A new route for the total synthesis of 6,7-dihydroeponemycin

A new synthesis of dihydroeponemycin (2), a peptide epoxide with potent cytotoxic and antiangiogenesis activity, has been developed. In the initial steps, Fmoc-Leu-Cl was converted into the key amino ketone intermediate 9 by Stille coupling with tributylvinyltin, conjugate addition of PhSAlMe2 to the derived enone, S-oxidation, and heat-induced syn elimination. Subsequent reaction of 9 with H2O2 and catalytic Triton B produced the corresponding epoxides as a 1:1 diastereomeric mixture in 89% yield. These epoxides were separated and individually converted into 2 and(2S)epidihydroeponemycin (24) in a four-step "one-pot" protocol (77% overall yield in both cases). ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).