Pyrrolidine-5, 5-trans-lactams. 1. Synthesis and incorporation into inhibitors of hepatitis C virus NS3/4A protease

DM Andrews, SJ Carey, H Chaignot, BA Coomber…

Index: Andrews, David M; Carey, Seb J; Chaignot, Helene; Coomber, Barry A; Gray, Norman M; Hind, S Lucy; Jones, Paul S; Mills, Gail; Robinson; Slater, Martin J Organic letters, 2002 , vol. 4, # 25 p. 4475 - 4478

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Citation Number: 27

Abstract

In this, the first of two letters, we outline the use of the pyrrolidine-5, 5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (eg, 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has ak obs/I of 400 M-1 s-1 and ...