Concise asymmetric synthesis of (S)-g-fluoroleucine ethyl ester

ORGN 112

Christian Nadeau, christian_nadeau@merck.com1, Francis Gosselin, francis_gosselin@merck.com1, Paul D. O'Shea, paul_oshea@merck.com1, and Ian W. Davies2. (1) Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Route Transcanadienne, Kirkland, QC H9H 3L1, Canada, (2) Department of Process Research, Merck Research Laboratories, PO BOX 2000, Rahway, NJ 07065
Fluorine-substituted molecules are extensively used in the preparation of biologically active agents. For example, fluorine substitution is commonly used in medicinal chemistry to increase lipophilic character and metabolic stability of drug candidates. As part of a drug development program, we were required to prepare multi-gram quantities of (S)-g-fluoroleucine ethyl ester sulfate salt. Herein we report a six-step, chromatography-free, through-process for the asymmetric synthesis of (S)-g-fluoroleucine ethyl ester sulfate salt that proceeds in 25% overall yield from inexpensive ethyl glyoxylate. This approach features a practical Ti/Zn-catalyzed glyoxylate-ene reaction - olefin hydrofluorination - amine alkylation as key steps.

 

Asymmetric Reactions and Syntheses, Metal-Mediated Reactions, Combinatorial, Parallel, and Solid-Phase Chemistry
8:00 PM-10:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Organic Chemistry

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