Highly Stereoselective Synthesis of the Chiral Fungicide’s Intermediate ( R )- N -(2,6-Dimethylphenyl) Aminopropionic Acid Methyl Ester via an Esterase-Lipase Cascade

Résumé fourni par la source

( R )- N -(2,6-dimethylphenyl) aminopropionic acid methyl ester (( R )-DMPM) is a key chiral intermediate for the fungicide N -(2,6-Dimethylphenyl)- N -(methoxyacetyl)-alanine methyl ester (( R )-Metalaxyl). The biological function of the ( R )-Metalaxyl is heavily dependent on its R -configuration, however, conventional chemical or single-esterase esterification for ( R )-DMPM production induces severe racemization, dramatically compromising the optical purity and the efficacy of ( R )-metalaxyl. In this study, a novel dual-enzyme cascade immobilized on polystyrene resin, combining the esterase PAE from Pseudochrobactrum asaccharolyticum WZZ003 for stereoselective hydrolysis of the substate (R,S) -(DMPM) to produce (S) -DMPM and (R)- MAP-acid, and the Novozym 435 for transmethylation of (R)- MAP-acid to produce (R) -DMPM, was applied. After a systematic optimization of dual-enzyme catalysis, the highest optical purity of (R) -DMPM ever reported with an e.e. p of 99.1% and an E value of 900 was obtained under the 49.2% conversion of (R,S) -DMPM and 96.2% of esterification yield conditions. The results overcome the limitations of racemization and provides a green, high-yield route for the industrial production of ( R )-DMPM.

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