Friday, April 6, 2012

Semisynthetic Terpenoid Antifungal Agents from Scynexis and Merck

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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