Biocatalytic resolution of sterically hindered alcohols, carboxylic acids and esters containing fully substituted chiral centers by hydrolytic enzymes

Carboxyl esters bearing a fully substituted chiral center adjacent to the ester moiety, i.e., esters of tert-alcohols and of α,α-disubstituted carboxylates, are usually not accepted as substrates for hydrolytic enzymes such as esterases, proteases, and lipases. In order to circumvent this limitation, three strategies, which are reviewed in this paper, have been developed. (i) Several proteases and (still unspecified) microbial esterases are capable of hydrolysing esters of tert-alcohols and α,α-disubstituted carboxylic acids despite their steric bulkiness, but the number of these highly useful enzymes is rather limited. Alternatively, (ii) the use of ‘activated esters’ bearing electron-withdrawing groups enhances the electrophilic properties of the ester moiety (thus increasing the enzymatic reaction rate) may help to overcome slow reaction rates. On the other hand, (iii) spatial separation of the bulky quarternary carbon atom bearing the chiral center from the ester group to be hydrolysed by a spacer moiety led to modified (non-activated) substrates which were readily accepted.