Flavin-dependent halogenases catalyze enantioselective olefin halocyclization
Dibyendu Mondal1, Brian F Fisher1,2, Yuhua Jiang1
1Department of Chemistry, Indiana University, Bloomington, IN, 47405, USA.
Nature Communications
|June 2, 2021
Summary
Engineered flavin-dependent halogenases (FDHs) unexpectedly catalyze enantioselective halocyclization of olefins. This discovery expands biocatalytic halogenation, offering synthetic value for complex molecule synthesis.
Area of Science:
- Synthetic organic chemistry
- Biocatalysis
- Enzyme engineering
Background:
- Enantioselective halocyclization of alkenes is crucial in organic synthesis and natural product biosynthesis.
- Catalyzing simple olefins with high enantioselectivity remains a significant challenge.
- Flavin-dependent halogenases (FDHs) are known to halogenate arenes and enol(ate)s.
Purpose of the Study:
- To identify enzymes capable of catalyzing enantioselective halocyclization of simple olefins.
- To explore the potential of engineered flavin-dependent halogenases for non-native halocyclization reactions.
Main Methods:
- Engineering FDHs for site-selective aromatic halogenation.
- Characterization of engineered FDHs for halocyclization activity on olefins.
- Mitigation of HOBr release through reaction optimization and protein engineering.
- Structural analysis of mutations conferring halocyclase activity.
Main Results:
- Engineered FDHs, designed for aromatic halogenation, demonstrated catalytic activity in non-native bromolactonization of olefins.
- High enantioselectivity and near-native catalytic proficiency were achieved in the halocyclization reactions.
- Strategies to mitigate HOBr release were identified and implemented, enhancing selectivity.
Conclusions:
- FDHs can be engineered to perform enantioselective halocyclization of olefins, expanding their catalytic repertoire.
- Protein engineering and reaction optimization are key to achieving high selectivity and mitigating side reactions.
- This work paves the way for developing novel biocatalytic halogenation reactions.
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