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

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.

Automated summary

By targeted synthesis of fragments and detailed NMR spectroscopic analysis, the stereochemical elucidation of a portion of the cytotoxic polyketide hemicalide is achieved, reducing the number of possible structural permutations to eight diastereomers.