Asymmetric Redox-Neutral Radical Cyclization Catalyzed by Flavin-Dependent ‘Ene’-Reductases

<p>Flavin-dependent ‘ene’-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. While these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyze reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here we demonstrate that these enzymes can catalyze redox-neutral radical cyclizations to produce enantioenriched oxindoles from a-haloamides. This transformation is a C–C bond forming reaction currently unknown in nature and one for which there are no catalytic asymmetric examples. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the vinylogous a-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.</p>

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Cobalt-catalyzed deoxygenative triborylation of allylic ethers to access 1,1,3-triborylalkanes

Nature Communications ◽

10.1038/s41467-020-19039-7 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Wei Jie Teo ◽

Xiaoxu Yang ◽

Yeng Yeng Poon ◽

Shaozhong Ge

Keyword(s):

Building Blocks ◽

Mechanistic Studies ◽

Deuterium Labeling ◽

Bond Forming ◽

Carbon Carbon Bond ◽

Synthetic Utility ◽

Reaction Proceeds ◽

Site Selective ◽

And Control ◽

Allylic Ethers

Abstract Polyborylated organic compounds have been emerging as versatile building blocks in chemical synthesis. Here we report a selective cobalt-catalyzed deoxygenative 1,1,3-triborylation reaction of allylic ethers with pinacolborane to prepare 1,1,3-triborylalkane compounds. With naturally abundant and/or synthetic cinnamic methyl ethers as starting materials, we have achieved the synthesis of a variety of 1,1,3-triborylalkanes (25 examples). The synthetic utility of these 1,1,3-triborylalkanes is demonstrated through site-selective allylation, protodeborylation, and consecutive carbon-carbon bond-forming reactions. Mechanistic studies including deuterium-labeling and control experiments suggest that this 1,1,3-triborylation reaction proceeds through initial cobalt-catalyzed deoxygenative borylation of allylic ethers to form allylic boronates followed by cobalt-catalyzed 1,1-diborylation of the resulting allylic boronates.

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Connecting Remote C–H Bond Functionalization and Decarboxylative Coupling Using Simple Amines

10.26434/chemrxiv.9863363.v1 ◽

2019 ◽

Author(s):

Francisco de Azambuja ◽

Ming-Hsiu Yang ◽

Alexander Bruecker ◽

Paul Cheong ◽

Ryan Altman

Keyword(s):

Organic Molecules ◽

Mechanistic Studies ◽

Bond Functionalization ◽

Bond Forming ◽

Decarboxylative Coupling

The manuscript describes a Pd-catalyzed reaction of benzylic electrophiles that gives para-substituted arene products. Mechanistic studies suggest a mechanism involving a dearomative C–C bond-forming step, followed by base-mediated rearomatization. This mechanism is uncommon and underappreciated in Pd-catalysis and further exploitation of this mechanism should enable access to other organic molecules.

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Activation modes in biocatalytic radical cyclization reactions

Journal of Industrial Microbiology & Biotechnology ◽

10.1093/jimb/kuab021 ◽

2021 ◽

Author(s):

Yuxuan Ye ◽

Haigen Fu ◽

Todd K Hyster

Keyword(s):

Heme Iron ◽

Radical Cyclization ◽

Cytochrome P450 Monooxygenases ◽

Radical Cyclizations ◽

Cyclization Reactions ◽

Complex Molecules ◽

P450 Monooxygenases ◽

Non Heme Iron ◽

Essential Reactions ◽

Isopenicillin N

Abstract Radical cyclizations are essential reactions in the biosynthesis of secondary metabolites and the chemical synthesis of societally valuable molecules. In this review, we highlight the general mechanisms utilized in biocatalytic radical cyclizations. We specifically highlight cytochrome P450 monooxygenases (P450s) involved in the biosynthesis of mycocyclosin and vancomycin, non-heme iron- and α-ketoglutarate-dependent dioxygenases (Fe/αKGDs) used in the biosynthesis of kainic acid, scopolamine, and isopenicillin N, and radical S-adenosylmethionine (SAM) enzymes that facilitate the biosynthesis of oxetanocin A, menaquinone, and F420. Beyond natural mechanisms, we also examine repurposed flavin-dependent ‘ene’-reductases (ERED) for non-natural radical cyclization. Overall, these general mechanisms underscore the opportunity for enzymes to augment and enhance the synthesis of complex molecules using radical mechanisms.

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C–C bond-forming reactions of ground-state aryl halides under reductive activation

Tetrahedron ◽

10.1016/j.tet.2016.05.083 ◽

2016 ◽

Vol 72 (48) ◽

pp. 7875-7887 ◽

Cited By ~ 9

Author(s):

Katie J. Emery ◽

Tell Tuttle ◽

Alan R. Kennedy ◽

John A. Murphy

Keyword(s):

Ground State ◽

Aryl Halides ◽

Reductive Activation ◽

Bond Forming ◽

Bond Forming Reactions

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The Eschenmoser coupling reaction under continuous-flow conditions

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.7.135 ◽

2011 ◽

Vol 7 ◽

pp. 1164-1172 ◽

Cited By ~ 13

Author(s):

Sukhdeep Singh ◽

J Michael Köhler ◽

Andreas Schober ◽

G Alexander Groß

Keyword(s):

Continuous Flow ◽

Elevated Temperatures ◽

Reaction Times ◽

Coupling Reaction ◽

Flow Chemistry ◽

Flow Conditions ◽

Reaction Conditions ◽

Bond Forming ◽

Carbon Carbon Bond ◽

Reaction Proceeds

The Eschenmoser coupling is a useful carbon–carbon bond forming reaction which has been used in various different synthesis strategies. The reaction proceeds smoothly if S-alkylated ternary thioamides or thiolactames are used. In the case of S-alkylated secondary thioamides or thiolactames, the Eschenmoser coupling needs prolonged reaction times and elevated temperatures to deliver valuable yields. We have used a flow chemistry system to promote the Eschenmoser coupling under enhanced reaction conditions in order to convert the demanding precursors such as S-alkylated secondary thioamides and thiolactames in an efficient way. Under pressurized reaction conditions at about 220 °C, the desired Eschenmoser coupling products were obtained within 70 s residence time. The reaction kinetics was investigated and 15 examples of different building block combinations are given.

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DFT study of free radical scavenging activity of erodiol

Chemical Papers ◽

10.2478/s11696-013-0402-0 ◽

2013 ◽

Vol 67 (11) ◽

Cited By ~ 7

Author(s):

Zoran Marković ◽

Jelena Đorović ◽

Milan Dekić ◽

Milanka Radulović ◽

Svetlana Marković ◽

...

Keyword(s):

Electron Transfer ◽

Radical Scavenging Activity ◽

Radical Scavenging ◽

Hydrogen Atom Transfer ◽

Free Radical Scavenging ◽

Single Electron Transfer ◽

Transfer Energy ◽

Dissociation Enthalpy ◽

Proton Dissociation ◽

Transfer Mechanisms

AbstractAntioxidant activity of erodiol was examined at the M05-2X/6-311+G(d,p) level of theory in the gas and aqueous phases. The structure and energy of radicals and anions of the most stable erodiol rotamer were analyzed. To estimate antioxidant potential of erodiol, different molecular properties were examined: bond dissociation enthalpy, proton affinity together with electron transfer energy, and ionization potential followed by proton dissociation enthalpy. It was found that hydrogen atom transfer is the prevailing mechanism of erodiol behavior in gas; whereas single electron transfer followed by proton transfer and sequential proton loss electron transfer mechanisms represent the thermodynamically preferred reaction paths in water.

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Intermolecular 3+3 Ring Expansion of Aziridines to Dehydropiperidines through the Intermediacy of Aziridinium Ylides

10.26434/chemrxiv.9961937.v1 ◽

2019 ◽

Author(s):

Jennifer Schomaker ◽

Josephine Eshon ◽

Kate A. Nicastri ◽

Steven C. Schmid ◽

William T. Raskopf ◽

...

Keyword(s):

Natural Product ◽

Functional Group ◽

Ring Expansion ◽

Sigmatropic Rearrangement ◽

Reactive Intermediate ◽

Mechanistic Studies ◽

Reaction Conditions ◽

Complex Molecules ◽

Form Complex ◽

Reaction Proceeds

Bicyclic aziridines undergo formal [3+3] ring expansion reactions when exposed to rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate the reaction proceeds through the formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a concerted, asynchronous, pseudo-[1,4]- sigmatropic rearrangement to directly furnish the heterocyclic products with net retention at the new C-C bond. In combination with an asymmetric silver-catalyzed aziridination developed in our group, this method quickly delivers enantioenriched scaffolds with up to three contiguous stereocenters. The mild reaction conditions, functional group tolerance, and high stereochemical retention of this method are especially well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates in strategies to convert small, strained rings to larger N-heterocycles.

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Cu/Pd-catalyzed borocarbonylative trifunctionalization of alkynes and allenes: synthesis of β-geminal-diboryl ketones

Science China Chemistry ◽

10.1007/s11426-021-1054-4 ◽

2021 ◽

Author(s):

Yang Yuan ◽

Fu-Peng Wu ◽

Anke Spannenberg ◽

Xiao-Feng Wu

Keyword(s):

Organic Synthesis ◽

Functional Group ◽

Building Blocks ◽

Mechanistic Studies ◽

Efficient Strategy ◽

New Class ◽

Reaction Proceeds

AbstractFunctionalized bisboryl compounds have recently emerged as a new class of synthetically useful building blocks in organic synthesis. Herein, we report an efficient strategy to synthesize β-geminal-diboryl ketones enabled by a Cu/Pd-catalyzed borocarbonylative trifunctionalization of readily available alkynes and allenes. This reaction promises to be a useful method for the synthesis of functionalized β-geminal-diboryl ketones with broad functional group tolerance. Mechanistic studies suggest that the reaction proceeds through borocarbonylation/hydroboration cascade of both alkynes and allenes.

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Radical Biocatalysis: Using Non-Natural Single Electron Transfer Mechanisms to Access New Enzymatic Functions

Synlett ◽

10.1055/s-0037-1611818 ◽

2019 ◽

Vol 31 (03) ◽

pp. 248-254 ◽

Cited By ~ 4

Author(s):

Todd K. Hyster

Keyword(s):

Electron Transfer ◽

Active Sites ◽

Hydrogen Atom Transfer ◽

Single Electron ◽

Great Promise ◽

Single Electron Transfer ◽

Radical Intermediates ◽

Redox Activation ◽

Transfer Mechanisms ◽

Ground State Electron

Exploiting non-natural reaction mechanisms within native enzymes is an emerging strategy for expanding the synthetic capabilities of biocatalysts. When coupled with modern protein engineering techniques, this approach holds great promise for biocatalysis to address long-standing selectivity and reactivity challenges in chemical synthesis. Controlling the stereochemical outcome of reactions involving radical intermediates, for instance, could benefit from biocatalytic solutions because these reactions are often difficult to control by using existing small molecule catalysts. General strategies for catalyzing non-natural radical reactions within enzyme active sites are, however, undeveloped. In this account, we highlight three distinct strategies developed in our group that exploit non-natural single electron transfer mechanisms to unveil previously unknown radical biocatalytic functions. These strategies allow common oxidoreductases to be used to address the enduring synthetic challenge of asymmetric hydrogen atom transfer.1 Introduction2 Photoinduced Electron Transfer from NADPH3 Ground State Electron Transfer from Flavin Hydroquinone4 Enzymatic Redox Activation in NADPH-Dependent Oxidoreductases5 Conclusion

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