Total synthesis of in silico designed (+)-discodermolide analogs via vinyl sulfone chemistry
Abstract
New (+)-discodermolide analogs were designed by Professor Mark A. Lipton using FEP calculations to simulate the interactions of the analogs with (+)-discodermolide biological target, β-tubulin. i-Pr Analogs at C12 and/or C20 showed higher affinity to β-tubulin compared to (+)-discodermolide. Progress in the synthesis of hyperdermolides 1.12, 1.13 and 1.14, analogs of the anti cancer agent (+)-discodermolide at C12 and C20, is described. Starting from enantiopure epoxy vinyl sulfone 1.18, whose preparation was optimized via a novel Jacobsen protocol, vinyl sulfone chemistry was employed to synthesize diastereomerically pure dipropionate units leading to (+)-discodermolide fragments and analogs. Ozonolysis of vinyl sulfones/phosphonates was also explored and provided termini differentiated C1-C7, C9-C13 and C15-C24 fragments and analogs of (+)-discodermolide. Completion of the synthesis of the desired fragments and their analogs was accomplished on a gram scale and couplings will be performed in the near future.
Degree
Ph.D.
Advisors
Fuchs, Purdue University.
Subject Area
Organic chemistry
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