Enantioselective Bromolactonization of Trisubstituted Olefinic Acids Catalyzed by Chiral Pyridyl Phosphoramides

Nishikawa, Yumiko; Hamamoto, Yuhta; Satoh, Rika; Akada, Naho; Kajita, Shuhei; Nomoto, Marina; Miyata, Megumi; Nakamura, Madoka; Matsubara, Chinatsu; Hara, Osamu

doi:10.1002/chem.201804630

Cited by 23 publications

(14 citation statements)

References 65 publications

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“…and 88:12 e.r., for the major and minor diastereomers, respectively, Supplementary Fig. 4), comparing favorably to the only report of a small molecule catalyst for this reaction 32 . While preliminary evaluation of chlorolactonization of 1 using a subset of the enzymes ultimately screened for bromolactonization revealed no hits, subsequent analysis of 4V + S revealed that it catalyzes chlorolactonization of 1 to give 1c in 32% yield and 89:11 e.r.…”

Section: Resultssupporting

confidence: 72%

Flavin-dependent halogenases catalyze enantioselective olefin halocyclization

et al. 2021

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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.

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Section: Resultssupporting

confidence: 72%

Flavin-dependent halogenases catalyze enantioselective olefin halocyclization

et al. 2021

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“…and 88:12 e.r., for the major and minor diastereomers, respectively, Fig. S4), comparing favorably to the only report of a small molecule catalyst for this reaction 32 .…”

Section: Textsupporting

confidence: 75%

Flavin-Dependent Halogenases Catalyze Enantioselective Olefin Halocyclization

Mondal¹,

Fisher²,

Jiang³

et al. 2020

Preprint

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<div><div><div><p>Catalytic enantioselective halocyclization of alkenes is a powerful bond forming tool in synthetic organic chemistry and a key step in the biosynthesis of several natural products. To date, however, no examples of enantioselective halocyclization of simple achiral olefins catalyzed by enzymes have been reported. Herein, we report that flavin-dependent halogenases (FDHs) previously engineered to catalyze site-selective aromatic halogenation can also catalyze bromolactonization of olefins with high enantioselectivity and near-native catalytic proficiency. Analysis of the selectivity of FDH variants along the lineage for the most selective enzymes reveals mutations responsible for the emergence of halocyclase activity, and docking simulations provide insight into the origins of improvements imparted by these mutations. High selectivity was achieved by characterizing and mitigating the release of HOBr from FDH variants using a combination of protein engineering and reaction optimization. Given the range of different halocyclization reactions and other organic transformations that proceed via oxidative halogenation, this expansion of FDH catalytic activity bodes well for the development of a wide range of biocatalytic halogenation reactions.</p></div></div></div>

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“…These methods are efficient and scalable, providing a modular means of assembling δ-aryl olefinic acids, which are versatile building blocks for synthesizing drugs and other biologically active compounds (Fig. 1c) 53–57 .…”

Section: Introductionmentioning

confidence: 99%

Nickel-catalyzed intermolecular oxidative Heck arylation driven by transfer hydrogenation

Kang

Zhou

et al. 2019

Nat Commun

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The conventional oxidative Heck reaction between aryl boronic acids and alkenes typically involved the PdII/Pd0/PdII catalytic cycle incorporating an external oxidant and often suffered C=C bond isomerization for internal alkyl-substituted alkenes via chain-walking. Herein, we demonstrate that the regioselectivity (γ-selectivity vs. δ-selectivity) and pathway selectivity (hydroarylation vs. oxidative Heck coupling) of a directed Ni-catalyzed alkene arylation can be controlled by judicious tuning of the coordination environment around the nickel catalyst via optimization of an appropriate phosphine ligand and directing group. In this way, the Ni(0)-catalyzed oxidative Heck arylation that relies on transfer hydrogenation of an acceptor olefin is developed with excellent E/Z selectivity and regioselectivity. Mechanistic investigations suggest that the addition of the acceptor is crucial for lowering the energy for carbometalation and for enabling catalytic turnover.

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Enantioselective Bromolactonization of Trisubstituted Olefinic Acids Catalyzed by Chiral Pyridyl Phosphoramides

Cited by 23 publications

References 65 publications

Flavin-dependent halogenases catalyze enantioselective olefin halocyclization

Flavin-dependent halogenases catalyze enantioselective olefin halocyclization

Flavin-Dependent Halogenases Catalyze Enantioselective Olefin Halocyclization

Nickel-catalyzed intermolecular oxidative Heck arylation driven by transfer hydrogenation

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