Controlling Radicals via Sulfonium Activation and Anion Binding Catalysis

通过锍活化和阴离子结合催化控制自由基

• 批准号: 9758850
• 负责人: Joseph Jeffery Gair
• 金额: $ 6.12万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758850
• 关键词: Active Sites; Adenosine Triphosphate; Anions; Binding; Biomimetics; Catalysis; Chemistry; Complex; Controlled Environment; Electrons; Elements; Engineering; Environment; Enzymes; Factor Analysis; Health; Human; Investigation; Ions; Libraries; Life; Mediating; Medicine; Methionine; Methods; Modification; Molecular; Nature; Outcome; Oxidation-Reduction; Pharmacologic Substance; Phenols; Process; Research; Research Proposals; S-Adenosylhomocysteine; Site; Structure; Synthesis Chemistry; Technology; adduct; base; carboxylate; catalyst; chemical bond; cofactor; cost; design; drug development; insight; molecular recognition; scaffold; screening; small molecule

Project Summary/Abstract The reactivity of organic radicals endows these species with the potential to mediate otherwise inaccessible transformations. This potential, however, has not been fully met in synthetic applications because the selectivity of these fleeting intermediates is exceedingly difficult to control. Nature, on the other hand, has evolved a strategy for generating and controlling a single radical to carry out a dizzying variety of challenging bond activations within the largest known enzyme superfamily, radical S-adenosyl-methionine (SAM) enzymes. This chemistry is enabled by activation of a redox-inert electrophile (adenosine triphosphate) with a Lewis base (methionine) to generate a sulfonium cofactor (SAM). This cofactor binds in tightly regulated environment such that, upon sulfonium reduction, the resulting radical is poised to react in a manner dictated by weak interactions in the enzyme active site. The research proposed in this application aims to mimic this method of generating and controlling these reactive species to harness the full potential of radical intermediates in synthetic chemistry. The proposed means of achieving this outcome involves activation of mild and readily available electrophiles (alkyl-carboxylates) by cooperative Lewis-base activation and anion-abstraction to generate ion-paired sulfonium intermediates in a pre-organized, chiral environment. Upon single-electron reduction, the resulting radical will react with selectivity controlled by attractive non-covalent interactions that were templated in the sulfonium precursor. By mimicking the mechanism that enables radical SAM enzymes to tame reactive intermediates, the proposed catalysts will provide an unprecedented degree of catalyst control over the reactivity of organic radicals.

项目总结/文摘