Enzymatic desymmetrization glutarate

Skrobo, B. Deska, 1. Oxonium ylide rearrangement of enzymatically desymmetrized glutarates. Org. Lett. 2013, 15, 5998-6001. 

Biocatalysis plays a central role in the manufacturing of statin side chains (Figure 6.2). A first set of approaches exploits enzymatic desymmetrization reactions, for example, of the methoxyacetyl ester of glutaric acid diethyl ester with commercially available a-chymotrypsin as explored by Ciba SC with a yield of 94% and enantiomeric excess of up to 98% [1]. In the optimized procedure, the substrate was available in a concentration of 1 M at an enzyme/substrate ratio of 7% (wt/wt), and the reaction took approximately a day. The subsequent steps to the final acetonide also involved a pig-liver esterase (PLE) catalyzed selective hydrolysis of the methoxyacetyl group (Figure 6.2a). 

NK1/NK2 dual antagonists enzymatic desymmetrization of diethyl 3-[3, 4 -dichlorophenyl] glutarate. 

Scheme 14. Synthesis of (-)-paroxetine using an asymmetric desymmetrization of a glutaric ester via enzymatic hydrolysis.

The known desymmetrization of prochiral 3-substituted glutarates via enzymatic hydrolysis [65] has been optimized by chemists at Ciba Speciality Chemicals for the synthesis on a large scale [66]. The a-chymotrypsin-catalyzed process is characterized by a high substrate concentration of 285 g L and an isolated yield of 94% product with an ee of 98.2% (route C). 

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