Controlling Radicals via Sulfonium Activation and Anion Binding Catalysis

项目概要/摘要 有机自由基的反应性赋予这些物种的潜力，以调解，否则无法达到 转变然而，这种潜力在合成应用中还没有得到充分满足，因为 这些短暂的中间体的选择性极难控制。另一方面，大自然 进化出了一种策略，可以产生和控制一个单一的激进分子， 最大的已知酶超家族，自由基S-腺苷甲硫氨酸（SAM）酶内的键活化。 这种化学反应是通过用刘易斯碱激活氧化还原惰性亲电试剂（三磷酸腺苷）来实现的 （甲硫氨酸）以产生锍辅因子（SAM）。这种辅因子在严格调控的环境中结合， 在锍还原时，所产生的自由基准备以弱反应决定的方式反应， 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涉及激活轻度和容易 可用的亲电体（烷基羧酸盐）通过合作路易斯碱活化和阴离子提取， 在预先组织的手性环境中产生离子配对的锍中间体。在单电子 还原时，所产生的自由基将以由吸引性非共价相互作用控制的选择性反应， 都是以锍前体为模板的通过模拟使自由基SAM酶能够 驯服活性中间体，拟议的催化剂将提供前所未有的催化剂控制程度 有机自由基的反应性。

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.