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

项目摘要/摘要 手性胺是自然界和医药中普遍存在的基元。相反，酒精是最便宜的。 以及最普遍的分子。该计划致力于开发新的远程C-H 官能化策略将简化从丰富的生物相关胺的合成 酒精前体。提出的方法的关键创新是设计了催化剂以利用 通过酰亚胺(β)和氨基(δ)自由基的区域选择性1，5-氢原子转移(HAT)机制。穿过 催化剂控制的含氮自由基的生成，以及最新实现的远程调节 对于(β或δ)终止，我们寻求获得新类型的反应性和选择性。例如，第一个 提出了几个自由基介导型变换的非对称例子。此外，还推出了一系列小说、 描述了单C-H功能化级联和双C-H功能化级联。对这些分歧的解释 拦截自由基中间体的机制将使人们能够新地访问有价值的远程转换， 包括几种与药物相关的支架的合成(例如α-氨基酸、β-氨基醇、氮杂- 杂环)以快速、模块化和选择性的方式合成。 这些策略对于自由基介导的远程C-H功能化的意义在于它们促进了 发现了原本不太可能的合成反应性。具体地说，通过使用瞬时亚胺基团 伴侣、醇可以选择性地转化为一类手性胺。两个金属催化类 提出了反应性(立体选择性HAT和终止，或HAT去对称化)的建议，以便于 不对称βC-H胺化和其他对映体选择性官能化。同时，新的方法可用于 金属介导的从胺产生的酰胺基也将促进它们更快速和直接的访问 作为它们与芳烃和其他亲核试剂远程交叉偶联的新途径。最新阐明的 利用新的δC-H反应性(通过酰胺基)的机制也将使进一步的开发成为可能 伴侣介导的βC-H官能化(通过亚胺类自由基)。总之，这些研究将进一步扩大 我们有选择地控制远程HAT机制并实现新颖、有用和前所未有的C-H的能力 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.