Exploiting Masked Alcohols to Guide Atom-Transfer Reactions

利用掩蔽醇来引导原子转移反应

基本信息

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
项目类别：
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

项目摘要

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.

这笔赠款支持研究质疑“氨基磺酸酯将引导自由基介导的 γ- 官能化反应，使我们能够利用普遍存在的官能团来取代 C-H 键通常无法直接功能化的位点。” 正在记录与健康相关的复杂小分子的技术，以便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，并实现后期功能化过程，其中催化剂直接出现。涉及自由基捕获事件，应评估催化剂控制的对映诱导的潜力。出于本设备补充摘要的目的，需要高压液体的理由上下文中将描述以分析和半制备规模运行的色谱仪 (HPLC) 正在进行的开发磺酰基自由基引导的光氧化还原介导的 Giese 反应的项目的一部分。记录的挑战与 1R35GM128741 的所有研究领域相关。磺酰基自由基引导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合成化学中对氮中心自由基的探索不足。然而，以氮为中心的自由基仍未得到充分利用：大多数产生它们的方法依赖于恶劣的条件来氧化氮中心以促进自由基最近，光催化策略已被开发为形成氮的温和过程。使用光氧化还原催化获得的中性氮中心自由基。在预氧化过程中，已知只有酰胺基自由基参与 C-H 抽象和随后的官能化。作为酰胺的补充，氨基甲酸酯可能是非直观的。对于氨基甲酸酯，实验性的。之前尚未公开过可以告知光氧化还原介导的氧化策略的测量结果，预计氨基磺酸酯的酸性明显高于类似的 N-取代酰胺。然而，氨基磺酸酯底物很有吸引力，因为它们源自醇，而醇是普遍存在的此外，氨基磺酸酯有望引导 γ- 官能化。 C(sp3)–H 键，通常无法通过已建立的定向过程获得，因此，这是一种策略。使用磺酰基直接进行 C-H 官能化可以实现以前未实现的合成断开。我们开发了第一个光氧化还原介导的过程来获取氨磺酰自由基，这是一种引导γ-C–的方法 H 官能化如报道的 Giese 反应所示（方案 1-3）。该吉斯反应的特征之一是许多亚甲基中心参与单个烷基化事件，优先于两个连续的烷基化事件，可能是由于空间阻碍（方案 1）。对于简单的底物，例如氨基磺酸酯 1a 和 1b，这些氨基磺酸酯参与很容易明显。一次烷基化事件分别提供 Giese 产物 2a 和 2b，其中包含叔γ-C(sp3)– 这些三级 C-H 中心比底物 1a 和 2 中的二级 γ-C(sp3)-H 中心弱。 1b，因此可能更容易进一步烷基化以提供完全取代的3a和3b。为了解释这种选择性，我们率先证明新生成的三级 γ-C(sp3)–H 键也可能被证明与这一假设一致，双烷基化似乎受到空间阻碍。仅使用狭义定制的基板子集进行，其中包含最小的空间阻碍亚甲基中心，例如空间阻碍较小的 1c，它会与叔丁基进行初始单烷基化丙烯酸酯，然后进行第二次 Giese 反应，生成完全取代的 3c 的特征。由于无法获得适当的分析和半成品，双烷基化所需的原料受到限制。制备型 HPLC 资源（参见方案 2）。方案1.氨基甲酸酯指导生物活性小分子的后期衍生化。