Photoenzymatic Generation of Unstabilized Alkyl Radicals: An Asymmetric Reductive Cyclization

Clayman, Phillip D.; Hyster, Todd K.

doi:10.1021/jacs.0c07918

Cited by 100 publications

(84 citation statements)

References 46 publications

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“…Hyster's group reported an asymmetric reductive cyclization through photoenzymatic generation of unstabilized alkyl radicals from alkyl iodide precursors (Scheme 58). [183] In this case, combining flavin with substrate firstly forms a CT complex 293 within the protein active site, which was supported by UV/vis spectra. Photoexcitation of the CT complex 293 produces the nucleophilic radical 294 , which further undergoes a radical cyclization to afford the intermediate 295 .…”

Section: Photoinduced Radical Cascade Cyclizations Promoted By Eda Complexesmentioning

confidence: 78%

Progress in Photoinduced Radical Reactions using Electron Donor‐Acceptor Complexes

et al. 2021

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Photocatalyzed organic synthesis transformation is a remarkable green synthetic strategy because of the advantages of operational simplicity, high chemoselectivities, cheap, and environmental benignancy, along with the extensive applications in the fields of organic, pharmaceutical and functional material chemistry. Generally, photoredox catalysts or photosensitizers are necessary for the generation of their excited states to perform the successive oxidative or reductive reactions through the single electron transfer (SET) or energy transfer (ET) process. Furthermore, the exploration of a colored electron donor-acceptor (EDA) complex or a charge transfer (CT) complex between an electron-rich and an electron-poor substrate provides the chance to deliver the excited intermediate under the irradiation of light, resulting in the formation of radical activate species through a single electron transfer to induce successive various radical reactions. These reactions were performed without the need of any external photocatalysts under mild reaction conditions. Herein, this review focuses on the recent progress on photoinduced radical addition reactions, radical borylations, reductive reactions, radical-radical cross-coupling reactions, degradation reactions and radical cascade cyclization via EDA complexes. We highlight these novel green synthetic methodologies and applications, as well as the mechanisms. This review will help to provide references for organic and medicinal chemists who are charmed by these green organic photochemical transformations based on EDA complexes.

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Section: Photoinduced Radical Cascade Cyclizations Promoted By Eda Complexesmentioning

confidence: 78%

Progress in Photoinduced Radical Reactions using Electron Donor‐Acceptor Complexes

et al. 2021

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“… [18] Upon SET oxidation‐mediated ring‐opening, the resulting non‐stabilized primary radical could be effectively intercepted with high stereocontrol to afford products 6 g and 6 h . This result is particularly relevant since the stereocontrolled interception of highly reactive primary alkyl radicals is a difficult goal, for which few asymmetric catalytic strategies are available [19] . Finally, the alkenoic acid 5 i , which generates a tertiary radical upon SET oxidation‐mediated anti‐Markovnikov lactonization, [20] afforded product 6 i (Figure 3 e).…”

Section: Resultsmentioning

confidence: 99%

A General Organocatalytic System for Enantioselective Radical Conjugate Additions to Enals

Saux

Bonilla

et al. 2021

Angewandte Chemie

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Herein, we report ag eneral iminium ion-based catalytic method for the enantioselective conjugate addition of carbon-centered radicals to aliphatic and aromatic enals.T he process uses an organic photoredox catalyst, whicha bsorbs blue light to generate radicals from stable precursors,i n combination with ac hiral amine catalyst, which secures ac onsistently high level of stereoselectivity.T he generality of this catalytic platform is demonstrated by the stereoselective interception of aw ide variety of radicals,i ncluding nonstabilized primary ones whichare generally difficult to engage in asymmetric processes.T he system also served to develop organocatalytic cascade reactions that combine an iminiumion-based radical trap with an enamine-mediated step,affording stereochemically dense chiral products in one-step.

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“…Overall, our study showcases how non-natural reactivities of native EREDs can be exploited, which also can be further enhanced by protein engineering, if needed, to expand the biocatalyst toolbox and address the long-standing selectivity challenge in radical chemistry. We foresee EREDs and other flavin-dependent enzymes can be further leveraged to generate new synthetically applicable reactivities; this is particularly true as other fields, such as photocatalysis, [20][21][22][35][36][37] are increasingly merging with biocatalysis. 38,39…”

Section: Discussionmentioning

confidence: 99%

Ground-State Electron Transfer as an Initiation Mechanism for Asymmetric Hydroalkylations in Radical Biocatalysis

Fu¹,

Lam²,

Emmanuel³

et al. 2021

Preprint

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Stereoselective bond-forming reactions are essential tools in modern organic synthesis. However, catalytic strategies for controlling the stereochemical outcome of radical-mediated C–C bond formation remain underdeveloped. Here, we report an ‘ene’-reductase catalyzed asymmetric hydroalkylation of olefins using α-bromoketones as radical precursors. In these reactions, radical initiation occurs via ground-state electron transfer from the flavin cofactor located within the enzyme active site, representing a mechanistic departure from previous photoenzymatic hydroalkylations. Four rounds of site saturation mutagenesis based on wild-type nicotinamide-dependent cyclohexanone reductase (NCR) were deployed to access a variant capable of catalyzing a cyclization to furnish β-chiral cyclopentanones with high levels of enantioselectivity. Additionally, the wild-type NCR was identified that could catalyze the intermolecular coupling with precise stereochemical control over the radical termination step. This report demonstrates this enzyme family’s catalytic versatility and highlights the opportunity for protein engineering to address reactivity and selectivity challenges in radical biocatalysis.

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Photoenzymatic Generation of Unstabilized Alkyl Radicals: An Asymmetric Reductive Cyclization

Cited by 100 publications

References 46 publications

Progress in Photoinduced Radical Reactions using Electron Donor‐Acceptor Complexes

Progress in Photoinduced Radical Reactions using Electron Donor‐Acceptor Complexes

A General Organocatalytic System for Enantioselective Radical Conjugate Additions to Enals

Ground-State Electron Transfer as an Initiation Mechanism for Asymmetric Hydroalkylations in Radical Biocatalysis

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