Ketoreductase-Mediated Stereodivergent Synthesis of 1,1-Disubstituted Cyclobutan-3-ols

Selective access to both cis- and trans-isomers of α-substituted 3-hydroxycyclobutane-1-carboxylic esters has been demonstrated using ketoreductase (KRED) enzymes. Two stereocomplementary KREDs were identified from a commercial panel that are highly selective for small α-substituents when the ester group was para-methoxybenzyl. Probing the substrate scope of these two enzymes revealed that the selectivity declined rapidly with both when increasing the steric bulk of the α-substituent. For methyl ester substrates with larger α-substituents, a different pair of KREDs was identified with excellent selectivity for both the cis- and trans-isomers for a small range of substrates. The cyclobutanol products serve as precursors to other synthetically useful building blocks such as amino acids.