Zhao_2026_Molecules_31_3290

alpha-Cyclopentylmandelic acid (CPMA) is a chiral alpha-hydroxycarboxylic acid valuable in pharmaceutical synthesis and asymmetric catalysis. However, it remains challenging to prepare with high optical purity due to its unique steric structure. This study established a chiral resolution strategy using derivatization-assisted lipase-catalyzed kinetic resolution to efficiently prepare optically pure CPMA. We employed acetoxyacetyl chloride derivatization to introduce a diester structure into CPMA that lipase recognizes efficiently and identified recombinant Cal B as the optimal catalyst through enzyme screening. Theoretical calculations suggested that the activity difference resulting from the derivatization strategy stems from spatial recognition rather than electronic effects; the significant difference in binding affinity between the R- and S-substrates provides the driving force for subsequent time-dependent separation. By controlling the reaction time, the (R)- and (S)-CPMA enantiomers could be selectively prepared. This achieved ee values exceeding 99.5% for both enantiomers, with isolated yields over 38% for each. Cal B was immobilized on an ESR carrier and retained good catalytic activity after 12 reuse cycles. The resulting (R)-CPMA was successfully used to synthesize sofpironium bromide, thereby validating the practical feasibility of this process. This strategy provides an effective, environmentally friendly enzymatic route to highly sterically hindered chiral alpha-hydroxycarboxylic acids.