A synthesis-enabled relative configurational assignment of the C31–C46 region of hemicalide

Abstract

With 21 unknown stereocentres embedded in spatially separated stereoclusters, the cytotoxic polyketide hemicalide represents a seemingly intractible structural assignment problem. Herein, through the targeted synthesis of configurationally defined fragments, as well as “encoded” mixtures of diastereomers, the stereochemical elucidation of the C31–C46 region of hemicalide is achieved. Detailed NMR spectroscopic analysis of candidate fragments and comparison with the related hemicalide data strongly supported a 31,32-syn, 32,36-anti and 42,46-anti relationship. In combination with previous work on hemicalide, this reduces the number of possible structural permutations down to a more manageable eight diastereomers.