Radical Chaperones to Harness Remote, Selective C-H Functionalization Mechanisms

项目总结/摘要 手性胺在自然界和医学中是普遍存在的基序。相反，酒精是最便宜的 和最普遍的分子。该计划致力于开发新的远程C-H 功能化策略，将简化生物相关胺的合成，从丰富的 酒精前体所提出的方法的关键创新是催化剂的设计利用 通过亚胺基（β）和酰胺基（δ）自由基的区域选择性1，5-氢原子转移（HAT）机制。通过 以氮为中心的自由基的催化剂控制的产生，以及新启用的对它们的远程调节， （β或δ）终止，我们寻求获得新类型的反应性和选择性。例如第一 提出了几个自由基介导的转化的不对称的例子。此外，一系列的小说， 描述了单和双C-H官能化级联。对这些分歧的解释 拦截自由基中间体的机制将使有价值的远程转化成为可能， 包括几种医学相关支架（例如α-氨基酸、β-氨基醇、氮杂-β-氨基-β- 杂环）。 这些用于自由基介导的远程C-H官能化的策略的意义在于它们促进了C-H官能化。 发现了不太可能的合成反应性。具体地，通过采用瞬时亚氨酸酯自由基， 在分子伴侣中，醇可以选择性地转化为手性胺家族。两类金属催化剂 反应性（立体选择性HAT和终止，或通过HAT的去对称化）， 不对称β C-H胺化和其他对映选择性官能化。与此同时， 金属介导的，酰胺基自由基的产生从胺将促进他们更迅速和直接的访问，以及 作为它们与芳烃和其它亲核试剂远程交叉偶联的新途径。新阐明的 利用新的δ C-H反应性（通过酰胺基自由基）的机制也将使进一步发展， 分子伴侣介导的β C-H功能化（通过亚胺基）。这些研究将进一步扩大 我们能够有选择地控制远程HAT机制，并实现新颖、有用和前所未有的C-H 编辑在医学相关分子中发现的醇和胺。

Project Summary/Abstract Chiral amines are prevalent motifs in nature and medicine. Conversely, alcohols are among the cheapest and most ubiquitous molecules. This program is dedicated to the development of new, remote C-H functionalization strategies that will streamline the synthesis of biologically relevant amines from abundant alcohol precursors. The key innovation of the proposed approach is the design of catalysts to harness regioselective 1,5-hydrogen atom transfer (HAT) mechanisms via imidate (β) and amidyl (δ) radicals. Through catalyst-controlled generation of nitrogen-centered radicals, as well as newly enabled regulation of their remote (β or δ) terminations, we seek to access new types of reactivity and selectivity. For example, the first asymmetric examples of several radical-mediated transformations are proposed. Additionally, a series of novel, single and double C-H functionalization cascades are described. The elucidation of these divergent mechanisms for intercepting radical intermediates will enable new access to valuable, remote transformations, including the synthesis of several medicinally relevant scaffolds (e.g. α-amino acids, β-amino alcohols, aza- heterocycles) in a rapid, modular, and selective fashion. The significance of these strategies for radical-mediated, remote C-H functionalization is their facilitation of the discovery of otherwise unlikely synthetic reactivity. Specifically, by employing transient imidate radical chaperones, alcohols may be selectively converted to a family of chiral amines. Two metal-catalyzed classes of reactivity (stereoselective HAT and termination, or desymmetrization by HAT) are proposed to facilitate asymmetric β C-H amination and other enantioselective functionalizations. In parallel, new approaches for metal-mediated, amidyl radical generation from amines will facilitate their more rapid and direct access, as well as new avenues for their remote cross-coupling with arenes and other nucleophiles. The newly elucidated mechanisms for harnessing novel δ C-H reactivity (by amidyl radicals) will also enable further developments of chaperone-mediated β C-H functionalizations (by imidate radicals). Together, these studies will further expand our ability to selectively control remote HAT mechanisms and enable novel, useful, and unprecedented C-H editing of alcohols and amines found in medicinally relevant molecules.