Trapp_2021_Mol.Catal_509_111578

Enantiomerically pure alpha-substituted beta-hydroxyesters are important chiral building blocks for ligands, auxiliaries and beta-lactam antibiotics. A two-step chemo-enzymatic procedure using lipase as biocatalyst is an efficient way to synthesize such products. To date, the methods described are limited to molecules that do not contain a chiral center adjacent to the racemic carbinol, and furthermore, they are limited to acylation. Here, we investigated the deracemization of diastereomerically pure syn- and anti-alpha-substituted beta-hydroxyesters containing two stereo centers, using experimental methods under neat conditions and classical molecule dynamics (MD) simulation. A screening of free and immobilized commercial lipases identified immobilized lipase B from Candida antarctica (Novozyme 435) as the most appropriate biocatalyst for sterically demanding alpha-substituted beta-hydroxyesters. Using Novozyme 435, reaction conditions were optimized and hydroxyesters (3S) or (3R) were achieved with enantiomeric excesses up to <=99% ee and maximum overall yields of 80%. The absolute configuration of the enantiomers was eventually determined by 1H-NMR spectroscopy after derivatization with Mosher's reagent (alpha-methoxy-alpha-trifluoromethylphenylacetic acid = MTPA).