Short, Enantioselective Total Synthesis of Stephacidin A

摘要

Prenylated indole alkaloids have been a vibrant source of inspiration for synthetic chemists for over half a century.[1] Representative members of this natural product family include the spirotryprostatins,[2] brevianamides,[3] austamides,[4] and okaramines.[5] Stephacidin A and B (1 and 2, respectively in Scheme 1), recently disclosed by scientists at Bristol-Myers Squibb, signify a new peak of structural complexity within this family.[6], [7] Isolated from the fungus Aspergillus ochraceus WC76466, stephacidin B (2) represents one of the most structurally complex and novel alkaloids occurring in Nature[6] and contains 15 rings, nine stereogenic centers, and the ubiquitous 6-oxyindole substructure. Furthermore, compounds 1 and 2 exhibit potent in vitro cytotoxic activity against a variety of human tumor cell lines. The bioactivity of the stephacidins is not mediated by p53, mdr, bcl2, tubulin, or topoisomerase II, which suggests a novel mechanism of action.[6] Taken together, these facts provided a strong impetus for the design of a concise total synthesis that employs 1 en route to 2 (Scheme 1) and that proceeds through the intermediacy of avrainvillamide[7] (3) and aspergamide B (4).