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Tag Archives: Biocatalysis
Savile, Janey, Mundorff, Moore, Tam, Jarvis, Colbeck, Krebber, Fleitz, Brands, Devine, Huisman, and Hughes. Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture. Science, 2010, 329, 305-309. DOI: 10.1126/science.1188934.
Here’s a short follow-up on this previous post, which covered a biocatalytic reaction developed by Codexis to make the key intermediate in the synthesis of Merck’s drug montelukast (aka Singulair). The 2010 Presidential Green Chemistry Awards were just announced, and the award for “Greener Reaction Conditions” went to Merck and Codexis for developing an enantioselective biocatalyst for the synthesis of sitagliptin, Merck’s blockbuster anti-diabetes drug (aka Januvia). This work is also the subject of a recently-published Science paper from Merck and Codexis.
The paper describes the development of an enzyme-catalyzed replacement for the final reaction in the synthesis of sitagliptin, in which a ketone functionality is converted into an amine. (more…)
Liang, Lalonde, Borup, Mitchell, Mundorff, Trinh, Kochrekar, Cherat, Pai. Development of a Biocatalytic Process as an Alternative to the (−)-DIP-Cl-Mediated Asymmetric Reduction of a Key Intermediate of Montelukast. Org. Process Res. Dev. 2010, 14, 193-198. DOI: 10.1021/op900272d
This article from researchers at Codexis describes the development of a biocatalytic (i.e. enzyme-catalyzed) method for creating the lone stereocenter in the synthesis of montelukast sodium, aka Merck’s asthma drug Singulair. The original Merck process route includes an enantioselective ketone reduction using a boron reagent derived from alpha-pinene called (-)-DIP-Cl. The reaction works well: high yield, high enantioselectivity (although still requiring a recrystallization step to upgrade from ~95% to 99% ee), and (-)-DIP-Cl is made in one step from cheap starting materials. The downside is that at least 1.5 equivalents of (-)-DIP-Cl must be used, and the reagent is moisture sensitive and corrosive. Codexis, being in the enzyme business, decided to find an enzyme that would catalyze this same reaction. (more…)