Dynamic Kinetic Resolution of tert-Alcohols via Combination of Lipase/Brønsted Acid in Biphasic Reaction Medium

Abstract

Chemoenzymatic dynamic kinetic resolution (DKR) provides a promising green approach for synthesizing optically active alcohols and their derivatives, which serve as widely used key intermediates in the fine chemical industry. While lipase-catalyzed DKR of secondary alcohols has been extensively studied, the DKR of tertiary alcohols remains a significant challenge, even in advanced organic synthesis. This is mainly because tert-alcohols are poorly reactive to esterification owing to steric hindrance and are prone to dehydrative side reactions. In this study, the combined use of a lipase and the strong Brønsted acid H₂SO₄ enabled the efficient DKR of racemic tert-alcohols to produce the corresponding esters with high enantiomeric excess (95–99% ee) in 56–91% isolated yields. In this DKR system, lipase-catalyzed kinetic resolution in the oil phase and H₂SO₄-catalyzed racemization of the unreacted enantiomer of the alcohol in the aqueous phase proceeded concurrently in one reactor. This simultaneous use of the inherently incompatible combination of lipase and a strong Brønsted acid was realized by integrating phase separation via a hydrophobic polydimethylsiloxane membrane and a recycling flow reaction system. In addition, side reactions were completely suppressed by conducting the racemization reaction in the aqueous phase, enabling the application of this DKR methodology to a range of tert-alcohols, thus demonstrating, for the first time, a generally applicable DKR system for tert-alcohols.