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.

项目摘要/摘要 有机自由基的反应性赋予了这些物种潜在的调节能力，否则无法获得 变形。然而，这种潜力在合成应用中还没有完全发挥出来，因为 这些转瞬即逝的中间体的选择性是非常难以控制的。另一方面，大自然有 进化出一种产生和控制单个词根的策略，以执行令人眼花缭乱的各种挑战 已知最大的酶超家族中的键激活，自由基S-腺苷-蛋氨酸(SAM)酶。 这种化学作用是通过用Lewis碱激活氧化还原惰性电泳体(三磷酸腺苷)而实现的 (蛋氨酸)产生一种硫辅助因子(SAM)。这种辅因子结合在严格监管的环境中，如 当硫还原时，生成的自由基准备以弱的方式进行反应 酶活性部位的相互作用。本申请中提出的研究旨在模仿这种方法 生成和控制这些活性物种，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而容易的 可利用的亲电性(烷基-羧酸盐)通过协同的Lewis碱活化和阴离子提取来实现 在预先组织的手性环境中生成离子配对的硫中间体。关于单电子 还原时，生成的自由基将以具有吸引力的非共价相互作用控制的选择性进行反应 都是在硫磺前体中模板化的。通过模仿使自由基SAM酶能够 驯服活性中间体，建议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。