Synthetic Study of Sarcophytol A, an Anticarcinogenic Cembranoid

Abstract

The first total synthesis of sarcophytol A, an anticarcinogenic marine cembranoid, was achieved in a highly stereo- and enantioselective manner starting with (E, E)-farnesol; it includes: 1) a newly developed Z-selective (Z: E=>35: 1) Horner-Emmons reaction using a phosphonate nitrile, 2) a modified cyanohydrin macrocyclization, and 3) an enantioselective (93% ee) reduction of macrocyclic ketone as its key steps. Enantiomerically pure sarcophytol A was obtained by a single recrystallization. An improved synthetic process appropriate for a large-scale preparation using geraniol as the starting material was also developed. It included a new ketal Claisen rearrangement using 2, 2-dimethoxy-2, 3-dimethylbutan-2-ol for α-ketol isoprene elongation, which was applied to sequences for highly stereoselective (E>99%) synthesis of trisubstituted γ, δ-unsaturated aldehydes and acids. Enantiomers of macrocyclic ethers, (2 Z, 4 E) and (2 E, 4 Z), were obtained from a product of the ketal Claisen rearrangement via baker's yeast reduction. [2, 3]-Wittig rearrangement of these compounds afforded enantiomers of both sarcophytol A and T with high enantioselectivity (91-98% ee) in high yields. Surprisingly, almost perfect reverse chirality transfer was observed between these geometrical isomers, i.e. (R)-ether gave (S)-alcohol in (2 Z, 4 E) isomer, while (R)-alcohol in (2 E, 4 Z) isomer. © 1995, The Society of Synthetic Organic Chemistry, Japan. All rights reserved.