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: 10180986
• 负责人: Joseph Jeffery Gair
• 金额: $ 7.11万
• 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/10180986
• 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.

项目概要/摘要 有机自由基的反应性赋予这些物质以介导其他方式无法达到的潜力 转变。然而，这种潜力在合成应用中尚未得到充分发挥，因为 这些转瞬即逝的中间体的选择性极难控制。另一方面，大自然有 进化出一种生成和控制单个自由基的策略，以执行各种令人眼花缭乱的挑战性任务 已知最大的酶超家族自由基 S-腺苷甲硫氨酸 (SAM) 酶中的键激活。 这种化学反应是通过用路易斯碱激活氧化还原惰性亲电子试剂（三磷酸腺苷）来实现的 （蛋氨酸）生成锍辅助因子（SAM）。该辅因子在严格调控的环境中结合，例如 在锍还原时，产生的自由基准备以弱的方式进行反应 酶活性位点的相互作用。本申请中提出的研究旨在模仿这种方法 产生和控制这些活性物质，以充分利用自由基中间体的潜力 合成化学。实现这一结果的拟议方法包括激活温和且容易的 通过协同路易斯碱活化和阴离子抽象可得到亲电子试剂（烷基羧酸盐） 在预组织的手性环境中生成离子对锍中间体。单电子时 还原时，生成的自由基将通过有吸引力的非共价相互作用控制选择性反应， 在锍前体中进行模板化。通过模仿自由基 SAM 酶的机制 驯服反应中间体，所提出的催化剂将提供前所未有的催化剂控制程度 超过有机自由基的反应性。