Enantioselective Construction of the Oxidized Tryptophan Fragment of TMC-95A and TMC-95B

TMC-95A-D are four cyclic peptides containing L-tyrosine, L-asparagine, highly oxidized L-tryptophan, (Z)-1-propenylmine and 3-methyl-2-oxo-pentanoic acid units. These compounds were recently isolated from the fermentation broth of Apiospora montagnei Sacc.TC 1093,isolated from a soil sample. Biological studies indicated that these natural products, especially TMC-95A, exhibit potent inhibiting activity towards proteasome (IC₅₀=5.4 nM). In this report, a stereocontrolled synthesis of the oxidized tryptophan fragment of TMC-95A and TMC-95B is described. Key steps include the condensation of the lithiated oxindole with D-Gamer aldehyde and subsequent dihydroxylatioa of the carbon-carbon double bond.