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Total synthesis of dictyostatin analogs for anticancer agents

by Jung, Won-Hyuk

Abstract (Summary)
()-Dictyostatin, isolated from a marine sponge, shows potent cancer cell antiproliferative activity by stabilizing microtubules. Following the structure proof of dictyostatin, efforts have focused on the design and synthesis of analogs on the basis of the structural similarities between dictyostatin and discodermolide. To this end, the C15 Z-alkene was introduced in dictyostatin and the C16 methyl group was removed to simplify the structure, which gave 16-normethyl-15,16-dehydrodictyostatin. The macrolactone was disconnected into three main fragments, each of which had a full carbon skeleton. The C1C9 fragment was synthesized via Brown crotylation and cross metathesis as key reactions. The C10C15 fragment was synthesized via Roush crotylation of the (S)-Roche ester and diimide reduction. The C16C26 fragment was synthesized via Evans aldol reaction of the (S)-Roche ester, syn 1,3-reduction and NozakiHiyama reaction. The C10C15 and C16C26 fragments were coupled via a Wittig reaction, and the C1C9 fragment was coupled with the lithium reagent derived from the C10C26 vinyliodide. Yamaguchi macrolactonization and global deprotection produced 16-normethyl-15,16-dehydrodictyostatin, along with C2E-, C9 isomers and an isomeric lactone. 16-Normethyl-15,16-dehydrodictyostatin showed a low nanomolar cancer cell antiproliferative activity and effectively competed with paclitaxel for binding to tubulin polymer. 6-epi-Dictyostatin showed potent cancer cell antiproliferative activity in preliminary results. Further biological evaluation of 6-epi-dictyostatin required the preparation of a large quantity. A common intermediate was made to reduce the number of reaction steps for constructing both the C11?C17 and C18C26 fragments. The C1C10? and C11?C17 fragments were coupled via a silicon-tethered ring-closing metathesis reaction. The C1C17 and C18C26 fragments were united via a HWE reaction. The Stryker and syn 1,3-reductions converted the C19 enone into the saturated alcohol regio- and diastereoselectively. A Shiina reagent used for macrolactonization suppressed the isomerization of the C2 Z-unsaturated ester. A mild grobal deprotection method was developed to complete the synthesis. As an effort to validate the routes for the large-scale synthesis, 33 mg of 6-epi-dictyostatin was synthesized.
Bibliographical Information:

Advisor:Kazunori Koide; Billy W. Day; Paul E. Floreancig; Dennis P. Curran

School:University of Pittsburgh

School Location:USA - Pennsylvania

Source Type:Master's Thesis

Keywords:chemistry

ISBN:

Date of Publication:06/13/2008

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