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1. Asymmetric Photocatalysis Enabled by Chiral Organocatalysts

   https://doi.org/10.1002/cctc.202101292  

   Yao, Wang; Bazan‐Bergamino, Emmanuel_A; Ngai, Ming‐Yu (November 2021, ChemCatChem)

   Abstract Visible‐light photocatalysis has advanced as a versatile tool in organic synthesis. However, attaining precise stereocontrol in photocatalytic reactions has been a longstanding challenge due to undesired photochemical background reactions and the involvement of highly reactive radicals or radical ion intermediates generated under photocatalytic conditions. To address this problem and expand the synthetic utility of photocatalytic reactions, a number of innovative strategies, including mono‐ and dual‐catalytic approaches, have recently emerged. Of these, exploiting chiral organocatalysis, such as enamine catalysis, iminium‐ion catalysis, Brønsted acid/base catalysis, andN‐heterocyclic carbene catalysis, to induce chirality transfer of photocatalytic reactions has been widely explored. This Review aims to provide a current, comprehensive overview of asymmetric photocatalytic reactions enabled by chiral organocatalysts published through June 2021. The substrate scope, advantages, limitations, and proposed reaction mechanisms of each reaction are discussed. This review should serve as a reference for the development of visible‐light‐induced asymmetric photocatalysis and promote the improvement of the chemical reactivity and stereoselectivity of these reactions. 

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2. Organocatalytic enantioselective dearomatization of thiophenes by 1,10-conjugate addition of indole imine methides

   https://doi.org/10.1038/s41467-021-25165-7  

   Li, Xingguang; Duan, Meng; Yu, Peiyuan; Houk, K. N.; Sun, Jianwei (December 2021, Nature Communications)

   Abstract Catalytic asymmetric dearomatization (CADA) is a powerful tool for the rapid construction of diverse chiral cyclic molecules from cheap and easily available arenes. This work reports an organocatalytic enantioselective dearomatization of substituted thiophenes in the context of a rare remote asymmetric 1,10-conjugate addition. By suitable stabilization of the thiophenyl carbocation with an indole motif in the form of indole imine methide, excellent remote chemo-, regio-, and stereocontrol in the nucleophilic addition can be achieved with chiral phosphoric acid catalysis under mild conditions. This protocol can be successfully extended to the asymmetric dearomatization of other heteroarenes including selenophenes and furans. Control experiments and DFT calculations demonstrate a possible pathway in which hydrogen bonding plays an important role in selectivity control. 

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3. Stereoselective amino acid synthesis by synergistic photoredox-pyridoxal radical biocatalysis

   https://doi.org/10.1126/science.adg2420  

   Cheng, Lei; Li, Dian; Mai, Binh Khanh; Bo, Zhiyu; Cheng, Lida; Liu, Peng; Yang, Yang (July 2023, Science)

   Developing synthetically useful enzymatic reactions that are not known in biochemistry and organic chemistry is an important challenge in biocatalysis. Through the synergistic merger of photoredox catalysis and pyridoxal 5′-phosphate (PLP) biocatalysis, we developed a pyridoxal radical biocatalysis approach to prepare valuable noncanonical amino acids, including those bearing a stereochemical dyad or triad, without the need for protecting groups. Using engineered PLP enzymes, either enantiomeric product could be produced in a biocatalyst-controlled fashion. Synergistic photoredox-pyridoxal radical biocatalysis represents a powerful platform with which to discover previously unknown catalytic reactions and to tame radical intermediates for asymmetric catalysis. 

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4. Dearomative Access to (−)-Thebaine and Derivatives

   https://doi.org/10.1021/acs.orglett.3c03270  

   Tolchin, Zachary A; Dukes, Dallas M; Gharbaoui, Leanna M; Smith, Joel M (December 2023, Organic Letters)

   A synthesis of the natural product thebaine is reported in eight steps from commercially available starting materials, hinging on the dearomatization and coupling of simple aromatic starting materials. This provides divergent access to two unnatural opioid derivatives and is aimed at the long-term development of synthetic opioid analogs of the “wonderdrug” Naloxone. Additionally, a formal enantioselective synthesis of all reported targets is disclosed that leverages a catalytic asymmetric dearomatization via anion-pairing catalysis. 

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5. Enantioselective decarboxylative alkylation using synergistic photoenzymatic catalysis

   https://doi.org/10.1038/s41929-023-01065-5  

   Sun, Shang-Zheng; Nicholls, Bryce T.; Bain, David; Qiao, Tianzhang; Page, Claire G.; Musser, Andrew J.; Hyster, Todd K. (January 2024, Nature Catalysis)

   Photoenzymatic catalysts are attractive for stereoselective radical reactions because the transformation occurs within tunable enzyme active sites. When using flavoproteins for non-natural photoenzymatic reactions, reductive mechanisms are often used for radical initiation. Oxidative mechanisms for radical formation would enable abundant functional groups, such as amines and carboxylic acids, to serve as radical precursors. However, excited state flavin is short-lived in many proteins because of rapid quenching by the protein scaffold. Here we report that adding an exogenous Ru(bpy)3 2+ cofactor to flavin-dependent ‘ene’-reductases enables the redox-neutral decarboxylative coupling of amino acids with vinylpyridines with high yield and enantioselectivity. Additionally, stereo-complementary enzymes are found to provide access to both enantiomers of the product. Mechanistic studies indicate that Ru(bpy)3 2+ binds to the protein, helping to localize radical formation to the enzyme’s active site. This work expands the types of transformation that can be rendered asymmetric using photoenzymatic catalysis and provides an intriguing mechanism of radical initiation. 

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