Concise Enantio- and Diastereoselective Total Syntheses of Fumagillol, RK-805, FR65814, Ovalicin, and 5-Demethylovalicin

摘要

The inhibition of angiogenesis is a promising method of treating diseases in which this process is involved, such as cancer and rheumatoid arthritis.[1] During our continuing research on angiogenesis inhibitors, we have identified and synthesized several novel compounds with such activity, including epoxyquinols A and B,[2] and azaspirene.[3] Recently, we also isolated RK-805 (3) from the fungus Neosartorya sp.[4] RK-805 is structurally similar to fumagillin (1 )[5] and TNP-470 (2),[6] a synthetic derivative of fumagillin, which are both inhibitors of angiogenesis. Ovalicin (6)[7] is another inhibitor of angiogenesis and is more stable than fumagillin and TNP-470, while 5-demethylovalicin (7)[8] was isolated recently and found to be as potent an angiogenesis inhibitor as ovalicin. While these natural products are anti-angiogenesis agents, FR65814 (5),[9] which has a similar structure, displays completely different biological activity and is an immunosuppressant.