論文 - 熊谷　直哉

DiQuinoline-MonoQuinazoline: A Flat Proton Binder and its Application as a Polyaromatic Hydrocarbon Scavenger and G4 Ligand

Karimata T., Xu W., Kumagai N.

Chemistry - A European Journal 2025年

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  09476539

　概要を見る

A new miniaturized framework for graphitic material featuring three neighboring pyridinic nitrogen atoms is disclosed. The quinoline/quinazoline hybridized pseudo trimeric macrocycle, DiQuinoline(Q)-MonoQuinazolines(Qz), Q2Qz1, was readily synthesized from the key macrocyclic amide precursor in a modular fashion. Its central cavity strongly captures a proton, and the thus-formed positively charged, highly planar architecture exhibits supramolecular complexation through π-interactions. Q2Qz1, with its unique properties, was applied as a scavenger for toxic polyaromatic hydrocarbons and as a G-quartet ligand for potential therapeutic agent for cancer chemotherapy.

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Recent Advances in Quinoline-Based Macrocycles: Synthesis, Properties, and Applications in Catalytic Reactions

Xu W., Kumagai N.

Synthesis (Germany) 56 （ 11 ） 1765 - 1774 2024年05月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00397881

　概要を見る

Macrocyclic compounds exhibit unique properties due to their large ring-shaped structures, which have captivated chemists in recent decades. These molecules exert specific functions in various applicable fields, such as chemistry, materials science, and biology. Crown ethers, calixarenes, and porphyrinoids, which contain several ether/phenol/pyrrole subunits, represent these molecular categories with unparalleled functional diversity. In contrast, quinoline-based macrocycles comprising the quinoline unit as a key element to construct specific ring shapes have received limited attention. In this minireview, we summarize the recent advances in oligoquinoline macrocycles TriQuinoline (TQ), oxa-TriQuinoline (o-TQ), TEtraQuinoline (TEQ), and other bridged quinoline-based macrocycles. Emphasis is placed on the synthesis, structure, and application of these molecules in organometallic and supramolecular chemistry, which may guide new molecular designs in the quinoline-based macrocycle family. 1 Introduction 2 Quinoline-Based Macrocycles 2.1 TriQuinoline (TQ) 2.2 Oxa-TriQuinoline (o-TQ) 2.3 TEtraQuinoline (TEQ) 2.4 Larger Quinoline-Based Macrocycles with Bridges 3 Conclusion.

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In2Q2: A New Entry of 16-Membered Tetraazamacrocycle Concatenating Indole and Quinoline Units

Kihara K., Kobayashi T., Xu W., Kumagai N.

Chemistry - A European Journal 30 （ 25 ）  2024年05月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  09476539

　概要を見る

A new family of 16-membered macrocycles comprising two indole (In) and two quinoline (Q) units, coined In2Q2, was synthesized. Each unit is diagonally located and concatenated in a head-to-tail fashion, furnishing a non-flat saddle-shaped architecture with C2 symmetry. The synthetic protocol utilizing macrocyclic diamide as a pivotal precursor allowed us to access a series of In2Q2 derivatives bearing various substituents on the periphery. The In2Q2 derivatives and their Zn2+ complexes were emissive in both solution phase and solid state. While the entire architecture of In2Q2 is similar to that of quinoline tetramer TEtraQuinoline, a couple of contrasting physicochemical properties were revealed.

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Chemoselective Catalytic Dehydrogenation of Benzylic Amines Driven by the TEtraQuinoline/FeCl<inf>2</inf> Complex

Nishiwaki M., Xu W., Kumagai N.

Asian Journal of Organic Chemistry （Asian Journal of Organic Chemistry）  12 （ 9 ）  2023年09月

最終著者, 責任著者, 査読有り,  ISSN  21935807

　概要を見る

A chemoselective dehydrogenation protocol for benzylic amines catalyzed by the TEtraQuinoline (TEQ)/FeCl2 complex is described. In combination with 2 equiv of tert-butyl hydroperoxide, as little as 0.1 mol% of catalyst loading was sufficient to convert primary and secondary benzylic amines to the corresponding imines and dimerized imines, respectively. Subsequent hydrolysis of the imines allowed for removal of the benzyl group on the nitrogen atom. Nonaromatic carbon-carbon multiple bonds and the O-Bn group remained intact in the present protocol, providing a complementary deprotection procedure to reductive removal conditions exerted by Pd catalysis.

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Oxa-TriQuinoline: A New Entry to Aza-Oxa-Crown Architectures**

Kobayashi T., Kumagai N.

Angewandte Chemie - International Edition （Angewandte Chemie - International Edition）  62 （ 32 ）  2023年08月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  14337851

　概要を見る

A new 15-membered-macrocyclic molecular entity, oxa-TriQuinoline (o-TQ), was designed and synthesized. In o-TQ, three oxygen atoms were joined onto three quinoline units at the 2- and 8-positions in a head-to-tail fashion by three-fold SNAr reactions, giving rise to the characteristic N3O3 aza-oxa-crown architecture. o-TQ can serve as a new tridentate nitrogen ligand to capture a CuI cation and adopt a bowl shape, before supramolecular complexation with corannulene and [12]cycloparaphenylene (CPP) occurs through π–π and CH–π interactions. In the presence of the CuI cation, the non-emissive o-TQ becomes a highly emissive material in the solid state, whereby the emission wavelengths depend on the ancillary ligand on the CuI cation. The o-TQ/CuI complex is able to promote carbene catalysis to provide a range of enamines with a gem-difluorinated terminus.

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A brief introduction to highly symmetric N-heteroarene-based macrocycles

Xu W., Kumagai N.

Tetrahedron （Tetrahedron）  141 2023年07月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00404020

　概要を見る

Nitrogen-containing macrocycles have attracted sustained attention because of their fascinating structures and extensive applications in organic chemistry, therapeutic developments, and materials science. The nitrogen atoms in the macrocycles play important roles in the interaction with metal cations or small molecules, endowing their potential in catalysis, fluorescent sensors, and host–guest chemistry. In this context, herein we summarize highly symmetric nitrogen-containing N3/N4/N6 macrocycles comprising pyrroles, pyridines, quinolines, and (iso)indoles as key N-heteroarenes. The direct and indirect connectivity of N-heteroarene subunits allows for the construction of both flat and non-flat cyclic architectures. The synthesis, structure, and properties of these macrocycles are highlighted.

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Expeditious Access to the B<inf>3</inf>NO<inf>2</inf> Heterocycle Enabling Modular Derivatization

Tsutsumi R., Kashiwagi N., Kumagai N.

Journal of Organic Chemistry （Journal of Organic Chemistry）  88 （ 9 ） 6247 - 6251 2023年05月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00223263

　概要を見る

DATB (1,3-dioxa-5-aza-2,4,6-triborinane) is a unique six-membered heterocycle exhibiting proficient catalytic activity in direct dehydrative amidation. Reported herein is an improved synthetic protocol for DATB derivatives featuring a concise two-step chromatography-free process. Suzuki-Miyaura coupling assembled 2,6-dibromoaniline derivatives and 1,2-phenylenediboronic acid to afford dimeric B-spiroborate salts. Acidic untying of the spiroborates gave rise to the DATB ring system with various substituents.

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Less Is More: N(BOH)<inf>2</inf> Configuration Exhibits Higher Reactivity than the B<inf>3</inf>NO<inf>2</inf> Heterocycle in Catalytic Dehydrative Amide Formation

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

Organic Letters （Organic Letters）  25 （ 4 ） 694 - 697 2023年02月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  15237060

　概要を見る

Diboron substructures have emerged as a promising scaffold for the catalytic dehydrative amidation of carboxylic acids and amines. This Letter describes the design, synthesis, and evaluation of the first isolable N(BOH)2 compound as an amidation catalyst. The new catalyst outperforms the previously reported B3NO2 heterocycle catalyst, with respect to turnover frequency, albeit the former gradually decomposes upon exposure to amines. This work opens up an avenue for designing a better catalyst for direct amidation.

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Azo-Tagged C4N4 Fluorophores: Unusual Overcrowded Structures and Their Applications to Fluorescent Imaging

Miki Kohei, Naoki Takizawa, Ryosuke Tsutsumi, Wei Xu, and Naoya Kumagai*

Org. Biomol. Chem. 2023年01月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

TEtraQuinolines: A Missing Link in the Family of Porphyrinoid Macrocycles

Xu W., Nagata Y., Kumagai N.

Journal of the American Chemical Society （Journal of the American Chemical Society）  145 （ 4 ） 2609 - 2618 2023年01月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  00027863

　概要を見る

Porphyrin contains four inwardly oriented nitrogen atoms. It is arguably the most ubiquitous multifunctional naturally occurring macrocycle that has inspired the design of novel nitrogen-containing heterocycles for decades. While cyclic tetramers of pyrrole, indole, and pyridine have been exploited as macrocycles in this category, quinoline has been largely neglected as a synthon. Herein, we report the synthesis of TEtraQuinoline (TEQ) as a ‘missing link’ in this N4 macrocycle family. In TEQs, four quinoline units are concatenated to produce an S4-symmetric architecture. TEQs are characterized by a highly rigid saddle shape, wherein the lone-pair orbitals of the four nitrogen atoms are not aligned in a planar fashion. Nevertheless, TEQs can coordinate a series of transition-metal cations (Fe2+, Co2+, Ni2+, Cu2+, Zn2+, and Pd2+). TEQs are inherently fluorescence-silent but become strongly emissive upon protonation or complexation of Zn(II) cations (ϕ = 0.71). TEQ/Fe(II) complexes can catalyze dehydrogenation and oxygenation reactions with catalyst loadings as low as 0.1 mol %.

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Less Is More: N(BOH)2 Configuration Exhibits Higher Reactivity than the B3NO2 Heterocycle in Catalytic Dehydrative Amide Formation

Christopher R. Opie, Hidetoshi Noda,* Masakatsu Shibasaki, and Naoya Kumagai*

Org. Lett. 2023年01月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

Azo-tagged C4N4 fluorophores: unusual overcrowded structures and their application to fluorescent imaging

Kohei M., Takizawa N., Tsutsumi R., Xu W., Kumagai N.

Organic and Biomolecular Chemistry （Organic and Biomolecular Chemistry）  21 （ 14 ） 2889 - 2893 2023年

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  14770520

　概要を見る

The C4N4 fluorophore is an intense fluorescence emitter featuring a 2,5-diaminopyrimidine core comprising four carbon and four nitrogen atoms. A series of C4N4 derivatives was photochemically dimerized at the 5-amino group, furnishing overcrowded ortho-tetraaryl-substituted diaryl azo compounds with a characteristic skewed structure revealed by X-ray crystallography. The photoquenched azo-C4N4s are useful for fluorescently visualizing cells under hypoxic conditions.

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Peripheral Modification of Tripodal Aza-Oxa-Crown Oxa-TriQuinoline

Kobayashi T., Sakurai T., Kumagai N.

Bulletin of the Chemical Society of Japan （Bulletin of the Chemical Society of Japan）  96 （ 10 ） 1139 - 1143 2023年

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00092673

　概要を見る

Oxa-TriQuinoline (o-TQ) is a new entry in the collection of aza-oxa-crown compounds featuring a semi-rigid flexible conformation and a tripodal ligation capability through three quinoline units. Herein, we describe the installation of functional groups and aromatic substituents on the outer edge of o-TQ to modulate its physicochemical properties. Amino and bromo substituents were regioselectively introduced at the 5-position, forming bowl-shaped Cu(I) complexes in which three quinoline units coordinated to Cu(I). X-ray crystallography indicated that these o-TQ derivatives preferred an almost identical geometry in both the absence and presence of Cu(I). In contrast to o-TQ, some new o-TQ derivatives exhibited photoluminescent properties in solution and/or in the solid state depending on the substituents.

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Oxygen-Fueled Iterative Hydride Transfer Driven by a Rigid Planar Architecture

Karimata T., Adachi S., Shibasaki M., Kumagai N.

Chemical and Pharmaceutical Bulletin （Chemical and Pharmaceutical Bulletin）  70 （ 9 ） 595 - 598 2022年09月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00092363

　概要を見る

An iterative hydride reduction/oxidation process was promoted under ambient conditions by a quasi-planar iminium cation rigidified by two concatenated quinoline units. The iminium proton was fixed by hydrogen bonding from neighboring quinoline nitrogen atoms, rendering the imine highly susceptible to hydride reduction with weak reductants, e.g., 1,4-dihydropyridines. The thus-formed amine was readily oxidized by molecular oxygen to regenerate the quasi-planar iminium cation under ambient conditions. This process was exploited for catalytic oxidation of 1,4-dihydropyridines as well as 9,10-dihydroacridine to highlight an intriguing rigidity- driven catalysis.

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Strategic Synthesis of Asymmetrically Substituted C4N4 Fluorophores

Xu W., Kohei M., Shibasaki M., Kumagai N.

Synthesis (Germany) （Synthesis (Germany)）  53 （ 18 ） 3355 - 3360 2021年09月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  00397881

　概要を見る

C4N4 fluorophores comprise a recently disclosed new class of emissive organic molecules with modular synthetic capabilities. Herein, we report a new synthetic protocol toward asymmetrically di arylated C4N4 fluorescent materials. Direct monoarylation of 1-naphthol is exploited to suppress undesired diarylation and to provide a free phenolic hydroxy group for prospective linking to a molecule of interest. Installation of the second aromatic unit in order to acquire fluorescent properties is achieved by Suzuki-Miyaura cross-coupling.

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Direct Catalytic Asymmetric Addition of Alkylnitriles to Aldehydes with Designed Nickel–Carbene Complexes

Saito A., Adachi S., Kumagai N., Shibasaki M.

Angewandte Chemie - International Edition （Angewandte Chemie - International Edition）  60 （ 16 ） 8739 - 8743 2021年04月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り,  ISSN  14337851

　概要を見る

A direct catalytic asymmetric addition of acetonitrile to aldehydes that realizes over 90 % ee is the ultimate challenge in alkylnitrile addition chemistry. Herein, we report achieving high enantioselectivity by the strategic use of a sterically demanding NiII pincer carbene complex, which afforded highly enantioenriched β-hydroxynitriles. This highly atom-economical process paves the way for exploiting inexpensive acetonitrile as a promising C2 building block in a practical synthetic toolbox for asymmetric catalysis.

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Highly Enantio- And Diastereoselective Synthesis of 1,2,3-Trisubstituted Cyclopropanes from α,β-Unsaturated Amides and Stabilized Sulfur Ylides Catalyzed by a Chiral Copper(I) Complex

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

ACS Catalysis （ACS Catalysis）     11597 - 11606 2021年

研究論文（学術雑誌）, 共著, 責任著者, 査読有り

　概要を見る

The stereoselective preparation of 1,2,3-substituted cyclopropanes from α,β-unsaturated carbonyl compounds in the carboxylic acid oxidation state through Michael addition-initiated ring-closure reactions is a significant challenge in organic synthesis. Herein, the previously elusive catalytic asymmetric cyclopropanation of α,β-unsaturated amides with stabilized sulfur ylides has been efficiently accomplished utilizing a chiral Cu(I) complex. This Lewis acid catalytic system effectively converts a wide range of electron-deficient alkenes into the corresponding 1,2,3-trisubstituted cyclopropanes under mild reaction conditions in good to excellent yields with both high to excellent enantio- and diastereoselectivities. The resulting enantiomerically enriched cyclopropane amides can be readily diversified into promising synthetic intermediates such as β-aminocyclopropanecarboxylic acids with the facile recovery of the 7-azaindoline auxiliary without influencing the optical purity of the cyclopropane unit, which highlights the synthetic efficacy of this catalytic approach.

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Direct Catalytic Asymmetric Addition of α-Fluoronitriles to Aldehydes

Balaji P.V., Li Z., Saito A., Kumagai N., Shibasaki M.

Chemistry - A European Journal （Chemistry - A European Journal）  26 （ 67 ） 15524 - 15527 2020年12月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り,  ISSN  09476539

　概要を見る

A fluorine-containing tetrasubstituted stereogenic center is a highly valued structural feature in medicinal chemistry. Herein, we describe the direct coupling of racemic α-fluoronitriles and aldehydes promoted by a chiral CuI/Barton's base catalytic system, delivering α-tetrasubstituted α-fluoro-β-hydroxynitriles with satisfactory stereoselection. The stereochemical course was positively biased by the combined use of asymmetrical achiral thiourea as a supplementary ligand for CuI, which significantly enhanced the stereoselectivity. Both aromatic and aliphatic aldehydes were implemented to provide densely and stereoselectively functionalized chiral building blocks with aliphatic and aromatic tails.

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The Different Faces of [Ru(bpy)<inf>3</inf>Cl<inf>2</inf>] and fac[Ir(ppy)<inf>3</inf>] Photocatalysts: Redox Potential Controlled Synthesis of Sulfonylated Fluorenes and Pyrroloindoles from Unactivated Olefins and Sulfonyl Chlorides

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

Organic Letters （Organic Letters）  22 （ 20 ） 7853 - 7858 2020年10月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り,  ISSN  15237060

　概要を見る

A cascade alkene sulfonylation that simultaneously forges C-S and C-C bonds is a highly efficient and powerful approach for directly accessing structurally diverse sulfonylated compounds in a single operation. The reaction was enabled by visible-light-mediated regioselective radical addition of sulfonyl chlorides to 2-arylstyrenes using fac[Ir(ppy)3] as a photocatalyst, demonstrating its unique role in a photocascade process to execute atom transfer radical addition (ATRA) followed by photocyclization. A new class of sulfonyl-substituted fluorenes and pyrroloindoles, which are useful in the field of photoelectronic materials and medicinal chemistry, was produced in excellent yields by this photocascade reaction. In contrast, the cyclization was interrupted when using the [Ru(bpy)3Cl2] catalyst having lower reduction potential, leading only to the formation of a C-S bond and the production of acyclic sulfonylated 2-arylstyrenes under identical reaction conditions. The synthetic utility of the present room-temperature photocatalysis is enhanced by the broad availability of bench-stable sulfonyl chlorides and unactivated olefins, thereby providing a cost-effective and broad-scope protocol.

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Design, synthesis, and application of multiboron heterocycle to direct amidation catalyst

Noda H., Shibasaki M., Kumagai N.

Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry （Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry）  78 （ 10 ） 971 - 978 2020年10月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  00379980

　概要を見る

The synthesis of a multiboron heterocycle and its application to a direct amidation catalyst are described. The heterocycle comprised of B3NO2is called DATB. The DATB-catalyzed direct amide formation is well suited for the synthesis of a wide range of amides, including previously intractable ones. The catalysis can also be applied to peptide synthesis and N-acylation of sulfoxi- mines. The most active DATB contains four boron atoms in its structure, and the detailed mecha- nistic study revealed their distinctive roles in the catalytic cycle, depending on the given chemical environment. A pyrimidine containing analog was also developed and evaluated as a more readily accessible amidation catalyst than the original one. The Pym-DATB is now available from a commercial vendor. Current trends and future perspective in the boron - catalyzed direct amidation are also discussed.

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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

　概要を見る

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

　概要を見る

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

　概要を見る

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

　概要を見る

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

　概要を見る

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

　概要を見る

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

　概要を見る

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

　概要を見る

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

　概要を見る

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

　概要を見る

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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Catalytic enantioselective addition of diethyl phosphite to N-thiophosphinoyl ketimines: Preparation of (R)-diethyl (1-amino-1-phenylethyl)phosphonate

Lin S., Otsuka Y., Yin L., Kumagai N., Shibasaki M.

Organic Syntheses （Organic Syntheses）  94 2018年06月

研究論文（国際会議プロシーディングス）, 共著, 査読有り,  ISSN  00786209

　概要を見る

Procedures yielding phosphinothioic amide 2 and ketimine 4 as colorless crystals and phosphonate 6 as a brown viscous oil are presented. Notes on instruments and chemicals required are provided.A brief discussion on construction of tetrasubstituted stereogenic centers in a catalytic and enantioselective manner as a significant progress in asymmetric catalysis.

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Direct Catalytic Asymmetric 1,6-Conjugate Addition of Amides to p-Quinone Methides

Sun Z., Sun B., Kumagai N., Shibasaki M.

Organic Letters （Organic Letters）  20 （ 10 ） 3070 - 3073 2018年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15237060

　概要を見る

Amide pronucleophiles were successfully incorporated into a 1,6-conjugate addition reaction manifold using p-quinone methides (p-QMs) as electrophiles. Four different types of functionalities were tolerated as α-substituents of the amides, allowing for expeditious access to a range of enantiomerically enriched diarylmethine products. The 7-azaindoline unit is critically important for in situ catalytic enolization of the amide pronucleophile, engaging in 1,6-conjugate addition to p-QMs with readily available catalyst components.

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Direct Catalytic Asymmetric Aldol Reaction of α-Vinyl Acetamide

Takeuchi T., Kumagai N., Shibasaki M.

Journal of Organic Chemistry （Journal of Organic Chemistry）  83 （ 10 ） 5851 - 5858 2018年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00223263

　概要を見る

A direct catalytic asymmetric aldol addition of an α-vinyl 7-azaindoline amide to both aromatic and aliphatic aldehydes was promoted by a cooperative acid/base catalyst in a stereodivergent manner. The key structural element, a 7-azaindoline moiety, facilitated catalytic enolization, allowing for subsequent stereoselective aldol addition. Enantioselective synthesis of the key intermediate of blumiolide C and kainic acid supported the synthetic utility of this protocol.

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Catalytic Asymmetric Synthesis of α-Trifluoromethylated Carbinols: A Case Study of Tertiary Propargylic Alcohols

Noda H., Kumagai N., Shibasaki M.

Asian Journal of Organic Chemistry （Asian Journal of Organic Chemistry）  7 （ 4 ） 599 - 612 2018年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  21935807

　概要を見る

Enantioenriched CF3-substituted tertiary alcohols have been applied in a broad range of chemical disciplines, including medicinal chemistry and agrochemistry. The widely prescribed anti-HIV pharmaceutical efavirenz is one particular example of the application of these chiral building blocks. Because the typical synthetic route to this small drug molecule involves the stoichiometric use of a chiral promoter, significant effort has been devoted to the development of catalytic alternatives for accessing this building block. In this Focus Review, we summarize the catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols based on three retrosynthetic approaches, namely one trifluoromethylation approach and two building-block strategies. The general challenges that are involved in the construction of a CF3-substituted tetrasubstituted stereogenic carbon species are highlighted and possible future directions in the field are discussed.

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Conquering amide planarity: Structural distortion and its hidden reactivity

Adachi S., Kumagai N., Shibasaki M.

Tetrahedron Letters （Tetrahedron Letters）  59 （ 13 ） 1147 - 1158 2018年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00404039

　概要を見る

Amides are generally considered as a low-reactive chemical entity among the carbonyl group, and therefore fewer opportunities to be involved in catalytic transformations as substrates. The origin of the stable nature of amides is resonance stabilization in the planar structure, which has drawn considerable attention from organic and physical chemists, leading to the discovery of distorted amides that exhibit a substantially reactive nature. Recent focus in this field is on the catalytic transformation of designed amides with moderate distortion or reduced resonance stabilization. This digest reviews the brief history of the quest for highly distorted amides and introduces a collection of recent studies on catalytic transformations of designed amides.

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Direct Catalytic Asymmetric Aldol Reaction of Thioamide with an α-Vinyl Appendage

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

Chemistry - A European Journal （Chemistry - A European Journal）  24 （ 11 ） 2598 - 2601 2018年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09476539

　概要を見る

The direct catalytic asymmetric aldol reaction is an emerging catalytic methodology that provides atom-economical access to functionalized chiral building blocks. Thioamides are useful aldol donors due to their high-fidelity chemoselective enolization and divergent post-aldol transformations. Herein we describe the incorporation of an α-vinyl appendage on a thioamide, which expands the utility of aldol adducts for natural product synthesis. This vinylated thioamide was not accommodated under the previously identified catalyst settings, but the newly developed catalytic conditions furnished aldol products containing the pendant vinyl group.

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Structural and Computational Investigation of Intramolecular N···H Interactions in α- and β-Fluorinated 7-Azaindoline Amides

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

European Journal of Organic Chemistry （European Journal of Organic Chemistry）  2018 （ 6 ） 714 - 722 2018年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1434193X

　概要を見る

Novel fluorinated N1-acylated 7-azaindolines have been synthesized and their conformations analyzed by X-ray diffraction and NMR spectroscopy: Unusual intramolecular interactions between the 7-nitrogen and amide α-hydrogen atoms were identified. The strength of these interactions correlate with the electron-withdrawing character of the amide α substituents. A combination of experimental and computational approaches revealed a significant substituent effect when the substituent (H, OMe, F, CN) at the 4-position of the 7-azaindoline scaffold was varied. As these intramolecular interactions also occur in non-fluorinated N1-acylated 7-azaindolines and similar heterocycles, this study is relevant to medicinal chemistry: The results will facilitate the prediction of the predominant conformations of N1-acylated-7-azaindoline-containing bioactive molecules and thus potentially contribute to drug discovery programs.

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Thieme Chemistry Journals Awardees - Where Are They Now? Bis(2-pyridyl)amides as Readily Cleavable Amides under Catalytic, Neutral, and Room-Temperature Conditions

Adachi S., Kumagai N., Shibasaki M.

Synlett （Synlett）  29 （ 3 ） 301 - 305 2018年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09365214

　概要を見る

Mild solvolytic cleavage of bis(2-pyridyl)amide under neutral and room-temperature conditions is described. The inherently stable amide was readily activated by catalytic amounts of metal cations to react with alcohols. Based on X-ray crystallographic analysis, the primary driving force was considered to be amide distortion induced by the metal coordination of two pyridyl groups in a bidentate fashion without affecting the amide functionality. The compatibility of the acid/base-sensitive functionalities and the absence of racemization during solvolysis highlight the mildness of the present protocol.

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Catalytic Oligopeptide Synthesis

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

Organic Letters （Organic Letters）  20 （ 3 ） 612 - 615 2018年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15237060

　概要を見る

Waste-free catalytic assembly of α-amino acids is fueled by a multiboron catalyst that features a characteristic B3NO2 heterocycle, providing a versatile catalytic protocol wherein functionalized natural α-amino acid units are accommodated and commonly used protecting groups are tolerated. The facile dehydrative conditions eliminate the use of engineered peptide coupling reagents, exemplifying a greener catalytic alternative for peptide coupling. The catalysis is sufficiently robust to enable pentapeptide synthesis, constructing all four amide bond linkages in a catalytic fashion.

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Direct Catalytic Asymmetric Mannich-Type Reaction en Route to α-Hydroxy-β-amino Acid Derivatives

Sun B., Pluta R., Kumagai N., Shibasaki M.

Organic Letters （Organic Letters）  20 （ 3 ） 526 - 529 2018年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15237060

　概要を見る

A direct catalytic Mannich-type reaction of α-oxygen-functionalized amides was achieved. The use of 7-azaindoline amide was crucial to facilitate direct enolization and subsequent stereoselective addition to imines in a cooperative catalytic system comprising a soft Lewis acid and Brønsted base. The operationally simple room-temperature protocol furnished a syn-Mannich adduct with high stereoselectivity. Divergent functional group transformation of the amide moiety of the product allowed for expeditious access to enantioenriched syn-configured α-hydroxy-β-amino carboxylic acid derivatives, highlighting the synthetic utility of the present catalysis.

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Heterogeneous Heterobimetallic Catalysis Enabling Expeditious Access to CF<inf>3</inf>-Containing vic-Amino Alcohols

Karasawa T., Kumagai N., Shibasaki M.

Organic Letters （Organic Letters）  20 （ 1 ） 308 - 311 2018年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15237060

　概要を見る

A highly anti-selective catalytic asymmetric nitroaldol reaction of trifluoromethyl ketones based on Nd/Na and Pr/Na heterobimetallic catalysts was developed. These catalysts function as heterogeneous catalysts to engage nitroethane and a range of trifluoromethyl ketones in a stereoselective assembly to afford CF3-appended vic-nitroalkanols that could be readily converted to enantioenriched vic-amino alcohols, which are privileged structural motifs in medicinal chemistry.

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Synthetic studies of viridiofungins, broad-spectrum antifungal agents and serine palmitoyl transferase inhibitors

Kumagai N., Shibasaki M.

Journal of Antibiotics （Journal of Antibiotics）  71 （ 1 ） 53 - 59 2018年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00218820

　概要を見る

Viridiofungins are alkyl citrate natural products characterized by their inhibitory effects on squalene synthase and serine palmitoyl transferase. Their activities as broad-spectrum antifungal agents as well as blocking agents for the biosynthesis of sphingolipids have inspired the development of several approaches toward their stereoselective total synthesis. Structurally, these natural products are a family of hybrid molecules comprising a longer alkyl chain and a citric acid unit, rendering an asymmetric structure that is difficult to access. Herein, we summarize the synthetic approaches to this attractive class of natural products, including proficient synthetic strategies for constructing the densely and chirally functionalized citric acid unit with high polarity. Particular emphasis is placed on methods for furnishing stereogenic centers in the highly constrained carbon framework.

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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.

Synlett 28 （ 16 ） A165 - A168 2017年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0936-5214

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alpha,beta-Unsaturated Amides as Dipolarophiles: Catalytic Asymmetric exo-Selective 1,3-Dipolar Cycloaddition with Nitrones

Zhang, M., Kumagai, N. and Shibasaki, M.

Chemistry-a European Journal 23 （ 51 ） 12450 - 12455 2017年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0947-6539

　概要を見る

1,3-Dipolar cycloaddition is a commonly exploited method to access 5-membered chemical entities with a variety of peripheral functionalities and their stereochemical arrangements. Nitrones are isolable 1,3-dipoles that exhibit sufficient reactivity toward electron-deficient olefins in the presence of Lewis acids to deliver highly substituted isoxazolidines. Herein we document that ,-unsaturated amides, generally regarded as barely reactive in a 1,3-dipolar reaction manifold, were effectively activated using the designed 7-azaindoline auxiliary in an In(OTf)(3)/bishydroxamic acid catalytic system. The broad substrate scope and clean removal of the 7-azaindoline auxiliary from the product highlight the synthetic utility of the present catalysis.

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Direct Catalytic Asymmetric Aldol Addition of an alpha-CF3 Amide to Arylglyoxal Hydrates

Matsuzawa, A., Noda, H., Kumagai, N. and Shibasaki, M.

Journal of Organic Chemistry 82 （ 15 ） 8304 - 8308 2017年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0022-3263

　概要を見る

Direct asymmetric aldol addition of an alpha-CF3 amide to arylglyoxal hydrates was promoted by a chiral catalyst comprising a soft Lewis acidic Cu(I), a chiral bisphosphine ligand, and DBU. The 7-azaindoline moiety of the amide facilitates its enolization and stabilizes the thus-generated Cu enolate, furnishing enantioenriched aldol adducts.

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Photocatalytic alpha-Acylation of Ethers

Sun, Z. D., Kumagai, N. and Shibasaki, M.

Organic Letters 19 （ 14 ） 3727 - 3730 2017年07月

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

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Direct coupling of ethers and acyl halides was promoted by a binary catalytic Sytem comprising an Ir-based photocatalyst and a Ni complex under blue-light irradiation. Photocatalysts with high triplet energy directed the catalysis, and the reaction likely proceeded by triplet-triplet energy transfer from the excited photocatalysts. chlorine radicals generated from an excited Ni Complex bearing, a Ni-Cl bond would be responsible for generating alpha-oxy radicals leading to the alpha-acylated ethers.

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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

　概要を見る

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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