Discovery through total synthesis: a retrospective on the himastatin problem.

Abstract

A total synthesis of a structure proposed for himastatin was accomplished. The non-identity of the fully synthetic material with himastatin necessitated a revision of the assigned structure. Confirmation of the revised stereostructure was subsequently confirmed through total synthesis. Among the achievements during this effort were i) stereospecific routes to both anti-cis and syn-cis pyrrolindoline substructures; ii) a practical synthesis to 5-hydroxypiperazic acid in enantiomerically pure form; iii) a Stille coupling leading to a complex bi-indole moiety, and iv) efficient protecting group management throughout the evolving depsipeptide domain. The outlines for a biological pharmacophore have been delineated. The alternating D- and L-substituents in the 6-mer as well as the biaryl linkage connecting the two identical subunits are critical for maintaining biological activity. This pattern is simulated in another antibiotic, and suggests a possible structural trend for future SAR investigations.

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@article{Kamenecka2001DiscoveryTT, title={Discovery through total synthesis: a retrospective on the himastatin problem.}, author={Theodore M. Kamenecka and Samuel J Danishefsky}, journal={Chemistry}, year={2001}, volume={7 1}, pages={41-63} }