Abstract
Halocyclization of alkenes is a powerful bond-forming tool in synthetic organic chemistry and a key step in natural product biosynthesis, but catalyzing halocyclization with high enantioselectivity remains a challenging task. Identifying suitable enzymes that catalyze enantioselective halocyclization of simple olefins would therefore have significant synthetic value. Flavin-dependent halogenases (FDHs) catalyze halogenation of arene and enol(ate) substrates. Herein, we reveal that FDHs engineered to catalyze site-selective aromatic halogenation also catalyze non-native bromolactonization of olefins with high enantioselectivity and near-native catalytic proficiency. Highly selective halocyclization is achieved by characterizing and mitigating the release of HOBr from the FDH active site using a combination of reaction optimization and protein engineering. The structural origins of improvements imparted by mutations responsible for the emergence of halocyclase activity are discussed. This expansion of FDH catalytic activity presages the development of a wide range of biocatalytic halogenation reactions.
Highlights
Halocyclization of alkenes is a powerful bond-forming tool in synthetic organic chemistry and a key step in natural product biosynthesis, but catalyzing halocyclization with high enantioselectivity remains a challenging task
Because many other oxidative halogenation reactions are initiated by similar electrophilic halogen species[13], we wondered whether Flavin-dependent halogenases (FDHs) might possess reactivity beyond aromatic halogenation, including enantioselective olefin halocyclization[14]
We show that FDHs can catalyze enantioselective halocyclization of simple olefins and establish how active site mutations and mitigation of hypohalous acid release from the FDH active site lead to the high enantioselectivities observed
Summary
Halocyclization of alkenes is a powerful bond-forming tool in synthetic organic chemistry and a key step in natural product biosynthesis, but catalyzing halocyclization with high enantioselectivity remains a challenging task. Analysis of FDH activity on 1 using crude enzyme extract (see supporting information) led to the identification of 50 variants that provided significant yields of bromolactonization product 1a (Supplementary Fig. 1).
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