Synthesis of the demospongic compounds, (6Z,11Z)-octadecadienoic acid and (6Z,11Z)-eicosadienoic acid Molecules

B. A. Kulkarni, S. Chattopadhyay*, A. Chattopadhyay and V. R. MamdapurBio-Organic Division, Bhabha Atomic Research Centre, Mumbai - 400 085, India. Tel. 91-22-5563060; Fax 91-22-5560750 (bod@magnum.barct1.ernet.in)Received: 20 December 1996 / Accepted: 10 January 1997 / Published: 29 January 1997Abstract: A stereoselective synthesis of (6 Z , 11Z )-octadecadienoic acid ( 1) and (6 Z , 11Z )-eicosadienoic acid ( 2)from easily accessible pentane-1,5-diol ( 3) is described. Thus, compound 3 on pyranylation and oxidation gavethe aldehyde 5 which was converted to the acid 7 by Wittig reaction with a suitable phosphorane. Its depyranylationand oxidation furnished the key aldehyde 9 which upon Wittig reaction with n-heptylidene and n-nonylidenephosphoranes, respectively followed by alkaline hydrolysis afforded the title acids.Keywords : Euryspongia rosea , phospholipid fatty acids, stereoselective synthesis, (6 Z , 11 Z )-octadecadienoicacids, (6 Z , 11 Z )-eicosadienoic acids, Wittig olefination.IntroductionThe marine environment [1] constitutes an exhaustible treas-ury of organisms generating a plethora of secondarymetabolites. In this regard, sponges, the primitive multicel-lular organisms have recently been the targets [2] of lipidchemistry not only for the product fatty acids but also due totheir biosyntheses. It is now believed that a combination ofde novo biosynthesis, dietary intake, and incorporation ofmicroorganic symbionts are responsible for the genesis ofthese varied types of novel fatty acids in sponges. Besidesthe presence of very long chain fatty acids, sponges haveprovided fatty acids with unusual unsaturation patterns, sub-stitutions with oxygenated functionalities (hydroxy, methoxy,acetoxy) and methyl branching.Recently, from the marine sponge, Euryspongia rosea ,two such compounds viz. (6Z , 11Z )-octadecadienoic acid ( 1)and (6 Z , 11 Z )-eicosadienoic acid ( 2) have been isolated [3]from the phospholipid fraction. This type of ∆


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

Results and Discussion
The synthesis was based on a "building-block" approach consisting of coupling between C 5 -and C 6 -units to furnish the common intermediate 9. Subsequent addition of the appropriate C 7 -and C 9 -moieties to it gives 1 and 2 respectively after proper functionalization.The stereo-selectivities of the incipient olefins were fixed by Z-selective Wittig reactions (Scheme 1).
Commercially available, pentane-1,5-diol (3) was monopyranylated to the compound 4 which on oxidation with "buffered PCC" [9] gave the aldehyde 5. Its Z-selective Wittig olefination [10] with the known phosphor-ane generated from 6 [11] furnished compound 7.Although Wittig reactions with carboxylic acids bearing phosphoranes are reported in the literature [12], we encountered difficulty in the isolation step leading to poor yield of the Wittig product.Consequently, a modified work-up was employed (see Experimental).Acidic deprotection of 7 led to the hydroxy compound 8 with concomitant esterification.Its oxidation followed by a second Wittig reaction of the resultant aldehyde 9 with the C 7 -phosphorane, generated from 10 [13] under the above condition afforded the ester 12 with 97% isomeric purity (by capillary GLC analysis).This was converted to 1 by alkaline hydrolysis.
The (Z)-geometry of the two olefinic bonds was established by the absence of any IR band at 960-980 cm -1 .Further confirmation of this was accomplished by the 13 C NMR spectrum of 12 which exhibited signals due to the allylic carbons at δ 27.2 and 27.8 ppm, characteristic of the internal (Z)-alkenes [14,15].
Likewise, the Wittig reaction of 9 with C 9 -phos-phorane, generated from 11 [16] gave 13 with 98% isomeric purity (by capillary GLC analysis) whose exclusive (Z)-geometry was also confirmed by 13 C NMR analysis as above.Its alkaline hydrolysis afforded the acid 2. The mass spectral data of 1 and 2 were consistent with the reported values [3].

Experimental Section
All bps are uncorrected.The IR spectra were scanned with a Perkin-Elmer 783 spectrophotometer.The PMR spectra were recorded in CDCl 3 with a Bruker AC-200 (200 MHz) spectrometer.The mass spectra (70 eV) were recorded with a Shimadzu GCMS-QP 1000A spectrometer using the direct probe injection.The GLC analyses were carried out on a Shimadzu GC-16A chromatograph fitted with a flame ionization detector and a quartz capillary column (OV-17).Anhydrous reactions were carried out under Ar using freshly dried solvents.All organic extracts were dried over anhy-