論文 - 熊谷　直哉

Direct N-acylation of sulfoximines with carboxylic acids catalyzed by the B3NO2 heterocycle

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

Chemical Communications 53 （ 54 ） 7447 - 7450 2017年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1359-7345

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In contrast to recent significant progress in the development of catalytic methodologies for nitrogen acylations, syntheses of N-acyl sulfoximines have been slow to evolve, and still largely rely on the use of stoichiometric amounts of activating reagents. Here we describe the direct acylation of the nitrogen atom in sulfoximines with carboxylic acids promoted by a heterocyclic catalyst featuring the B3NO2 ring system. The protocol used was found to be operationally simple and to tolerate a wide range of functional groups, furnishing the N-acylated sulfoximines in good yield. The multiboron catalyst tamed previously intractable nitrogen nucleo-philes, allowing for the short synthesis of a factor Xa inhibitor by catalyzing two consecutive nitrogen acylations in the same pot.

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Unique physicochemical and catalytic properties dictated by the B3NO2 ring system

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

Nature Chemistry 9 （ 6 ） 571 - 577 2017年06月

共著, 査読有り,  ISSN  1755-4330

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The expansion of molecular diversity beyond what nature can produce is a fundamental objective in chemical sciences. Despite the rich chemistry of boron-containing heterocycles, the 1,3-dioxa-5-aza-2,4,6-triborinane (DATB) ring system, which is characterized by a six-membered B3NO2 core, remains elusive. Here, we report the synthesis of m-terphenyltemplated DATB derivatives, displaying high stability and peculiar Lewis acidity arising from the three suitably arranged boron atoms. We identify a particular utility for DATB in the dehydrative amidation of carboxylic acids and amines, a reaction of high academic and industrial importance. The three boron sites are proposed to engage in substrate assembly, lowering the entropic cost of the transition state, in contrast with the operative mechanism of previously reported catalysts and amide coupling reagents. The distinct mechanistic pathway dictated by the DATB core will advance not only such amidations, but also other reactions driven by multisite activation.

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Cu/Pd Synergistic Dual Catalysis: Asymmetric alpha-Allylation of an alpha-CF3 Amide

Saito, A., Kumagai, N. and Shibasaki, M.

Angewandte Chemie-International Edition 56 （ 20 ） 5551 - 5555 2017年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1433-7851

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Despite the burgeoning demand for fluorine-containing chemical entities, the construction of CF3-containing stereogenic centers has remained elusive. Herein, we report the strategic merger of CuI/base-catalyzed enolization of an alpha-CF3 amide and Pd-0-catalyzed allylic alkylation in an enantioselective manner to deliver chiral building blocks bearing a stereogenic carbon center connected to a CF3, an amide carbonyl, and a manipulable allylic group. The phosphine complexes of Cu-I and Pd-0 engage in distinct catalytic roles without ligand scrambling to render the dual catalysis operative to achieve asymmetric alpha-allylation of the amide. The stereoselective cyclization of the obtained alpha-CF3-gamma, delta-unsaturated amides to give tetrahydropyran and g-lactone-fused cyclopropane skeletons highlights the synthetic utility of the present catalytic method as a new entry to non-racemic CF3-containing compounds.

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Catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols via direct aldol reaction of alpha-N-3 amide

Noda, H., Amemiya, F., Weidner, K., Kumagai, N. and Shibasaki, M.

Chemical Science 8 （ 4 ） 3260 - 3269 2017年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2041-6520

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Organofluorine compounds are found in several important classes of chemicals, such as pharmaceuticals, agrochemicals, and functional materials. Chemists have been immensely interested in the development of methodologies for expeditious access to fluorine containing building blocks. In this study, we report a new method for the catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols with two contiguous stereogenic centers via the direct aldol reaction of an alpha-N-3 amide to trifluoromethyl ketones. The key to the success of this method is the identification of a catalyst comprising Cu(II)/chiral hydroxamic acid to promote the desired aldol reaction, constructing a tetrasubstituted carbon in a highly stereoselective fashion. Despite substantial prior advances in asymmetric catalysis, this class of catalysts has not been utilized for the formation of carbon-carbon bond-forming reactions. Our mechanistic study sheds light on the unique profile of this catalytic system, where the Cu(II) complex plays a bifunctional role of serving as a Lewis acid and a Bronsted base. Furthermore, the densely functionalized aldol adducts undergo chemoselective transformations, affording a series of fluorine containing chiral building blocks with widespread application.

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Strategic Immobilization of Molecular Catalysts onto Carbon Nanotubes via Noncovalent Interaction for Catalytic Organic Transformations

Kumagai, N. and Shibasaki, M.

Israel Journal of Chemistry 57 （ 3-4 ） 270 - 278 2017年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0021-2148

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Since their discovery, carbon nanotubes (CNTs) continue to attract growing interest from scientists in a wide range of fields, likely due to their fascinating nanoarchitecture as well as their electronic and physical properties. From the viewpoint of synthetic chemistry, the chemical and physical stability, high surface area, and -stacking nature of CNTs are attractive features for their application as solid supports for molecular catalysts. The chemical functionalization of CNTs has been explored for various applications, including covalent and noncovalent grafting of molecular catalysts. Although noncovalent grafting provides less stable immobilized catalysts compared with covalently grafted hybrid molecular catalysts and CNTs, the preparation protocol is expeditious and repetitive use of the catalysts is well demonstrated, confirming their potential broad utility in synthetic organic chemistry.

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Asymmetric flow catalysis: Mix-and-go solid-phase Nd/Na catalyst for expeditious enantioselective access to a key intermediate of AZD7594

Nonoyama, A., Kumagai, N. and Shibasaki, M.

Tetrahedron 73 （ 11 ） 1517 - 1521 2017年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0040-4020

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An anti-selective catalytic asymmetric nitroaldol reaction was implemented in a continuous-flow reaction platform for the synthesis of a key intermediate of a drug candidate. The requisite solid-phase catalyst was readily prepared by mixing an amide-based chiral ligand and inexpensive inorganic salts, NdCl3 center dot 6H(2)O and (NaOBu)-Bu-t, without covalent bond linkages. The flow system was operated with 2-Me-THE as the eluent for ca. 400 h to provide a crude nitroaldol adduct in a highly stereoselective manner with no work-up procedure, reaching turnover number over 1600. Facile reduction of the nitro group of the product afforded a key intermediate of AZD7594, a therapeutic candidate for asthma and chronic obstructive pulmonary disease. (C) 2017 Elsevier Ltd. All rights reserved.

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Reversible Stereoselective Folding/Unfolding Fueled by the Interplay of Photoisomerism and Hydrogen Bonding

Opie, C. R., Kumagai, N. and Shibasaki, M.

Angewandte Chemie-International Edition 56 （ 12 ） 3349 - 3353 2017年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1433-7851

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A linear molecular architecture equipped with complementary three-fold hydrogen-bonding units embedded with a photoswitchable trans-tetrafluoroazobenzene moiety was synthesized. The transto cis photoisomerism of the azobenzene unit induced drastic changes in the molecular architecture as a result of intramolecular hydrogen bonding as evidenced by NMR spectroscopy and size exclusion chromatography. A minute stereogenic element in the linear trans state enabled stereoselective folding into the cis state, thus producing a globular architecture with enhanced chiroptical property.

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Direct Catalytic Asymmetric Aldol Reaction of alpha-Alkylamides

Liu, Z., Takeuchi, T., Pluta, R., Arteaga, F. A., Kumagai, N. and Shibasaki, M.

Organic Letters 19 （ 3 ） 710 - 713 2017年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1523-7060

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A catalytic asymmetric aldol reaction directly employing amides as latent enolates has remained elusive because of the resistance of amides to enolization. A direct aldol reaction of alpha-alkylarnides without any electron-withdrawing group harnessed by specific activation of 7-azaindoline amides under soft Lewis acid/Bronsted base cooperative catalysis is reported. Diastereo- and enantioselective coupling with ynals and aromatic aldehydes as well as divergent functional group interconversion of the amide provided expeditious access to a variety of aliphatic and aromatic chiral building blocks.

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Catalytic asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines as useful building blocks for SAR-studies

Brewitz, L., Kumagai, N. and Shibasaki, M.

Journal of Fluorine Chemistry 194   1 - 7 2017年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0022-1139

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The first protocol for the asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines which function as fluorinated surrogates for alpha-isopropylbenzylamines in SAR-studies is presented herein. Crucial for the successful synthesis was the application of a recently developed direct catalytic asymmetric Mannich-type reaction of fluorinated amide for the key bond-forming step. The utility of this versatile protocol was demonstrated by the synthesis of fluorinated analogues of a T-type selective Ca2+ channel blocker and a prolylcarboxypeptidase inhibitor. The predominant conformation of their fluorinated analogues was investigated by X-ray crystallography and NMR spectroscopy which revealed a strong influence of a fluorine mediated gauche effect. (C) 2016 Elsevier B.V. All rights reserved.

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Pyramidalization/twisting of the amide functional group via remote steric congestion triggered by metal coordination

Adachi, S., Kumagai, N. and Shibasaki, M.

Chemical Science 8 （ 1 ） 85 - 90 2017年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2041-6520

　概要を見る

For decades, the planarity of the amide functional group has garnered sustained interest in organic chemistry, enticing chemists to deform its usually characteristic high-fidelity plane. As opposed to the construction of amides that are distorted by imposing rigid covalent bond assemblies, we demonstrate herein the deformation of the amide plane through increased steric bulk in the periphery of the amide moiety, which is induced by coordination to metal cations. A crystallographic analysis revealed that the thus obtained amides exhibit significant pyramidalization and twisting upon coordination to the metals, while the amide functional group remained intact. The observed deformation, which should be attributed to through-space interactions, substantially enhanced the solvolytic cleavage of the amide, providing compelling evidence that temporary crowding in the periphery of the amide functional group may be used to control the reactivity of amides.

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Recent Advances in Rare Earth Metal Asymmetric Catalysis Toward Practical Synthesis of Therapeutics

Kumagai, N. and Shibasaki, M.

New Horizons of Process Chemistry: Scalable Reactions and Technologies    1 - 10 2017年

研究論文（学術雑誌）, 共著, 査読有り

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Two case studies regarding the development of rare earth metal-based asymmetric catalysts are summarized, with particular focus on the process of refining catalysts amenable to industrial applications. Amide-based chiral ligands in combination with lanthanum or neodymium cations furnished robust catalytic systems for asymmetric amination or nitroaldol reactions, respectively. Although rare earth metal catalysis is generally characterized by a peculiar coordination chemistry and Lewis acidic catalytic functions, its wide availability and moderate tolerance to moisture are also important features to be noted, making the application of rare earth metal catalysis beneficial for industrial large-scale synthesis.

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An efficient method for the synthesis of versatile intermediates leading to 13-deoxy- and 9,13-dideoxyphorbols

Sekine, A., Kumagai, N., Uotsu, K., Ohshima, T. and Shibasaki, M.

Tetrahedron Letters 41 （ 4 ） 509 - 513 2000年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0040-4039

　概要を見る

An efficient method for the synthesis of versatile intermediates for biologically interesting 13-deoxy- and 9,13-dideoxyphorbol ester analogs is described. First,more efficient synthetic routes to the bicyclic ketones 7 and 8, which are well-known intermediates for the synthesis of 13-deoxyphorbols, than the previous one were established. Second, 7 and 8 were successfully converted to the intermediates 19, 25 and 27 for the synthesis of 9,13-dideoxyphorbols using Peterson reaction, oxymercuration and nitrile oxide cycloaddition as key steps. (C) 2000 Elsevier Science Ltd. All rights reserved.

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