Diastereoselective preparation of substituted α-amino-(1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetates as inhibitors of HCV NS5B polymerase

ORGN 604

Matthew G. LaPorte, mlaporte@tetralogicpharma.com1, Tandy L. Draper1, Lori E. Miller2, Christopher J. Burns1, Srinivas K. Chunduru3, Dorothy C. Young2, and Stephen M. Condon, scondon@tetralogicpharma.com1. (1) Department of Medicinal Chemistry, ViroPharma Inc, 397 Eagleview Boulevard, Exton, PA 19341, (2) ViroPharma Inc, Exton, PA 19341, (3) Department of Biology, ViroPharma Inc, 397 Eagleview Boulevard, Exton, PA 19341
The pyranoindole-based inhibitor of the HCV NS5B RNA-dependent RNA polymerase, HCV-371, binds to an allosteric site located on the thumb domain of the enzyme. In order to further explore the pyranoindole binding site, we designed a synthetic route that would allow for substitution from the α-position of the (1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetate core template. Using rac-2, the (R*,R)-isomer (3) was formed in a 2:1 ratio indicating that the stereochemistry at the C1 position of the pyranoindole can be controlled by adjacent substitution. Subsequent oxidation and manipulation of the α-amino side chain afforded analogs with modest HCV NS5B inhibition.

 

New Reactions and Methodology, Heterocycles and Aromatics, Bioorganic Chemistry
8:00 PM-10:00 PM, Tuesday, 12 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Organic Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006