A Highly Efficient, Asymmetric Synthesis of Benzothiadiazine-Substituted Tetramic Acids: Potent Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase

Abstract

[reaction: see text] An efficient two-pot, asymmetric synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available alpha-amino acids or esters, reductive amination followed by a novel one-pot amide bond formation/Dieckmann cyclization provided the desired products in high yield and optical purity. An analogous solid-phase approach to the same targets is also presented. These compounds were found to be potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.