Papers - Kumagai, Naoya

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

Research paper (scientific journal), Joint Work, Accepted,  ISSN  14770520

　View Summary

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.

• Access to Document (DOI)

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

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00397881

　View Summary

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.

• Access to Document (DOI)

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 2018.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00027863

　View Summary

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.

• Access to Document (DOI)

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 2018.06

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00404020

　View Summary

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.

• Access to Document (DOI)

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 2018.06

Research paper (international conference proceedings), Joint Work, Accepted,  ISSN  00786209

　View Summary

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.

• Access to Document (DOI)

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 2018.05

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15237060

　View Summary

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.

• Access to Document (DOI)

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 2018.05

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00223263

　View Summary

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.

• Access to Document (DOI)

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 2018.04

Research paper (scientific journal), Joint Work, Accepted,  ISSN  21935807

　View Summary

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.

• Access to Document (DOI)

Conquering amide planarity: Structural distortion and its hidden reactivity

Adachi S., Kumagai N., Shibasaki M.

Tetrahedron Letters (Tetrahedron Letters)  59 ( 13 ) 1147 - 1158 2018.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00404039

　View Summary

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.

• Access to Document (DOI)

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 2018.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09476539

　View Summary

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.

• Access to Document (DOI)

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 2018.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1434193X

　View Summary

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.

• Access to Document (DOI)

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 2018.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09365214

　View Summary

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.

• Access to Document (DOI)

Catalytic Oligopeptide Synthesis

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

Organic Letters (Organic Letters)  20 ( 3 ) 612 - 615 2018.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15237060

　View Summary

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.

• Access to Document (DOI)

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 2018.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15237060

　View Summary

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.

• Access to Document (DOI)

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 2018.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15237060

　View Summary

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.

• Access to Document (DOI)

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 2018.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00218820

　View Summary

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.

• Access to Document (DOI)

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 2017.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0936-5214

• Access to Document (DOI)

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 2017.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0947-6539

　View Summary

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.

• Access to Document (DOI)

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 2017.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0022-3263

　View Summary

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.

• Access to Document (DOI)

Photocatalytic alpha-Acylation of Ethers

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

Organic Letters 19 ( 14 ) 3727 - 3730 2017.07

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1523-7060

　View Summary

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.

• Access to Document (DOI)