Aphidicolin synthetic studies: a stereocontrolled end game

Abstract

A highly efficient, stereocontrolled synthesis of (+)-aphidicolin 1 from the well-known degradation product, acetonide 17-nor ketone 2a, has been achieved. Key steps included palladium(0)catalysed carbonylation of the enol triflate derived from 2a and stereoselective epoxidation of the resultant α,β-unsaturated ester. Hydride reduction then furnished the C(16,17) vicinal diol moiety of 1. Similarly transformed to aphidicolin were the Corey 2,2-dimethylpropylidenedioxy synthetic intermediate 2b and the bis-tert-butyldimethylsilyl ether 2c. The latter further served as synthetic precursor to the naturally occurring derivative (+)-aphidicolin 17-acetate 26. The preparation and biological evaluation of the unnatural 16-methoxycarbonyl congeners 28 and 29 are also discussed.