Lipase-mediated acylation of 3-hydroxymethylcuneane-1-carboxylic acid esters: enantioselective access to 1,3-disubstituted cuneanes

Abstract We report the first enzymatic kinetic resolution (EKR) of a 1,3-disubstituted cuneane derivative, 3-hydroxymethylcuneane-1-carboxylic acid ester. Owing to the geometric positioning of their substituents, 1,3-disubstituted cuneanes closely resemble m-substituted benzenes in spatial arrangement, making them attractive as rigid, 3-dimensional benzene bioisosteres for medicinal and materials chemistry. Using various lipases and acyl donors, we evaluated solvents, temperatures, and alcohol-derived fragments in the ester group to optimize enantioselectivity. Notably, the phenyl ester combined with Burkholderia cepacia lipase (Amano PS) and isopropenyl acetate in tert-butyl methyl ether (TBME) at 20 °C gave a high E-value (E = 16), enabling efficient kinetic resolution. At >60% conversion, the recovered alcohol having P-configuration showed excellent enantiomeric excess (>90% ee), providing a synthetically useful route to optically active 1,3-disubstituted cuneane frameworks. This study demonstrates the first successful EKR of a 1,3-disubstituted cuneane and the feasibility of stereoselective enzymatic access to this structurally unique class of polyhedral compounds.