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Enantioselective Synthesis of α-Methyl Carboxylic Acids from Readily Available Starting Materials via Chemoenzymatic Dynamic Kinetic Resolution

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journal contribution
posted on 15.10.2010, 00:00 by Lisa K. Thalén, Anna Sumic, Krisztián Bogár, Jakob Norinder, Andreas K. Å. Persson, Jan-E. Bäckvall
An enantioselective method for the synthesis of α-methyl carboxylic acids starting from trans-cinnamaldehyde, a readily available and inexpensive compound, has been developed. Allylic alcohol 1 was obtained via a standard Grignard addition to trans-cinnamaldehyde. Dynamic kinetic resolution was applied to allylic alcohol 1 utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion of stereochemistry. Subsequent C−C double bond cleavage afforded pharmaceutically important α-methyl substituted carboxylic acids in high ee and overall yields of up to 76%.