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

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

References

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1

World Health Organization (WHO) Hepatitis C Fact Sheet No. 164: http://www.who.int/mediacentre/factsheets/fs164/en/ July 9, 2009.

5

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.

15

Amine borane bulletin, Callery Chemical Company: http://www.scribd.com/doc/30133102/Boron%E2%80%93Nitrogen-Compounds-Organic.