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Enantioselective syntheses of the proposed structures of cytotoxic macrolides iriomoteolide-1a and -1b.

ABSTRACT: Enantioselective total syntheses of the proposed structures of macrolide cytotoxic agents iriomoteolide-1a and -1b have been accomplished. The synthesis was carried out in a convergent and stereoselective manner. However, the present work suggests that the reported structures have been assigned incorrectly. The synthesis features Julia-Kocienski olefination, Sharpless asymmetric epoxidation, Brown asymmetric crotylboration, a Sakurai reaction, an aldol reaction, and enzymatic resolution as the key steps.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC2920059 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Enantioselective syntheses of the proposed structures of cytotoxic macrolides iriomoteolide-1a and -1b.

Ghosh Arun K AK Yuan Hao H

Organic letters 20100701 14

Enantioselective total syntheses of the proposed structures of macrolide cytotoxic agents iriomoteolide-1a and -1b have been accomplished. The synthesis was carried out in a convergent and stereoselective manner. However, the present work suggests that the reported structures have been assigned incorrectly. The synthesis features Julia-Kocienski olefination, Sharpless asymmetric epoxidation, Brown asymmetric crotylboration, a Sakurai reaction, an aldol reaction, and enzymatic resolution as the k ...[more]

PMID: 20560539

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Total Syntheses of the Proposed Structure of Iriomoteolide-1a, -1b and Synthesis of Three Derivatives for Structural Studies.

Project description:Iriomoteolide-1a and iriomoteolide-1b are very potent cytotoxic agents, isolated from marine dinoflagellates. We carried out the enantioselective syntheses of the proposed structures of these natural products. However, our analysis of the NMR spectra of the synthetic iriomoteolide-1a and the natural products revealed that the structures of iriomoteolide-1a and iriomoteolide-1b were assigned incorrectly. Based upon our detailed analysis of the spectral data of the synthetic iriomoteolide-1a and the natural products, we rationally designed three diastereomers of the proposed structure of 1 in an effort to assign the correct structures. The key steps of our syntheses of the proposed structures of iriomoteolides involved a highly diastereoselective ene reaction, a carbocupration that utilized a Gilman reagent, a Julia-Kocienski olefination to couple fragments, and Yamaguchi macrolactonization to form the target macrolactone. This synthetic route was then utilized to carry out syntheses of three diastereomers to the proposed structure of 1. These diastereomeric structures show close similarities to natural iriomoteolide-1a; however, there were differences in their spectral data. While natural iriomoteolides exhibited potent cytotoxicies, our preliminary biological evaluation of synthetic iriomoteolide-1a, iriomoteolide-1b, and all three synthetic derivatives did not show any appreciable cytotoxic properties.

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