Development of core technology for chemical biology and drug discovery based on Cope-type hydroamination

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06973
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: Tamura Osamu 昭和薬科大学, 薬学部, 教授 (30257141)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: イソシアネート / オキシム / ニトロン / 付加環化反応 / ヘテロCope型ヒドロアミノ化

Outline of Final Research Achievements

(1) Development of intermolecular Cope-type hydroamination reaction accelerated by ring strain and development to bioorthogonal reaction: Due to successive papers published by competing groups, we were unable to advance this theme.
(2) Development of hetero-Cope hydroamination reaction and development to click reaction: We have developed that Cope-type hydroamination reaction caused by isocyanates and oximes generating nitrones, which immediately undergo cycloaddition reaction with dipolarophile intermoleculaly (about 30 examples, up to 94% yield). Moreover, using computational chemistry, we were able to determine the transition state for the nitrone formation. Furthermore, it was clarified that the reaction between isocyanate and alkylhydroxylamine proceeded easily in the same manner.

Free Research Field

有機化学

Academic Significance and Societal Importance of the Research Achievements

ジポラロフィル、イソシアネート類及びオキシムを混合するだけでイソオキサゾリジン環が得られる３成分連結型の分子間付加環化反応を開発した。これらの３成分に種々のクリック反応に用いられる官能基を予め導入しておき本反応を行うと、３つの区別された官能基を有するコア化合物が得られる。これらの区別された官能基にそれぞれ種々のペンダント化合物を連結することにより多様性のある中分子群の合成が可能となり、ライブラリ合成の有力な手法となる。一方、イソシアナートとアルキルヒドロキシルアミンとの反応は、非常に速く、新たなクリック反応となる可能性が示された。