Total synthesis of TMC-95A and -B via a new reaction leading to Z-enamides. Some preliminary findings as to SAR.

Songnian Lin, Zhi-Qiang Yang, Benjamin H B Kwok, Michael Koldobskiy, Craig M Crews, Samuel J Danishefsky

Index: J. Am. Chem. Soc. 126 , 6347, (2004)

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Abstract

A full account of the total syntheses of proteasome inhibitors TMC-95A and -B is provided. A key feature of the syntheses involved installation of a cis-propenylamide moiety by a thermal rearrangement of an alpha-silylallyl amide. The scope and mechanism of the enamide-forming reaction are discussed. Also provided are some preliminary results from SAR studies. It was found that simplified analogues can retain the full potency of proteasome inhibition.