Exploiting Masked Alcohols to Guide Atom-Transfer Reactions

利用掩蔽醇来引导原子转移反应

• 批准号: 9895368
• 负责人: Jennifer L Roizen
• 金额: $ 7.48万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895368
• 关键词: Acrylates; Address; Alcohols; Alkylation; Amides; Area; Biochemical; Biological; Carbon; Catalysis; Chemicals; Complement; Complex; Development; Dissociation; Drug Formulations; Equipment; Esters; Event; Generations; Grant; Health; Human; Hydrogen; Hydrogen Bonding; Kinetics; Liquid substance; Masks; Measurement; Mediating; Medical; Methods; Nitrogen; Nitrogen Oxides; Preparation; Process; Reaction; Reporting; Research; Research Support; Resources; Scheme; Site; Synthesis Chemistry; Technology; base; carbene; catalyst; functional group; imaging agent; oxidation; preference; pressure; programs; small molecule; sulfamate

This grant supports research to interrogate the hypothesis that “sulfamate esters will guide radical-mediated γ- functionalization reactions, and enable us to harness a ubiquitous functional group to replace a C–H bond at a site that is not generally accessible to direct functionalization.” The substrate tolerance of the developed technologies is being documented within the context of health-relevant complex small molecules so as to determine the extent to which these research advances complement available methods, are diastereoselective, and enable late-stage functionalization processes. For developed processes in which a catalyst appears directly involved in the radical trapping event, the potential for catalyst controlled enantioinduction should be evaluated. For the purposes of this equipment supplement abstract, the justification of need for a High Pressure Liquid Chromatograph (HPLC) that operates on analytical and semi-preparative scales will be described in the context of an ongoing project to develop a sulfamyl radical-directed photoredox-mediated Giese reaction. Nevertheless, the documented challenges are relevant to all of the Research Areas of 1R35GM128741. The development of a sulfamyl radical-directed photoredox-mediated Giese reaction is an early step to address the underexploration of nitrogen-centered radicals in synthetic chemistry. Nitrogen-centered radicals are an important and versatile class of chemical intermediates. Yet, nitrogen-centered radicals remain underutilized: most methods for their generation rely on harsh conditions to oxidize the nitrogen center to facilitate radical generation. Recently, photocatalytic strategies have been developed as mild processes to form nitrogen- centered radicals. Of neutral nitrogen-centered radicals accessed using photoredox catalysis without substrate pre-oxidation, only amidyl radicals are known to engage in C–H abstraction and subsequent functionalization. As a complement to amides, sulfamate esters may be non-intuitive. For sulfamate esters, experimental measurements that would inform a photoredox-mediated oxidation strategy have not been previously disclosed, and sulfamate esters are predicted to be significantly more acidic than similarly N-substituted amides. Nevertheless, sulfamate ester substrates are attractive because they derive from alcohols, which are ubiquitous in biologically active small molecules. Additionally, sulfamate esters are expected to guide functionalization to γ- C(sp3)–H bonds, which are not generally accessible to established directed processes. As such, a strategy to direct C–H functionalization using a sulfamyl radical could enable previously unrealized synthetic disconnections. We have developed the first photoredox-mediated process to access sulfamyl radicals, a method to guide γ-C– H functionalization as demonstrated in the reported Giese reactions (Schemes 1–3). One of the features of this Giese reaction is that many methylene centers engage in a single alkylation event, in preference to two sequential alkylation events, likely owing to steric encumbrance (Scheme 1). This is most readily evident with simple substrates, such as sulfamate esters 1a and 1b. These sulfamate esters engage in a single alkylation event to furnish Giese products 2a and 2b, respectively, which incorporate tertiary γ-C(sp3)– H bonds. These tertiary C–H centers are weaker than the secondary γ-C(sp3)–H centers in substrates 1a and 1b, and might thereby have been more susceptible to further alkylation to furnish fully-substituted 3a and 3b. To explain this selectivity, we hypothesized that the newly generated tertiary γ-C(sp3)–H bond may prove too sterically hindered to engage in further functionalization. Consistent with this hypothesis, bisalkylation seems to proceed only with a narrowly tailored subset of substrates that incorporate minimally sterically encumbered methylene centers, such as less sterically encumbered 1c, which undergoes initial monoalkylation with tert-butyl acrylate, followed by a second Giese reaction to generate fully-substituted 3c. Interrogation of the features that are required for bisalkylation has been limited by insufficient access to appropriate analytical and semi- preparative HPLC resources (see Scheme 2). Scheme 1. Sulfamate esters guide late-stage derivatization of bioactive small molecules.

这项拨款支持研究，以质疑"氨基磺酸酯将引导自由基介导的γ- 官能化反应，使我们能够利用无处不在的官能团来取代C-H键， 通常不能直接官能化的位点。"显影液的基质耐受性 在与健康有关的复杂小分子的背景下， 确定这些研究进展在多大程度上补充了现有方法，是非对映选择性的， 并且能够进行后期官能化过程。对于催化剂直接出现在 参与自由基捕获事件，应评估催化剂控制的对映体诱导的可能性。 出于本设备补充摘要的目的，需要高压液体的理由 在分析和半制备规模上操作的色谱仪（HPLC）将在上下文中描述 一个正在进行的项目，以开发氨磺酰基自由基导向的光氧化还原介导的吉斯反应。然而，尽管如此， 记录的挑战与1R35GM128741的所有研究领域相关。 氨磺酰基自由基导向的光氧化还原介导的Giese反应的发展是解决这一问题的早期步骤。 在合成化学中对氮中心自由基的探索不足。以氮为中心的自由基是 一类重要而用途广泛的化学中间体。然而，以氮为中心的自由基仍然没有得到充分利用： 大多数产生它们的方法依赖于苛刻的条件来氧化氮中心以促进自由基 一代最近，光催化策略已被开发为温和的过程，以形成氮- 中心的激进分子使用无底物光氧化还原催化获得中性氮中心自由基 在预氧化中，已知仅酰胺基自由基参与C-H提取和随后的官能化。 作为酰胺的补充，氨基磺酸酯可能是非直观的。对于氨基磺酸酯，实验 以前没有公开过将告知光氧化还原介导的氧化策略的测量， 和氨基磺酸酯被预测为比类似的N-取代的酰胺明显更酸性。 然而，氨基磺酸酯底物是有吸引力的，因为它们源自普遍存在的醇 在生物活性小分子中。另外，氨基磺酸酯预期引导γ-氨基甲酸酯的官能化。 C（sp3）-H键，其通常不可用于已建立的定向过程。因此， 使用氨磺酰基自由基的直接C-H官能化可以实现先前未实现的合成断开。 我们已经开发了第一个光氧化还原介导的过程，以获得氨磺酰基自由基，一种引导γ-C- H官能化，如在报道的Giese反应（方案1 - 3）中所证明的。 该Giese反应的特征之一是许多亚甲基中心参与单个烷基化事件， 优选两个连续的烷基化事件，可能是由于空间位阻（方案1）。这是最 用简单的底物如氨基磺酸酯1a和1b很容易看出。这些氨基磺酸酯参与 单一烷基化事件，分别提供Giese产物2a和2b，其结合叔γ-C（sp3）- H键。这些三级C-H中心比基质1a和1b中的二级γ-C（sp3）-H中心弱。 1b，从而可能更易于进一步烷基化，得到完全取代的3a和3b。到 解释这种选择性，我们假设新产生的叔γ-C（sp3）-H键也可以证明 空间位阻以进行进一步的官能化。与这一假设一致，双烷基化似乎 仅用包含最小空间阻碍的狭窄定制的基底子集进行 亚甲基中心，例如空间位阻较小的1C，其经历与叔丁基的初始单烷基化 丙烯酸酯，然后进行第二次Giese反应以产生完全取代的3c。询问的特点， 由于无法充分获得适当的分析和半 制备型HPLC资源（参见方案2）。 方案1.氨基磺酸酯指导生物活性小分子的后期衍生化。