Updated on 2024/12/21

写真a

 
YAMAMOTO, Kana
 
Affiliation
Faculty of Science and Engineering, Global Center for Science and Engineering
Job title
Associate Professor(without tenure)
Profile
Experienced Scientist with a demonstrated history of working in the research industry. Skilled in Synthetic Organic Chemistry, Medicinal Chemistry, and Process Development. Strong research professional with a Ph.D. in Organic Chemistry from University of California, Berkeley.

Research Experience

  • 2018.04
    -
    Now

    Waseda University   Global Center for Science and Engineering   Associate Professor

  • 2016.11
    -
    2018.03

    Rapafusyn Pharmaceutical   Department of Medicinal Chemistry   Senior Scientist

  • 2015.05
    -
    2016.10

    University of Toledo   Department of Chemical and Environmental Engineering   Research Associate Professor

  • 2008.08
    -
    2015.05

    University of Toledo   Department of Chemistry and Biochemistry   Assistant Professor

  • 2003.06
    -
    2008.07

    Bristol-Myers Squibb Pharmaceutical   Department of Process Research and Development   Research Investigator

  • 2000.08
    -
    2003.05

    Sloan Kettering Cancer Research Institute   Laboratory of Medicinal Chemistry   Postdoctoral Researcher

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Education Background

  • 1995.06
    -
    2000.08

    University of California, Berkeley   Department of Chemistry  

  • 1993.04
    -
    1995.03

    Nagoya University   Graduate School of Science  

  • 1989.04
    -
    1993.03

    Nagoya University   School of Science   Department of Chemistry  

Professional Memberships

  • 　
    　
    　

    THE SOCIETY OF SYNTHETIC ORGANIC CHEMISTRY, JAPAN

  • 　
    　
    　

    AMERICAN CHEMICAL SOCIETY

  • 　
    　
    　

    THE CHEMICAL SOCIETY OF JAPAN

Research Areas

  • Bioorganic chemistry / Synthetic organic chemistry   Synthetic Organic Chemistry

Research Interests

  • Nucleotides and Nucleic acids

  • Medicinal Chemistry

  • Green Chemistry

 

Papers

  • Cross-Metathesis approach to a,w-Bifunctional Compounds from Methyl Oleate and cis-2-Butene-1,4-diol

    Ajith Mudiyanselage, Sridhar Viamajala, Sasidhar Varanasi, Kana Yamamoto

    ChemRXiv    2022.05

    Authorship：Corresponding author

    　View Summary

    The cross metathesis (CM) of methyl oleate (1) and cis-2-butene-1,2-diol (2) was investigated to access alpha, omega-bifunctional compounds. The optimal CM conditions involve Stewart-Grubbs catalyst at 0 °C, delivering CM product 3 in excellent yield. 3 was converted, in a single step and in >90% yields, to alcohol 7, aldehyde 8, and olefin 10, the useful synthetic intermediates for many specialty chemicals, including PA11 precursor. A tandem CM/isomerization process was also demonstrated for the first time.

    DOI

  • Toward Sustainable Synthesis of PA12 (Nylon-12) Precursor from Oleic Acid Using Ring-Closing Metathesis

    Godwin Ameh Abel, Sridhar Viamajala, Sasidhar Varanasi, Kana Yamamoto

    ACS SUSTAINABLE CHEMISTRY & ENGINEERING   4 ( 10 ) 5703 - 5710  2016.10  [Refereed]

    Authorship：Corresponding author

    　View Summary

    The efficient reaction conditions for ring-closing metathesis of homoallyloleamide (2) for the synthesis of PA12 (Nylon-12) precursor (4) are presented. Systematic screening of a series of commercially available metathesis catalysts identified. a catalyst that promotes the reaction at low temperature (60 degrees C), enabling use of nonhalogenated solvents, ethyl acetate and hexanes. The catalyst was adsorbed on mesoporous silica gel to aid its postreaction recovery and reuse, which was demonstrated in hexanes up to three cycles without significant loss of reaction conversion (>90%). The identification of reaction-compatible green solvents as well as the demonstration of the potential for recycling of the supported catalyst are steps further toward establishing environmentally sustainable production of the polyamide precursors from oleic acid.

    DOI

    Scopus

    13
    Citation
    (Scopus)

  • Self-Assembled Ion–pair Organocatalysis – Asymmetric Baeyer-Villiger Oxidation Mediated by Flavinium-Cinchona Alkaloid Dimer

    Pramod Prasad Poudel, Kenji Arimitsu, Kana Yamamoto

    Chemical Communications   52 ( 22 ) 4163 - 4166  2016.02  [Refereed]  [International journal]

    Authorship：Corresponding author

    　View Summary

    An ion-pair catalyst generated by assembly of a chiral flavinium and a cinchona alkaloid dimer for use in asymmetric Baeyer-Villiger oxidation is presented. Ion-pair formation is essential for enhancing the catalytic activity and stereoselectivity. The catalyst is applicable to structurally diverse 3-substituted cyclobutanones, providing good to excellent enantioselectivities (up to 98 : 2 e.r.). This study provides the first example of self-assembly of a flavin derivative and a base to form a chiral reaction site that enables a highly stereo-selective reaction to occur.

    DOI

    Scopus

    37
    Citation
    (Scopus)

  • Efficient production of alkanolamides from microalgae

    Yapa Mudiyanselage, A., Yao, H., Viamajala, S., Varanasi, S., Yamamoto, K.

    Industrial and Engineering Chemistry Research   54 ( 16 ) 4060 - 4065  2015  [Refereed]

    Authorship：Corresponding author

    　View Summary

    Fatty acid alkanolamides (FAAA) at lipid derivatives with industrial applications as biosurfattants and bioltbricants. Although conventionally produced from vegetable oils, use of alternative renewable sources-that do not compete with the food supply chain, such as microalgae, is desirable. We studied the production of FAAA through direct in situ afnidation of algal biomass or by amidation of fatty,acid methyl esters (FAME) recovered from in situ transesterification of alpae. In situ tfansesterification resulted in spontaneous, formation of a distinct FAME phase, which could be easily recoveied and converted to FAAA. With this two-step transesterification-followedby-amidation method, >95% of algal lipids were recovered as FAAA products. In situ amidation Jolla not result in a separate product phase, likely because of the amphiphilit nature of the product. However, extraction with ethyl acetate allowed recovery of nearly 90% of the biomass lipids as FAAA after in situ athidation.

    DOI

    Scopus

    14
    Citation
    (Scopus)

  • Cross-metathesis approach to produce precursors of nylon 12 and nylon 13 from microalgae

    Ameh Abel, G., Oliver Nguyen, K., Viamajala, S., Varanasi, S., Yamamoto, K.

    RSC Advances   4 ( 98 ) 55622 - 55628  2014  [Refereed]

    Authorship：Corresponding author

    　View Summary

    A two-step synthesis for producing methyl 12-aminododecanoate and 13-aminotridecanoate, the precursors of nylon 12 and nylon 13, from methyl oleate is described. First, methyl 11-cyano-9-undecenoate or 12-cyano-9-dodecenoate were prepared by cross metathesis of methyl oleate with either allyl cyanide or homoallyl cyanide, respectively. Subsequently, all the unsaturation of the two intermediates was hydrogenated to deliver the final products. This method represents the first synthesis of nylon 12 and 13 precursors from methyl oleate, an ester of an abundant and renewable natural fatty acid present in vegetable oil or microalgae. It also represents the shortest synthesis of nylon precursors from fatty acids, and as demonstrated in this study, can be directly applied to crude fatty acid methyl ester extracts from microalgae.

    DOI

    Scopus

    27
    Citation
    (Scopus)

  • Simple ring-closing metathesis approach for synthesis of PA11, 12, and 13 precursors from oleic acid

    Mudiyanselage, A.Y., Viamajala, S., Varanasi, S., Yamamoto, K.

    ACS Sustainable Chemistry and Engineering   2 ( 12 ) 2831 - 2836  2014  [Refereed]

    Authorship：Corresponding author

    　View Summary

    Due to the concerns over limited fossil resources and increasing CO2 emissions, there is a strong interest in use of renewable resources in production of valuable synthetic materials. PA11, 12, and 13, more commonly known as Nylon, are high-strength polymers that find use in various industrial sectors. They are traditionally produced from petroleum-derived material or exotic fatty acids using reaction sequences that involve 4-6 steps. Herein we report a simple three-step synthesis of these polyamide precursors from oleic acid, an abundant natural fatty acid available from common plant sources as well as oleaginous micro-organisms such as microalgae. This approach represents the first example where ring-closing metathesis was used for the key C-C bond forming step, featuring introduction of amine functionality required in the final product. Our versatile approach allows preparation of nylon precursors of various chain-lengths from a single starting material for economical and sustainable production of these polymers.

    DOI

    Scopus

    25
    Citation
    (Scopus)

  • Metal-free oxidative amide formation with N-hydroxysuccinimide and hypervalent iodine reagents

    Yao, H., Tang, Y., Yamamoto, K.

    Tetrahedron Letters   53 ( 38 ) 5094 - 5098  2012  [Refereed]

    Authorship：Corresponding author

    　View Summary

    An oxidative amide formation using N-hydroxysuccinimide and hypervalent iodine reagents was developed. The method enables a wide range of aldehydes and amines to be coupled under mild reaction conditions providing amide in good to excellent yield. The radical species in the reaction mixture was observed for the first time using ESR measurement, and along with other mechanistic investigations, a plausible mechanism of the reaction was proposed. Published by Elsevier Ltd.

    DOI

    Scopus

    39
    Citation
    (Scopus)

  • Aerobic amide bond formation with N-hydroxysuccinimide

    Yao, H., Yamamoto, K.

    Chemistry - An Asian Journal   7 ( 7 ) 1542 - 1545  2012  [Refereed]

    DOI

    Scopus

    42
    Citation
    (Scopus)

  • Development of a scaleable process for the synthesis of a next-generation statin

    Hobson, L.A., Akiti, O., Deshmukh, S.S., Harper, S., Katipally, K., Lai, C.J., Livingston, R.C., Lo, E., Miller, M.M., Ramakrishnan, S., Shen, L., Spink, J., Tummala, S., Wei, C., Yamamoto, K., Young, J., Parsons Jr., R.L.

    Organic Process Research and Development   14 ( 2 )  2010  [Refereed]

    DOI

    Scopus

    24
    Citation
    (Scopus)

  • Oxidative dehydrogenation of dihydropyrimidinones and dihydropyrimidines

    Yamamoto, K., Chen, Y.G., Buono, F.G.

    Organic Letters   7 ( 21 ) 4673 - 4676  2005  [Refereed]

    　View Summary

    A mild, practical procedure for oxidative dehydrogenation with catalytic amounts of a Cu salt, K2CO3, and tert-butylhydroperoxide (TBHP) as a terminal oxidant has been developed. This oxidation procedure is generally applicable to dihydropyrimidinones and most dihydropyrimidines.

    DOI

    Scopus

    95
    Citation
    (Scopus)

  • Effects of temperature and concentration in some ring closing metathesis reactions

    Yamamoto, K., Biswas, K., Gaul, C., Danishefsky, S.J.

    Tetrahedron Letters   44 ( 16 ) 3297 - 3299  2003  [Refereed]

    Authorship：Corresponding author

    　View Summary

    Ring closing metathesis (RCM) has emerged as a powerful tool to construct macrocyclic ring systems. However, the product distribution of monomer and oligomers is often a problem in the formation of medium to large rings. In the course of synthetic studies on the natural product radicicol and its analogs, we have found that the reaction temperature, along with concentration, has significant impact on the outcome of the product ratio. Specifically, carrying out the RCM reaction in refluxing toluene (110degreesC) at higher dilution affords improved yields of the monomeric macrocycle. Similar observations for another family of macrolactone natural products, the epothilones, are also reported. (C) 2003 Elsevier Science Ltd. All rights reserved.

    DOI

    Scopus

    70
    Citation
    (Scopus)

  • On the total synthesis and determination of the absolute configuration of rishirilide B: Exploitation of subtle effects to control the sense of cycloaddition of o-quinodimethides

    Yamamoto, K., Hentemann, M.F., Allen, J.G., Danishefsky, S.J.

    Chemistry - A European Journal   9 ( 14 ) 3242 - 3252  2003  [Refereed]

    　View Summary

    The total synthesis of racemic rishirilide B has been accomplished. The synthesis serves to define the relative relationships of its stereogenic centers. Also, starting with readily available chiral pool, ent-rishirilide B was synthesized, thereby demonstrating that natural configuration of rishirilide B. The defining step in our total synthesis is the facile cycloreversion of the bis(siloxy)-benzocyclobutane and the intermolecular o-quinodimethide Diels-Alder cycloaddition. We believe that the tight regiochemical guidance in this step arises from a meshing of the electron-donating effects of the symmetry-perturbing aromatic OTBS group of the o-quinodimethide diene with the reactivity differential of the dienophile (enedione), modulated by the hydroxyl group at the alpha-position. The validity of the hypothesis of hydroxy-directed activation of its vicinal ketone function in the context of the enedione dienophile warrants further study. This type of activation may find broader applications in distinguishing reactivity profiles of key closely related functional groups in organic substrates.

    DOI

    Scopus

    31
    Citation
    (Scopus)

  • Total synthesis as a resource in the discovery of potentially valuable antitumor agents: Cycloproparadicicol

    Yamamoto, K., Garbaccio, R.M., Stachel, S.J., Solit, D.B., Chiosis, G., Rosen, N., Danishefsky, S.J.

    Angewandte Chemie - International Edition   42 ( 11 ) 1280 - 1284  2003  [Refereed]

    DOI

    Scopus

    77
    Citation
    (Scopus)

  • α,β-epoxy vinyl triflates in Pd-catalyzed reactions

    Kana Yamamoto, Clayton H. Heathcock

    Organic Letters   2 ( 12 ) 1709 - 1712  2000  [Refereed]

    　View Summary

    [GRAPHICS]
    Reactions of steroidal alpha,beta-epoxy vinyl triflates in Pd-catalyzed reactions are described. Oxidative insertion of Pd-0 into the C-O bond, giving vinylpalladium 12, is faster than formation of the pi-allyl derivative from the vinyl epoxide. Although 12 can be trapped under certain conditions, it eventually rearranges to palladium alkoxide 14, which is in equilibrium with 15 and/or 10.

    DOI

    Scopus

    21
    Citation
    (Scopus)

  • A development of scalable synthesis of an HMG-CoA Inhibitor

    Lindsay A Hobson, Otute Akiti, Subodh S. Deshmukh, Shannon Harper, Kishta Katipally, Chiajen J. Lai, Robert C. Livingston, Ehrlic Lo, Michael M. Miller, Srividya Ramakrishnan, Lifen Shen, Jan Spink, Srinivas Tummala, Chenkou Wei, Kana Yamamoto, John Young, Rodney L, Parsons, Jr

    Org. Proc. Res. Dev.   14   441 - 458  [Refereed]

  • Progress towards the total synthesis of Cephalostatin 1

    Kana Yamamoto

    University of California Berkeley  

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Books and Other Publications

  • e-EROS (Encyclopedia of Reagents for Organic Synthesis)

    Kana Yamamoto( Part： Contributor, 2-Amino-6-hydroxy-4(3H)-pyrimidinone)

    John Wiley & Sons, Ltd  2013.08

Presentations

  • Understanding the Mechanism: Exploring Catalytic Asymmetric Phosphine Oxidation

    Ruiqi Zhu, Ziying Jin, Masahiro, Kobayashi, Kana Yamamoto

    Gordon Research Conference, Organic Reactions and Processes 

    Presentation date： 2023.07

    Event date：
    2023.07
    　
    　

  • Towards a new pathway to P-chirogenic compounds: asymmetric oxidation of phosphines

    Ruiqi Zhu, Ziying Jin, Masahiro, Kobayashi, Kana Yamamoto  [Invited]

    23rd Tateshina Conference on Organic Chemistry 

    Presentation date： 2023.06

    Event date：
    2023.06
    　
    　

  • Oxygenation of phosphorus compounds promoted by flavin cofactor derivatives

    Ruiqi Zhu, Ziying Jin, Eika Suruga, Kana Yamamoto  [Invited]

    22nd Tateshina conference on organic chemistry 

    Presentation date： 2022.11

    Event date：
    2022.11
    　
    　

  • Phosphorous oxygenation promoted by flavin cofactor derivatives

    Kana Yamamoto, Ruiqi Zhu, Ziying Jin, Eika Suruga

    Presentation date： 2022.11

    Event date：
    2022.11
    　
    　

  • Catalytic P-oxygenation promoted by Cofactor Flavin Derivative

    Rui-Qi Zhu, Ziying Jin, Kana Yamamoto

    American Chemical Society Annual Meeting, Fall 2022 

    Presentation date： 2022.08

    Event date：
    2022
    -
    2022.08

  • Oxygenation of phosphorous compounds promoted by flavin cofactor derivatives

    Ruiqi Zhu, Ziying Jin, Eika Suruga, Kana Yamamoto

    Gordon Research Conference on Organic Reactions and Processes 

    Presentation date： 2022

    Event date：
    2022.07
    　
    　

  • Aerobic oxidation of phosphines to phosphine oxides promoted by cofactor flavin derivatives

    Rui-Qi Zhu, Zi-Ying Jin, Kana Yamamoto

    The 102nd JCS Annual Meeting 

    Presentation date： 2022.03

  • Aerobic oxygenation of phosphites by cofactor Flavin derivatives

    Masahiro Kobayashi, Eika Suruga, Haruno Tajima, Kana Yamamoto

    The 102nd CSJ Annual Meeting 

    Presentation date： 2022.03

  • Reactions promoted by Flavin Derivatives

    Kana Yamamoto, Junya Fujimoto, Eika Suruga, Zinying Jin, Masahiro Kobayashi

    American Chemical Society Annual Spring Meeting 

    Presentation date： 2021.04

  • Chemoselective oxidation of phosphines and phosphites to their oxides promoted by Flavin cofactor derivatives

    Eika Suruga, Ziying Jin, Masahiro Kobayashi, Kana Yamamoto

    101st Japan Chemical Society Annual Meeting, Tokyo Japan 

    Presentation date： 2021.03

  • Stereoselective oxidation of P-chirogenic phosphorous compounds promoted by cofactor Flavin derivatives

    Zinying Jin, Kana Yamamoto

    101st Japan Chemical Society Annual Meeting, Tokyo Japan 

    Presentation date： 2021.03

  • Stereoselective Baeyer–Villiger oxidation of 3-substituted cyclobutanones promoted by Flavin-derived ion-pair catalysts (Sch. Adv. Sci. Eng., Waseda University) 〇Junya Fujimoto, Kana Yamamoto

    Junya Fujimoto, Kana Yamamoto

    101st Japan Chemical Society Annual Meeting, Tokyo 

    Presentation date： 2021.03

  • Stereoselective Baeyer–Villiger oxidation of cyclobutanones mediated by flavinium–cinchona alkaloid dimer ion-pair catalyst”

    Junya Fujimoto, Kana Yamamoto

    100th Japan Chemical Society Annual Spring Meeting, Tokyo, Japan 

    Presentation date： 2020.03

    Event date：
    2020.03
    　
    　

  • Stereoselective oxidation of P-chirogenic phosphorous compounds promoted by cofactor Flavin derivatives

    Ziying Jin, Kana Yamamoto

    100th Japan Chemical Society Annual Spring Meeting, Tokyo, Japan 

    Presentation date： 2020.03

  • Reactions Promoted by Flavin co-Factor Derivatives

    Kana Yamamoto  [Invited]

    The 2nd Nagoya Seminar on Green Synthesis & Catalysis (NSGSC-2), Nagoya, Japan 

    Presentation date： 2019.12

  • Reactions promoted by Flavin co-Factor Derivatives

    Kana Yamamoto

    Gordon Conference, Organic Processes and Reactions, Smith College, Eaton, MA 

    Presentation date： 2019.07

    Event date：
    2019.07
    　
    　

  • Tandem Metathesis-Isomerization Route from Methyl Oleate to Nylon 11 Precursor

    Kana Yamamoto, Ajith Yapa Mudiyanselage

    Presentation date： 2018.07

    Event date：
    2018.07
    　
    　

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Misc

  • 光学活性な1,2‐diphenylethylene構造を有する新規フラビン触媒の合成

    有光健治, ALMALITI Jehad S, 山本佳奈

    日本薬学会年会要旨集(CD-ROM)   134th   ROMBUNNO.29PMM-097  2014

    J-GLOBAL

  • Lewis acid activation of N-hydroxyimides and its application to oxidative functionalization

    Haoyi Yao, Kana Yamamoto

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   244  2012.08

    Research paper, summary (international conference)  

  • ORGN 276-Process development efforts toward a scalable synthesis of a next generation statin

    Michael M. Miller, Lindsay Hobson, Kishta Katipally, Robert Livingston, Jan Spink, Kana Yamamoto, Otute Akiti, Subodh Deshmuk, Shannon Harper, Ehrlic Lo, Srinivas Tummala, John Young, Rodney L. Parsons

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   235  2008.04

    Research paper, summary (international conference)  

Industrial Property Rights

  • Rapafucin derivative compounds and methods thereof

    Jun Liu, Sam Hong, Brett R. Ullman, Joseph E. Semple, Kana Yamamoto, Puneet Kumar, Magesh Sadaopan, Jennfer C. Schmitt

    Patent

  • Production of alkanolamides from microalgal biomass

    特許US 9,562,210 B1

    Kana Yamamoto, Sridhar Viamakala, Sasidhar Varanasi, Ajith Yapa Mudiyanselage, Pramod, Prasad Poudel

    Patent

  • Process for the preparation of 4-(8-(2-chlorophenoxy)-[1,2,4]-trizolo[4,3-A]pyridin-3-yl)bicyclo[2.2.1]heptan-1-ol and novel intermediates thereof

    Xinhua Qian, Keming Zhu, Joerg Deerberg, Wendy Yang, Kana Yamamoto, Mathew R. Hickey

    Patent

  • Ring-closing metathesis approach to produce precursors of nylon 11, 12, and 13 from oleic acid.

    特許US 9,845,294 B2

    Kana Yamamoto, Sridhar Viamajala, Sasidhar Varnasi, Ajith Yapa Mudiyanselage, Godwin Ameh Abel

    Patent

  • Cross metathesis approach to C11–13 fatty-chain amino esters from oleic acid derivatives.

    特許US 10,087,137 B2

    Kana Yamamoto, Sridhar Viamajala, Sasidhar Varnasi, Kim Oliver Nguyen, Godwin Ameh Abel, Ajith Yapa Mudiyanselage

    Patent

 

Syllabus

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Research Institute

  • 2022
    -
    2024

    Waseda Research Institute for Science and Engineering   Concurrent Researcher

Internal Special Research Projects

  • リン不斉修飾核酸の実用的合成に向けたリン不斉中心構築法の開発

    2023  

    　View Summary

    　本研究の目的は、修飾核酸の一つであるホスホロチオエート核酸（天然型核酸のリン酸部位水酸基の一つがチオールに交換された核酸）の効率的な立体選択的合成法の開発である。申請時には、新規合成法として核酸の触媒的かつ立体選択的縮合反応の開発を提案したが、多くの場合オリゴ核酸の合成は固相でされること、一般的に触媒反応は僅かな反応条件の違いに左右されやすいことから、より現実的な提案としてリン酸部位がすでに不斉化された核酸伸長ユニットを用いた立体選択的手法の開発という目標に切り替えた。この目標に向け、まずは立体特異的に且つ高収率でカップリングの進行する核酸伸長ユニットの構造を検討することとした。　このようなコンセプトの核酸伸長ユニットは1990年代にStecおよびLesnikovskiらにより研究されている。いずれの研究でも、核酸伸長ユニットはジアステレオマー混合物として合成されたものを分割して用いており、またそのカップリング収率はオリゴ核酸合成として用いるには低すぎることが課題となっていた。　そこで、まずLesnikovskiらが手がけた核酸伸長ユニットの構造の改良を試みることとした。具体的には、彼らの核酸伸長ユニットでは、カップリングの際の脱離基としてp-nitrophenoxy基が用いられるが、その脱離基をより活性の高いものに変換することでカップリング収率を向上できないかを検討することとした。　その結果、まずLesnikovskiらの報告している核酸伸長ユニットの合成は達成できたが、カップリング収率は最高でも25％程度と、報告されている収率(75-85%）がそもそも再現できなかった。また、脱離基をさらに活性の高いpentafluorophenoxy あるいは3,5-bis(trifluoro)phenoxy 基に変換した伸長ユニットの合成を試みたが、いずれもそれぞれのユニットの電子吸引基のため、それらをリボースに取り付ける反応段階が進行せず、従ってカップリングの検討にまで至っていない。そこで、現在はStecらが開発した構造を基盤としたユニットのデザインに焦点を切り替え検討を続けている。

  • フラビン誘導体を触媒とする、リンの不斉酸化反応の開発

    2023  

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    　本研究の目的は、３価リン５価リンへの不斉酸化(酸素化）反応の確立である。当研究室では、これまでに補酵素フラビン誘導体を触媒とした空気酸化反応により収率99%以上、立体選択性27%ee.の系を確立している。研究助成期間中では、その立体選択性の向上を目指し、様々な構造のフラビン誘導体を用いた場合の寄与を調べた。　本反応系は前年度までの研究より、立体保持もしくは立体反転を伴う二つの反応経路により酸化反応が進行することが分かっている。しかし、そのような反応系の立体選択性の向上には困難が伴うため、本年度は一方の経路を遮断するような触媒あるいは基質を検討した。特に、反応機構の観点から観測された立体選択性は立体保持経路からのもので、反転経路に選択性はないと仮説を立てているため、反転経路が遮断あるいは遅延させる触媒／基質に焦点を置くこととした。　フラビン誘導体はアミノアルコールまたはアミノ酸から4−5段階で調製した。これまでに調製したフラビン誘導体を含めた13の誘導体を合成し、其々について酸化反応を追跡した。誘導体はその架橋部位にある2本の側鎖（アミノアルコールの側鎖にあたる）およびアロキサン構造のA環部位に置換基を加えたものをデザインした。この実験の結果、２本ある側鎖は一方のみで立体制御可能であること、選択性を左右する構造の傾向など知見が得られた。また、A環に置換基をつけたものに関しては立体選択性は左右されなかったが電子吸引基により反応速度が著しく低下することが分った。今回は電子供与基をつけたものは調製しなかったので、今後の課題となる。　また、立体反転経路を遮断する手段として、環状リン含有化合物の基質を合成し酸化反応における選択性を検討することとした。既知の環状のリン化合物である2,3-dihydro-1-phenylbenzo[b]-phospholeを6段階で合成し、酸化反応を試みた。しかし、この基質は非環状の基質よりも自動酸化が早いため、結果の確定には更なる検討が必要である。

  • 動的速度論光学分割を伴う縮合反応を用いた、リン不斉修飾核酸の立体選択的合成法

    2022  

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    本研究の目的は、核酸医薬品によく用いられるリン不斉修飾核酸（リン酸部位の水酸基が別の基に置換された核酸）の立体選択的合成法の開発である。このような医薬品のリンの立体化学は生理活性に大きく影響するため、立体選択的に合成する必要があるが、既存の合成法は核酸伸長の段階数や多くの廃棄物が問題である。そこで、本研究では核酸合成に用いる単位ユニットを工夫した立体特異的かつ２段階縮合反応を提案した。今年度はその単位ユニット合成の鍵反応となる不斉酸化反応の反応機構解析に注力した。その結果、本反応は基質の立体保持経路と立体反転経路が同時に進行する、新しい型のパラレル型速度論光学分割を伴うことが分かった。

  • 立体選択的酸化反応と動的速度分割を用いるP-キラルなPV化合物の実用的不斉合成

    2020  

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    本研究の目的は、様々な分野で用いられるP-キラルなリン含有化合物の実用的合成法の確立である。2020年度にはは、モデル化合物MeP(Ph)(o-An)を基質とし、キラルなフラビン誘導体とアミンを組み合わせたイオン対触媒を用いた空気酸化によるリン不斉中心構築法の確立を目指した。　予備実験より、既にフラビン誘導体と光学活性なアミンの一つである(+)-BINAMにより室温、10~24時間で定量的に目的物が得られていたが、さらに基質、フラビン触媒、(+)-BINAMの誘導体を用いて、立体選択性の向上を検討した。その結果、最適条件では24%eeまで立体選択性が向上し、また触媒系で選択性を左右する要となる部分構造が同定できた。今後は要の部分構造に着目し更なる選択性の向上を目指す。

  • リン原子の立体選択的酸化を鍵とする、リン原子修飾オリゴヌクレオチドの不斉合成

    2019  

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    　本研究では、オリゴホスホロチオエート核酸の試薬制御カップリングによる合成法を確立することを目標としており、そのための試薬の不斉合成およびカップリングの検討を行う予定であった。しかし試薬合成に必須であるリン原子不斉酸化反応が得られなかったため、まず新規リン原子不斉酸化反応の開発に焦点を絞ることとした。　その結果フラビン誘導体とアミン補助剤を触媒系、空気を酸化剤とすると目的物がほぼ当論量で得られることがわかった。また光学活性な触媒系による不斉誘起も確認でき、目的とする反応開発の有用な手がかりが得られた。今後は触媒の構造および反応機構の検討から立体選択性の向上を目指し、また試薬合成の検討も再開する。

  • 分子集合を鍵とする、補酵素フラビンによる立体選択的バイヤービリガー反応の開発

    2019  

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    　当研究室では低環境負荷の生体内酸化反応を模倣した反応触媒開発に取り組んでおり、これまでに補酵素フラビン誘導体とアルカロイド２量体を組み合わせたイオン対触媒により、立体選択的バイヤービリガー（BV）反応を開発している。本課題はこの反応に関し、高い立体選択性を示す基質および触媒の原理的裏付けを同定することであり、助成期間中には（１）基質構造-立体選択性相関、および（２）反応律速を求める目的で速度論解析を行った。その結果、（１）電子効果による反応速度と立体選択性の制御の可能性、（２）Hammettプロットおよび同位体効果の解析により、反応律速が酸化剤の付加段階であること、が示唆された。今後は得られた情報を元に、本反応の基質汎用性および立体選択性の向上、位置選択性の制御などを目指す。

  • フラビン骨格を基盤とした(不斉)酸化反応の開発

    2018  

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    酸化還元酵素反応を司る補酵素フラビンの誘導体は、多彩な反応を副産物なしで触媒する低環境負荷型の反応触媒となる。本研究ではフラビン誘導体を用い、ナトリウム塩をハロゲン源とするハロゲン化反応の開発を目指した。モデル反応として酵素の基質と類似構造を持つN,N-ジメチルアニリンを基質として反応条件の検討を行った結果、フラビン誘導体を触媒、過酸化水素、および塩化ナトリウム存在下45℃の加熱条件で、目的物（４位と２位への塩素化〜２：１）が最高69％収率で生成した。また、臭化ナトリウムを用いると同様の条件下で４位選択的にブロモ化も進行した。今後は更なる反応条件の改良により、収率向上を検討する。

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