Journal
JOURNAL OF MOLECULAR CATALYSIS B-ENZYMATIC
Volume 122, Issue -, Pages 275-281Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molcatb.2015.10.005
Keywords
Bacillus megaterium epoxide hydrolase; Biocatalytic resolution; Biphasic reaction; Naphthyl glycidyl ether; Chemoenzymatic synthesis; Beta-blocker; Propranolol
Funding
- National Natural Science Foundation of China [21276082, 21536004]
- Ministry of Science and Technology, PR China [2011CB710800]
- Shanghai Commission of Science and Technology [11431921600]
- DSM Research, The Netherlands [ACER 9808-0126]
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Simultaneous synthesis of the R- and S-enantiomers of biologically active propranolol, a typical p-blocker, was achieved in high optical purity via an epoxide hydrolase-catalyzed resolution of racemic alpha-naphthyl glycidyl ether (rac-1). A preparative resolution of 100 g/L rac-1 was accomplished with high enantio-selectivity (E=92) using a variant of Bacillus megaterium epoxide hydrolase (BmEHF(128T)). A biphasic system (isopropyl ether/isooctane/aqueous) was used, in which the product 3-(1'-naphthyloxy)-propane-1,2-dial (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% cc) 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 [136 g L-1 days(-1) for (S)-1 and 139 g L-1 days(-1) for (R)-2] under mild reaction conditions. It provides a new and eco-friendly route that complements other methods using organometallic catalysts. (C) 2015 Elsevier B.V. All rights reserved.
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