Molecules 1997, 2, 3 – 6

molecules ISSN 1420-3049

Synthesis of the Demospongic Compounds,

(6Z, 11Z)-Octadecadienoic Acid and (6Z, 11Z)-Eicosadienoic Acid

B. A. Kulkarni, S. Chattopadhyay*, A. Chattopadhyay and V. R. Mamdapur

Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai - 400 085, India. Tel. 91-22-5563060; Fax 91-22-
5560750 ([email protected])

Received: 20 December 1996 / Accepted: 10 January 1997 / Published: 29 January 1997

Abstract: A stereoselective synthesis of (6Z, 11Z)-octadecadienoic acid (1) and (6Z, 11Z)-eicosadienoic acid (2)
from easily accessible pentane-1,5-diol (3) is described. Thus, compound 3 on pyranylation and oxidation gave
the aldehyde 5 which was converted to the acid 7 by Wittig reaction with a suitable phosphorane. Its depyranylation
and oxidation furnished the key aldehyde 9 which upon Wittig reaction with n-heptylidene and n-nonylidene
phosphoranes, respectively followed by alkaline hydrolysis afforded the title acids.

Keywords: Euryspongia rosea, phospholipid fatty acids, stereoselective synthesis, (6Z, 11Z)-octadecadienoic
acids, (6Z, 11Z)-eicosadienoic acids, Wittig olefination.

Introduction from the phospholipid fraction. This type of ∆ 6,11 -

diunsaturation present in these compounds is rather scarce
The marine environment [1] constitutes an exhaustible treas- in both plant and animal kingdoms. Earlier, a similar
ury of organisms generating a plethora of secondary olefination pattern was found exclusively in the fatty acids
metabolites. In this regard, sponges, the primitive multicel- of phosphatidylcholine of Teytrahymena species [4]. Our in-
lular organisms have recently been the targets [2] of lipid terest in these compounds stems from the reported [5] anti-
chemistry not only for the product fatty acids but also due to fungal activities of some of the olefinic acids. However, the
their biosyntheses. It is now believed that a combination of low natural abundance of 1 and 2 precludes their systematic
de novo biosynthesis, dietary intake, and incorporation of bioassay. Hence, in continuation of our work [6,7] on the
microorganic symbionts are responsible for the genesis of syntheses of marine natural products, we have developed a
these varied types of novel fatty acids in sponges. Besides stereoselective synthesis of both these compounds from a
the presence of very long chain fatty acids, sponges have single synthon, amenable from commercially available in-
provided fatty acids with unusual unsaturation patterns, sub- expensive materials. This has also led to unequivocal struc-
stitutions with oxygenated functionalities (hydroxy, methoxy, tural assignment of compound 2. Earlier, in connection with
acetoxy) and methyl branching. GLC study of some related fatty acids, compound 12, the
Recently, from the marine sponge, Euryspongia rosea, progenitor of 1 was prepared [8] via an acetylenic route. How-
two such compounds viz. (6Z, 11Z)-octadecadienoic acid (1) ever, to the best of our knowledge, this is the first synthesis
and (6Z, 11Z)-eicosadienoic acid (2) have been isolated [3] of 2.

* To whom correspondence should be addressed

© 1997 MDPI. All rights reserved
4 Molecules 1997, 2
Results and Discussion The (Z)-geometry of the two olefinic bonds was estab-
lished by the absence of any IR band at 960-980 cm-1. Fur-
The synthesis was based on a “building-block” approach ther confirmation of this was accomplished by the 13C NMR
consisting of coupling between C5- and C6-units to furnish spectrum of 12 which exhibited signals due to the allylic car-
the common intermediate 9. Subsequent addition of the ap- bons at δ 27.2 and 27.8 ppm, characteristic of the internal
propriate C 7- and C9-moieties to it gives 1 and 2 respec- (Z)-alkenes [14,15].
tively after proper functionalization. The stereo-selectivities Likewise, the Wittig reaction of 9 with C9-phos-phorane,
of the incipient olefins were fixed by Z-selective Wittig re- generated from 11 [16] gave 13 with 98% isomeric purity
actions (Scheme 1). (by capillary GLC analysis) whose exclusive (Z)-geometry
Commercially available, pentane-1,5-diol ( 3) was was also confirmed by 13C NMR analysis as above. Its alka-
monopyranylated to the compound 4 which on oxidation line hydrolysis afforded the acid 2. The mass spectral data of
with “buffered PCC” [9] gave the aldehyde 5. Its Z-selec- 1 and 2 were consistent with the reported values [3].
tive Wittig olefination [10] with the known phosphor-ane
generated from 6 [11] furnished compound 7. Although Experimental Section
Wittig reactions with carboxylic acids bearing phosphoranes
are reported in the literature [12], we encountered difficulty All bps are uncorrected. The IR spectra were scanned with a
in the isolation step leading to poor yield of the Wittig prod- Perkin-Elmer 783 spectrophotometer. The PMR spectra were
uct. Consequently, a modified work-up was employed (see recorded in CDCl 3 with a Bruker AC-200 (200 MHz)
Experimental). Acidic deprotection of 7 led to the hydroxy spectrometer. The mass spectra (70 eV) were recorded with
compound 8 with concomitant esterification. Its oxidation a Shimadzu GCMS-QP 1000A spectrometer using the direct
followed by a second Wittig reaction of the resultant alde- probe injection. The GLC analyses were carried out on a
hyde 9 with the C7-phosphorane, generated from 10 [13] Shimadzu GC-16A chromatograph fitted with a flame ioni-
under the above condition afforded the ester 12 with 97% zation detector and a quartz capillary column (OV-17). An-
isomeric purity (by capillary GLC analysis). This was con- hydrous reactions were carried out under Ar using freshly
verted to 1 by alkaline hydrolysis. dried solvents. All organic extracts were dried over anhy-

i iii iv
HO(CH2) 5OH R(CH2) 4OTHP HO2C(CH 2) 4 (CH2) 4OTHP MeO2 C(CH2 )4 (CH2) 4OH

3
4 R = CH2OH 7 8
ii
5 R = CHO

v vi
8 MeO2 C(CH2 )4 (CH2) 3CHO RO 2C(CH 2) 4 (CH2 )3 (CH2 )5 CH3

9 12 R = CH2 OH
vii
1 R = CHO

viii
RO2 C(CH2 )4 (CH2) 3 (CH2) 7CH 3

13 R = Me
vii
2R=H

i) DHP/PPTS/CH 2Cl2, 61%; ii) PCC/NaOAc/CH2Cl2, 68%; iii) NaH/DMSO/Ph3P (CH 2)5CO2H (6), 53%; iv) MeOH/HCl/∆, 91%; v) PCC/CH2Cl2, 71%; vi)
NaH/DMSO/C 7H15PPh3Br (10), 61%; vii) Alcoholic KOH, 88-92%; viii) NaH/DMSO/C 9H19PPh3Br (11), 58%.

Scheme 1.
Molecules 1997, 2 5
drous Na2SO4. and dried. Removal of solvent gave pure 8 (2.8 g, 91%): IR:
3400, 1740, 1655 cm-1; PMR: δ 1.4-1.7 (m, 8H), 1.83 (br. s,
5-(2-Tetrahydropyranyloxy)-pentan-1-ol (4) D2O exchangeable, 1H), 1.9-2.5 (m, 6H), 3.60 (s, 3H), 3.72
(t, J = 6 Hz, 2H), 5.4-5.6 (m, 2H). Anal. Calcd. C12H22O3: C,
A mixture of 3 (10.0 g, 0.096 mol), PPTS (0.2 g) and 67.25; H, 10.35; Found: C, 67.08; H, 10.22.
dihydropyran (8.1 g, 0.096 mol) in CH2Cl2 (50 mL) was
stirred at 0 oC for 2 h and at room temperature for an addi- (5Z)-10-Carbomethoxydec-5-enal (9)
tional 2 h. It was then poured into aqueous NaHCO3 and
extracted with ether. Usual isolation followed by column chro- As described earlier, compound 8 (2.8 g, 0.013 mol) was
matography over neutral alumina (gr. II) eluting it with 0- oxidized with PCC (4.3 g, 0.02 mol) in CH2Cl2 (30 mL) to
20% EtOAc/hexane afforded pure 5 (11.0 g, 61%) along with give the aldehyde 9 (1.96 g, 71%): IR: 2720, 1740, 1715,
a little dipyranylated product: bp 92-94 oC/0.2 mm; IR: 3400, 1660 cm-1; PMR: δ 1.2-1.8 (m, 6H), 1.9-2.2 (m, 4H), 2.3-2.5
1010, 900, 860, 800 cm-1; PMR: δ 1.5 (br. s, 12H), 2.23 (s, (m, 4H), 3.66 (s, 3H), 5.3-5.5 (m, 2H), 9.7 (t, J = 1.5 Hz,
D2O exchangeable OH, 1H), 3.3-4.2 (m, 6H), 4.63 (s, 1H); 1H).
Anal. Calcd. C10H20O3: C, 63.79; H, 10.71; Found: C, 63.57;
H, 10.89. (6Z,11Z)-Octadeca-6,11-dienoic acid (1)

5-(2-Tetrahydropyranyloxy)-pentanal (5) Wittig olefination between 9 (0.98 g, 4.6 mmol) and the phos-
phonium salt 10 (2.65 g, 6.0 mmol) using dimsyl ion as the
Oxidation of 4 (8.0 g, 0.043 mol) with PCC (13.9 g, 0.065 base gave the ester 12 (0.82 g, 61%): glc (quartz capillary
mol) in presence of NaOAc (0.41 g, 5.0 mmol) in CH2Cl2 column OV-17, 50 Mt., id. 0.25 mm, split 1:100, FID, N 2 2
(40 mL) furnished the aldehyde 5 (5.4 g, 68%) which was mL/min, temp. 210 oC): t R = 13.20 min (97%); IR: 1740,
found to be reasonably pure and used as such for the next 1640 cm-1; PMR: δ 0.87 (dist. t, 3H), 1.2-1.4 (m, 14H), 1.9-
step due to its instability: IR: 2720, 1730, 1005, 910, 860, 2.1 (m, 8H), 2.31 (t, J = 7.5 Hz, 2H), 3.66 (s, 3H), 5.3-5.5
805 cm-1; PMR: δ 1.4 (br. s, 10H), 2.3-2.6 (m, 2H), 3.3-4.1 (m, 4H); 13C NMR: δ 14.0, 22.6, 24.5, 26.8, 27.2, 28.9, 29.1,
(m, 4H), 4.60 (s, 1H), 9.8 (t, J = 1.5 Hz, 1H). 29.7, 29.8, 30.7, 31.7, 33.9, 51.4, 129.1, 129.4, 130.1 130.2,
174.1. Anal. Calcd. C 19H34O2: C, 77.49; H, 11.64; Found:
(6Z)-11-(2-Tetrahydropyranyloxy)-undec-6-enoic acid (7) C, 77.28; H, 11.78.
The above ester 12 (0.5 g, 1.7 mmol) was hydrolyzed
To a stirred solution of 6 (16.9 g, 0.037 mol) in DMSO (20 with alcoholic KOH (2N). The usual work-up followed by
mL) at room temperature was added a solution of dimsyl column chromatography (silica gel, 0-30% EtOAc/hexane)
solution (0.074 mol, prepared separately by heating NaH and of the crude product gave 1 (0.44 g, 92%): IR: 3600-3400,
DMSO to 55 oC) in DMSO (30 mL) at room temperature. 1720 cm-1; PMR: δ 0.87 (dist. t, 3H), 1.2-1.5 (m, 14H), 1.9-
After 1 h, the aldehyde 5 (5.2 g, 0.028 mol) in DMSO (10 2.2 (m, 8H), 2.32 (t, J = 6 Hz, 2H), 5.3-5.5 (m, 4H), 8.6 (br.
mL) was added to the resulting red solution and stirring con- s, D2O exchangeable, 1H). Anal. Calcd. C18H32O2: C, 77.09;
tinued for 18 h at the same temperature. Most of the solvent H, 11.50; Found: C, 76.96; H, 11.42.
was removed at 35-40 oC under 0.1 mm vacuum, water added
to the residue and the content extracted with EtOAc. The (6Z,11Z)-Eicosa-6,11-dienoic acid (2)
aqueous extract was acidified with 50% aqueous oxalic acid
to pH 2 and reextracted with ether-hexane (1:1). The extract As above, reaction between 9 (0.98 g, 4.6 mmol) and the
was washed with water and brine and dried. Removal of sol- phosphonium salt 11 (2.8 g, 6.0 mmol) gave the ester 13 (0.86
vent followed by column chromatography of the residue g, 58%): glc (quartz capillary column OV-17, 50 Mt., id. 0.25
(silica gel, 0-30% EtOAc/hexane) afforded compound 7 (4.2 mm, split 1:100, FID, N2 2 mL/min, temp. 210 oC): tR = 17.85
g, 53%): IR: 3700-3500, 1710, 1010, 910, 860, 800 cm-1; min (98%); IR: 1735, 1660 cm -1; PMR: δ 0.88 (dist. t, 3H),
PMR: δ 1.2-1.7 (m, 14H), 1.9-2.1 (m, 4H), 2.3 (t, J = 6 Hz, 1.2-1.4 (m, 18H), 1.9-2.1 (m, 8H), 2.31 (t, J = 7.5 Hz, 2H),
2H), 3.2-3.6 (m, 4H), 4.65 (s, 1H), 5.3-5.5 (m, 2H), 9.5 (br. 3.68 (s, 3H), 5.3-5.5 (m, 4H); 13C NMR: δ 14.1, 22.6, 24.5,
s, D2O exchangeable, 1H); Anal. Calcd. C16H28O4: C, 67.57; 25.5, 26.8, 27.2, 27.6, 29.3, 29.5, 29.7, 30.7, 31.6, 34.0, 51.4,
H, 9.92; Found: C, 67.68; H, 9.89. 129.2, 129.4, 130.1 130.2, 174.1. Anal. Calcd. C21H38O2: C,
78.20; H, 11.88; Found: C, 78.17; H, 11.97.
Methyl (6Z)-11-hydroxyundec-6-enoate (8) Hydrolysis of 13 (0.5 g, 1.6 mmol) with alcoholic KOH
(2N) followed by usual work-up and column chromatogra-
A solution of 7 (4.1 g, 0.014 mol) in MeOH (100 mL) con- phy (silica gel, 0-30% EtOAc/hexane) of the crude product
taining HCl (2N, 3-4 drops) was refluxed for 8 h. Most of the gave 2 (0.42 g, 88%): IR: 3700-3500, 1715 cm-1; PMR: δ
solvent was removed in vacuo, the residue was taken up in 0.89 (dist. t, 3H), 1.2-1.6 (m, 18H), 1.9-2.2 (m, 8H), 2.35 (t,
ether and the organic extract washed with water and brine J = 6 Hz, 2H), 5.4-5.6 (m, 4H), 9.8 (br. s, D2O exchangeable,
6 Molecules 1997, 2
1H). Anal. Calcd. C20H36O2: C, 77.86; H, 11.76; Found: C, Synth. Commun. 1992, 22, 2921-2925.
77.75; H, 11.83. 7. Kulkarni, B. A.; Chattopadhyay, S.; Chattopadhyay, A.;
Mamdapur, V. R. J. Org. Chem. 1993, 58, 5964-5966.
Acknowledgment: One of the authors (B. A. K.) gratefully 8. Lie Ken Jie, M. S. F. J. Chromatography 1975, 109,
acknowledges the award of a senior research fellowship from 81-87.
the Department of Atomic Energy, India. 9. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647-
2650.
10. Crabbe, P.; Garcia, G. A.; Rius, C. J. Chem. Soc. Perkin
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6. Kulkarni, B. A.; Chattopadhyay, A.; Mamdapur, V. R. Sample Availability: Samples available from the author.