論文 - 熊谷　直哉

Direct catalytic asymmetric and: Anti-selective vinylogous addition of butenolides to chromones

Cui J., Kumagai N., Watanabe T., Shibasaki M.

Chemical Science （Chemical Science）  11 （ 27 ） 7170 - 7176 2020年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  20416520

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An anti-selective catalytic asymmetric Michael-type vinylogous addition of β,γ-butenolides to chromones was developed. The catalyst system developed herein is characterized by tuning of the steric and electronic effects using a proper Biphep-type chiral ligand to invert the diastereoselection, and improvement of the catalyst turnover by a coordinative phenolic additive. The catalytic protocol renders potentially biologically active natural product analogs accessible in good yield with moderate diastereoselectivity and high enantiomeric purity, mostly greater than 99% ee. This journal is

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Introduction of a 7-aza-6-MeO-indoline auxiliary in Lewis-acid/photoredox cooperative catalysis: highly enantioselective aminomethylation of a,ß-unsaturated amides

Pagire S.K., Kumagai N., Shibasaki M.

Chemical Science （Chemical Science）  11 （ 20 ） 5168 - 5174 2020年05月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り,  ISSN  20416520

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An efficient cooperative chiral Lewis acid/photoredox catalytic system for engaging highly reactive radicals in highly enantioselective conjugate addition to a,ß-unsaturated carbonyls is highly desirable. Direct photoexcitation of unbound substrates typically induces undesired background pathways for racemic products and remains a formidable challenge to be addressed in the area of enantioselective photocatalysis. Herein, we report a cooperative catalytic system comprising a chiral Cu(i) complex and an Ir(iii) photocatalyst fueled by visible-light irradiation that allows for seamless integration of the catalytic formation of a-amino alkyl radicals and subsequent enantioselective addition to a,ß-unsaturated amides. A 7-aza-6-MeO-indoline attachment on the amide substrates plays a pivotal role in suppressing the undesired pathways, resulting in excellent enantioselectivity and enabling expedited access to valuable ?-aminobutyramides. The indoline amide was readily diversified with full recovery of the azaindoline attachment, highlighting the synthetic utility of this cooperative catalytic system.

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(2R,3S)-3,4,4,4-Tetrafluorovaline: A Fluorinated Bioisostere of Isoleucine

Brewitz L., Noda H., Kumagai N., Shibasaki M.

European Journal of Organic Chemistry （European Journal of Organic Chemistry）  2020 （ 11 ） 1745 - 1752 2020年03月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り,  ISSN  1434193X

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The synthesis of (2R,3S)-3,4,4,4-tetrafluorovaline, a fluorinated derivative of the canonical α-amino acid l-valine, is reported for the first time. A highly enantio- and diastereoselective direct catalytic asymmetric Mannich-type reaction was applied as the key C–C bond-forming step to afford gram quantities of a central synthetic intermediate. The conformation of the novel fluorinated α-amino acid was analyzed by X-ray crystallography, NMR spectroscopy, and computational methods, which, together with its calculated and experimental physicochemical properties, indicated that the fluorinated valine is a bioisostere of l-isoleucine.

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Z-Enolate Geometry in the Thioamide Aldol Reaction Illuminated by the 7-Azaindoline Auxiliary

Pluta R., Li Z., Kumagai N., Shibasaki M.

Organic Letters （Organic Letters）  22 （ 3 ） 791 - 794 2020年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15237060

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Z or E enolate geometry is the primary determinant of diastereoselectivity in the aldol reaction. Although amide and thioamide enolates are anticipated to have predominantly the E geometry because of the intrinsic steric demand, spectroscopic confirmation of the geometry in solution has remained elusive, particularly in the realm of highly stereoselective catalytic asymmetric aldol reactions. Herein we demonstrate that the 7-azaindoline auxiliary enables direct observation of the exclusive formation of the Z-enolate of the thioamide en route to a highly syn-selective aldol reaction.

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Catalytic asymmetric 1,3-Dipolar Cycloaddition of α,β-Unsaturated amide and Azomethine Imine

Li Z., Kumagai N., Shibasaki M.

Chemical and Pharmaceutical Bulletin （Chemical and Pharmaceutical Bulletin）  68 （ 6 ） 552 - 554 2020年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00092363

　概要を見る

α,β-Unsaturated amides were incorporated as viable dipolarophiles in a catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines. The use of a 7-Azaindoline auxiliary was essential to acquire sufficient reactivity with excellent diastereoselectivity, likely due to the chelating activation of the amide by the In(III)/ bishydroxamic acid complex. Although the enantioselectivity remains unsatisfactory, this work is an important step toward the development of an asymmetric catalysis utilizing stable and low-reactive substrates. Key words 1,3-dipolar cycloaddition; indium; 7-Azaindoline; amide; enantioselective.

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TriQuinoline

Adachi S., Shibasaki M., Kumagai N.

Nature Communications （Nature Communications）  10 （ 1 ）  2019年12月

研究論文（学術雑誌）, 共著, 査読有り

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The bottom-up synthesis of structurally well-defined motifs of graphitic materials is crucial to understanding their physicochemical properties and to elicit new functions. Herein, we report the design and synthesis of TriQuinoline (TQ) as a molecular model for pyridinic-nitrogen defects in graphene sheets. TQ is a trimer of quinoline units concatenated at the 2- and 8-positions in a head-to-tail fashion, whose structure leads to unusual aromatisation behaviour at the final stage of the synthesis. The central atomic-sized void endows TQ with high proton affinity, which was confirmed empirically and computationally. TQ•H+ is a two-dimensional cationic molecule that displays both π–π and CH–π contact modes, culminating in the formation of the ternary complex ([12]cycloparaphenylene(CPP) ⊃ (TQ•H+/coronene)) that consists of TQ•H+, coronene (flat), and [12]cycloparaphenylene ([12]CPP) (ring). The water-miscibility of TQ•H+ allows it to serve as an efficient DNA intercalator for e.g. the inhibition of topoisomerase I activity.

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Direct Catalytic Asymmetric Addition of Acetonitrile to Aldimines

Saito A., Kumagai N., Shibasaki M.

Organic Letters （Organic Letters）  21 （ 20 ） 8187 - 8190 2019年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15237060

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Despite significant advances in catalytic asymmetric reactions with decent stereocontrol, those using acetonitrile as a pronucleophile are often disregarded due to their low reactivity and insufficient enantioselectivity. Herein we report the resurgence of this reaction in the chemical toolbox with high enantioselectivity (avg. > 95% ee). The combined use of a Ni(II) complex ligated with a chiral biscarbene and tBuOK engages acetonitrile in the catalytic generation of an α-cyanocarbanion and subsequent highly enantioselective addition to aldimines.

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Solvent-Dependent Enantiodivergence in anti-Selective Catalytic Asymmetric Nitroaldol Reactions

Karasawa T., Saito A., Kumagai N., Shibasaki M.

Organic Letters （Organic Letters）  21 （ 10 ） 3581 - 3583 2019年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15237060

　概要を見る

anti-Selective catalytic asymmetric nitroaldol reactions of α-keto esters promoted by a heterogeneous Nd/Na heterobimetallic catalyst exhibited a significant, unexpected disparity in enantioselection that was solvent-dependent. This phenomenon exclusively occurred when the stereogenic center of a diamide ligand had the smallest substituent (Me group, derived from l-Ala), which behaved uniquely in comparison with other structurally similar ligands to provide antipodal products under otherwise identical conditions.

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All Non-Carbon B <inf>3</inf> NO <inf>2</inf> Exotic Heterocycles: Synthesis, Dynamics, and Catalysis

Opie C.R., Noda H., Shibasaki M., Kumagai N.

Chemistry - A European Journal （Chemistry - A European Journal）  25 （ 18 ） 4648 - 4653 2019年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09476539

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The B 3 NO 2 six-membered heterocycle (1,3-dioxa-5-aza-2,4,6-triborinane=DATB), comprising three different non-carbon period 2 elements, has been recently demonstrated to be a powerful catalyst for dehydrative condensation of carboxylic acids and amines. The tedious synthesis of DATB, however, has significantly diminished its utility as a catalyst, and thus the inherent chemical properties of the ring system have remained virtually unexplored. Here, a general and facile synthetic strategy that harnesses a pyrimidine-containing scaffold for the reliable installation of boron atoms is disclosed, giving rise to a series of Pym-DATBs from inexpensive materials in a modular fashion. The identification of a soluble Pym-DATB derivative allowed for the investigation of the dynamic nature of the B 3 NO 2 ring system, revealing differential ring-closing and -opening behaviors depending on the medium. Readily accessible Pym-DATBs proved their utility as efficient catalysts for dehydrative amidation with broad substrate scope and functional-group tolerance, offering a general and practical catalytic alternative to reagent-driven amidation.

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A C4N4 Diaminopyrimidine Fluorophore

Noda H., Asada Y., Maruyama T., Takizawa N., Noda N.N., Shibasaki M., Kumagai N.

Chemistry - A European Journal （Chemistry - A European Journal）  25 （ 17 ） 4299 - 4304 2019年03月

研究論文（学術雑誌）, 査読有り,  ISSN  09476539

　概要を見る

A new scaffold for producing efficient organic fluorescent materials was identified: 2,5-diamino-4,6-diarylpyrimidine featuring a C4N4 elemental composition. Single-step installation of two aryl groups at the 4,6-positions of the pyrimidine core delivered fluorescent organic materials in a modular fashion. A range of fluorescent compounds with distinct absorption/emission properties was readily accessed by changing the aromatic attachments. A generally high absorption coefficient and quantum yield were observed, including C4N4 derivatives that could fluoresce even in the solid state. The two amino groups at the 2,5-positions of the pyrimidine were essential for intense fluorescence with a large Stokes shift, which was corroborated by structural relaxation to a p-iminoquinone-like structure in the excited state. Besides live-cell imaging capabilities, fluorescent labeling of a protein involved in autophagy elucidated a new protein–protein interaction, supporting potential utility in bioimaging applications.

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Achiral Trisubstituted Thioureas as Secondary Ligands to Cu ^I Catalysts: Direct Catalytic Asymmetric Addition of α-Fluoronitriles to Imines

Balaji P.V., Brewitz L., Kumagai N., Shibasaki M.

Angewandte Chemie - International Edition （Angewandte Chemie - International Edition）  58 （ 9 ） 2644 - 2648 2019年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14337851

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Thioureas have emerged as effective hydrogen-bonding catalysts over the last two decades, and they are broadly utilized in asymmetric catalysis. We report that achiral trisubstituted thioureas function as beneficial secondary ligands to Cu I catalysts, thereby enabling highly diastereo- and enantioselective addition of α-fluoronitriles to imines. The structure of the thiourea significantly affects the reaction outcome, and kinetic experiments indicate that the thioureas enhance the stereocontrol by binding to the Cu I complex. The reaction products can be readily transformed into valuable β-amino acid derivatives bearing a fluorinated tetrasubstituted stereogenic center.

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Direct Catalytic Asymmetric Aldol Reaction of α-Alkoxyamides to α-Fluorinated Ketones

Pluta R., Kumagai N., Shibasaki M.

Angewandte Chemie - International Edition （Angewandte Chemie - International Edition）  58 （ 8 ） 2459 - 2463 2019年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14337851

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α-Oxygen-functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α-fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn- and anti-aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2-dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.

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Neighboring Protonation Unveils Lewis Acidity in the B <inf>3</inf> NO <inf>2</inf> Heterocycle

Noda H., Asada Y., Shibasaki M., Kumagai N.

Journal of the American Chemical Society （Journal of the American Chemical Society）  141 （ 4 ） 1546 - 1554 2019年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00027863

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Boron serves a distinctive role in a broad range of chemistry disciplines. The utility of the element lies in its Lewis acidity, and thus, it is crucial to understand the properties of the boron atom in chemically different contexts. Herein, a combination of experiments and computations reveals the nuanced nature of boron in direct amidation reactions catalyzed by recently disclosed 1,3-dioxa-5-aza-2,4,6-triborinanes (DATBs). The most active DATB catalyst has been shown to bear an azaborine ring in its structure, thus having four boron atoms in a single molecule. Three chemically distinct boron atoms in the catalyst framework have been shown to serve different roles in the catalytic cycle, depending on their innate Lewis acidity. More specifically, the most Lewis acidic boron interacts with the amine, whereas the two boron atoms in the B-N-B substructure acquire Lewis acidity only upon protonation of the center nitrogen atom. Furthermore, although the least acidic boron atom in the azaborine ring did not act as a Lewis acid, it still plays an important role in the catalytic cycle by forming a hydrogen bond between carboxylic acid and the B-OH moiety. The mechanistic insights obtained from this study not only extend the knowledge on catalytic direct amidation but also provide a guiding principle for the further exploration of multi-boron compounds.

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A thirst for enantioselectivity in catalytic addition of alkylnitriles

Kumagai N., Shibasaki M.

Chemistry Letters （Chemistry Letters）  48 （ 11 ） 1322 - 1327 2019年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03667022

　概要を見る

This Highlight Review sheds light on a neglected aspect of alkylnitriles in synthetic organic chemistry. The chemical inertness and highly polar nature of alkylnitriles have particular utility as a reaction solvent. Alkylnitriles, however, also serve as potential building blocks for constructing carbon frameworks of interest. Two decades of exploratory studies of this elusive reaction revealed competent catalytic systems that allow for catalytic and enantioselective coupling of alkylnitriles with electrophiles.

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A fluorogenic C4N4 probe for azide-based labelling

Noda H., Asada Y., Shibasaki M., Kumagai N.

Organic and Biomolecular Chemistry （Organic and Biomolecular Chemistry）  17 （ 7 ） 1813 - 1816 2019年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14770520

　概要を見る

The design, synthesis and photophysical properties of a new fluorogenic probe are described. The structure is based on the recently identified 2,5-diaminopyrimidine (C4N4) fluorophore. The strain-promoted [3 + 2] cycloaddition of the azido-C4N4 probe furnished a triazole that exhibited more than 30-fold enhancement in fluorescence intensity as compared to the azide.

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7-Azaindoline Auxiliary: A Versatile Attachment Facilitating EnantioselectiveC-C Bond-Forming Catalysis

Kumagai N., Shibasaki M.

Synthesis (Germany) （Synthesis (Germany)）  51 （ 1 ） 185 - 193 2019年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00397881

　概要を見る

This short review provides an overview of 7-azaindoline auxiliaries in asymmetric catalysis. 7-Azaindoline serves as a useful attachment to carboxylic acids, and the thus-formed 7-azaindoline amides are amenable to atom-economical C-C bond-forming reactions with high stereoselectivity. The attachment is used for the sake of gaining traction in promoting the reaction of interest and can be easily removed after enantioselective reactions. Both nucleophilic and electrophilic catalyses are realized with broad tolerance for functional groups, showcasing the usefulness of 7-azaindoline auxiliaries for practical and streamlined synthesis of a wide range of acyclic chiral building blocks. 1 Introduction 2 7-Azaindoline as a Key Auxiliary 3 7-Azaindoline Amide as a Pronucleophile 3.1 α-Carbon-Substituted 7-Azaindoline Amide 3.2 α-Nitrogen-Substituted 7-Azaindoline Amide 3.3 α-Oxygen-Substituted 7-Azaindoline Amide 3.4 α-Fluorocarbon-Substituted 7-Azaindoline Amide 3.5 α-Halogen-Substituted 7-Azaindoline Amide 3.6 α-Sulfur-Substituted 7-Azaindoline Amide 4 7-Azaindoline Amide as an Electrophile 4.1 Conjugate Addition of Butenolides 4.2 1,3-Dipolar Cycloaddition of Nitrones 5 Transformation of 7-Azaindoline Amide 6 Conclusion.

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Catalytic Asymmetric Synthesis of syn Aldols with Methyl Ketone Functionality and anti Aldols with a Thioamide Group

Ota Y., Li Z., Kumagai N., Shibasaki M.

Synlett （Synlett）  30 （ 5 ） 620 - 624 2019年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09365214

　概要を見る

Catalytic asymmetric syntheses of syn aldols with a methyl ketone functionality were studied to confirm the generality of the methodology. In addition, catalytic asymmetric synthesis of anti aldols with a thioamide group was carefully examined, giving the desired products, albeit with moderate diastereoselectivity.

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Direct Catalytic Asymmetric Mannich-Type Reaction of an α-CF <inf>3</inf> Amide to Isatin Imines

Yu J., Noda H., Kumagai N., Shibasaki M.

Synlett （Synlett）  30 （ 4 ） 488 - 492 2019年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09365214

　概要を見る

An α-CF 3 amide underwent direct asymmetric Mannich-type reaction to isatin imines in the presence of a chiral catalyst comprising a soft Lewis acid Cu(I), a chiral bisphosphine ligand, and Barton's base. The Mannich adduct was converted in one step into a unique tricycle bearing a trifluoromethylated chiral center and an α-tertiary amine moiety.

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Anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients

Karasawa T., Oriez R., Kumagai N., Shibasaki M.

Journal of the American Chemical Society （Journal of the American Chemical Society）  140 （ 38 ） 12290 - 12295 2018年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00027863

　概要を見る

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.

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Direct enolization chemistry of 7-azaindoline amides: A case study of bis(tetrahydrophosphole)-type ligands

Li Z., Noda H., Kumagai N., Shibasaki M.

Tetrahedron （Tetrahedron）  74 （ 26 ） 3301 - 3305 2018年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00404020

　概要を見る

7-Azaindoline amides are particularly useful in direct enolization chemistry due to their facilitated enolization in soft Lewis acid/Brønsted base cooperative catalysis. The Cu(I) complex of (R,R)-Ph-BPE, a bis(tetrahydrophosphole)-type chiral bisphosphine ligand, exhibits consistently high catalytic performance and stereoselectivity irrespective of the nature of the α-substituent of the amides. Unexpectedly, however, alkyl-substituted bis(tetrahydrophosphole)-type ligands have substantially inferior catalytic performance. Evaluation of the optimized structures of Cu(I)/amide and Cu(I)/enolate complexes provided clues to dissecting the diverted reaction outcomes.

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