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

Abstract

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.