Medicinal chemists at Scynexis, Inc. and Merck have developed semisynthetic antifungal derivatives of the triterpenoid glycoside natural product enfumafungin (1) that exhibit oral efficacy in a murine model of disseminated candidiasis. Glucan synthase inhibitors 2 and 3 were prepared in 12 to 13 linear steps from 1. The critical transformation in this sequence is a chemoselective allylic oxidation of the congested C12 position of enfumafungin's carbocyclic framework. It was found that a C18 alpha-disposed primary carboxamide was required to facilitate the catalytic palladium(II)-mediated Corey-Yu allylic oxidation protocol. The optimized kilogram-scale procedure that was recently disclosed by process chemists from Merck Research Laboratories is illustrated above. The bulky oxidant cumene hydroperoxide was deployed in order to promote oxidation of a radical intermediate from the concave alpha-face. A related oxidation of the steroidal C12 position has been discussed here previously in the context of the partial synthesis of the hedgehog antagonist cyclopamine. Given that I have participated in a portion of this research, I will not comment further here on the enfumafungin medicinal chemistry program, except to say that it has culminated in the selection of a candidate for clinical development and that this unique antifungal agent (MK-3118) is the first orally active glucan synthase inhibitor.
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