Journal
CHEMICAL SCIENCE
Volume 12, Issue 18, Pages 6307-6314Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1sc00317h
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Funding
- National Natural Science Foundation of China [21778060, 21977104]
- Qingdao Innovative Leading Talent Project [18-1-2-9-zhc]
- QIBEBT [I201901, Y872361901]
- Director Innovation Fund of Key Laboratory of Biofuels, Chinese Academy of Sciences [Y872131901]
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The study demonstrates the efficient H2O2-dependent (R)-enantioselective epoxidation of unfunctionalized styrene and its derivatives by site-mutated variants of a unique non-natural P450BM3 peroxygenase in combination with a dual-functional small molecule. The synergistic use of protein engineering and an exogenous DFSM represents an effective strategy to control the enantioselectivity of styrene epoxidation, significantly expanding the chemical scope of P450 enzymes as useful bio-oxidative catalysts.
Unlike the excellent (S)-enantioselective epoxidation of styrene performed by natural styrene monooxygenases (ee > 99%), the (R)-enantioselective epoxidation of styrene has not yet achieved a comparable efficiency using natural or engineered oxidative enzymes. This report describes the H2O2-dependent (R)-enantioselective epoxidation of unfunctionalized styrene and its derivatives by site-mutated variants of a unique non-natural P450BM3 peroxygenase, working in tandem with a dual-functional small molecule (DFSM). The observed (R)-enantiomeric excess (ee) of styrene epoxidation is up to 99% with a turnover number (TON) of 918 by the best enantioselective mutant F87A/T268I/L181Q, while the best active mutant F87A/T268I/V78A/A184L (with 98% ee) gave a catalytic TON of 4350, representing the best activity of a P450 peroxygenase towards styrene epoxidation to date. Following this approach, a set of styrene derivatives, such as o-, m-, p-chlorostyrenes and fluorostyrenes, could also be epoxidized with modest to very good TONs (362-3480) and high (R)-enantioselectivities (95-99% ee). The semi-preparative scale synthesis of (R)-styrene oxide performed at 0 degrees C with high conversion, maintaining enantioselectivity, and moderate isolated yields, further suggests the potential application of the current P450 enzymatic system in styrene epoxidation. This study indicates that the synergistic use of protein engineering and an exogenous DFSM constitutes an efficient strategy to control the enantioselectivity of styrene epoxidation, thus substantially expanding the chemical scope of P450 enzymes as useful bio-oxidative catalysts.
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