Zwitterionic Acridinium Amidate: A Nitrogen-Centered Radical Catalyst for Photoinduced Direct Hydrogen Atom Transfer.

The development of small organic molecules that can convert light energy into chemical energy to directly promote molecular transformation is of fundamental importance in chemical science. Herein, we report a zwitterionic acridinium amidate as a catalyst for the direct functionalization of aliphatic C-H bonds. This organic zwitterion absorbs visible light to generate the corresponding amidyl radical in the form of excited-state triplet diradical with prominent reactivity for hydrogen atom transfer to facilitate C-H alkylation with a high turnover number.

Catalytic 1,1-Cyanoalkylation of Electron-Deficient Olefins.

A catalytic 1,1-dicarbofunctionalization of electron-deficient olefins was effected on the basis of the three-component coupling reactions involving olefins bearing vicinal electron-withdrawing groups, potassium cyanide, and an alkyl halide, which afforded geminally cyanoalkylated products in high yields via conjugate cyanation, 1,2-proton transfer, and enolate alkylation. The use of suitable chiral phase-transfer catalysts enabled asymmetric induction in this transformation.

Zwitterionic Diphenylphosphinyl Amidate as a Powerful Photoinduced Hydrogen-Atom-Transfer Catalyst for C-H Alkylation of Simple Alkanes.

The chemical and physical properties of amides change substantially when the electron-withdrawing groups attached to the nitrogen are varied. Herein, we report the superior performance of -diphenylphosphinyl 1,2,3-triazolium amidate as a photoinduced hydrogen-atom transfer catalyst compared to its -benzoyl analog. A binary catalyst system of the phosphinyl amidate and an Ir-based photocatalyst enables the alkylation of unbiased C-H bonds.

Hydrogen-Atom Transfer Catalysis for C-H Alkylation of Benzylic Fluorides.

A photoinduced catalytic C(sp)-H alkylation of benzylic fluorides is developed. The use of zwitterionic 1,2,3-triazolium amidate as a hydrogen-atom transfer catalyst is uniquely effective for promoting this transformation. The combination of C-H alkylation with subsequent displacement of the C-F bond enables 1,1-difunctionalization of benzylic fluorides, providing rapid access to an array of functionalized molecular entities.

In Silico Analysis and Synthesis of Nafamostat Derivatives and Evaluation of Their Anti-SARS-CoV-2 Activity.

Inhibition of transmembrane serine protease 2 (TMPRSS2) is expected to block the spike protein-mediated fusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nafamostat, a potent TMPRSS2 inhibitor as well as a candidate for anti-SARS-CoV-2 drug, possesses the same acyl substructure as camostat, but is known to have a greater antiviral effect. A unique aspect of the molecular binding of nafamostat has been recently reported to be the formation of a covalent bond between its acyl substructure and Ser441 in TMPRSS2.

Catalytic Asymmetric Cyanoalkylation of Electron-Deficient Olefins with Potassium Cyanide and Alkyl Halides.

The stereoselective cyanoalkylation of electron-deficient olefins with potassium cyanide and alkyl halides was developed based on the utilization of modular chiral 1,2,3-triazolium salts featuring a hydrogen bond-donor ability as catalysts. The reaction involving multiple carbon-carbon bond formations proceeds via the enantioselective conjugate addition of a cyanide ion and the consecutive catalyst-controlled diastereoselective alkylation of intermediary chiral triazolium enolates. Control experiments revealed that the use of a properly tuned chiral triazolium ion as a catalyst and the presence of the cyano functionality in the intermediary enolate are of crucial importance for achieving high levels of acyclic absolute and relative stereocontrol.

Exploiting Transient Radical Cations as Brønsted Acids for Allylic C-H Heteroarylation of Enol Silyl Ethers.

Intermediary radical cations, generated through single-electron oxidation of enol silyl ethers by excited Ir-based photocatalysts, can be exploited as Brønsted acids for the activation of heteroarylcyanides. This strategy enables the direct allylic C-H heteroarylation of enol silyl ethers under visible-light irradiation.

Mannich-type allylic C-H functionalization of enol silyl ethers under photoredox-thiol hybrid catalysis.

The synergy of an Ir-based photosensitizer with mild oxidizing ability and a thiol catalyst enables efficient allylic C-H functionalization of enol silyl ethers with imines under visible light irradiation. Subsequent transformations of the aminoalkylated enol silyl ethers allow for the facile construction of unique molecular frameworks such as functionalized octahydroisoindol-4-one.

Cationic Organic Catalysts or Ligands in Concert with Metal Catalysts.

Cooperative dual catalysis and bifunctional catalysis have emerged as reliable strategies for the development of hitherto difficult asymmetric transformations because they could deliver new reactivity and selectivity, and allow for the employment of substrates not amenable to reaction systems relying on a single, monofunctional catalysts. Furthermore, these modes of catalysis often improve yields and stereoselectivities via the precise recognition and simultaneous activation of nucleophiles and electrophiles. Efforts towards utilizing chiral cationic organic catalysts for asymmetric cooperative catalysis with metal complexes have provided a unique platform to address the challenging issues associated with reaction development.

Direct allylic C-H alkylation of enol silyl ethers enabled by photoredox-Brønsted base hybrid catalysis.

Strategies for altering the reaction pathway of reactive intermediates are of significant importance in diversifying organic synthesis. Enol silyl ethers, versatile enolate equivalents, are known to undergo one-electron oxidation to generate the radical cations that spontaneously form electrophilic α-carbonyl radicals via elimination of the silyl groups. Here, we demonstrate that close scrutiny of the property of the radical cations as strong C-H acids enables the identification of a catalyst system consisting of an iridium-based photosensitizer and 2,4,6-collidine for the generation of nucleophilic allylic radicals from enol silyl ethers through one-electron oxidation-deprotonation sequence under light irradiation without the desilylation of the radical cation intermediates.

Diastereo- and enantioselective phase-transfer alkylation of 3-substituted oxindoles with racemic secondary alkyl halides.

A catalytic asymmetric alkylation of fully substituted enolates with racemic, non-activated secondary alkyl halides is described. The chiral 1,2,3-triazolium ion enables excellent diastereo- and enantiocontrol via enantiofacial discrimination of prochiral enolates and kinetic resolution of secondary halides.

Determination of the absolute configuration of compounds bearing chiral quaternary carbon centers using the crystalline sponge method.

Determination of the absolute configuration of chiral tetra-substituted carbon centers is one of the most taxing steps in the enantioselective construction of this structural motif in asymmetric synthesis. Here, we demonstrate that the crystalline sponge method provides an effective way to crystallographically determine the absolute configuration of organic compounds bearing chiral quaternary carbons (including tetra-substituted ones) that are synthesized by recently developed enantioselective catalytic reactions.

Ligand-controlled E/Z selectivity and enantioselectivity in palladium-catalyzed allylation of benzofuranones with 1,2-disubstituted allylic carbonates.

The first highly E- and enantioselective allylic alkylation of prochiral carbon nucleophiles with 1,2-disubstituted allylic carbonates is reported. The key to the successful development of this protocol is the ability of modular ion-paired chiral ligands to simultaneously control the E/Z selectivity and enantioselectivity.

Ligand-enabled multiple absolute stereocontrol in metal-catalysed cycloaddition for construction of contiguous all-carbon quaternary stereocentres.

The development of a general catalytic method for the direct and stereoselective construction of contiguous all-carbon quaternary stereocentres remains a formidable challenge in chemical synthesis. Here, we report a highly enantio- and diastereoselective [3+2] annulation reaction of 5-vinyloxazolidinones and activated trisubstituted alkenes catalysed by a palladium complex bearing a newly devised phosphine ligand with a chiral ammonium salt component, which enables the single-step construction of three contiguous stereocentres, including vicinal all-carbon quaternary stereocentres, in a five-membered heterocyclic framework. This stereoselective cycloaddition protocol relies on the remarkable ability of the chiral ligand to rigorously control the absolute stereochemistry of each chiral centre associated with the multiple bond-forming events, and provides a reliable catalytic process for the asymmetric synthesis of densely functionalized pyrrolidines.

Asymmetric substitution at the tetrasubstituted chiral carbon: catalytic ring-opening alkylation of racemic 2,2-disubstituted aziridines with 3-substituted oxindoles.

A highly diastereo- and enantioselective ring-opening alkylation of racemic 2,2-disubstituted aziridines with 3-substituted oxindoles is achieved under the catalysis of a chiral 1,2,3-triazolium salt. This reaction represents a hitherto unknown, catalytic stereoselective carbon-carbon bond formation through direct substitution at the tetrasubstituted chiral carbon.

Exploiting the modularity of ion-paired chiral ligands for palladium-catalyzed enantioselective allylation of benzofuran-2(3H)-ones.

A highly enantioselective allylation of benzofuran-2(3H)-ones is achieved under Pd catalysis by taking full advantage of the structural modularity of ion-paired chiral ligands.

Catalytic asymmetric Mannich-type reactions of α-cyano α-sulfonyl carbanions.

An efficient asymmetric Mannich-type reaction of α-cyano α-sulfonyl carbanions has been achieved by exploiting the structural modularity and anion-recognition ability of chiral 1,2,3-triazolium ions. This protocol has proven to be applicable to a variety of N-Boc imines and cyanosulfones, affording β-amino α-cyanosulfones in excellent yields with high stereoselectivities.

Ion-paired chiral ligands for asymmetric palladium catalysis.

Conventional chiral ligands rely on the use of a covalently constructed, single chiral molecule embedded with coordinative functional groups. Here, we report a new strategy for the design of a chiral ligand for asymmetric transition-metal catalysis; our approach is based on the development of an achiral cationic ammonium-phosphine hybrid ligand paired with a chiral binaphtholate anion. This ion-paired chiral ligand imparts a remarkable stereocontrolling ability to its palladium complex, which catalyses a highly enantioselective allylic alkylation of α-nitrocarboxylates.

Catalytic asymmetric ring openings of meso and terminal aziridines with halides mediated by chiral 1,2,3-triazolium silicates.

Catalytic asymmetric chloride and bromide ring openings of meso aziridines with trimethylsilyl halides have been developed using modular chiral 1,2,3-triazolium chlorides as catalysts. Control experiments suggest the reaction pathway involving hypervalent silicate ions as reactive intermediates. The application of this system to the efficient kinetic resolution of terminal aziridines is also reported.

Chiral 1,2,3-triazoliums as new cationic organic catalysts with anion-recognition ability: application to asymmetric alkylation of oxindoles.

Chiral 1,2,3-triazoliums have been designed, and the rational structural modification based on their unique anion-binding abilities has led to the establishment of the highly enantioselective alkylation of 3-substituted oxindoles.

An "anti-Baldwin" 3-exo-dig cyclization: preparation of vinylidene cyclopropanes from electron-poor alkenes.

Stabilized carbanions undergo an uncommon 3-exodig cyclization onto propargyl halides through an SN2' substitution. Propargyl iodides as electrophiles are necessary to achieve good yields (36-95%) for most substrates, although the usefulness of chlorides and bromides is documented. A variety of monocyclic and bicyclic vinylidene cyclopropanes can be prepared.

Practical stereoselective synthesis of beta-branched alpha-amino acids through efficient kinetic resolution in the phase-transfer-catalyzed asymmetric alkylations.

Phase-transfer-catalyzed alkylation of glycinate Schiff base with racemic secondary alkyl halides proceeded with excellent levels of syn- and enantioselectivities under the influence of chiral quaternary ammonium bromide 1d and 18-crown-6. The alkylation product can be selectively converted to the corresponding anti isomer, allowing the preparation of all the stereoisomers of beta-alkyl-alpha-amino acid derivatives, an extremely valuable chiral building block.