Stereoselective Total Synthesis of iso-Cladospolide B

Abstract

A simple and efficient stereoselective total synthesis of iso-cladospolide B and a formal total synthesis of cladospolide B, using Jacobsen's hydrolytic kinetic resolution, is described.Marine fungi are emerging as a potential source of new pharmaceuticals and pharmaceutical leads. 1 Recently, isocladospolide B (1), obtained from the fermentation of fungal isolate I962S215, was also isolated from ethyl acetate extracts of cladosporium species and from red sea sponge Niphates rowi. 2 It closely resembles the natural product cladospolide B (2), a highly phytotoxic compound 3 produced from Cladosporium tenuissimum. Though there have been two earlier synthesis reported for iso-cladospolide B, 4 there is still need for a simple, short and efficient synthetic route for further biological studies. Our group has recently initiated an academic programme focused on the synthesis of several lactone-containing natural products 5 and their analogues for further evaluation of their biological properties. As part of this programme, herein we report the stereoselective total synthesis of isocladospolide B and the formal total synthesis of cladospolide B, with Jacobsen's kinetic resolution and a modified Wadsworth-Emmons reaction being the key steps.Our retrosynthetic analysis for both iso-cladospolide B and cladospolide B (Figure 1) revealed a common key intermediate 3, which could be prepared by a Wittig reaction of the ylide generated from intermediate 4 and aldehyde 5. The intermediate 4 could be prepared from the chiral epoxide obtained from resolution of the racemic epoxide 6.The synthesis of intermediate 4 started with commercially available 5-hexen-1-ol (Scheme 1). Accordingly, 5-hexen-1-ol was protected as its benzyl ether 7 with sodium hydride and benzyl bromide, then epoxidized with mchloroperoxybenzoic acid (MCPBA) to give the racemic oxirane 6. The oxirane 6 was hydrolyzed employing (S,S)-Salen-Co-(OAc) catalyst 6 to give the chiral epoxide 8. The epoxide was reduced with lithium aluminum hydride to generate the secondary alcohol 9, which was then protected as its tert-butyldiphenylsilyl ether 10. Debenzylation of 10 with carbon-supported palladium afforded alcohol 11. The alcohol was coupled with mercaptobenzothiazole under Mitsunobu conditions 7 to afford the thioether 12 which, on oxidation with MCPBA, resulted in sulphone 13. Unfortunately, attempts at reacting 13 with the known aldehyde 5 under Julia conditions 8a failed to give the expected alkene 16 (Scheme 2). 8b We therefore converted the alcohol 11 into the corresponding phosphorane salt 15, with the intention of using this as one of the components in a Wittig reaction with 5. The conversion of 11 to 15 was accomplished using I 2 , triphenylphosphine and imidazole, 9 followed by treatment of the resulting iodide 14 with triphenyl phosphine.The other key fragment, aldehyde 5, was prepared from L-(+)-diethyltartaric acid according to a known procedure. 10 The Wittig salt 15 was treated with n-butyllithium and reacted with aldehyde 5 to afford 16a, which w...

Alkyne‐Mediated Approach for Total Syntheses of Cladospolides A, B, C and iso‐Cladospolide B

“…The specific rotations observed for 2 {[ α ] D 20 = +21.2 ( c = 0.6, MeOH); ref 1d. [ α ] D 22 = +26.9 ( c = 0.4, MeOH)} and 3 {[ α ] D 20 = –98.0 ( c = 0.70, MeOH); ref 3,7a–7c. [ α ] D = –90.0 ( c = 0.23, MeOH)} were comparable with the reported values.…”

“…The residue was purified by flash chromatography (hexanes/EtOAc) on silica gel to give iso ‐cladospolide B ( 3 , 34 mg, 89 %). [ α ] D 20 = –98.0 ( c = 0.7, MeOH); ref 3,7a–7c. [ α ] D = –90.0 ( c = 0.23, MeOH).…”

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