Chemoenzymatic synthesis of (R)- and (S)-propranolol using an engineered epoxide hydrolase with a high turnover number

Abstract

Simultaneous synthesis of the R- and S-enantiomers of biologically active propranolol, a typical β-blocker, was achieved in high optical purity via an epoxide hydrolase-catalyzed resolution of racemic α-naphthyl glycidyl ether (rac-1). A preparative resolution of 100g/L rac-1 was accomplished with high enantioselectivity (E=92) using a variant of Bacillus megaterium epoxide hydrolase (BmEHF128T). A biphasic system (isopropyl ether/isooctane/aqueous) was used, in which the product 3-(1⿲-naphthyloxy)-propane-1,2-diol (2) precipitated instantly, facilitating its separation and increasing the enantiopurity of (R)-2 (>99.5% ee). This enzymatic resolution had a total turnover number of 70,000, affording enantiopure epoxide (S)-1 (>99% ee) and 1,2-diol (R)-2 (>99% ee) in 45.3% and 42.4% yields, respectively. (R)-2 and (S)-1 were subsequently converted to (R)- and (S)-propranolol (3) (>99% ee) in overall yields of 31.4% and 44.8%. To the best of our knowledge, this is the best case for enzymatic resolution of rac-1 using an epoxide hydrolase, giving high space-time yields [136gL⿿1days⿿1 for (S)-1 and 139gL⿿1days⿿1 for (R)-2] under mild reaction conditions. It provides a new and eco-friendly route that complements other methods using organometallic catalysts.