Nucleophilic fluorination via single electron transfer and its application to preparation of PET tracers.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07704
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52040:Radiological sciences-related
• Research Institution: Nagasaki University
• Principal Investigator: Mizuta Satoshi 長崎大学, 医歯薬学総合研究科(医学系), 助教 (50717618)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: フッ素化 / アジリジノン / DFT計算 / トリフルオロメチルチオ化 / PET

Outline of Final Research Achievements

We developed a silver-promoted C-F bond formation method in α-bromoamides using AgF under mild conditions. This simple method enables access to tertiary, secondary, and primary alkyl fluorides involving biomolecular scaffolds. This transformation is available to primary and secondary amides, revealing a broad functional group tolerance. Kinetic experiments exhibited that the reaction rate increased in the order of 3°>2°>1°α-carbon. In addition, we found that the acidic amide proton has an important role in accelerating the reaction. Mechanistic studies suggested that the generation of an aziridinone intermediate undergoes subsequent nucleophilic addition to form the C-F bond with the stereospecificity (i.e. retention of configuration). We also demonstrated the DFT calculations to elucidate the mechanism and intermediacy of aziridinone. Examples of the reaction of α-bromoamides with AgSCF3 were conducted.

Free Research Field

放射線科学

Academic Significance and Societal Importance of the Research Achievements

フッ化水素やアルカリ金属フッ化物をフッ素源とした求核的フッ素化反応（SN2プロセス）が、[18F]標識化法の主流となっていることから、嵩高い基質には適さず、基質適用範囲が狭い。ゆえに、本研究成果である嵩高い第2、3級アルキル基を有するカルボン酸、エステル・アミドといったα位への求核的フッ素化は、有機合成化学における課題を克服するに至った。本研究成果は、これまで合成が困難であったPET診断に利用できる[18F]標識カルボニル化合物を構築するための新たな手法となることから、学術的意義、社会的意義があるといえる。