Visible-Light-Driven C-H Imidation of Arenes and Heteroarenes by a Phosphonium Ylide Organophotoredox Catalyst: Application to C-H Functionalization of Alkenes.

Phosphonium ylide catalysis through an oxidative quenching cycle has been developed for visible-light-driven C-H imidation of arenes and heteroarenes. The present protocol could be applied not only to trihalomethylative lactonization reactions involving trifluoromethyl, trichloromethyl, and tribromomethyl radicals but also to the first example of an organophotoredox-catalyzed imidative lactonization reaction involving a nitrogen-centered electrophilic radical species.

Base-mediated synthesis of cyclic dithiocarbamates from 1-amino-3-chloropropan-2-ol derivatives and carbon disulfide.

An efficient method for the preparation of six-membered cyclic dithiocarbamates is described, in which triethylamine effectively promotes the reaction of 1-amino-3-chloropropan-2-ol derivatives with carbon disulfide. On the basis of the experimental and theoretical studies, a reaction mechanism is proposed to explain the difference between the present reaction and our previously reported carbon dioxide fixation.

Enantioselective Protonation of Cyclic Carbonyl Ylides by Chiral Lewis Acid Assisted Alcohols.

Chiral Lewis acid-catalyzed asymmetric alcohol addition reactions to cyclic carbonyl ylides generated from N-(α-diazocarbonyl)-2-oxazolidinones featuring a dual catalytic system are reported. Construction of a chiral quaternary heteroatom-substituted carbon center was accomplished in which the unique heterobicycles were obtained in good yields with high stereoselection. The alcohol adducts were successfully converted to optically active oxazolidine-2,4-diones by hydrolysis. Mechanistic studies by DFT calculations revealed that alcohols could be activated by Lewis acids, enabling enantioselective protonation of the carbonyl ylides.

A Phosphonium Ylide as a Ligand for [3 + 2] Coupling Reactions of Epoxides with Heterocumulenes under Mild Conditions.

The potential of carbonyl-stabilized phosphonium ylides as ligands for novel catalysis was explored. We found that the combination of phosphonium ylides and metal halide salts efficiently catalyzed the reaction of epoxides with carbon dioxide under mild conditions. Five-membered cyclic carbonates, including disubstituted cyclic carbonates, were obtained in good yields with the use of 1 atm of carbon dioxide at 35 °C. Terminal epoxides could be converted to N-aryl oxazolidinones in the reaction with isocyanates under a similar catalytic system.

Methoxy Groups Increase Reactivity of Bifunctional Tetraarylphosphonium Salt Catalysts for Carbon Dioxide Fixation: A Mechanistic Study.

The development of carbon dioxide fixation under mild conditions is a central theme in organic synthesis. Despite the tremendous progress in the field of organocatalysis in the past two decades, the coupling reactions of epoxides with carbon dioxide that proceed at atmospheric pressure at temperatures of less than 100 °C have remained challenging. In our aspirational studies of tetraarylphosphonium salts (TAPS) catalysis, we report here the bifunctional TAPS-catalyzed synthesis of five-membered cyclic carbonates by chemical fixation using 1 atm of carbon dioxide at 60 °C. Intriguing substituent effects of TAPS were observed, in which electron-donating groups enhanced their reactivity. In addition, the mechanism was thoroughly investigated by undertaking both experimental and theoretical studies, suggesting that the electronic properties of TAPS affect carbon dioxide insertion into halohydrin intermediates. The results provided fruitful information to understand the origin of the TAPS behavior, which would contribute to the design of novel catalysts for carbon dioxide capture.

Use of trichloroacetonitrile as a hydrogen chloride generator for ring-opening reactions of aziridines.

Regioselective ring-opening reactions of 2-aryl-N-tosylaziridines are described, in which hydrogen chloride is generated by photodegradation of trichloroacetonitrile. HCl adducts are obtained in high yields in 1,4-dioxane, whereas methanol adducts are predominantly obtained in methanol. Trichloroacetonitrile can serve as a photoresponsive molecular storage generator for hydrogen chloride.

Amine-Urea-Mediated Asymmetric Cycloadditions between Nitrile Oxides and o-Hydroxystyrenes by Dual Activation.

The first example of asymmetric 1,3-dipolar cycloadditions between nitrile oxides and o-hydroxystyrenes, mediated by cinchona-alkaloid-based amine-ureas is reported. The method is based on a dual activation involving both LUMO and HOMO activations. In addition to the stoichiometric asymmetric induction, a catalytic amount of amine-urea enables the cycloadditions to proceed in an enantioselective manner. Computational studies strongly support the HOMO activation of o-hydroxystyrenes and LUMO activation of nitrile oxides by hydrogen-bonding interactions with the Brønsted acid/base bifunctional catalyst.

Chiral Lewis Acid-Catalyzed Enantioselective Cycloadditions between Indoles and Cyclic Carbonyl Ylides Derived from Diazodiketone or Diazoketoester Derivatives.

Asymmetric 1,3-dipolar cycloaddition reactions between N-methylindoles and several cyclic carbonyl ylides that were derived from diazodiketone or diazoketoester precursors in the presence of both achiral Rh and chiral lanthanoid metal catalysts are described. For the six-membered cyclic carbonyl ylides derived from 1-diazo-5-aryl-2,5-pentanedione precursors, the cycloaddition reactions were carried out using Rh2(OAc)4 (2 mol %) and the chiral Pybox-Ph2-Lu(OTf)3 complex (10 mol %) as catalysts, resulting in high enantioselectivities (83% to >98% ee (exo)) along with relatively good exo-selectivities (exo:endo = 65:35 to 94:6) and yields (63-85%). For the five-membered cyclic carbonyl ylide derived from 1-diazo-2,4-pentandione precursor, the cycloaddition reaction with 5-bromo-1-methylindole was carried out in the presence of Rh2(OAc)4 (2 mol %) and the chiral Pybox-Ph2-Er(OTf)3 complex (30 mol %) as catalysts, resulting in relatively good enantioselectivity (78% ee) and endo-selectivity (endo:exo = 81:19).

Photochemically-induced C-C bond formation between tertiary amines and nitrones.

Photoexcited nitrones serve as excellent electron acceptors as well as radical acceptors in the presence of tertiary amines to give ß-amino hydroxylamines via photochemically-induced direct sp(3) C-H functionalization of the tertiary amines. The combined use of an organophotosensitizer and photoirradiation was highly effective in accelerating addition reactions. Several nitrones and tertiary amines were successfully utilized to give ß-amino hydroxylamines in good yield. Highly regioselective generation of primary α-aminoalkyl radicals based on Lewis's stereoelectronic rule and diastereoselective addition reactions of primary α-aminoalkyl radicals with nitrones were successfully achieved. Furthermore, a highly diastereoselective reaction of an α-aminoalkyl radical with a chiral (E)-geometry-fixed α-alkoxycarbonylnitrone was performed.

Chiral Lewis acid catalyzed asymmetric cycloadditions of carbonyl ylides generated from diazoimide derivatives and their synthetic applications to indolizidine alkaloids.

Highly enantioselective 1,3-dipolar cycloaddition reactions, catalyzed by chiral Lewis acids, between several 3-(2-alkenoyl)-2-oxazolidinones and carbonyl ylides that were generated from N-diazoacetyl lactams are described. Reactions of N-diazoacetyl lactams that possess 5-, 6-, and 7-membered rings were transformed to the corresponding epoxy-bridged indolizidines, quinolizidines, and 1-azabicyclo[5.4.0]undecanes with good to high enantioselectivities. Regio- and stereoselective ring-opening of the epoxy-bridged indolizidine cycloadduct gave the corresponding alcohol as a single diastereomer. The sequence of asymmetric cycloaddition followed by ring-opening was applied to the syntheses of several chiral indolizidine derivatives, including (+)-tashiromine.

Diastereoselective synthesis of tetrahydrofurans by Lewis acid catalyzed intermolecular carbenoid-carbonyl reaction-cycloaddition sequences: unusual diastereoselectivity of Lewis acid catalyzed cycloadditions.

The effects of including metal salts for three-component reactions involving α-alkyl-α-diazo esters, aromatic aldehydes, and 3-(2-alkenoyl)-2-oxazolidinones are described, in terms of yields and diastereoselectivities. Metal tetrafluoroborates (10-30 mol %) such as Co(BF4)2·6H2O, Ni(BF4)2·6H2O, and AgBF4 were effective in delivering high yields and diastereoselectivities (93:7 to 99:1) of the corresponding tetrahydrofuran derivatives while suppressing the competitive formation of 1,3-dioxolane. Using (S)-3-(2-alkenoyl)-4-isopropyl-2-oxazolidinones as the dipolarophiles in the three-component reactions, in the presence of Ni(BF4)2·6H2O or Co(ClO4)2·6H2O (10-30 mol %), optically active tetrahydrofurans that possess four successive asymmetric centers were synthesized in high diastereoselectivities (99:1). On the basis of the configuration of the cycloadduct using the X-ray analysis, the high diastereoselectivity could be explained by the unusual Re-face approach to the dipolarophile in the presence of the Lewis acid, proceeding through the s-cis conformer of the 3-(2-alkenoyl)-2-oxazolidinone with the two carbonyls in opposing directions (dipole-dipole interaction).

Implementation of a transhydrogenase-like shunt to counter redox imbalance during xylose fermentation in Saccharomyces cerevisiae.

Three enzymes responsible for the transhydrogenase-like shunt, including malic enzyme (encoded by MAE1), malate dehydrogenase (MDH2), and pyruvate carboxylase (PYC2), were overexpressed to regulate the redox state in xylose-fermenting recombinant Saccharomyces cerevisiae. The YPH499XU/MAE1 strain was constructed by overexpressing native Mae1p in the YPH499XU strain expressing xylose reductase and xylitol dehydrogenase from Scheffersomyces stipitis, and native xylulokinase. Analysis of the xylose fermentation profile under semi-anaerobic conditions revealed that the ethanol yield in the YPH499XU/MAE1 strain (0.38 ± 0.01 g g⁻¹ xylose consumed) was improved from that of the control strain (0.31 ± 0.01 g g⁻¹ xylose consumed). Reduced xylitol production was also observed in YPH499XU/MAE1, suggesting that the redox balance was altered by Mae1p overexpression. Analysis of intracellular metabolites showed that the redox imbalance during xylose fermentation was partly relieved in the transformant. The specific ethanol production rate in the YPH499XU/MAE1-MDH2 strain was 1.25-fold higher than that of YPH499XU/MAE1 due to the additional overexpression of Mdh2p, whereas the ethanol yield was identical to that of YPH499XU/MAE1. The specific xylose consumption rate was drastically increased in the YPH499XU/MAE1-MDH2-PYC2 strain. However, poor ethanol yield as well as increased production of xylitol was observed. These results demonstrate that the transhydrogenase function implemented in S. cerevisiae can regulate the redox state of yeast cells.

Ring-fused hexahydro-1,2,4,5-tetrazines: synthesis, structure, and mechanistic studies on isolable rotational isomers.

We designed conformationally stable rotational isomers around the C(sp2)-C(sp3) axis at the C3-position of hexahydro-1,2,4,5-tetrazines. Isolation of each rotamer by silica gel column chromatography was successfully achieved at room temperature. The proposed isomerization mechanism of the rotamers was supported by NMR kinetic studies.

Tetraarylphosphonium salt-catalyzed formal [3+2] cycloaddition between epoxides and trichloroacetonitrile for the synthesis of ß-amino alcohol derivatives.

Efficient regioselective synthesis of ß-amino alcohol derivatives, including enantioenriched ones, by a tetraarylphosphonium salt-catalyzed coupling reaction of epoxides with trichloroacetonitrile is described. Formal [3+2] cycloaddition, followed by hydrolysis, proceeded smoothly to afford N-protected ß-amino alcohols in good yields.

Asymmetric Cycloadditions of Acyclic Carbonyl Ylides with Aldehydes Catalyzed by a Chiral Binaphthyldiimine-Ni(II) Complex: Enantioselective Synthesis of 1,3-Dioxolanes and Mechanistic Studies by DFT Calculations.

Chiral binaphthyldiimine-Ni(II)-catalyzed asymmetric 1,3-dipolar cycloaddition reactions between acyclic carbonyl ylides generated from donor-acceptor oxiranes and aldehydes are reported. Both aromatic and aliphatic aldehydes could be used as dipolarophiles, providing cis-1,3-dioxolanes with high diastereo- and enantioselectivities. On the basis of mechanistic studies, a monomeric chiral Ni(II) complex was hypothesized to act as the active species for the cycloaddition. The high levels of asymmetric induction are satisfactorily explained by a concerted-asynchronous endo Si-face approach of the aldehyde.

The Assessment of the Efficacy and Safety of Favipiravir for Patients with SARS-CoV-2 Infection: A Multicenter Non-randomized, Uncontrolled Single-arm Prospective Study.

Objective Among treatment options for coronavirus infectious disease 2019 (COVID-19), well-studied oral medications are limited. We conducted a multicenter non-randomized, uncontrolled single-arm prospective study to assess the efficacy and safety of favipiravir for patients with COVID-19. Methods One hundred participants were sequentially recruited to 2 cohorts: cohort 1 (Day 1: 1,600 mg/day, Day 2 to 14: 600 mg/day, n=50) and cohort 2 (Day 1: 1,800 mg/day, Day 2 to 14: 800 mg/day, n=50). The efficacy endpoint was the negative conversion rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the odds ratio (OR) of cohort 2 to cohort 1 for negative conversion on Day 10 was calculated. Characteristics of all participants and profiles of adverse events (AEs) were collected and analyzed. Results The mean age of participants was 62.8±17.6 years old. Thirty-four patients (34.0%) experienced worsening pneumonia, 7 (7.0%) were intubated, and 4 (4.0%) died during the observation period. Cohort 2 showed a higher negative conversion rate than cohort 1 [adjusted OR 3.32 (95% confidence interval (CI), 1.17 to 9.38), p=0.024], and this association was maintained after adjusting for the age, sex, body mass index, and baseline C-reactive protein level. Regarding adverse events, hyperuricemia was most frequently observed followed by an elevation of the liver enzyme levels (all-grade: 49.0%, Grade ≥3: 12.0%), and cohort 2 tended to have a higher incidence than cohort 1. However, no remarkable association of adverse events was observed between patients <65 and ≥65 years old. Conclusion The antiviral efficacy of favipiravir was difficult to interpret due to the limitation of the study design. However, no remarkable issues with safety or tolerability associated with favipiravir were observed, even in elderly patients with COVID-19.

Asymmetric cycloaddition reactions of diazoesters with 2-alkenoic acid derivatives catalyzed by binaphthyldiimine-Ni(II) complexes.

The catalytic activity of chiral binaphthyldiimine (BINIM)-Ni(II) complexes for asymmetric enantioselective diazoalkane cycloadditions of ethyl diazoacetate with 3-acryloyl-2-oxazolidinone and 2-(2-alkenoyl)-3-pyrazolidinone derivatives was evaluated. The cycloadditions of 3-acryloyl-2-oxazolidinone and its 5,5-dimethyl derivative, in the presence of the BINIM-Ni(II) complex (10 mol %; prepared from (R)-BINIM-4Ph-2QN (ligand C) and Ni(ClO(4))(2)·6H(2)O) afforded 2-pyrazolines having a methine carbon substituted with an oxazolidinonyl group in moderate ratios (70:30 to 72:28), along with high enantioselectivities (90-92% ee) via 1,3-proton migration. On the basis of the investigations on the counteranions of the Ni(II) complex, the N-substituent of pyrazolidinone, and reaction temperatures, the optimal enantioselectivity (97% ee) and ratio (85:15) of 2-pyrazoline were obtained for the reaction of 2-acryloyl-1-benzyl-5,5-dimethyl-3-pyrazolidinone in the presence of (R)-BINIM-4Ph-2QN-Ni(II) ((R)-C/Ni(II)) complex prepared using Ni(BF(4))(2)·6H(2)O. In the cases of 1-benzyl-2-crotonoyl-5,5-dimethyl-3-pyrazolidinone, 1-benzyl-2-(2-butenoyl)-5,5-dimethyl-3-pyrazolidinone, and 1-benzyl-5,5-dimethyl-2-(3-ethoxycarbonyl)propenoyl-3-pyrazolidinone, the use of the (R)-BINIM-2QN-Ni(II) ((R)-A/Ni(II)) complex gave good to high enantioselectivities (85-93% ee) with the sole formation of the 2-pyrazoline having a methine carbon substituted with a pyrazolidinonyl group. Relatively good enantioselectivity (77% ee) was observed for the reaction between 2-acryloyl-5,5-dimethyl-1-naphthylmethyl-3-pyrazolidinone and an α-substituted diazo ester, ethyl 2-diazo-3-phenylpropanoate, which has yet to be employed as a diazo substrate in asymmetric cycloaddition reactions catalyzed by a chiral Lewis acid.

Switchable synthesis of cyclic carbamates by carbon dioxide fixation at atmospheric pressure.

The base-promoted switchable synthesis of five- and six-membered cyclic carbamates using atmospheric pressure carbon dioxide as the C1 source was developed. The chemoselectivity of products was simply controlled by changing bases and solvents. The reaction proceeds effectively under mild conditions, affording valuable cyclic carbamates. Experimental results and DFT studies revealed the reaction mechanism.

A phosphonium ylide as a visible light organophotoredox catalyst.

A phosphonium ylide-based visible light organophotoredox catalyst has been designed and successfully applied to halohydrin synthesis using trichloroacetonitrile and epoxides. An oxidative quenching cycle by the ylide catalyst was established, which was confirmed by experimental mechanistic studies.

Preparation of new nitrogen-bridged heterocycles 72. A new approach to 1-acyl-3-(substituted methylthio)thieno[3',4':4,5]imidazo[1,2-a]pyridine derivatives. [corrected]

The alkaline treatment of the pyridinium salts, readily available from the S-alkylations of 3-amino-4-(1-pyridinio)thiophene-5-thiolates with various alkyl halides, in chloroform at room temperature afforded the corresponding thieno[3',4':4,5]imidazo[1,2-a]pyridine derivatives in low to moderate yields via the intramolecular cyclization of the resulting 1,5-dipoles followed by the aromatization of the primary cycloadducts. Interestingly, the reactions using unsymmetrical 3-amino-4-[1-(3-methylpyridinio)]thiophene-5-thiolates afforded only 8-methylthieno[3',4':4,5]imidazo[1,2-a]pyridines and the other 6-methyl derivatives were not formed at all. In addition the isolation of a byproduct in the condensation reaction of pyridinium salt with the solvent (CHCl3) is also discussed.