63(P-41) Catalytic Enantioselective Total Synthesis of Fostriecin
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Fostriecin (1, CI-920) is a structurally interesting novel metabolite of Streptomyces pulveraceus that was first isolated in 1983 by a research group at Warner Lambert-Parke Davis. It displays antitumor activity against a broad range of cancerous cell lines in vitro that is suggested to be intimately related to the potent and highly selective inhibitory activity against serine/threonine phosphatase PP2A. Therefore, fostriecin is a novel lead compound for anticancer drugs, as well as an important biological tool. We report herein our formal total synthesis of fostriecin 1. Common intermediates (2 and 24) were synthesized using a unique method that combines four catalytic asymmetric reactions. First, we constructed the chiral tertiary alcohol at C-8 with 85% ee through the catalytic enantioselective cyanosilylation of ketone 9, using titanium-based Lewis acid-Lewis base bifunctinal asymmetric catalyst 14. This reaction could be performed in a 50-g scale. After converting to 17, enantiomerically pure compound was obtained through recrystallization. The second chiral center at the α,β-unsaturated latone was constructed through H. Yamamoto's AgF-(R)-tol-BINAP catalyzed asymmetric allylation of aldehyde 8 (d.r.=28:1). The third chiral center at C-9 was next constructed through the novel direct catalytic asymmetric aldol reaction with aldehyde 6, using acetylene ketone 7 as a donor and Lewis acid-Bronsted base bifunctinal complex (S)-LLB as an asymmetric catalyst (d.r.=3.6:1). Finally, the fourth chiral center was constructed through Noyori reduction (d.r.=>97:3). Combined these four catalytic asymmetric reactions, we achieved the formal catalytic asymmetric synthesis of fostriecin. This methodology may have advantages for synthesizing stereoisomers of fostriecin.
