Formal total synthesis of cortistatin A and J

Abstract

We have developed a silyl-triflate catalyzed intramolecular (4+3) cycloaddition using epoxy enolsilanes as precursors to the oxyallyl cation dienophile.1 The use of enantiomerically enriched epoxy enol silanes affords cycloadducts bearing multiple stereocenters and with conservation of ee, thereby efficiently providing optically enriched intermediates that could be used in total synthesis. We have used this cycloaddition as the key step to achieve the formal asymmetric synthesis of cortistatin J, a member of a family of rearranged steroids isolated from the marine sponge, Corticium simplex, which have been found to be nanomolar angiogenesis inhibitors.2 We have developed a route that efficiently intersects intermediates in the Nicolaou-Chen and the Hirama syntheses of cortistatin J.3,4