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.

该赠款支持研究，以审问这样的假设：“硫酸酯将指导自由基介导的γ- 功能化反应，使我们能够利用无处不在的官能团替换在A处的C – H键 通常无法直接功能化的站点。 在与健康相关的复杂小分子的背景下，正在记录技术 确定这些研究在多大程度上提高可用方法，具有映选择性， 并启用后期功能化过程。对于催化剂直接出现的开发过程 应评估催化剂控制的对映体诱导的潜力。 出于本设备补充摘要的目的，高压液体的需求的理由 将在上下文中描述以分析和半游行量表运行的色谱仪（HPLC） 一个正在进行的项目，以开发磺胺自由基指导的光电氧介导的GIESE反应。尽管如此， 记录的挑战与1R35GM128741的所有研究领域有关。 磺酰基自由基指导的光毒素介导的GIESE反应的发展是解决的早期步骤 在合成化学中以氮气为中心的自由基的不足。以氮为中心的自由基是 重要且多才多艺的化学中间体。然而，以氮为中心的自由基仍未充分利用： 其一代的大多数方法都依靠危害条件来氧化氮中心氧化 一代。最近，已经开发了光催化策略，以形成氮 - 集中的自由基。使用Photoredox催化没有底物访问的中性氮气中性自由基的 氧化前，只有氨基二基自由基参与C – H抽象和随后的功能化。 作为酰胺的完整性，硫酸酯可能是非直觉的。对于硫酸酯，实验性 以前尚未披露将告知光电素介导的氧化策略的测量值 预计硫酸酯和硫酸酯的酸性明显高于类似的N-取代酰胺。 然而，硫酸酯底物很有吸引力，因为它们源自无处不在的酒精 在生物活性的小分子中。此外，预计硫酸酯将引导功能化至γ- c（sp3）–h债券，通常无法使用已建立的定向过程。因此，一种策略 使用磺胺自由基的直接C – H官能化可以实现先前未实现的合成断开连接。 我们已经开发了第一个光电毒介导的过程来访问磺胺自由基，这是一种指导γ-C –的方法 H官能化如报道的GIESE反应中所示（方案1-3）。 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，即 优先于两个顺序的酒精事件，可能是由于空间负担而引起的（方案1）。这是最大的 很容易证明简单的底物，例如硫酸酯1a和1b。这些硫酸酯参与 分别提供GIESE产品2A和2B的单一酗酒事件，该事件融合了第三纪γ-C（SP3） - H键。这些三级C – H中心比二次γ-C（SP3） - 底物1a中的中心弱弱 1B，因此可能更容易进一步提供烷基化完全取代的3A和3B。到 解释这种选择性，我们假设新生成的第三纪γ-C（SP3） - H键也可能证明 在空间上阻碍了进一步的功能化。与该假设一致，双烷基化似乎 仅使用一个狭义的基板子集进行，这些子材料包含微小的空间 亚甲基中心，例如较少的空间限制1c，它用丁基进行初始单烷基化 丙烯酸，然后进行第二个GIESE反应，以产生完全取代的3C。询问功能 双烷基化所必需的已受到限制，因为无法获得适当的分析和半分析 准备的HPLC资源（请参阅方案2）。 方案1。硫化酯引导生物活性小分子的晚期衍生化。