Expedient Synthesis of (−)‐Amphidinolide X

Abstract

À)-Amphidinolide X (1, Scheme 1) is one of the cytotoxic macrolides isolated by Kobayashi and co-workers from the laboratory-cultured dinoflagellates Amphidinium sp., which are symbionts of the Okinawan marine flatworms Amphiscolops sp. [1] Amphidinolide X (1) is known to possess cytotoxic activity with IC 50 values of 0.6 and 7.5 mg mL À1 against murine lymphoma L1210 and human epidermoid carcinoma KB cells, respectively, in vitro. It is the only naturally occurring macrodiolide known to date that consists of a diacid and a diol unit, and it has been a popular target for synthetic studies because of its scarcity and unique structure. [2] The most characteristic feature in the structure of 1 is the substituted 3-hydroxyoxolane structure, which is derived from a tertiary alcohol. Construction of this type of motif [3] normally utilizes the nucleophilicity of hydroxy groups, and indeed, hydroxy addition to allenes, [2a,b] epoxides, [2e,g] or olefins [2f] is a key step in the synthesis of 1. We intended to obtain the key structural element A through 5-exo cyclization of aldehydo b-alkoxyvinyl sulfoxide B (Scheme 1). It is known [4] that 5-exo cyclizations of aldehydo b-alkoxyvinyl sulfoxides derived from secondary alcohols proceed under carbinol chirality control, and cis-2,5-disubstituted oxolanes are formed regardless of the sulfoxide chirality. For (E)-and (Z)-b-alkoxyvinyl sulfoxides derived from tertiary alcohols, will the reactions proceed under sulfoxide or carbinol chirality control? Scheme 3. SmI 2 -mediated cyclization of aldehydo b-alkoxyvinyl sulfoxides. a) DMP, CH 2 Cl 2 , 08C; b) SmI 2 , MeOH, THF, 0 8C; c) m-CPBA, CH 2 Cl 2 . DMP: Dess-Martin periodinane; m-CPBA: m-chloroperoxybenzoic acid.Scheme 4. Comparison of the cyclization products from b-alkoxyvinyl sulfoxides derived from secondary (the previous study) [4] and tertiary alcohols (the present work). Bn: benzyl.Scheme 5. Transition-state structures for the reactions of 8-11. AngewandteChemie 5809