Total synthesis of the cytotoxic cyclodepsipeptide (-)-doliculide: the "ester" effect in acyclic 1,3-induction of deoxypropionates.

Abstract

The total synthesis of the marine cyclodepsipeptide (-)-doliculide is described. An acyclic (2S,4S,6R)-trimethyl alkanoic acid precursor to the "hydrocarbon" portion of doliculide was synthesized starting with l-ascorbic acid based on a stereocontrolled iterative conjugate addition of lithium dimethylcuprate to acyclic delta-Cmethyl alpha,beta-unsaturated ester derivatives. syn/syn selectivity was achieved by relying on 1,3-induction in preferred folded conformations that avoid 1,5-syn-pentane interactions in the transition states. The nature of the ester moiety seems to play an important role in determining the syn/anti ratios of C-methyl adducts. The 1-methyl-1-cyclopentyl ester group was found to confer the best syn selectivity to the cuprate addition products, especially in seven-carbon enoates.