School of Chemistry, University of Manchester, Manchester M13 9PL, U.K.
Acc Chem Res. 2015 May 19;48(5):1263-75. doi: 10.1021/acs.accounts.5b00083. Epub 2015 Apr 14.
Reductive electron transfer (ET) to organic compounds is a powerful method for the activation of substrates via the formation of radicals, radical anions, anions, and dianions that can be exploited in bond-cleaving and bond-forming processes. Since its introduction to the synthetic community in 1977 by Kagan, SmI2 has become one of the most important reducing agents available in the laboratory. Despite its widespread application in aldehyde and ketone reduction, it was widely accepted that carboxylic acid derivatives could not be reduced by SmI2; only recently has our work led to this dogma being overturned, and the reduction of carboxylic acid derivatives using SmI2 can now take its place alongside aldehyde/ketone reduction as a powerful activation mode for synthesis. In this Account, we set out our studies of the reduction of carboxylic acid derivatives using SmI2, SmI2-H2O, and SmI2-H2O-NR3 and the exploitation of the unusual radical anions that are now accessible in unprecedented carbon-carbon bond-forming processes. The Account begins with our serendipitous discovery that SmI2 mixed with H2O is able to reduce six-membered lactones to diols, a transformation previously thought to be impossible. After the successful development of selective monoreductions of Meldrum's acid and barbituric acid heterocyclic feedstocks, we then identified the SmI2-H2O-NR3 reagent system for the efficient reduction of a range of acyclic carboxylic acid derivatives that typically present a significant challenge for ET reductants. Mechanistic studies have led us to propose a common mechanism for the reduction of carboxylic acid derivatives using Sm(II), with only subtle changes observed as the carboxylic acid derivative and Sm(II) reagent system are varied. At the center of our postulated mechanism is the proposed reversibility of the first ET to the carbonyl of carboxylic acid derivatives, and this led us to devise several strategies that allow the radical anion intermediates to be exploited productively in efficient new processes. First, we have used internal directing groups in substrates to "switch on" productive ET to esters and amides and have exploited such an approach in tag-removal cyclization processes that deliver molecular scaffolds of significance in biology and materials science. Second, we have exploited external ligands to facilitate ET to carboxylic acid derivatives and have applied the strategy in telescoped reaction sequences. Finally, we have employed follow-up cyclizations with alkenes, alkynes, and allenes to intercept radical anion intermediates formed along the reaction path and have employed this strategy in complexity-generating cascade approaches to biologically significant molecular architectures. From our studies, it is now clear that Sm(II)-mediated ET to carboxylic acid derivatives constitutes a general strategy for inverting the polarity of the carbonyl, allowing nucleophilic carbon-centered radicals to be formed and exploited in novel chemical processes.
还原电子转移（ET）是一种将有机化合物激活为自由基、自由基阴离子、阴离子和二阴离子的有效方法，可用于键断裂和键形成过程。自 1977 年 Kagan 将其引入合成界以来，SmI2 已成为实验室中可用的最重要的还原剂之一。尽管它在醛和酮的还原中得到了广泛的应用，但人们普遍认为羧酸衍生物不能被 SmI2 还原；直到最近，我们的工作才推翻了这一教条，现在羧酸衍生物的还原可以与醛/酮还原一起作为一种强大的合成激活模式。在本专题介绍中，我们阐述了使用 SmI2、SmI2-H2O 和 SmI2-H2O-NR3 还原羧酸衍生物的研究工作，以及在前所未有的碳-碳键形成过程中利用现在可获得的异常自由基阴离子的研究工作。本专题介绍从我们偶然发现 SmI2 与 H2O 混合能够将六元内酯还原为二醇开始，这是一种以前认为不可能的转化。在成功开发出 Meldrum 酸和巴比妥酸杂环原料的选择性单还原之后，我们又确定了 SmI2-H2O-NR3 试剂体系可有效还原一系列环状羧酸衍生物，这些衍生物通常对 ET 还原剂构成重大挑战。通过对反应机理的研究，我们提出了一个使用 Sm(II)还原羧酸衍生物的共同机制，只有在羧酸衍生物和 Sm(II)试剂体系发生变化时才会观察到细微的变化。我们提出的反应机理的核心是羧酸衍生物的羰基的第一个 ET 可逆性，这使我们设计了几种策略，可以有效地利用自由基阴离子中间体在高效的新反应中发挥作用。首先，我们在底物中使用了内部导向基团来“开启”酯和酰胺的有效 ET，并在 tag-removal 环化反应中利用了这种方法，这些反应提供了在生物学和材料科学中具有重要意义的分子支架。其次，我们利用外部配体促进羧酸衍生物的 ET，并将该策略应用于缩合反应序列。最后，我们使用烯烃、炔烃和丙二烯进行后续环化反应，拦截反应路径中形成的自由基阴离子中间体，并将该策略应用于复杂的级联方法中，以获得具有生物学意义的分子结构。从我们的研究中可以清楚地看出，Sm(II)介导的羧酸衍生物的 ET 构成了反转羰基极性的一般策略，允许形成亲核碳中心自由基，并在新的化学过程中加以利用。
