixture of the dehydro-
Exaltolides 271 has recently been introduced to the market under the name Habanolide (271). 238
2. pTsOH
267 272 273
2. H2 165 C
OH
274 275
110 C
0 0
276 214
Muscenone Muscone
7674 G. Fr~iter et al. /Tetrahedron 54 (1998) 7633-7703
An early synthesis of muscone (214) starting from cyclododecanone(267) involved the reduction and
dehydration of the bicyclic enone 272 to give 273, which was ozonized and reduced to the ring-enlarged diol
274. 239 Copper-catalyzed pyrolysis furnished the dihydropyran 275, which upon treatment with acid yielded the
dehydro-muscone 276.
2X~Mg-CI
I
267 277
200 C
278 279
Ambretone, Musk TM II
An efficient ring-enlargement with four carbon atoms using the oxy-Cope rearrangement transforms
cyclododecanone (267) into cyclohexadec-5-en- 1-one (279), 240-242 which is a valuable, musky compound known
under the trade names Ambretone , and Musk TM II . Chlorination of 267 with sulfuryl chloride yields 277,
which when treated with two mole equivalents of vinyl magnesium chloride provides the hydroxydivinyl compound
278 as a cisltrans-mixture. Thermal rearrangement of 278 furnishes the target compound (E/Z)-279.
0 I. LDAI / 0 ~ I. 0 3,
HMPA (H2N)2CS
2. T B S O ' ~ I 2. H2NNH2Ts
281 / 3. (PPh3)2CuBH4
280 3. Amberlyst 15 282
259
(98.8% ee)
Employing chiral building blocks readily available from bioorganic hydroxy acids, e.g. 281 from (+)-(2S)-
methyl 3-hydroxy-2-methylpropanoate, macrolides could also be synthesized in high optical purity via a ring-
enlargement sequence. 243 The first stereoselective synthesis of (+)-(12R)-12-methyl-13-tridecanolide (259)
commenced with the HMPA-mediated alkylation of cyclodecanone (280) with chiral building block 281, followed
by Amberlyst15 catalyzed cyclisation to 282. Ozonolysis and selective reduction of the resulting carbonyl
group furnished 259 with 98.8 %ee. This synthetic sequence was applied to several other macrolides with overall
yields of isolated material up to 37%, 244 and enantiomeric excesses of up to 99.8 %ee. 245
12-Methyl- 13-tridecanolide (259) is not only interesting because of itsfine musk odour and the significantly
different odour of its enantiomer, its biogenesis inArchangelica officinalis Hoffm. is also not obvious. Only very
recently was the final proof of structure made by coinjection with synthetic material, 246 and (+)-(12R)-259 was
found to be the main enantiomer, though the ratio of (+)-(12R)-259 to (-)-(12S)-259 was only 72% to 28%. 246
This reminds us, that quite often nature is not just as selective as we may assume, or as synthetic chemistry is, for
that matter.
3,5 Floral Odorants

The kingdom of blooms is the domain of monoterpenes and Cl3-degraded carotenes. [~-Damascenone
(285) is a prominent example of the latter class of compounds. Its biosynthesis has been suggested247 to proceed
via the oxidative degradation at C-9 of allenic carotenes such as neoxanthin (283). Dehydration of 284 followed
by Rupe rearrangement could explain the formation of 285, while deoxy-neoxanthin might be the biochemical
precursor for ~- and [~-damascones (286 and 287). In a similar way megastigmatrienone (2,88) may be formed,
while ionones, like 13-ionone (7), are accessible by oxidative degradation of a great variety of carotenes.
The history of the isolation and structure elucidation of [3-damascenone (285) from Bulgarian rose oil
(Rosa damascena), as told by Kastner, 248 is one of the most exciting chapters of fragrance chemistry-the origi-
nal analytical results were published 20 years later, in 1987. 249
Three years after the structure elucidation of the damascones, in 1970, the first technical process to ct-
damascone was established and started from dehydrolinalool (289). 25o Coupling of 289 with allyl chloride led to
290, which was transformed by Cue-catalyzed Claisen rearrangement (Saucy-Marbet reaction) of the
acetylenecarbinol acetate and isomerization to 291. Acid-catalyzed cyclization finally gave ~-damascone (286).
[0]
~ OH
HO 283 neoxanthin H~/~HL ~" 284
Analogous
degradations
of carotenes
Rupe lead to ...
285 286
~-damascenone ot-damascone
287
I~larnascone megastigmatrienone ~-ionone
7676 G. Fr6ter et al. / Tetrahedron 54 (1998) 7633-7703
I. Ac20
2. CuOAc/
NaOAc
289~ "~ 290"/
o
H2S04
-20oc
286
291 ct-damascone
NOH 0 N
7 292 293 287

~ionone ~3mascone
An interesting 1,3-transposition of the carbonyl group from ionones to damascones is possible via an
isoxazole intermediate. 251 For instance, [3-ionone (7) was transformed into its ketoxime 292, which then was
oxidized to the corresponding isoxazole 293. Birch reduction and thermolysis, or acidic hydrolysis provided 13-
damascone (287).
_ D,
2. H30~
286
294 295 296 (~-damascone
Another route to ct-damascone (286) started from t~-cyclogeranic acid 294. 252 The latter was first
transformed to its acid chloride 295, then dehydrohalogenated to provide ketene 296, which was further reacted
with the Grignard reagent of allyl chloride, hydrolyzed and isomerized to the target molecule 286.
While I~-damascenone (285) smells floral-waxy, typically of Bulgarian rose blooms, [I-damascone (287) is
floral-woody, somewhat tobacco-like, and tx-darnascone (286) smells floral-fruity, green, apple-like with a harsh
camphoraceous cork-note. This cork-stopper off-note is due to the (R)-(+)-tx-damascone [(R)-(+)-286], whereas
the (S)-(-)-isomer [(S)-(-)-286] is linear, clean and more intense--in addition it possesses a pleasant wine-like
nuance. Fehr achieved a stereoselective synthesis of (S)-(-)-ct-damascone [(S)-(-)-286], and developed an ele-
gant method for the enantioselective protonation of enolates. 253
0 ~N-~
r
297 Ph~cY~Li
~. 298
(s)-1-)-286 2. H30 *
(S)-(-)-a-damascone 299
The most interesting, catalytic modification of this approach was published in 1994.254 Lithium enolate
297 is stereoselectively protonated to give 298 by substoichiometric amounts of (1R,2S)-(-)-N-isopropylephedrine.
The lithiated chiral auxiliary is protonated by an acidic allylic hydrogen of 298, thus providing lithium enolate
299, and regenerating the chiral auxiliary to close the catalytic cycle. Reaction of 299 with trimethylsilyl chloride
and hydrolysis provides (S)-(-)-(z-damaseone [(S)-(-)-286] in 86% yield with 93% ee.
~N,,,,H:0,,Li:X
sS
300
The high stereoselectivity of the protonation was rationalized by Fehr with model 300, in which the proton
is transferred via a nine-membered transition state with the nitrogen actively participating. The nitrogen atom,
the proton, and the double bond are situated over each other, and the bulky phenyl as well as the methyl group of
the chiral auxiliary point in the opposite direction. 255
However, the synthesis of the enolate 297 is quite complicated. Methyl o~-cyclogeranate (301) has first to
be lithiated, reacted with allylmagnesium chloride to give 303, and finally transmetallated via trimethylsilyl enol
ether. That makes the technical application of this elegant stereoselective approach very demanding, and up to
now (S)-(-)-ct-damascone [(S)-(-)-286] has neither been used in perfumery nor seen on the market.
7678 G. Frtiter et al. / Tetrahedron 54 (1998) 7633-7703
OMe nBuLim ~ "OLi ~MgCI
301 302
~ 303
MeOLi
1. TMSCI
2. MeLi
297
A more academic synthesis of (S)-(-)-(~-damascone [(S)-(-)-286] was carded out by Mori et al. 256 The
chiral building block (R)-304, prepared by enzymatic resolution of the corresponding acetate with pig liver
esterase, was O-alkylated to give 305. The chirality was then transferred by means ofa [2.3]-Wittig rearrangement,
and the triple-bond of the resulting product 306 was reduced with lithium aluminium hydride to provide 307.
Manganese dioxide oxidation of the allylic alcohol moiety furnishes the target molecule S-(-)-(~-damascone
[(S)-(-)-2~6]. 256
OH
fBr rBuLi
TMEDA
~ L ~
(rBu)4N I 54*/0
NaOH aq O J
0H gt*/.
(R)-304 305 306
O
LAH Me-zCO
7b'% 84*/0 (S)-(-)-286
307 (S)-(-)-a-damascone
In addition to the cork note of (R)-(+)-o~-damascone[(R)-(+)-286], the green aspect of technical ct-damascone
(2,86) varied in the early syntheses and often could not be tolerated. Analytical investigations showed this off-
note to be due to a powerful impurity with the structure 310/311. z57 This was formed by dehydration of 290,
acid-catalyzed cyclization of 308, and hydrolysis of the product to the mixture of 310 and 311.
- H~
290 308 309
+ H20
(H~
310 0 311 0
o-Dynascone ~Dynascone
, ~ [ ~ 2 ~,,MgCI
C O2Me C O2Me
312 O 313 310 O
oL-Dynascone
o o o
314 315 316
317 318
8-damascone
The pure mixture 310/311 possesses a green, galbanum-type odour with pineapple-like, hyacinth and
metallic facets, and was found so interesting, that it was immediately developed.258 It has been named Dynascone,
and contributes, for example, markedly to ,>Cool Water,, (Davidoff, 1988).
In contrast to tx-Dynascone (310), the ~-isomer 311 is much weaker, has no galbanum character, and is
much more ionone-like, thus less interesting. Hence, selective routes to ~-dynascone (310) were developed,257
one of which starts from 312, which is reduced and dehydrated to 313. Double addition of a vinyl Grignard
reagent to the methyl ester 313 then selectively yields ct-Dynascone (310).
Naturally, the success of the damascones (285-287) and Dynascone (310/311) triggered a lot of work on
derivatives, and related structures. Isodamascone (314), introduced in 1971 by Dragoco, was one of the first,
and one of the few outstanding derivatives.259 The shift of the gem-dimethyl substituent from the C- 1 to the C-
3 position changes the ot-damascone odour to a fresher, apple-purde-like tonality, though both still share many
common aspects. Isodamascone (314) has been used, for instance, in 1% in ,>Burberrys<<(Burberrys, 1992).
The connecting link from tx-damascone (286) to Isodamascone (314) would be 315 with the gem-dimethyl
substituent at C-2. Together with related structures, 315 was prepared by Weyerstahl et al. in 1996. 260 Its odour,
however, was described as apple-like, nutty and woody, apparently the floral character was lost. From all the 2,2-
dimethyl analogues only 316, the 13-damascenone (285) derivative, smelled damascone-like with plum andfig
undertones.
A shift of the double bond oftz-damascone (286) from A4,5 to A3,4 leads to ~-damascone (317), a commercial
product of IFF.261 Increasing the steric bulk at C-1 by substituting the gem-dimethyl group by an isopropyl
group, finally leads to 318, which was patented by Quest. 262 The odour of 318 still is damascone-like, with
fruity-woody nuances.
H~04 :30*/o
dioxane
319
OH O
Epoxy 13-damasco1319 now leads us to megastigmaenones. Its acid-catalyzed rearrangement via 320 gives
the megastigmadienone 321, which possesses a very impressive fine floral-fruity odour with a tobacco note. 263
It was isolated in trace quantifies from Virginia tobacco and passion fruit.
O
Se02 OMe
..... ~
2 323 dioxane v "~, 324
7,11-Epoxymegastigma-5(6)-en-9-one (322) was found by Kaiser to be present in the astonishing high

amount of 79% 264 in the headspace of the strong ionone-floral smelling Houlletia odoratissima Lind. ex Lindl.
ex Paxt., a rare terrestrial orchid native to the northern part of South America. Compound 322 was also found in
38% in the scent of the recently described Peruvian orchidaceae Gongora cruciformis Whitten & D. E. Benn, 265
together with 2% of a new compound, which was proposed to have the structure 323. 266 This was confirmed by
selenium dioxide oxidation of methyl 13-cyclogeranate(324).266
325 326 327 0 ~ 0 / 328

irone damascone irone rnegastigmatrienone theaspirane c~ -theaspirone
G. Frciter et al./ Tetrahedron 54 (1998) 7633-7703 7681
To complete the chemistry of carotene degradation products, it should be mentioned that the irone
homologues of damascone 325, 267 and of megastigmatrienone 326268 have also been synthesized. The odour of
the latter was evaluated as being similar to the tobacco, sweet, plum, and orris-like scent of megastigmatrienone
288.268
Derivatives of theaspirane (327) also belong to the class of degraded carotenoids, and some interesting
work on the structure-odour correlation has been carded out in this class of compounds. 269 They have fruity,
especially blackcurrant-like odours and therefore will not be discussed here. cis-Theaspirone (328), however,
does belong to the floral odorants--it smells orris-like, sweet-powdery, floral, and has tea-like nuances. 27
O ~ 102~ ~ ~ 1" N
S
2a30
H Sens. NO 2. H~
330
OOH 331
(-)-citronellol roseoxide
Only a few years earlier than [3-damascenone (285), another trace constituent of Bulgarian rose oil had
attracted the interest of perfumers and fragrance chemists. Following the identification of rose oxide (331) in
1961, 271 process development started immediately, and the monoterpene soon became an important perfumery
ingredient. Some prominent examples include >>RiveGauche<< (St. Laurent, 1971), ~>Metal<<(Paco Rabanne,
1979), and >~Drakkar Noir<< (Guy Laroche, 1982) with 0.5 % of 331. Its photochemical synthesis by Ohloff et
aL 272 is a prominent example for the reactivity of singlet-oxygen in industrial production. (-)-Citronellol (329)
is irradiated in methanol in the presence of oxygen with rose bengal as sensitizer. After consumption of one
equivalent of oxygen, aqueous sodium sulfite is added to 330. The reduced reaction product is then isolated and
treated with dilute sulfuric acid to provide 331 as a diastereomeric mixture.
Though Ohloff et al.273 had synthesized and evaluated the enantiomers of both cis- and trans-rose oxide, it
was only recently found by Takasago that (4R)-cis-rose oxide [(4R)-331] has a threshold of 0.5 ppb, 274 ten times
lower than that of its enantiomer (4S)-331.
Et2NH Et2N 100C,Rh- Et2N~ 1

(nBuLi) I~ (R)-BINAP
333 334 .,'~~
JL
1. H2S04 i~ ~,1 1. Br2 (Na2C03)
2. NaBH4 HO 2. KOH
(Cel17)3
l NMeCl
329
(-)-citronellol
~ 335 (4 -ci
The elegant asymmetric isomerization 276of allylamine 333, which is also used in the Takasago (-)-menthol
process, 275 provides the chiral enamine 334 in excellent 98 %ee. Enamine hydrolysis and reduction give (-)-
citroneUol (329), which is transformed to dehydrocitronellol (335) by bromine addition, and subsequent elimination
in the presence of Aliquat 336. The following acid-catalyzed cyclization to (R)-cis-rose oxide [(R)-cis-331]
proceeds with high diastereoselectivity. 277
OH i
1. M e ~ L i .L .L 1. Ac2O
2. NaBH4 2. Me2CuLi
3. LAH
336 OH
Pd-(R)-BINAP
(S)-338 ~,' cis -rich 31~
Pd-(S)-BINAP
J
" ~ ~ O H (R)-338 =
Pd-(R)-BINAP
tram-rich 3
rose oxide
Another interesting approach to cis-rich (4R)-331 is the Pd-BINAP catalyzed cyclization274b of allene
338. 278 This is available from 3-methyl 5-valerolactone (336) by addition of l-propynyl lithium, sodium
borohydride reduction, esterification with acetic anhydride, alkylation by the Gilman reagent, and LAH
reduction. 278 However, introducing the stereochemistry in the ~-methyl lactone 336 remains the major problem
of this approach. Once solved on an industrial scale, the diastereoselective cyclization by Pd-BINAP becomes
attractive. For example, the cis-rich (4R)-cis-331 was obtained from (R)-allene alcohol (R)-338 by the use of the
Pd-(S)-BINAP complex, while the cis-rich enantiomer (4S)-cis-331 was produced from the (S)-allene alcohol (S)-
338 and the Pd-(R)-BINAP complex.
1. H~,~
H ~
340 3
Rorol Doremox Clarycet
Besides the natural rose oxide (331), three analogues have attained commercial importance, i. e. Florol
(339), Doremox (340), 279 and Clarycet (343). 280 Doremox (340) with its strong floral-green, rose odour
reminiscent of rose oxide is a prime example for the old rule, 281 that isobutenyl can be replaced by phenyl
without change in the odour characteristics. The most interesting variation of the rose oxide theme is Clarycet
(343) of IFF. It combines the floral, green-rosy note with clary-sage, camomile-like and lavender aspects, and is
produced by acid-catalyzed reaction of 3-methylbut-3-en-l-ol (341) with butan-l-al (342), and subsequent
esterification with acetic acid anhydride. 28
An in-depth study of the structural requirements for the rose oxide odour was carried out by Weyerstahl
and Hoepfner in 1986. 282 They found an ether oxygen and an a-branching with an at least C3-alkyl chain to be
indispensable for the rose oxide odour. The six-membered ring can be replaced by a five-membered ring, and
even imitated by alkyl groups.
~ H 1. Br2
2.
~0~~
BuOH~ r KOtBu ~/!0
~I~M~cMIIg
I ~Jo~
I
344 345 346 347
The best seco-analogue of rose oxide (331) was compound 347, which has a rose oxide odour with a
herbaceous-fruity tonality. Since prenal polymerized too readily, and formed 1,1,3-trialkoxy derivatives upon
direct acetalization, the synthesis of 347 commenced with the bromo acetalization of isovaleraldehyde (344)
with n-butanol. Elimination and Mukaiyama--Grignard reaction283 then provided the target molecule 347. 282
What I]-darnascenone (285) and rose oxide (331) were for Bulganrian rose oil, so was methyl (-)-trans-
(Z)-jasmonate (348) for jasmine absolute (Jasminium grandiflorum L.). 284 However, in this case it was not the
natural product, but the dihydro derivative, commercially known as Hedione (352) and first synthesized in the
course of the structure elucidation of 348, that became famous. Patented in 1960, 285 Hedione (352) had its
olfactory debut as a 3% constituent of )>Eau Sauvage<< (Dior, 1966). Later it was used at higher concentrations:
22% in )>First<( (Van Cleef & Arpels, 1976), and at about 30% in ,,Cristalle,< (Chanel, 1993). Hedione (352)
with its light, smooth-floral, sweet, jasmine-like odour even set up a new fragrance category, the eauxfratches,
and was the starting point for the unisex fragrances. Its industrial synthesis from cyclopentanone (349) by aldol
condensation with pentanal, subsequent isomerization to intermediate 350, and Michael addition of malonic
ester yields Hedione (352) almost exclusively as the trans-isomer. However, it is the cis-isomer of 352 that is
much more intense, and much more distinct in its odour characteristics.
...'.~C02Me
0 0
348 349 350
o
MeO"~
MeO
.-"
0
\ ..-
MeO.~
0
r
0 0
351 352
Hedione
0 O
p /~ Na2C03 ,, /~ Cepionate
~0
352 <
Hedione
180C
> 353 I 0I
/ ~
y " . , , ~
OMe Fractional ~
distillation
(25--30"/.c/s)
Hedione HC
(65-70*/,~)
Therefore, in 1989 a process was worked out at Nippon Zeon to increase the amount of cis-isomer (353). 286
By heating 352 with sodium carbonate, about 10% of cis-isomer (353) is formed, which is further increased to
about 25-30% by fractional distillation. The resulting product was introduced as Cepionate . A high-cis quality
of Hedione (353) is also manufactured by Firmenich. This so called Hedione HC (65-70% cis) was important
for the creation of >>CKone<< (C. Klein, 1994). The use of the more expensive Hedione HC is limited, because
the cis-isomer (353) isomerizes outside a narrow 5.5-6.5 pH range.
o
1. Ru-(-)-(R,R)- .,~ /~
EI-DuPHOS ~, / ~ OMe
H2, P ~/ y . . , , , ~
2. CH2N2 -,~
O 354 90%ee O (+)-(1R)-353 :-" ....(N~ j

355
Et-DuPHOS
The next step to improve the qualtity of Hedione (352) would be an industrial route to the (1R)-cis
enantiomer (+)-(1R)-353, which is the most intense and most characteristic component of Hedione (352).
Catalytic asymmetric hydrogenation of the cyclopentenone 354 could be feasible on an industrial scale. 287 Using
the ethyl DuPHOS ruthenium catalyst 355 the (+)-(1R)-cis enantiomer (+)-(1R)-353 was prepared with 90 %ee
and a cisltrans ratio of 96:4. 288
~~._.~O ~ O2H
oJ , o#O 1. CsH6
2. LiOH
1. KOH
2. A
o To ro 3. KI3 ~0~ ~H 3, NaOH

4. "Ru04" 0
0 357 358
O
1. HI 1.,-
"se/~
2. Zn
3. MCPBA 1. NaOH 0~2 OMe
4, (COCI)2 2. CH2N2
I==
5. H2 / Pd(BaSO4) 3. PDC
6. R13PCHOMe
7. AcOH 35C
8. F~3PCHCH2CH3 (+)-(1R,2S)-360
G. Frtter et aL / Tetrahedron 54 (1998) 7633-7703 7685
A 17-step synthesis of enantiopure (+)-(1R)-353 starting from levoglucosenone, a pyrolytic product of

cellulose, was also reported. 289
It is again the (1R,2S)-enantiomer that carries the jasmine fragrance in the naturally occurring methyl
jasmonate. Compared with the (+)-(1R,2S)-methyl epi-jasmonate [(+)-(1R,2S)-360], which has an odour threshold
of 0.012 ng/L, the threshold of the epimeric (-)-(1R,2R)-360 is 20 times higher, while the other jasmonates were
described as odourless. 29 The first stereoselective synthesis of (+)-(1R,2S)-methyl epi-jasmonate [(+)-(1R,2S)-
360] was carded out in 1990 by Helmchen, Goeke et aL, 291 starting with the stereoselective Diels-Alder
cycloaddition of the fumaric ester of ethyl lactate 356 to cyclopentadiene. V/a a decarboxylation-elimination
reaction the tricyclic ketocarboxylic acid 358 was constructed, that was further transformed to the bicyclic lactone
359. Hydrolysis, esterification and PCC oxidation finally provided the odoriferous target molecule (+)-(1R,2S)-
360.
01tt~
" C02M e ~
~ 1. HS(CH2)aSH SePh
0~,,~ 2. pTsOH
3. HgO / HgCI2
OMe 4. BrPh3P(CH2)3SePh
361 362
0 O
1. H202, /~( OH OMe

NaHCO8 ~ 1. CH2N2
IP, "",t~ ~-- "s#l,~
2. 2 N KOH aq./ [ 2. Dess-Martin
MeOH (4:1) HO ~ ' ~ periodinane o ~
363 (+)-(1R,2S)-364
Cymbidium goeringii (Rchb. E) Rchb. f. is a widespred Asian Orchid with apleasant, lily-of-the-valley-
type, fresh-citrusy, floral odour. While the lily of the valley aspect is due to nerolidol and (E,E)-famesol, the
fresh-floral odour note reminiscent of ripe lemons and jasmine, as discovered by Kaiser, 292 is caused by methyl
cis-(Z)-dehydrojasmonate 364. Its absolute configuration was determined by Kitahara eta/. 293 to be (1R,2S) by
a stereoselective synthesis starting from acetal ester 361, which was converted to the bridged phenylselenide
lactone 362 in four steps. Oxidative elimination of the phenylselenide moiety afforded the corresponding diene,
which after alkaline hydrolysis provided 363. Treatment with diazomethane and Dess-Marfin oxidation completed
the enantioselective synthesis of (+)-(1R,2S)-364, which was shown to be identical with the natural isolate by
capillary GC.
1. I-I,2, P d / C . . . . .
"~ . . . , , ~ +
2. AcO2H 0 0
NaOAc
0 365 366 367
Aerangis lactone
7686 G. Frtiteret al. / Tetrahedron 54 (1998) 7633-7703
Aerangis lactone (366) was discovered by Kaiser 294 as the main odour component of the African "moth
orehids"Aerangis confusa J. Stewart and Aerangis kirkii (Rolfe) Schltr., and is characterized by aspects reminiscent
of tuberose and gardenia. Its synthesis by hydrogenation of dihydrojasmone (365) and subsequent Baeyer-
V'tlliger oxidation is straightforward. 294 By enantioselective multidimensional capillary GC, cis-(4S)-methyl-
(5S)-decanolide was identified as the unique stereoisomer of Aerangis lactone [(4S,5S)-366, 99.9 %ee]. 295
H H
H ~0~ 3 6 8 14
Lyral IJlial
H H
OH'~ / 370 371 OH 372

hydroxycitronellal Dupical Mugetanol
In 1994, 1,1-dimethyl-3-cyclohexylpropan- 1-ol (368) had its debut at 10% in ,>L'eau d'Issey pour homme<<
(Miyake, 1994).296 With its sweet,floral fresh-muguet, and lilac-like odour it leads us to lily-of-the-valleyodorants.
Lilial(14) 297 with >2500 t/a ,298 Lyral (369)299 with 520 t/a, 298 and hydroxycitronellal (370) with 1100 t/a 298
are the commercially most important compounds of this class of odorants, and even in the 2D structural formulas
their molecular similarities become apparent. Dupical (371) of Quest, 30 and Mugetanol (372) of H&R 31 are
two more recently developed lily-of-the-valley odorants, though Mugetanol (372) had actually been discovered
and patented by Monsanto in 1975. 32 By transesterification with vinyl laurate in the presence of Pseudomonas
lipase, 33 all stereoiomers of 372 were prepared. They all possess lily-of-the-valley odours, but the (-)-(1S)-cis-
enantiomer [ (-)-(IS)-372] turned out to the most intense and distinct one.
Lilial (14) with its very powerful fresh, floral note reminiscent of liUy of the valley, lindenblossom, and
cyclamen, was used at 2% in the masculine Foug~re >>PacoRabanne<< (Rabanne, 1973), and even at 20% in the
feminine fruity-floral fragrance >>Calyx<,(Prescriptives, 1987). To find out if an enantioselective approach to
this important industrial product would pay in terms of odour intensity, Enders and Dyker34 synthesized both
enantiomers of Lilial (14) via the SAMP/RAMP hydrazone method. The SAMPhydrazone 373 was ct-alkylated
by deprotonation with lithium diisopropylamide and treatment with dimethyl sulfate. The resulting product was
then cleaved by heating with excess methyl iodide, and subsequent hydrolysis with aqueous hydrochloric acid
provided (-)-(R)-14 in 95 %ee. This (-)-(R)-enantiomer was found to be the most intense, though the differences
were small, and both enantiomers smelled of lily of the valley.
OMe
I%
~ N 1. LDA
" 2. Me2S04 0
3. exc.Mel
4. 4N HCI aq
373 (-)-(R)-14
With the idea to fix the side chain of Lilial (14) in a cyclic ether in an energetically favourable conformation
Skouroumounis and Winter 35 synthesized compound 374, which, however, was found to be weak and vague,
without the slightest lily-of-the-valley aspect. The motivation for the synthesis of 374 and related ethers was the
replacement of the labile aldehyde group of many lily-of-the-valley odorants by a more stable functional group.
After several attempts in this direction36 Anselmi, Pelosi et aL 307 found in the easily accessible keta1375
a white-floral, lily-of-the-valley-like odorant without aldehyde or hydroxy function. With regard to the occurrence
of cyclic ethers in the essential oil of lily-of-the-valley (Convallaria majalis L.), Boelens et aL 3 synthesized
the tetmhydrofuran derivative 376,which biogenetically may arise from citral. Indeed, the synthezised compound
376 with some structural resemblance to hydroxycitronellal (370) was found to possess a fresh, white-floral
odour with a fruity-citrusy note.
74 375 6
At the end of this chapter, we revisit the terpenes. A series of sila derivatives of odoriferous terpenes has
been synthezised by Wannagat et al., 38 and summarized in two reviews. 309 The substitution of carbon by
silicon increases the electronic charge on the adjacent oxygen, stretches the molecule, and increases its mass. In
effect, the odour of the sila linalool 377 is shifted from lily of the valley to hyacinth, that of sila terpineol 378
from lilac to lily of the valley, and that of sila 13-ionone 379 from violet to freesia.
377 /Si\OH 378 379 3

liguloxide
That terpenes still have surprises in store can be seen in liguloxide (380), which was isolated from the
essential oil of an Olearia phlogopappa clone. 31 One might expect afloral-herbaceous odour; however, liguloxide
(380) was found to possess a typical tomato ketchup note. 31
7688 G. Frdter et aL /Tetrahedron 54 (1998) 7633-7703
4 CONCLUDING REMARKS
As mentioned at the beginning, we did not aim at a comprehensive review. We chose from a wealth of
material, publications and patents, led by our own interests, and those of our industry. We did not even touch the
topics of herbaceous-spicy and fruity odorants. Nevertheless, we tried to show the interested reader the fantastic
diversity of fragrance chemistry and its long and intellectually very rewarding passage from natural essences,
tinctures, absolues etc.
A constantly recurring question is -and it is well justified- how to find a new odorant which fulfills the
necessary conditions of it being: "new," "aesthetically pleasing," "non-toxic," "cheap," "stable and biodegradable,"
and "better/more useful" in comparison with the hundreds of existing compounds.
In section 2 we discussed the limited knowledge of the olfactory mechanisms, the sorry state of structure-
odour relationships (SOR), and consequently of the rational design of new odorants. Thus, the finding of a new
odorant with all the above mentioned attributes is still very empirical--based almost exclusively on a broad
chemical knowledge, experience, fantasy, and instinct, but backed up with modem tools for carrying out molecular
similarity studies.
Natural products are, as ever, an important source of leads, both for new odour tonalities, and for new
structures. The headspace technique, Le. the trapping of scent of the living flower is today a generally used
method. 311-314 Trace components of essential oils can also contribute significantly to the odour characteristics,
as was demonstrated by the identification of powerful alkaloids.31s
It is well known that the perception of an odour is very subjective, influenced by physiology and psychology,
which obviously makes a meaningful evaluation of odorants difficult. As Sell put it,31 "odour is not a physical
property."
In order to cancel out large individual differences of odours and their thresholds, normally a panel is used
for the evaluation of new substances. In order to rate the odour strength the odour value (OW) 319 has been
introduced:
vapour pressure (ng/L)

OV= threshold conc. (ng/L)
The OV of commercial odorants is in the range of 10-107, the vapour pressure being 50 ng/L-50 mg/L,
whereas the threshold is in the range of 2 pg/L to about 2 I.tg]L. 319'320 Without considering the hedonics, the
higher the OV, the more powerful (useful) is the compound, in principle--although odour value alone does not
account for all the complexity of odour perception.
Several attempts have been made to establish an alternative to the unsatisfactory, because so individual,
descriptive method of characterizing odours. One of these approaches, at least for the similarity if not for the
quality of odours, has been made by examining panel correlation diagrams, obtained from odour threshold
measurements with odorants of similar and dissimilar odour notes. 321
Substantivity, besides the odour quality and odour strength, is the most important characteristic of a fragrance
molecule.l The substantivity defines the duration of perceptibility of a fragrance (molecule) on skin, hair, fabric,
etc. Some of the fragrance molecules display themselves also a fixative influence on a mixture--they are
substantive and fixative.266,322-324 The substantivity of fragrances in detergents and softeners on laundry is of
profound economical and ecological interest. The "more odour" remains on the laundry, the more effective is the
fragrance, the less is washed out, and the less burdened is the ecosystem. 325-327 Especially in this context, it is
essential that fragrance chemicals are biodegradable. One increasingly researched route for higher substantivity
is that of precursors, the aim of which is to prepare a derivative of the desired compound that displays a better
stability or a lower solubility, etc., and that under the influence of a pH-temperature change or an enzyme
releases the compound at the right place and the right time. 328 These compounds are supposed to be stable in
detergent powders (pH up to 9) or in softeners (pH down to 2-3). They should not be washed out during the
washing process, then be cleaved, and deposit the fragrance on the laundry. 11
G. Frdteret al. /Tetrahedron 54 (1998) 7633-7703 7689
Acknowledgement
For proof-reading of the manuscript, and for useful comments we are most grateful to P Naegeli.
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Biographical sketch
Georg Fr~ter Jerzy A. Bajgrowicz
Philip Kraft
G. Frtiter et al./ Tetrahedron 54 (1998) 7633-7703 7703
GeorgFrffter, born 1941 in Budapest (Hungary), obtained his Ph. D. working with Professor H. Schmid at
the University of Ziirich, and spent postdoctoral years in Leiden, The Netherlands, and Edmonton, Canada. After
more than ten years of agrochemical research with Hoffmann-La Roche, he joined Givaudan Roure in Switzerland,
and became head of its synthetic chemistry research. CJeorg Fnfter has authored a large number of publications
and patents, and contributed significantly to modern synthetic methodology. He is also senior lecturer at the
University of Ztidch.
Jerzy A. Bajgrowicz, born 1950 in Wroclaw (Poland), graduated from the Technical University of Cracow,
and obtained his doctorate in organic chemistry at the Technical University of Wroclaw in 1977. He spent several
years doing research in the domain of azaaromatics and asymmetric synthesis of aminoacids, and teaching
chemistry at his alma mater, then at the Ecole Normale Sup6deure of Rabat (Morocco), and the University of
MontpeUier (France). After the next four years dedicated to the pharmaceutical research (Laboratoires Foumier,
Dijon, France), in 1989, he joined Givaudan Roure Research, where he is now the head of the Fragrance Chemistry
group. His main research interests are focused on the design -using CAMD techniques- and synthesis of new
odorants.
Philip Kraft, born 1969 in Rendsburg (Germany), studied chemistry at the University of Kiel. He received
his diploma in 1994, and obtained his doctorate summa cum laude in 1996, doing organic syntheses of medium
and large ring compounds under the supervision of Professor W. Tochtermann. In 1996, he joined Givaudan
Roure Research as a laboratory head in Organic Synthesis. He was awarded a scholarship of the Studienstiftung
des Deutschen Volkes from 1990-94, the Chemiefonds-Stipendium des Verbandes der Chemischen Industrie
1994-96, and the faculty prize of the University of Kiel in 1997.

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TETRAHEDRON

Tetrahedron 54 (1998) 7633-7703

Tetrahedron report number 456

Received 26 February 1998

Absm~t."ThisTetrahedronReporton frasrancechemistrysummarizesthe recentprogressin the chemistry

0040-4020/98/$19.00 1998 Elsevier Science Ltd. All rights reserved.

yyc.o ( c.o <o c.o

2 RATIONAL DESIGN OF ODORANTS

2.1 Olfactory Mechanism--Molecular Complementarity

Top view of Lilial (14) docked at a possible binding site

7,2 O(factopbor $earcb---Molecular $imtlafay

Naipawer et al. so Ce-~O(H) ca. 4 A

Chastrette et al. 71 Ce._>O(H) 6.5-7.1 A

Dimoglo et aL ss Ce-)C d 5.15 + 0.15 A

3.1. Amber Odorants

OH CrCka .,,O O LAH

Me2CuLi H[~~OMe NaOCI

OMe 1. 03,-70 OMe 1. i - M g B r

3. LDA, TMSCI ~TMS 2. MeLi, Et20

101 102 103 104

127 128 129

133 134 (-)-135

> C 02M e >

3.3 Sandalwood Odorants

nor-ct-santalenone (E)-ct-santalal woody, ambergris,sandalwood

183 184 185

192 Bao:lanol, 193

202 "-., 203 (25%) |

(1'S,2S)-194 3. Na, Et20 204 frS*/.) O ~ ......

205 | ~,ln 206 207

3.4 Musk Odorants

214 215 216

222 223 224

02, cat. H2SO4 H~:~SO4

trans- 238 cis- 238

()-214 246 216

Olefmmetathesis is an established technique for ring-closure of macrocycles,223,224but recently new catalytic

260 261 262

TMSI EtO Me2N

" " "2 S ' "3

3,5 Floral Odorants

HO 283 neoxanthin H~/~HL ~" 284

7 292 293 287

OMe nBuLim ~ "OLi ~MgCI

290 308 309

314 315 316

7,11-Epoxymegastigma-5(6)-en-9-one (322) was found by Kaiser to be present in the astonishing high

325 326 327 0 ~ 0 / 328

Et2NH Et2N 100C,Rh- Et2N~ 1

O 354 90%ee O (+)-(1R)-353 :-" ....(N~ j

o To ro 3. KI3 ~0~ ~H 3, NaOH

A 17-step synthesis of enantiopure (+)-(1R)-353 starting from levoglucosenone, a pyrolytic product of

1. H202, /~( OH OMe

OH'~ / 370 371 OH 372

377 /Si\OH 378 379 3

vapour pressure (ng/L)

5 REFERENCES AND NOTES

Ambedyn for Quest, and Ambrofix for Givaudan Roure.

124. Maleczka, R. E.; Paquette, L. A. J. Org. Chert 1991, 56, 6538-6546.