A highly efficient, asymmetric synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase

Duke M Fitch; Karen A Evans; Deping Chai; Kevin J Duffy

doi:10.1021/ol052371w

A highly efficient, asymmetric synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase

Org Lett. 2005 Nov 24;7(24):5521-4. doi: 10.1021/ol052371w.

Authors

Duke M Fitch¹, Karen A Evans, Deping Chai, Kevin J Duffy

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, Pennsylvania 19426-0989, USA. [email protected]

PMID: 16288546
DOI: 10.1021/ol052371w

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.

MeSH terms

Antiviral Agents / chemical synthesis*
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Benzothiadiazines / chemical synthesis*
Benzothiadiazines / chemistry
Benzothiadiazines / pharmacology*
Combinatorial Chemistry Techniques
Cyclization
Hepacivirus / drug effects*
Hepacivirus / enzymology
Molecular Structure
Pyrrolidinones / chemical synthesis*
Pyrrolidinones / chemistry
Pyrrolidinones / pharmacology*
RNA-Dependent RNA Polymerase / antagonists & inhibitors*

Substances

Antiviral Agents
Benzothiadiazines
Pyrrolidinones
tetramic acid
RNA-Dependent RNA Polymerase