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Synthesis 2010(23): 4015-4020  
DOI: 10.1055/s-0030-1258276
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Reductive Condensation between β-Keto Esters and Aldehydes: Preparation of Novel Carbon-Linked Dihydropyrone Inhibitors of Hepatitis C Virus Polymerase

Maria Angelica Linton*, Javier Gonzalez, Hui Li, John Tatlock, Tanya Jewell, Sarah Johnson, Matt Drowns, Leena Patel, Julie Blazel, Martha Ornelas
Pfizer Global Research & Development, 10770 Science Center Drive, San Diego, CA 92121, USA
Fax: +1(858)6788156; e-Mail: angelica.linton@pfizer.com;
Further Information

Publication History

Received 9 July 2010
Publication Date:
30 September 2010 (online)

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Abstract

The route for the preparation of carbon-linked pyrone libraries involving an optimized one-step reductive condensation between active methylene compounds and aldehydes is described. The initial synthesis of these analogues utilizing conventional alkylation methods proved to be unsuitable for singleton or library application. The chemistry was not only low-yielding but presented serious purification challenges. The optimized route reported herein utilizes a Lewis base-borane complex that acts in situ first as a catalyst for the condensation, then as a mild reducing agent to cleanly yield the desired product in a one-pot reaction.

Key words

Knoevenagel condensation - C-C bond formation - HCV polymerase inhibitor - dihydropyrone - amine-borane reagents

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Gonzalez, J.; Tatlock J.; Linton, A.; Li, H.; Dragovich P.; Jewell, T.; Prins, T.; Zhou, R.; Blazel, J.; Ornelas, M.; Truesdale, L.; Moore, M.; Rahavendran, S. V.; Parge, H.; Love, R.; Hickey, M.; Doan, C.; Shi, S.; Duggal, R.; Lewis, C.; Borchardt, A.; Thomson, J.; Wriggers, H.; Fuhrman, S. ; Document in preparation.

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