First and catalytic enantioselective total synthesis of 5-demethoxyfumagillol

Abstract

Inhibitors of angiogenesis are expected to be of great clinical potential in the treatment of many diseases including solid tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis and obesity.1 Recent clinical studies showed that when given in combination with chemotherapies, some antiangiogenic agents produced much better responses in cancer treatment.2 Among antiangiogenic agents, fumagillin and related naturally occurring or semisynthetic analogues 1-4 have received significant attention.3 5-Demethoxyfumagillol 5 is one of the potent angiogenesis inhibitors isolated in 2004 from Aspergillus fumigatus, and its structure was confirmed by independent synthesis from fumagillol.4 Herein we describe the first and catalytic enatioselective total synthesis of 5-demethoxyfumagillol in nine steps from simple starting materials with an overall yield of 28%, via an efficient, catalytic, regioselective and stereoselective carbonyl ene cyclization method.5