ORGN 157 |
| Practical routes for the enantioselective synthesis of 1,5-diaryl pyrazole acids, selective cholecystokinin 1 (CCK1) receptor antagonists, have been developed. A feature common to two routes is an efficient, regioselective construction of the pyrazole nucleus by reacting an aryl hydrazine with a disubstituted acetylenic ketone. In our first synthetic route, the desired stereochemistry was obtained by utilizing SFC to separate our racemic acid. In our second generation route involving 4 steps, the desired S-enantiomer was obtained in high optical purity (>92% ee) by a kinetic resolution using enzyme-catalyzed hydrolysis of the racemic ester. In our third synthetic route involving 6 steps, the desired stereochemistry at the chiral center was generated at an early stage by an enantioselective enol-protonation strategy using inexpensive (S)-(-)-ethyl lactate. All three methods furnished optically pure (>99% ee) final product as its crystalline sodium salt.
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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 |