Mechanoenzymology in the Kinetic Resolution of β-Blockers: Propranolol as a Case Study

Abstract

Recent advances in biotechnology, protein engineering, and enzymatic immobilization have made it possible to carry out biocatalytic transformations through alternative non-conventional activation strategies. In particular, mechanoenzymology (i.e., the use of the mechanical force produced by milling or grinding to activate a biotransformation) has become a new area in so-called "green chemistry", reshaping key fundaments of biocatalysis and leading to the exploration of enzymatic transformations under more sustainable conditions. Significantly, numerous chiral active pharmaceutical ingredients have been synthesized via mechanoenzymatic methods, boosting the use of biocatalysis in the synthesis of chiral drugs. In this regard and aiming to widen the scope of the young field of mechanoenzymology, a dual kinetic resolution of propranolol precursors was explored. The biocatalytic methodology mediated by Candida antarctica Lipase B (CALB) and activated by mechanical force allowed the isolation of both enantiomeric precursors of propranolol with high enantiomeric excess (up to 99% ee), complete conversion (c = 50%), and excellent enantiodifferentiation (E > 300). Moreover, the enantiomerically pure products were used to synthesize both enantiomers of the β-blocker propranolol with high enantiopurity.

Figure 1

Selected β-blockers sold commercially as racemic mixtures.

Figure 2

Mirror images of propranolol enantiomers.

Scheme 1. Dual Mechanoenzymatic Kinetic Resolution via (a) Enantioselective Esterification and (b) Enantioselective Hydrolysis

Figure 3

Results of the evaluation of the milling-jar material. SS: stainless steel milling jar. iPrA = isopropenyl acetate.

Figure 4

Enzyme kinetics for the mechanoenzymatic resolution of rac-1 by enantioselective esterification. (a) Agate milling jar and balls were used. (b) Teflon milling jar and ball were used. (c) Stainless steel milling jar and ball were used.

Scheme 2. Mechanoenzymatic Resolution of rac-2 via Enantioselective Hydrolysis

Scheme 3. Synthetic Strategy for the Mechanosynthesis of Both Enantiomers of Propranolol