Formal Total Synthesis of Cortistatin A, an Anti-angiogenic Natural Product

Abstract

The cortistatins are a family of natural products isolated from the Indonesian marine sponge Corticium simplex.1 Biological evaluations revealed that cortistatin A has potent and selective anti-angiogenic and anti-leukemic activities.1,2 Recently, the Valente group patented the didehydro derivative of cortistatin A as a potent anti-HIV agent.3 We have developed a silyl-triflate catalyzed intramolecular (4+3) cycloaddition using epoxy enolsilanes to react as the chiral dienophile.4 The use of enantiomerically enriched epoxy enolsilanes 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 A5 that efficiently intersects an intermediate in the Yamashita-Hirama strategy.6