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Development of an Efficient, Scalable, Aldolase-Catalyzed Process for Enantioselective Synthesis of Statin Intermediates
William A. Greenberg, Alexander Varvak, Sarah R. Hanson, Kelvin Wong, Hongjun Huang, Pei Chen, Mark J. Burk and Barry M. Trost
Proceedings of the National Academy of Sciences of the United States of America
Vol. 101, No. 16 (Apr. 20, 2004), pp. 5788-5793
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3371914
Page Count: 6
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A process is reported for efficient, enantioselective production of key intermediates for the common chiral side chain of statin-type cholesterol-lowering drugs such as Lipitor (atorvastatin) and Crestor (rosuvastatin). The process features a one-pot tandem aldol reaction catalyzed by a deoxyribose-5-phosphate aldolase (DERA) to form a 6-carbon intermediate with installation of two stereogenic centers from 2-carbon starting materials. An improvement of almost 400-fold in volumetric productivity relative to the published enzymatic reaction conditions has been achieved, resulting in a commercially attractive process that has been run on up to a 100-g scale in a single batch at a rate of 30.6 g/liter per h. Catalyst load has been improved by 10-fold as well, from 20 to 2.0 wt % DERA. These improvements were achieved by a combination of discovery from environmental DNA of DERAs with improved activity and reaction optimization to overcome substrate inhibition. The two stereogenic centers are set by DERA with enantiomeric excess at >99.9% and diastereomeric excess at 96.6%. In addition, downstream chemical steps have been developed to convert the enzymatic product efficiently to versatile intermediates applicable to preparation of atorvastatin and rosuvastatin.
Proceedings of the National Academy of Sciences of the United States of America © 2004 National Academy of Sciences