Lipase–V‐MPS Co‐Catalyzed Dynamic Kinetic Resolution of Tertiary Alcohols: Process Intensification Through Catalyst Compartmentalization

Chemoenzymatic dynamic kinetic resolution (DKR) of racemic alcohols represents a straightforward and sustainable strategy for synthesizing enantiomerically pure alcohols and their derivatives, which serve as important synthetic intermediates in the fine chemical industry, yet its application to tert ‐alcohols remains challenging due to steric hindrance of the alcohols and inefficient racemization methods. This study presents significant advancement in the chemoenzymatic DKR of tert ‐alcohols by a compartmentalization strategy using a polydimethylsiloxane (PDMS) thimble, which physically separates involved two reactions, i.e., the lipase‐catalyzed enantioselective esterification and racemization, in a single flask. Using commercially available immobilized lipase A from Candida antarctica (CAL‐A) and our original, vanadium‐based racemization catalyst V‐MPS4, we thoroughly optimized the reaction conditions and found that the use of excess Na 2 CO 3 and prewashing of CAL‐A were effective in ensuring a high stability of V‐MPS4. With additional adjustments of some factors, such as the amount of V‐MPS4, applying our protocol led to the synthesis of enantiomerically enriched esters with up to 99% enantiomeric excess (ee) from seven tert ‐alcohols, in 52%–62% isolated yields in 48 h. These results demonstrate significant improvements in reaction time, catalyst stability, substrate scope, and reaction procedure, highlighting the practical utility of compartmentalized chemoenzymatic DKR for challenging tert ‐alcohol substrates.