Dimethyldioxirane → (E)-9,10-dehydroepothilone B

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We considered whether the incorporation of C9-C10 olefin in epothilone B (51, EpoB) would alter its biological profile in the same direction as was the case with its 12,13 desoxy counterparts. Toward this end, we studied the epoxidation of 28 with 2,2′-dimethydroxirane (DMDO). The reaction indeed proceeded with high chemoselectively at the more substituted C12-C13 olefin. There was obtained an 87% yield of a 1:2.6 ratio of the (E)-9,10-dehydroepothilone B (49) and its diastereomer bearing the α-12,13-oxirane (structure not shown). In vitro studies with 49 (whose configurations at C12 and C13 was established by its reduction to afford Epo B) revealed it to be roughly 2-4 fold more potent than the parent EpoB (51) in various cell lines. While compound 49 proved to be the most potent epothilone we encountered in our program, its narrow therapeutic index in xenografts, as well as its difficult accessibility (vide supra) served to discourage further its pre-clinical development. Interestingly, the unnatural α-oxirane was virtually devoid of activity.

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