Mechanism-Guided Development of Bifunctional Cyclooctenes as Active, Practical, and Light-Gated Bromination Catalysts.
Tagui Nagano, Takuto Shimazu, Yusuke Ono, Kazuma Kaneko, Seijiro Matsubara, Masahiro Yamanaka, Daisuke Uraguchi, Keisuke Asano
Chemistry (Weinheim an der Bergstrasse, Germany), e202404011, 16 Dec. 2024, [International Magazine]
English, Scientific journal, Most molecular catalysts have been developed employing polar functional groups as catalytic sites. However, the use of non-polar functional groups for catalysis has received less attention due to their modest molecular interactions while the bioorthogonal reactivity of non-polar alkenes as substrates is frequently used in click chemistry. In this study, we conducted mechanistic studies on the catalysis of trans-cyclooctene (TCO) derivatives with the strained olefin as the catalytic site using kinetic and computational analyses to aid the design of more active olefin catalysts. The analysis reveals the significant role of the benzyl substituents in accelerating the generation of bromonium species through dispersion interaction in the rate-determining step. Guided by the mechanistic insights, we developed bifunctional TCO catalysts bearing a functionalized benzyl group, taking advantage of the remarkable substituent effects. Experimental studies confirmed the theoretical model and revealed that TCO with a para-hydroxybenzyl group provided excellent catalytic activity. Furthermore, inclusion of the functionalized benzyl groups allowed more readily available and robust cis-cyclooctenes to be used as active catalysts, expanding the practical utility of the olefin catalysts. By using a photochemically labile masking group on the para-hydroxybenzyl substituent, the first light-gated bromination catalyst was developed, enabling spatiotemporal control of the transformation.

BODNs as biocompatible brominating reagents: visible-light photocatalytic tyrosine modification under physiologically favorable conditions.
Rakuto Yoshida, Yuichiro Hori, Daisuke Uraguchi, Keisuke Asano
Chemical communications (Cambridge, England), 07 Oct. 2024, [International Magazine]
English, Scientific journal, The photochemical reactivity of 1-bromo-2-oxo-1,2-dihydronaphthalene-1-carboxylates (BODNs) was demonstrated. They are inert in the dark under physiological conditions but become active as brominating reagents for tyrosine modification under visible light irradiation in the presence of a photocatalyst. The BODNs can be applied to protein labeling with bromo groups as sensitive mass tags.

Synthesis of Substituted Cyclooctenes through Cross-Coupling Reactions
Ryuichi Murata, Rakuto Yoshida, Daisuke Uraguchi, Keisuke Asano
Synlett, 36, 1, 69, 74, 03 Jun. 2024
Scientific journal, Cross-coupling methods for the introduction of various substituents onto the olefin moiety of cyclooctenes were developed. A range of 1-substituted cis -cyclooctenes were synthesized. These protocols unlocked routes to previously inaccessible derivatives, permitting the syntheses of cis -cyclooctenes bearing various functional groups. Moreover, the method was applied to the synthesis of a 1,2-disubstituted trans -cyclooctene for the first time, which proved to be a significantly more active organocatalyst than the previously developed monosubstituted trans -cyclooctene.

trans-Cyclooctenes as Scavengers of Bromine Involved in Catalytic Bromination
Ryuichi Murata, Kenta Shitamichi, Masatsugu Hiramatsu, Seijiro Matsubara, Daisuke Uraguchi, Keisuke Asano
Chemistry - A European Journal, 30, 8, e202303399, 07 Feb. 2024, [International Magazine]
English, Scientific journal, Scavengers that capture reactive chemical substances are used to prevent the decomposition of materials. However, in the field of catalysis, the development of scavengers that inhibit background pathways has attracted little attention, although the concept will open up an otherwise inaccessible reaction space. In catalytic bromination, fast non-catalyzed background reactions disturb the catalytic control of the selectivity, even when using N-bromoamide reagents, which have a milder reactivity than bromine (Br2). Here, we developed a trans-cyclooctene (TCO) bearing a 2-pyridylethyl group to efficiently retard background reactions by capturing Br2 in bromocyclization using N-bromosuccinimide. The use of less than a stoichiometric amount of the TCO was sufficient to inhibit non-catalyzed reactions, and mechanistic studies using the TCO revealed that in situ-generated Br2 provides non-catalyzed reaction pathways based on a chain mechanism. The TCO is useful as an additive for improving enantioselectivity and regioselectivity in catalytic reactions. Cooperative systems using the TCO with selective catalysts offer an alternative strategy for optimizing catalyst-controlled selectivity during bromination. Moreover, it also served as an indicator of Br2 involved in catalytic reaction pathways; thus, the TCO was useful as a probe for mechanistic investigations into the involvement of Br2 in bromination reactions of interest.

Organocatalytic Access to Tetrasubstituted Chiral Carbons Integrating Functional Groups
Keisuke Asano, Seijiro Matsubara
CHEMICAL RECORD, WILEY-V C H VERLAG GMBH, Sep. 2022
English, Scientific journal, Three-dimensional organic structures containing sp(3) carbons bearing four non-hydrogen substituents can provide drug-like molecules. Although such complex structures are challenging targets in synthetic organic chemistry, efficient synthetic approaches will open a new chemical space for pharmaceutical candidates. This review provides an account of our recent achievements in developing organocatalytic approaches to attractive molecular platforms based on optically active sp(3) carbons integrating four different functional groups. These methodologies include asymmetric cycloetherification and cyanation of multifunctional ketones, both of which take advantage of the mild characteristics of organocatalytic activation. Enzyme-like but non-enzymatic organocatalytic systems can be used to precisely manufacture molecules containing complex chiral structures without substrate specificity problems. In addition, these catalytic systems control not only stereoselectivity but also site-selectivity and do not induce side reactions even from substrates with rich functionality.

【計画的セレンディピティが医学・創薬を革新する!】有機触媒探索からの計画的セレンディピティ
生長 幸之助, 浅野 圭佑, 上田 善弘
医学のあゆみ, 282, 9, 826, 828, 医歯薬出版(株), Aug. 2022
Japanese, "第3の触媒"ともよばれる有機触媒は、医薬品をはじめとする高付加価値物質の持続的生産プロセスの確立に多大な貢献を果たし、2021年のノーベル化学賞が授与された研究領域である。一方で、さらなる高次機能の要請や研究コストの肥大化を背景に、探索効率の飛躍的向上をもたらす新たな発想が求められてもいる。本稿では、医薬探索との共通項・差異に着目したうえで技術転用していく発想から、有機触媒探索においても探索範囲の拡大と評価の高速化を達成しうる事例を取り上げる。このような探索法は、予想外の低確率発生事象を意図的に見出していく"計画的セレンディピティ"を体現するための重要基盤となる。有機触媒探索から"計画的セレンディピティ"が達成されることでひらかれる未来はどのようなものか、ということにも触れてみたい。(著者抄録)

Non-enzymatic catalytic asymmetric cyanation of acylsilanes
Tagui Nagano, Akira Matsumoto, Ryotaro Yoshizaki, Keisuke Asano, Seijiro Matsubara
COMMUNICATIONS CHEMISTRY, 5, 1, NATURE PORTFOLIO, Mar. 2022
English, Scientific journal, Catalytic asymmetric cyanation of ketones is a straightforward method to construct tetrasubstituted chiral carbon centers, but for acylsilanes this method has been limited to enzymatic approaches. Here, non-enzymatic catalytic asymmetric cyanation of acylsilanes is accomplished using a chiral Lewis base as an enantioselective catalyst.The asymmetric cyanation of acylsilanes affords densely functionalized tetrasubstituted chiral carbon centers bearing silyl, cyano, and hydroxy groups, which are of particular interest in synthetic and medicinal chemistry. However, this method has been limited to a few enzymatic approaches, which employ only one substrate because of substrate specificity. Here we show the non-enzymatic catalytic asymmetric cyanation of acylsilanes using a chiral Lewis base as an enantioselective catalyst, trimethylsilyl cyanide as a cyanating reagent, and isopropyl alcohol as an additive to drive catalyst turnover. High enantio- and site-selectivities are achieved in a catalytic manner, and a variety of functional groups are installed in optically active acylsilane cyanohydrins, thus overcoming the limitations imposed by substrate specificity in conventional enzymatic methods. A handle for the synthetic application of the products is also established through the development of a catalyst for protecting acylsilane cyanohydrins, which are unstable and difficult to protect alcohols.

Catalytic asymmetric cycloetherification via intramolecular oxy-Michael addition of enols
Ryuichi Murata, Keisuke Asano, Seijiro Matsubara
TETRAHEDRON, 97, 132381, PERGAMON-ELSEVIER SCIENCE LTD, Sep. 2021
English, Scientific journal, Carbonyl compounds employed as carbon nucleophiles have played a dominant role in synthetic organic chemistry; however, there is very limited use of these compounds as oxygen nucleophiles. In particular, there are only a few reports on the oxy-Michael addition of the enol forms of carbonyl nucleophiles. In this study, we present the asymmetric cycloetherification of enols, which are generated in situ from enone-bearing ketones, using chiral bifunctional organocatalysts bearing amino and squaramide groups. This transformation chemo-and enantioselectively afforded dihydropyran derivatives, which are the core structures of building blocks for synthesizing glycans. (c) 2021 Elsevier Ltd. All rights reserved.

Multipoint Recognition of Molecular Conformations with Organocatalysts for Asymmetric Synthetic Reactions
Keisuke Asano
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, 94, 2, 694, 712, CHEMICAL SOC JAPAN, Feb. 2021
English, Organocatalysts activate substrates through mild noncovalent and covalent interactions, and their cooperative actions at multiple catalytic sites are essential even in intrinsically rapid organic reactions such as intramolecular cyclizations. The enzyme-like catalytic system is effective for recognizing specific molecular conformations of substrates, which continually change under reaction conditions, through multipoint interactions, thereby leading to high stereoselectivity. On the basis of this concept, we developed a range of organocatalytic asymmetric synthetic reactions, which are challenging using other categories of catalysts. The proposed catalysis was applied to various manners of asymmetric induction including those accompanied by not only facial selectivity but also by kinetic resolution (KR), dynamic kinetic resolution (DKR), desymmetrization, and dynamic kinetic asymmetric transformation (DYKAT). They enabled various asymmetric transformations through intramolecular hetero-Michael addition, construction of axial chirality, and alpha,beta-unsaturated acylammonium catalysis, which advanced the methods for asymmetric heterocycle synthesis, construction of tetrasubstituted chiral carbons, enantioselective synthesis of axially chiral compounds, and asymmetric library synthesis of pharmaceutically potential compounds. This study also expanded the chemistry of bifunctional organocatalysis. This review provides a comprehensive account of our achievements regarding multipoint recognition of molecular conformations with organocatalysts for asymmetric synthetic reactions.

trans-Cyclooctenes as Chiral Ligands in Rhodium-Catalyzed Asymmetric 1,4-Additions
Tagui Nagano, Shunsuke Einaru, Kenta Shitamichi, Keisuke Asano, Seijiro Matsubara
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2020, 46, 7131, 7133, WILEY-V C H VERLAG GMBH, Dec. 2020
English, Scientific journal, trans-Cyclooctenes serve as asymmetric ligands for the rhodium-catalyzed 1,4-additions of organotin reagents to enones. We demonstrate, for the first time, that these chiral olefins can provide efficient coordination spheres for asymmetric metal catalysis. As the asymmetric environment around the reaction site is constructed by thetrans-cyclooctene framework, the introduction of a substituent at the allylic position further improves enantioselectivity to 93 %ee. These findings provide new chiral framework designs for the asymmetric ligands of metal catalysts.

Desymmetrization of gem-diols via water-assisted organocatalytic enantio- and diastereoselective cycloetherification
Ryuichi Murata, Akira Matsumoto, Keisuke Asano, Seijiro Matsubara
CHEMICAL COMMUNICATIONS, 56, 82, 12335, 12338, ROYAL SOC CHEMISTRY, Oct. 2020
English, Scientific journal, The first desymmetrization of gem-diols forming chiral hemiketal carbons was accomplished via organocatalytic enantio- and diastereoselective cycloetherification, which afforded optically active tetrahydropyrans containing a chiral hemiketal carbon and tetra-substituted stereocenters bearing synthetically versatile fluorinated groups. The desymmetrization of silanediols was also demonstrated as an asymmetric route to chiral silicon centers.

Enantio- and Diastereoselective Construction of Contiguous Tetrasubstituted Chiral Carbons in Organocatalytic Oxadecalin Synthesis
Yuuki Wada, Ryuichi Murata, Yuki Fujii, Keisuke Asano, Seijiro Matsubara
Organic Letters, American Chemical Society (ACS), 03 Jun. 2020, [Peer-reviewed], [Corresponding author]
English, Scientific journal

Enantioselective bromination of axially chiral cyanoarenes in the presence of bifunctional organocatalysts
Yuuki Wada, Akira Matsumoto, Keisuke Asano, Seijiro Matsubara
RSC Advances, 2019, 9, 31654–31658., 9, 54, 31654, 31658, Royal Society of Chemistry (RSC), Oct. 2019, [Peer-reviewed], [Corresponding author]
English, Scientific journal,

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported.

Asymmetric syn-1,3-dioxane construction via kinetic resolution of secondary alcohols using chiral phosphoric acid catalysts　　　　　　　　　　　　　　　
Matsumoto, A, Asano, K, Matsubara, S
Asian Journal of Organic Chemistry, 2019, 8, 814–818., Apr. 2019, [Peer-reviewed]
English, Scientific journal

Organocatalytic enantio- and diastereoselective construction of syn-1,3-diol motifs via dynamic kinetic resolution of in situ generated chiral cyanohydrins　　　　　　　　　　　　　　　
Matsumoto, A, Asano, K, Matsubara, S
Organic Letters, 2019, 21, 2688–2692., Apr. 2019, [Peer-reviewed]
English, Scientific journal

Asymmetric cycloetherification of in situ generated cyanohydrins through the concomitant construction of three chiral carbon centers　　　　　　　　　　　　　　　
Kurimoto, Y, Nasu, T, Fujii, Y, Asano, K, Matsubara, S
Organic Letters, 2019, 21, 2156–2160., Mar. 2019, [Peer-reviewed]
English, Scientific journal

Kinetic resolution of acylsilane cyanohydrins via organocatalytic cycloetherification　　　　　　　　　　　　　　　
Matsumoto, A, Asano, K, Matsubara, S
Chemistry—An Asian Journal, 2019, 14, 116–120., Nov. 2018, [Peer-reviewed]
English, Scientific journal

trans-Cyclooctenes as halolactonization catalysts　　　　　　　　　　　　　　　
Einaru, S, Shitamichi, K, Nagano, T, Matsumoto, A, Asano, K, Matsubara, S
Angewandte Chemie International Edition, 2018, 57, 13863–13867., Aug. 2018, [Peer-reviewed]
English, Scientific journal

Asymmetric cycloetherification by bifunctional organocatalyst　　　　　　　　　　　　　　　
Asano, K, Matsubara, S
Synthesis, 2018, 50, 4243–4253., Jun. 2018, [Peer-reviewed]
English, Scientific journal

Catalytic approaches to optically active 1,5-benzothiazepines　　　　　　　　　　　　　　　
Asano, K, Matsubara, S
ACS Catalysis, 2018, 8, 6273–6282., May 2018, [Peer-reviewed]
English, Scientific journal

Organocatalytic Enantio- and Diastereoselective Cycloetherification via Dynamic Kinetic Resolution of Chiral Cyanohydrins
Naoki Yoneda, Yuki Fuji, Akira Matsumoto, Keisuke Asano, Seijiro Matsubara
SYNTHESIS-STUTTGART, 50, 5, A33, A35, GEORG THIEME VERLAG KG, Mar. 2018, [Peer-reviewed]
English, Scientific journal

生物活性複素環の迅速不斉ライブラリー合成　　　　　　　　　　　　　　　
浅野 圭佑
上原記念生命科学財団研究報告集, 32, 6p, 上原記念生命科学財団, 2018, [Peer-reviewed]
Japanese, Scientific journal

Organocatalytic enantio- and diastereoselective cycloetherification via dynamic kinetic resolution of chiral cyanohydrins
Naoki Yoneda, Yuki Fujii, Akira Matsumoto, Keisuke Asano, Seijiro Matsubara
NATURE COMMUNICATIONS, 8, NATURE PUBLISHING GROUP, Nov. 2017, [Peer-reviewed]
English, Scientific journal, Enantioselective approaches to synthesize six-membered oxacycles with multiple stereogenic centres are in high demand to enable the discovery of new therapeutic agents. Here we present a concise organocatalytic cycloetherification for the highly enantio-and diastereoselective synthesis of tetrahydropyrans involving simultaneous construction of two chiral centres, one of which is fully substituted. This method involves dynamic kinetic resolution of reversibly generated chiral cyanohydrins. A chiral bifunctional organocatalyst selectively recognizes a specific chair-like conformation of the intermediate, in which the small steric effect of the linear cyano group as well as its anomeric effect play important roles in controlling stereoselectivity. The products offer additional utility as synthetic intermediates because the cyano group can be further transformed into a variety of important functional groups. This strategy provides a platform to design efficient approaches to obtain a wide range of optically active tetrahydropyrans, which are otherwise synthetically challenging materials.

Asymmetric net cycloaddition for access to diverse substituted 1,5-benzothiazepines　　　　　　　　　　　　　　　
Fukata, Y, Yao, K, Miyaji, R, Asano, K, Matsubara, S
The Journal of Organic Chemmistry, 2017, 82, 12655–12668., Nov. 2017, [Peer-reviewed]
English, Scientific journal

Bifunctional organocatalysts for the asymmetric synthesis of axially chiral benzamides
Ryota Miyaji, Yuuki Wada, Akira Matsumoto, Keisuke Asano, Seijiro Matsubara
BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, 13, 1518, 1523, BEILSTEIN-INSTITUT, Aug. 2017, [Peer-reviewed]
English, Scientific journal, Bifunctional organocatalysts bearing amino and urea functional groups in a chiral molecular skeleton were applied to the enantioselective synthesis of axially chiral benzamides via aromatic electrophilic bromination. The results demonstrate the versatility of bifunctional organocatalysts for the enantioselective construction of axially chiral compounds. Moderate to good enantioselectivities were afforded with a range of benzamide substrates. Mechanistic investigations were also carried out.

Induction of Axial Chirality in 8-Arylquinolines through Halogenation Reactions Using Bifunctional Organocatalysts
Ryota Miyaji, Keisuke Asano, Seijiro Matsubara
CHEMISTRY-A EUROPEAN JOURNAL, 23, 42, 9996, 10000, WILEY-V C H VERLAG GMBH, Jul. 2017, [Peer-reviewed]
English, Scientific journal, The enantioselective syntheses of axially chiral heterobiaryls were accomplished through the aromatic electrophilic halogenation of 3-(quinolin-8-yl)phenols with bifunctional organocatalysts that control the molecular conformations during successive halogenations. Axially chiral quinoline derivatives, which have rarely been synthesized in an enantioselective catalytic manner, were afforded in moderate-to-good enantioselectivities through bromination, and an analogous protocol also enabled enantioselective iodination. In addition, this catalytic reaction, which allows enantioselective control through the use of mono-ortho-substituted substrates, allowed the asymmetric synthesis of 8-arylquinoline derivatives bearing two different halogen groups in high enantioselectivities.

s Asymmetric Syntheses Utilizing Mild Activations by Organocatalysts
Keisuke Asano
JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN, 74, 12, 1194, 1205, SOC SYNTHETIC ORGANIC CHEM JPN, Dec. 2016, [Peer-reviewed]
Japanese, Scientific journal, Organocatalysts utilize various molecular interactions for catalysis. However, molecular interactions for organocatalysis are in general not as strong as those for metal-catalysis. Thus, because of this character, multiple activations are often necessary to catalyze a reaction, however, in other words, it enables the use of multipoint interactions in the transition state of a catalytic reaction, thereby leading to high stereoselectivity, even if it is a very rapid reaction. On the basis of this concept, we developed asymmetric reactions affording various heterocycles via organocatalytic hetero-Michael additions and the applied synthetic transformations. In order to accomplish high enantioselectivity, we designed reactions utilizing different activation manners by organocatalysts depending on the substrate type; it is a key to utilize simultaneous multipoint interactions between a catalyst and a substrate.

Asymmetric Cycloetherification via the Kinetic Resolution of Alcohols Using Chiral Phosphoric Acid Catalysts
Naoki Yoneda, Akira Matsumoto, Keisuke Asano, Seijiro Matsubara
CHEMISTRY LETTERS, 45, 11, 1300, 1303, CHEMICAL SOC JAPAN, Nov. 2016, [Peer-reviewed]
English, Scientific journal, In this study, novel asymmetric cycloetherification via the kinetic resolution of secondary or tertiary alcohols using chiral phosphoric acid catalysts was developed, affording tetrahydropyrans (THPs) with two stereogenic centers. The cyclization of the recovered optically active alcohols afforded other stereoisomers of THPs. These protocols offer efficient synthetic routes to various optically active THP derivatives, which are important structures found in a range of biologically active agents.

有機分子触媒による分子内不斉オキシマイケル付加反応を利用した光学活性ポリケチド合成法の開発　　　　　　　　　　　　　　　
浅野 圭佑
旭硝子財団助成研究成果報告 Reports of research assisted by the Asahi Glass Foundation, 1, 8, 旭硝子財団, Jan. 2016, [Peer-reviewed]
Japanese, Scientific journal

Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts
Naoki Yoneda, Yukihiro Fukata, Keisuke Asano, Seijiro Matsubara
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 54, 51, 15497, 15500, WILEY-V C H VERLAG GMBH, Dec. 2015, [Peer-reviewed]
English, Scientific journal, Chiral spiroketal skeletons are found as core structures in a range of bioactive compounds. These natural compounds and their analogues have attracted much attention in the field of drug discovery. However, methods for their enantioselective construction are limited, and easily available optically active spiroketals are rare. We demonstrate a novel catalytic asymmetric synthesis of spiroketal compounds that proceeds through an intramolecular hemiacetalization/oxy-Michael addition cascade mediated by a bifunctional aminothiourea catalyst. This results in spiroketal structures through the relay formation of contiguous oxacycles, in which multi-point recognition by the catalyst through hydrogen bonding imparts high enantioselectivity. This method offers facile access to spiroketal frameworks bearing an alkyl group at the 2-position, which are prevalent in insect pheromones. Optically active (2S,5S)-chalcogran, a pheromone of the six-spined spruce bark beetle, and an azide derivative could be readily synthesized from the bicyclic reaction product.

穏やかな触媒がもたらす精密有機合成　　　　　　　　　　　　　　　
浅野 圭佑
化学と工業, 2015, 68, 832–833., Sep. 2015, [Peer-reviewed], [Invited]
Japanese, Scientific journal

Diastereoselective Reduction of beta-(1,3-Dioxan-4-yl)ketones
Akira Matsumoto, Keisuke Asano, Seijiro Matsubara
SYNLETT, 26, 13, 1872, 1874, GEORG THIEME VERLAG KG, Aug. 2015, [Peer-reviewed]
English, Scientific journal, Stereoselective reduction of beta-(1,3-dioxan-4-yl) ketones is an important step in the efficient synthesis of chiral 1,3-polyols, a typical structure of polyketides. In this study, we carried out investigations to optimize the conditions for diastereoselective reduction.

Bifunctional organocatalysts for the enantioselective synthesis of axially chiral isoquinoline n -oxides
Ryota Miyaji, Keisuke Asano, Seijiro Matsubara
Journal of the American Chemical Society, 137, 21, 6766, 6769, American Chemical Society, 03 Jun. 2015, [Peer-reviewed]
English, Scientific journal, Bifunctional catalysts bearing amino and urea functional groups have been applied for a novel, highly enantioselective synthesis of axially chiral isoquinoline N-oxides, which are promising chiral ligands or organocatalysts in organic synthesis. This is the first example of highly enantioselective synthesis of axially chiral biaryls by bifunctional organocatalysts. Good-to-excellent enantioselectivities were obtained with a range of substrates.

Facile Net Cycloaddition Approach to Optically Active 1,5-Benzothiazepines
Yukihiro Fukata, Keisuke Asano, Seijiro Matsubara
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 137, 16, 5320, 5323, AMER CHEMICAL SOC, Apr. 2015, [Peer-reviewed]
English, Scientific journal, The 1,5-benzothiazepine moiety is well-known as a versatile pharmacophore, and its derivatives are expected to have antagonism against numerous diseases. Thus, it is desirable to develop a synthetic route that enables facile enantioselective preparation of a wide range of such derivatives. Although the cycloaddition approach could be considered a possible route to these compounds, to date, there has been no precedent of such a protocol. We therefore present the first example of a highly enantioselective net [4 + 3] cycloaddition to afford 1,5-benzothiazepines by utilizing alpha,beta-unsaturated acylammonium intermediates generated by chiral isothiourea catalysts, which undergo two sequential chemoselective nucleophilic attacks by 2-aminothiophenols. This protocol provided cycloadducts in extremely high regioselectivity, with a good-to-excellent stereoselectivity being achieved regardless of the steric and electronic properties of the substrates. This method therefore offers promising synthetic routes for the construction of a library of optically active 1,5-benzothiazepines for assay evaluation.

A chiral phosphoric acid catalyst for asymmetric construction of 1,3-dioxanes
Akira Matsumoto, Keisuke Asano, Seijiro Matsubara
CHEMICAL COMMUNICATIONS, 51, 58, 11693, 11696, ROYAL SOC CHEMISTRY, 2015, [Peer-reviewed]
English, Scientific journal, A novel method of enantioselective 1,3-dioxane construction via a hemiacetalization/intramolecular oxy-Michael addition cascade by a chiral phosphoric acid catalyst was developed. The product was successfully transformed into an optically active 1,3-polyol motif, indicating that the proposed reaction can provide useful chiral building blocks for the de novo synthesis of polyketides.

Asymmetric Oxy-Michael Addition to gamma-Hydroxy-alpha,beta-Unsaturated Carbonyls Using Formaldehyde as an Oxygen-Centered Nucleophile
Naoki Yoneda, Ayano Hotta, Keisuke Asano, Seijiro Matsubara
ORGANIC LETTERS, 16, 23, 6264, 6266, AMER CHEMICAL SOC, Dec. 2014, [Peer-reviewed]
English, Scientific journal, Formaldehyde was utilized as an oxygen-centered nucleophile in an asymmetric oxy-Michael addition to gamma-hydroxy-alpha,beta-unsaturated carbonyl compounds using bifunctional organocatalysts through hemiacetal intermediates. The cyclic acetal product could be further transformed into beta-hydroxycarbonyl compounds, useful synthetic intermediates leading to various important target molecules. As such, this method is an example of a novel formal asymmetric hydration of alpha,beta-unsaturated carbonyl compounds.

One fluorine atom changes selectivity—suggestion of new synthetic auxiliary group　　　　　　　　　　　　　　　
Keisuke Asano
Kagaku, 2014, 69 (9), 64–65., Sep. 2014, [Peer-reviewed], [Invited]
Japanese, Scientific journal

Asymmetric Isomerization of omega-Hydroxy-alpha,beta-Unsaturated Thioesters into beta-Mercaptolactones by a Bifunctional Aminothiourea Catalyst
Yukihiro Fukata, Takaaki Okamura, Keisuke Asano, Seijiro Matsubara
ORGANIC LETTERS, 16, 8, 2184, 2187, AMER CHEMICAL SOC, Apr. 2014, [Peer-reviewed]
English, Scientific journal, We present a novel methodology for the asymmetric synthesis of beta-mercaptolactones via isomerization of cohydroxy-alpha,beta-unsaturated thioesters by means of a bifunctional aminothiourea catalyst. The catalyst interacts with the substrate through the cooperative action of both a covalent bond at the amino group and noncovalent bonding at the thiourea group. The potential for an enantiodivergent synthesis could also be demonstrated by carrying out the reaction in a different solvent system.

Enantioselective Synthesis of Axially Chiral Compounds by Organocatalysts
Keisuke Asano
JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN, 72, 2, 185, 186, SOC SYNTHETIC ORGANIC CHEM JPN, Feb. 2014, [Peer-reviewed], [Invited]
Japanese, Scientific journal, Several enantioselective syntheses of axially chiral compounds have been recently accomplished by means of various organocatalysts. The strategies reported thus far can be classified into three manners including atroposelective formation of chiral axis, dynamic kinetic resolution, and desymmetrization. These organocatalytic methods opened new avenues for the construction of axial chirality, thereby leading to the synthesis of axially chiral compounds which have been synthetically challenging through conventional methods.

Asymmetric chroman synthesis via an intramolecular oxy-Michael addition by bifunctional organocatalysts
Ryota Miyaji, Keisuke Asano, Seijiro Matsubara
ORGANIC & BIOMOLECULAR CHEMISTRY, 12, 1, 119, 122, ROYAL SOC CHEMISTRY, Jan. 2014, [Peer-reviewed]
English, Scientific journal, Cinchona-alkaloid-urea-based bifunctional organocatalysts facilitate the catalytic asymmetric synthesis of chroman derivatives via an intramolecular oxy-Michael addition reaction. Phenol derivatives bearing an easily available (E)-alpha,beta-unsaturated ketone or a thioester moiety are useful substrates for the title transformation. This method represents a facile synthesis of various optically active 2-substituted chromans in high yield.

Procedure-controlled enantioselectivity switch in organocatalytic 2-oxazolidinone synthesis
Yukihiro Fukata, Keisuke Asano, Seijiro Matsubara
Journal of the American Chemical Society, 135, 33, 12160, 12163, 21 Aug. 2013, [Peer-reviewed]
English, Scientific journal, In a novel organocatalytic formal [3 + 2] cycloaddition to afford chiral 2-oxazolidinones, an enantioselectivity switch could be induced by changing the manner of addition of the reactants, even when the reaction components (cinchona-alkaloid-derived aminothiourea catalyst, substrates, and solvent) were the same. © 2013 American Chemical Society.

Asymmetric Indoline Synthesis via Intramolecular Aza-Michael Addition Mediated by Bifunctional Organocatalysts
Ryota Miyaji, Keisuke Asano, Seijiro Matsubara
ORGANIC LETTERS, 15, 14, 3658, 3661, AMER CHEMICAL SOC, Jul. 2013, [Peer-reviewed]
English, Scientific journal, A novel method for the asymmetric synthesis of 2-substituted indolines, employing bifunctional amino(thio)urea catalysts, was developed. The reaction proceeded via an intramolecular aza-Michael addition mediated by activation through hydrogen bonding. The catalytic process was shown to be highly versatile and applicable to a wide range of substrates due to the flexible catalytic mechanism utilizing a noncovalent interaction.

Pauson-Khand Reactions in a Photochemical Flow Microreactor
Keisuke Asano, Yuki Uesugi, Jun-ichi Yoshida
ORGANIC LETTERS, 15, 10, 2398, 2401, AMER CHEMICAL SOC, May 2013, [Peer-reviewed]
English, Scientific journal, Pauson-Khand reactions were achieved at ambient temperature without any additive using a photochemical flow microreactor. The efficiency of the reaction was better than that in a conventional batch reactor, and the reaction could be operated continuously for 1 h.

Asymmetric Synthesis of 1,3-Oxazolidines via Intramolecular Aza-Michael Addition by Bifunctional Organocatalysts
Yukihiro Fukata, Keisuke Asano, Seijiro Matsubara
CHEMISTRY LETTERS, 42, 4, 355, 357, CHEMICAL SOC JAPAN, Apr. 2013, [Peer-reviewed]
English, Scientific journal, A novel synthetic route to optically active 1,3-oxazolidines via formal [3 + 2] cycloaddition in the presence of cinchona-alkaloid-thiourea-based bifunctional organocatalysts is reported. This protocol gives easy access to a wide range of chiral 1,3-oxazolidines. In addition, the results show that bifunctional organocatalysts can effect the intramolecular aza-Michael addition, leading to the asymmetric synthesis of nitrogen-containing heterocycles.

Asymmetric cycloetherifications by bifunctional aminothiourea catalysts: The importance of hydrogen bonding
Yukihiro Fukata, Ryota Miyaji, Takaaki Okamura, Keisuke Asano, Seijiro Matsubara
Synthesis (Germany), 45, 12, 1627, 1634, 2013, [Peer-reviewed]
English, Scientific journal, Chiral oxacyclic frameworks are prevalent in many natural products and bioactive compounds. In addition, a number of them are important synthetic intermediates. Thus, the synthesis of such structures is a significant goal in the field of organic chemistry. However, the development of catalytic asymmetric cycloetherification for the straightforward synthesis of these compounds remains a challenge. In this study, we propose the use of aminothiourea catalysis as an effective way to accomplish such a challenge. The asymmetric synthesis of chiral oxygen heterocycles, including tetrahydrofurans, tetrahydropyrans, and 1,3-dioxolanes, is demonstrated herein using intramolecular oxy-Michael addition mediated by bifunctional aminothiourea catalysts. © Georg Thieme Verlag Stuttgart · New York.

Asymmetric Synthesis of 1,3-Dioxolanes by Organocatalytic Formal [3+2] Cycloaddition via Hemiacetal Intermediates
Keisuke Asano, Seijiro Matsubara
ORGANIC LETTERS, 14, 6, 1620, 1623, AMER CHEMICAL SOC, Mar. 2012, [Peer-reviewed]
English, Scientific journal, A novel asymmetric formal [3 + 2] cycloaddition reaction for the synthesis of 1,3-dioxolanes using cinchona-alkaloid-thiourea-based bifunctional organocatalysts is reported. The reaction proceeds via the formation of hemiacetal intermediates between gamma-hydroxy-alpha,beta-unsaturated ketones and aldehydes.

Organocatalytic asymmetric oxy-Michael addition to a gamma-hydroxy-alpha,beta-unsaturated thioester via hemiacetal intermediates
Takaaki Okamura, Keisuke Asano, Seijiro Matsubara
CHEMICAL COMMUNICATIONS, 48, 42, 5076, 5078, ROYAL SOC CHEMISTRY, 2012, [Peer-reviewed]
English, Scientific journal, We report an asymmetric oxy-Michael addition to a gamma-hydroxya, alpha,beta-unsaturated thioester via hemiacetal intermediates in the presence of Cinchona-alkaloid-thiourea-based bifunctional organo-catalysts. This method provides a novel enantioselective route to beta-hydroxy carboxyl compounds, which in turn can be used to synthesize valuable chiral building blocks.

Asymmetric Catalytic Cycloetherification Mediated by Bifunctional Organocatalysts
Keisuke Asano, Seijiro Matsubara
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 133, 42, 16711, 16713, AMER CHEMICAL SOC, Oct. 2011, [Peer-reviewed]
English, Scientific journal, Oxacyclic structures such as tetrahydrofuran (THF) rings are commonly found in many bioactive compounds, and this has led to several efforts toward their stereoselective syntheses. However, the process of catalytic asymmetric cycloetherification for their straightforward synthesis has remained a challenge. In this study, we demonstrate a novel asymmetric synthesis method for THF via the catalytic cycloetherification of epsilon-hydroxy-alpha,beta-unsaturated ketones mediated by cinchona-alkaloid-thiourea-based bifunctional organocatalysts. This catalytic process represents a highly practical cycloetherification method that provides excellent enantioselectivities, even with low catalyst loadings at ambient temperature.

Effects of a Flexible Alkyl Chain on an Imidazole Ligand for Copper-Catalyzed Mannich Reactions of Terminal Alkynes
Takaaki Okamura, Keisuke Asano, Seijiro Matsubara
SYNLETT, 20, 3053, 3056, GEORG THIEME VERLAG KG, Dec. 2010, [Peer-reviewed]
English, Scientific journal, Copper-catalyzed Mannich reactions of terminal alkynes and secondary amines with aqueous formaldehyde can be accelerated by the use of a catalytic amount of an imidazole ligand carrying a long alkyl chain. The alkyl chain shows an efficient steric effect and helps the reaction. This imidazole ligand is efficient for various substrates, including even bulky alkynes.

Effects of a Flexible Alkyl Chain on a Ligand for CuAAC Reaction
Keisuke Asano, Seijiro Matsubara
ORGANIC LETTERS, 12, 21, 4988, 4991, AMER CHEMICAL SOC, Nov. 2010, [Peer-reviewed]
English, Scientific journal, Imidazole derivatives substituted by a normal alkyl group are shown to be efficient as a ligand for the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. An alkyl chain on the imidazole ligands shows an efficient steric effect and benefits the reaction. Such functionalities of an alkyl chain allow a rapid CuAAC reaction of even a bulky alkyne, which has been difficult to perform under conventional conditions.

DESIGN OF REACTION MEDIA FOR NUCLEOPHILIC SUBSTITUTION REACTIONS BY USING A CATALYTIC AMOUNT OF AN AMPHIPHILIC IMIDAZOLIUM SALT IN WATER
Keisuke Asano, Seijiro Matsubara
HETEROCYCLES, 80, 2, 989, 1002, PERGAMON-ELSEVIER SCIENCE LTD, Mar. 2010, [Peer-reviewed]
English, Scientific journal, Molecules of an amphiphilic imidazolium salt assemble in water to form a hydrophobic membrane including an interface consisting of ammonium species. Such an interface works as a reaction medium like an ionic liquid. We used the medium for nucleophilic substitution reactions between alkyl halides and anionic nucleophiles. This procedure allowed the reactions to proceed efficiently in water without any organic solvent.

Morita-Baylis-Hillman Reaction on Water without Organic Solvent, Assisted by a 'Catalytic' Amount of Amphiphilic Imidazole Derivatives
Keisuke Asano, Seijiro Matsubara
SYNTHESIS-STUTTGART, 19, 3219, 3226, GEORG THIEME VERLAG KG, Oct. 2009, [Peer-reviewed]
English, Scientific journal, A Morita-Baylis-Hillman (MBH) reaction using water as a solvent without any organic solvent call be performed by using ail amphiphilic N-alkylimidazole. This reaction is accelerated by the addition of water and is the first example of a 'catalytic' MBH reaction Without organic solvent in the presence of water.

Amphiphilic Organocatalyst for Schotten-Baumann-Type Tosylation of Alcohols under Organic Solvent Free Condition
Keisuke Asano, Seijiro Matsubara
ORGANIC LETTERS, 11, 8, 1757, 1759, AMER CHEMICAL SOC, Apr. 2009, [Peer-reviewed]
English, Scientific journal, A Tosylation of primary alcohol with tosyl chloride was performed effectively with an N-hexadecylimidazole catalyst in water containing K2CO3aggregation of the catalyst carrying a hydrophobic methylene chain worked as a substitute for organic solvent.

Stereoselective Preparation of 3-Alkanoylprop-2-en-1-ol Derivatives
Mutsumi Sada, Shizue Ueno, Keisuke Asano, Kenichi Nomura, Seijiro Matsubara
SYNLETT, 5, 724, 726, GEORG THIEME VERLAG KG, Mar. 2009, [Peer-reviewed]
English, Scientific journal, 3-Alkanoylprop-2-en-1-ol derivatives were prepared stereoselectively by ring-opening reaction of beta,gamma-epoxyketone with amines.

N-Alkylimidazole as Amphiphilic Organocatalyst: 'Catalytic' Morita-Baylis-Hillman Reaction on Water without Organic Solvent
Keisuke Asano, Seijiro Matsubara
SYNLETT, 1, 35, 38, GEORG THIEME VERLAG KG, Jan. 2009, [Peer-reviewed]
English, Scientific journal, In the presence of water, a Morita-Baylis-Hillman reaction between methyl vinyl ketone and various aldehydes was performed with a catalytic amount of an imidazole carrying a hydrophobic group.

DIASTEREOSELECTIVE NUCLEOPHILIC CYCLOPROPANATION OF 1,2-DIKETONES AND alpha-KETOIMINES WITH BIS(IODOZINCIO)METHANE
Kenichi Nomura, Keisuke Asano, Takuya Kurahashi, Seijiro Matsubara
HETEROCYCLES, 76, 2, 1381, 1399, PERGAMON-ELSEVIER SCIENCE LTD, Nov. 2008, [Peer-reviewed]
English, Scientific journal, A reaction of 1,2-diketones and alpha-ketoimines with bis(iodozincio)methane gave cyclopropan-1,2-diol and 2-aminocyclopropanol respectively via nucleophilic [2+1]cycloaddition. The reaction proceeded via a sequential nucleophilic attack of the dizinc reagent to vicinal two carbonyl group. The reaction showed high diastereoselectivity to give cis-isomer via a face-to-face coordination between the substrate and bis(iodozincio)methane.

C-H bond activation by water on a palladium or platinum metal surface
Seijiro Matsubara, Keisuke Asano, Yuichi Kajita, Mitsuru Yamamoto
SYNTHESIS-STUTTGART, 13, 2055, 2059, GEORG THIEME VERLAG KG, Jul. 2007, [Peer-reviewed]
English, Scientific journal, A water molecule is partially cleaved on a palladium or platinum metal surface under hydrothermal conditions to form an active platinum species. The species is effective for C-H bond functionalization which can be applied for H/D-exchange reactions, CC bond-forming reactions, and C-N bond-forming reactions.

Photocatalytic Bromination toward Biomolecular Labeling　　　　　　　　　　　　　　　
Keisuke Asano
The 17th International Conference on Cutting-Edge Organic Chemistry in Asia (ICCEOCA-17), 01 Dec. 2024, English, Invited oral presentation
29 Nov. 2024 - 02 Dec. 2024, Academia Sinica, Taiwan, Province of China, [Invited], [International presentation]

触媒・反応ツールの開発が拓く臭素化の科学　　　　　　　　　　　　　　　
Keisuke Asano
若手研究者のための有機化学札幌セミナー, 31 Oct. 2024, 有機合成化学協会 北海道支部, Japanese, Invited oral presentation
北海道大学 薬学部, [Invited]

Photocatalytic Bromination for Biomolecular Labeling　　　　　　　　　　　　　　　
Keisuke Asano
International Symposium of Institute for Catalysis 2024: Sustainable synthesis by use of efficient catalyst, 29 Jul. 2024, English, Invited oral presentation
[Invited]

選択的触媒反応空間を拡張する反応ツールの創製　　　　　　　　　　　　　　　
Keisuke Asano
山口大学 講演会, 18 Jun. 2024, Host: 川本 拓治 准教授, Japanese, Invited oral presentation
山口大学 常盤キャンパス, [Invited]

選択的触媒反応空間を拡張する反応ツールの創製　　　　　　　　　　　　　　　
Keisuke Asano
学際統合物質科学研究機構（IRCCS） 成果報告会・産学ワークショップ, 30 Jan. 2024, Japanese, Invited oral presentation
30 Jan. 2024 - 31 Jan. 2024, [Invited]

オレフィンを利用した二官能性有機触媒　　　　　　　　　　　　　　　
Keisuke Asano
第15回 有機触媒シンポジウム, 30 Nov. 2022, 有機触媒研究会・日本学術振興会産学協力研究委員会『分子性触媒による高度分子変換技術』第194委員会, Japanese, Invited oral presentation
30 Nov. 2022 - 01 Dec. 2022, [Invited]

有機触媒の速度論を活かした反応制御　　　　　　　　　　　　　　　
Keisuke Asano
第5回 有機化学学生ウェビナー, 04 Sep. 2022, 有機化学学生ウェビナー, Japanese, Invited oral presentation
Japan, [Invited]

有機触媒に特有の速度論を活かした精密有機合成反応　　　　　　　　　　　　　　　
Keisuke Asano
第440回 触媒科学研究所コロキウム, 22 Jul. 2022, 北海道大学 触媒科学研究所, Japanese, Invited oral presentation
[Invited]

炭素–炭素二重結合の有機触媒機能開拓　　　　　　　　　　　　　　　
Keisuke Asano
第24回 ケムステVシンポ「次世代有機触媒」, 13 Jan. 2022, Chem-Station, Japanese, Invited oral presentation
[Invited]

Organocatalytic Access to Tetrasubstituted Chiral Carbons Integrating Functional Groups　　　　　　　　　　　　　　　
Keisuke Asano
PACIFICHEM 2021, 18 Dec. 2021, English, Invited oral presentation
[Invited]

多点活性化有機触媒による選択的反応　　　　　　　　　　　　　　　
Keisuke Asano
第1回 若手重水素研究会, 10 Sep. 2021, 学術変革領域研究（B）「重水素学」, Japanese, Invited oral presentation
[Invited]

有機触媒による官能基集積型四置換不斉炭素の構築　　　　　　　　　　　　　　　
Keisuke Asano
第13回 有機触媒シンポジウム, 17 Dec. 2020, 有機触媒研究会・日本学術振興会産学協力研究委員会『分子性触媒による高度分子変換技術』第194委員会, Japanese, Invited oral presentation
[Invited]

有機触媒ならではのモノづくり　　　　　　　　　　　　　　　
Keisuke Asano
ふれデミックカフェ＠KRP with京大オリジナル Vol. 4, 27 Nov. 2020, 京都リサーチパーク, Japanese, Invited oral presentation
[Invited]

有機触媒が拓く不斉反応スペース　　　　　　　　　　　　　　　
Keisuke Asano
京都大学大学院 工学研究科 材料化学特論第一 2020, 28 Jul. 2020, Graduate School of Engineering, Kyoto University, Japanese, Invited oral presentation
[Invited]

Organocatalytic Enantio- and Diastereoselective Cycloetherification of Chiral Cyanohydrins　　　　　　　　　　　　　　　
Keisuke Asano
The 2nd Japanese-Sino Symposium on Catalysis for Precision Synthesis, 07 Dec. 2019, Grant-in-Aid for Scientific Research on Innovative Area, MEXT, Japan "Precise Formation of a Catalyst Having a Specified Field for Use in Extremely Difficult Substrate Conversion Reactions", English, Invited oral presentation
[Invited], [International presentation]

触媒活性部位の特徴を活かした有機触媒反応開発　　　　　　　　　　　　　　　
浅野 圭佑
日本化学会 生産技術・製品開発ディビジョン & 京都大学 化学研究所 共催 若手講演会 2019, 30 Jul. 2019, 日本化学会 生産技術・製品開発ディビジョン, 京都大学 化学研究所, Japanese, Invited oral presentation
[Invited], [Domestic Conference]

Design of Organic Bases for Enantioselective Catalysis　　　　　　　　　　　　　　　
Keisuke Asano
The 99th CSJ Annual Meeting, Asian International Symposium - Organic and Green Chemistry -, 18 Mar. 2019, The Chemical Society of Japan, English, Invited oral presentation
甲南大学 岡本キャンパス, [Invited], [International presentation]

有機触媒を利用した分子配座の多点認識に基づく不斉合成反応　　　　　　　　　　　　　　　
Keisuke Asano
日本化学会第99春季年会 進歩賞受賞講演, 16 Mar. 2019, 日本化学会, Japanese, Invited oral presentation
甲南大学 岡本キャンパス, [Invited]

有機触媒による分子配座の認識に基づく不斉合成　　　　　　　　　　　　　　　
浅野 圭佑
第2回 有機若手ワークショップ, 30 Nov. 2017, 京都大学 理学部, Japanese, Invited oral presentation
[Invited], [Domestic Conference]

Mild Activations in Organocatalysis for Enantioselective Transformations　　　　　　　　　　　　　　　
Keisuke Asano
International Symposium on Pure & Applied Chemistry 2017 (ISPAC 2017), Ho Chi Minh City, Vietnam, 10 Jun. 2017, the Chemical Society of Vietnam (CSV), Institut Kimia Malaysia (IKM), Asia Chem Corporation (ACC), the Foundation for Interaction between Science and Technology (FIST) Japan, English, Invited oral presentation
[Invited], [International presentation]

Chemistry of Catalysts through Studies on Organocatalysts　　　　　　　　　　　　　　　
Keisuke Asano
The 1st ACE meeting, 26 Nov. 2016, ACE, Japanese, Invited oral presentation
Kyoto University, [Invited], [Domestic Conference]

Chemistry of Catalysts through Studies on Organocatalysts　　　　　　　　　　　　　　　
Keisuke Asano
静岡大学 研究講演会 兼 第3回G研セミナー, 13 May 2016, Host: 間瀬 暢之 教授, Japanese, Invited oral presentation
静岡大学 浜松キャンパス, [Invited]

有機触媒の穏和な活性化を利用した不斉合成　　　　　　　　　　　　　　　
浅野 圭佑
日本化学会第96春季年会 コラボレーション企画「未来を創る有機分子触媒」, 26 Mar. 2016, 研究開発専門委員会「有機分子触媒による高度分子変換技術」（共催：日本化学会, 新学術領域研究・総括班「有機分子触媒による未来型分子変換」）, Japanese, Invited oral presentation
同志社大学 京田辺キャンパス, [Invited], [International presentation]

Asymmetric Synthesis Utilizing Mild Activations by Organocatalysts　　　　　　　　　　　　　　　
Keisuke Asano
Senimar at The University of Texas at Austin, Austin, USA, 04 Dec. 2015, Host: Prof. Michael J. Krische, English, Invited oral presentation
[Invited]

Asymmetric Synthesis Utilizing Mild Activations by Organocatalysts　　　　　　　　　　　　　　　
Keisuke Asano
Senimar at Massachusetts Institute of Technology, Boston, USA, 01 Dec. 2015, Host: Prof. Timothy F. Jamison, English, Invited oral presentation
[Invited]

有機触媒による多点活性化が拓く多彩な不斉複素環合成　　　　　　　　　　　　　　　
Keisuke Asano
日本化学会第95春季年会『第29回若い世代の特別講演会』, 27 Mar. 2015, 日本化学会, Japanese, Invited oral presentation
日本大学 理工学部船橋キャンパス／薬学部, [Invited]

有機触媒による多点活性化が拓く多彩な不斉複素環合成　　　　　　　　　　　　　　　
浅野 圭佑
東京大学 内山研究室セミナー, 11 Sep. 2014, Host: 内山 真伸 教授, Japanese, Invited oral presentation
東京大学, [Invited]

不斉有機分子触媒によるヘテロ原子官能基化　　　　　　　　　　　　　　　
浅野 圭佑
第一回 大阪大学 南方研究室 若手研究者セミナー, 07 Jun. 2014, Host: 南方 聖司 教授, 武田 洋平 助教, Japanese, Invited oral presentation
大阪大学, [Invited]

Heteroatom Functionalization by Asymmetric Organocatalysis　　　　　　　　　　　　　　　
Keisuke Asano
Organic Chemistry Senimar at University of California-Irvine, Irvine, USA, 19 Mar. 2014, Host: Prof. David L. Van Vranken, English, Invited oral presentation
[Invited]

Study on Reactions Using Amphiphilic Imidazole Derivatives　　　　　　　　　　　　　　　
Keisuke Asano
Seminar at Philipps-Universität Marburg, Marburg, Germany, 03 Aug. 2009, Host: Prof. Reinhard W. Hoffmann, Prof. Ulrich Koert, English, Invited oral presentation
[Invited]

‘Catalytic’ Morita-Baylis-Hillman Reaction on Water Using Organic Catalysts Carrying Hydrophobic Group　　　　　　　　　　　　　　　
Keisuke Asano
Seminar at University of Heidelberg, Heidelberg, Germany, 11 Jul. 2008, Host: Prof. Motomu Tanaka, English, Invited oral presentation
[Invited]

Light-Gated Relay Catalysis to Chemically Identify Glycan-Protein Interactions
Grants-in-Aid for Scientific Research
23 Aug. 2021 - 31 Mar. 2024
浅野 圭佑
独自に開発したシクロオクテン触媒に関するこれまでの実績（ACIE 2018, 57, 13863）を基盤に、シクロオクテン触媒によるチロシンの求電子的ハロゲン化反応を開発した。特に、実験と計算による反応機構解析を通して触媒活性の詳細を理解することで、シクロオクテン触媒の活性が置換基により制御可能なことを見いだし、既に報告したシクロオクテン触媒と比較してもさらに劇的に高活性になった二官能性シクロオクテン触媒を開発した。また、この二官能性シクロオクテン触媒の活性が置換基を保護することで抑制できることも見いだした。そこでこれ利用して、光分解性保護基を付けることで光照射により活性をオフ/オン制御できる光駆動触媒を開発した。本触媒は、本研究で目指している生体分子標識に必要な反応の時空間制御に利用可能である。さらに、触媒開発だけではなく、生理的条件（水系溶媒、反応温度37 ℃）にてバックグランド反応は起こさないが、シクロオクテン触媒存在下では速やかに反応する生体適合ハロゲン化剤も独自に開発した。
これらの研究成果に関しては学会にて既に発表を行った。
Japan Society for the Promotion of Science, Grant-in-Aid for Transformative Research Areas (B), Kyoto University, 21H05076

Regulation of membrane dynamics by glycan chemical knock-in
Grants-in-Aid for Scientific Research
23 Aug. 2021 - 31 Mar. 2024
生長 幸之助, 堀 雄一郎, 真鍋 良幸, 浅野 圭佑, 上田 善弘
Japan Society for the Promotion of Science, Grant-in-Aid for Transformative Research Areas (B), 21H05073

Asymmetric Construction of Tetrasubstituted Chiral Carbons Integrating Functional Groups
Grants-in-Aid for Scientific Research
01 Apr. 2020 - 31 Mar. 2023
浅野 圭佑
本研究では、申請者がこれまでに確立してきた有機触媒による穏和な活性化法を利用する反応技術を基盤に、中性に近い多点認識型不斉反応場を設計することで、酵素触媒に頼らず高い一般性で官能基集積型四置換炭素を不斉構築する反応の実現を目指している。穏和な水素結合により基質を多点で活性化する二官能性有機触媒やキラル二点Lewis塩基触媒とケイ素がつくる不斉反応場を利用して、触媒による基質の多点認識により高いエナンチオ選択性を実現しながら目的の生成物を高収率で得るための高効率触媒を設計・開発した。
まず、二官能性有機触媒による複素環形成を経由する四置換不斉炭素の構築について研究を進めた。2020年度に開発したシアノヒドリンの動的速度論的分割を伴う環化反応やgem-ジオールの非対称化伴う環化反応により四置換不斉炭素を持つ光学活性テトラヒドロピラン環を構築する反応からさらに展開し、ケトンから系内で生成するエノールが求核剤になる不斉分子内オキシマイケル付加反応も開発した。この生成物は糖類縁体の不斉合成中間体になり、変換により四置換不斉炭素を構築できた。
また、多点認識型触媒による多官能性ケトンの官能基・エナンチオ選択的シアノ化反応の研究もさらに進めた。アシルシラン・オルトキノンモノアセタールの不斉シアノ化反応、およびカルボニル化合物のトリハロメチル化反応を開発した。いずれの触媒系も、様々な官能基を有する基質からでも副反応を起こさず目的の高エナンチオ選択的反応を実現し、官能基集積型四置換不斉炭素の構築につながった。また、アシルシランのシアノ化反応の生成物（アシルシランシアノヒドリン）は不安定なため、導入したシアノ基をさらに変換することが不可能だったが、アシルシランシアノヒドリンを保護する触媒反応を独自に開発し、この問題を解決した。
これらの研究成果に関しては論文および学会にて既に発表を行った。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Kyoto University, 20K05491

Catalytic Stereoselectivity Control of Rapid Reactions
Grants-in-Aid for Scientific Research
01 Apr. 2018 - 31 Mar. 2021
Asano Keisuke
Mild activations by bifunctional organocatalysts allowed for asymmetric cyclizations involving simultaneous construction of multiple stereogenic centers including tetrasubstituted chiral carbons. This method is useful for the short-step synthesis of bioactive compounds. In addition, organocatalysts for halolactonization and chiral ligands for metal catalysts were developed using the strained olefins of trans-cyclooctene derivatives, which demonstrated the potential for controlling the reactivity and stereoselectivity of carbanions generated from organohalides
Japan Society for the Promotion of Science, Grant-in-Aid for Early-Career Scientists, Kyoto University, 18K14214

水素結合ネットワークに基づく精密環化反応場の設計
科学研究費助成事業
01 Apr. 2018 - 31 Mar. 2020
浅野 圭佑
一度の反応で複数の不斉炭素を一挙に構築しながら複雑な有機骨格をつくり上げる有機合成手法は、機能性分子合成の短工程化に直結するため重要である。特に、高難度な四置換不斉炭素の構築を伴う分子変換は効果的である。我々は、水素結合による穏和な活性化をもたらす触媒活性部位を分子骨格に複数配置した有機触媒を設計することで、触媒による多点活性化に必然性を与え、分子内環化反応に効果的な不斉環境を提供する触媒的手法を開発してきた。本研究では、この手法を発展させ、四置換不斉炭素を含む複数の不斉炭素を持つ複素環化合物を一段階で高立体選択的に合成する触媒反応の開発に取り組んだ。その中で今年度は、以下に述べるような精密環化反応を開発した。また、同様の多点認識型触媒作用を利用した軸不斉構築反応も開発した。
ケトンから可逆的に発生させたシアノヒドリンの動的速度論的分割により、四置換不斉炭素を構築しながら環形成する反応により、縮環骨格橋頭位の連続四置換不斉炭素を含む複数の不斉炭素を一挙に構築しながら、生物活性化合物にしばしば含まれるオキサデカリン誘導体を高立体選択的に合成する手法を見いだした。置換基の種類に応じてシスオキサデカリン骨格・トランスオキサデカリン骨格をそれぞれ選択的に構築でき、その選択性は触媒により制御されていることも明らかにした。これらの結果は立体分岐型合成反応の実現につながる重要な知見を与えている。また、gem-ジオールの非対称化を経由する環化によりテトラヒドロピラン環にヘミケタール炭素を不斉構築する反応も開発した。この反応にシランジオールの非対称化を利用することで不斉ケイ素中心を構築することもできた。
日本学術振興会, 新学術領域研究(研究領域提案型), 京都大学, 18H04258

Development of precise synthetic reaction by reaction integration using a dissipative structure system
Grants-in-Aid for Scientific Research
29 Jun. 2015 - 31 Mar. 2020
MATSUBARA SEIJIRO
A middle-sized molecule is effective in inhibiting protein-protein interactions, which cause various diseases; it should have hydrophobic groups to extend in at least three directions in order to interact with protein surface in a wide range. Therefore, we paid attention to three kinds of molecules, those are a molecule with multiple chiral centers, an axial chiral molecule, and an asymmetric cubic molecule, were synthesized very efficiently by the reaction integration method. To achieve this goal, we also investigated the flow method, which means a dissipative structure, but the tandem reaction in which the reactive species were automatically controlled was effective.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Kyoto University, 15H05845

Creation of Innovative Organocatalysts Utilizing Unique Properties of Unsaturated Medium-size Rings
Grants-in-Aid for Scientific Research
01 Apr. 2016 - 31 Mar. 2018
Asano Keisuke
The creation of molecular catalysts bearing novel core frameworks offers new systems for organic reactions, and it will advance manufacturing technologies. In this study, we developed organocatalysts utilizing planar chiral medium-size ring structures bearing an olefin and a chiral platform including the olefin, as olefins have hardly been utilized for functional groups for catalysis.
Using trans-cyclooctene catalysts, which were newly synthesized, halogenations of alkenes were investigated; high catalytic activity and large substituent effects, which are important for additional design of the catalysts, were observed. In addition, the hydrophobicity of the hydrocarbon organocatalysts could be applied to phase-transfer catalysis. Furthermore, they were also useful as asymmetric ligands for transition metal catalysts, affording high enantioselectivity.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Kyoto University, 16K13994

Creation of Novel Asymmetric Catalytic Processes by Biomimetic Multifunctional Molecular Catalysts
Grants-in-Aid for Scientific Research
30 Aug. 2013 - 31 Mar. 2015
ASANO Keisuke
Utilizing α,β-unsaturated acylammonium intermediates generated from carboxylic acid derivatives and tertiary amine catalysts, we accomplished the facile asymmetric syntheses of heterocyclic compounds through the enantioselective introduction of a sulfur atom at the β-position of carboxylic acid derivatives via sulfa-Michael addition. This method enabled the catalytic enantioselective syntheses of β-mercaptolactones and 1,5-benzothiazepines. These heterocycles are highly important as candidates of pharmaceutical agents, and this research can be expected to contribute to the field of drug discovery.
Japan Society for the Promotion of Science, Grant-in-Aid for Research Activity Start-up, Kyoto University, 25888012

両親媒性有機分子を触媒的に用いる効率的水中有機反応の開発
科学研究費助成事業
2010 - 2011
浅野 圭佑
昨年度、アミン触媒による水中反応の検討を行う中できっかけを見いだした二官能性アミノチオウレア触媒による分子内ヘテロマイケル付加反応を利用した不斉複素環合成法に関して今年度さらに検討を進めた。
ヘテロ原子によるα,β-不飽和カルボニル化合物へのマイケル付加反応は有用な炭素-ヘテロ原子結合形成反応であり、これを分子内反応として行えば簡便にキラルな複素環化合物を合成することができる。しかしその不斉反応は、適切な不斉環境の構築が困難なことや分子内過程が迅速であることなどから容易ではなく、特に触媒的に行うことは難しい。今回、この課題に対して同一分子内にアミノ基とチオウレア基を持つ二官能性有機分子触媒を用いることが有効であることを見いだした。二官能性触媒による多点での認識は環化過程における不斉誘導に効果的であり、また両触媒活性点でともに穏和な性質の水素結合を活用したことにより迅速な分子内反応においてもその多点認識を維持しやすかったものと思われる。
検討の結果、シンコナアルカロイドから誘導した二官能性アミノチオウレア触媒を用い、ε位またはδ位に求核性ヘテロ原子を有する様々なα,β-不飽和カルボニル化合物から分子内ヘテロマイケル付加反応を行うと、高エナンチオ選択的に反応が進行し、テトラヒドロフラン、テトラヒドロピラン、1,3-ジオキソラン、スピロアセタール、インドリン、オキサゾリジン、オキサゾリジノンといった含酸素及び含窒素複素環化合物の触媒的不斉合成が行えることを見いだした。これらは天然物や生理活性物質をはじめ様々な化合物に見られる重要な部分骨格であり、本手法が合成化学分野にもたらす貢献度は大きい。また、本手法は単純な分子内環化のみではなく形或的環化付加反応にも展開できるなど強力なものであり、今後さらなる発展が期待できる点でも意義深い。さらに、複素環合成のみではなく、生成物の変換により幅広い光学活性化合物の合成にも繋がることを示しており、不斉合成法としての有用性は大変高い。
日本学術振興会, 特別研究員奨励費, 京都大学, 10J04974