Enantioselective Thioetherification of Olefins Guided by CuH Catalysis

CuH 催化下烯烃的对映选择性硫醚化

• 批准号: 10464729
• 负责人: Michael Strauss
• 金额: $ 6.68万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-25 至 2025-04-24
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464729
• 关键词: Academia; Adopted; Alkenes; Architecture; Area; Biological Models; Catalysis; Chemicals; Chemistry; Complex; Copper; Development; Educational process of instructing; Environment; Goals; Greek; Industry; Institution; Laboratories; Learning; Ligands; Mentors; Methods; Modeling; Organic Chemistry; Oxides; Pattern; Petroleum; Pharmacologic Substance; Preparation; Prevalence; Procedures; Process; Reaction; Reagent; Research; Research Training; Scheme; Silanes; Site; Source; Styrenes; Sulfhydryl Compounds; Sulfones; Sulfoxide; Sulfur; Surveys; System; Therapeutic; Thiazines; Training; base; career; design; electron density; forging; functional group; improved; method development; novel; novel strategies; nucleophilic addition; oxidation; skills; sulfenamide; targeted treatment; thioether; tool

PROJECT SUMMARY/ABSTRACT Olefins are abundant chemical feedstocks that many industries, including pharmaceutical development, rely on to prepare essential synthons in a stereo- and regioselective manner. Similar to the ubiquity of olefins, sulfur- containing molecules have been used in a medicinal context since antiquity, and continue to represent a large portion of new FDA approvals. The ability of sulfur to adopt five stable oxidation states further contributes to the structural diversity predicated on forming crucial C–S bonds. As such, the development of a chemo- and enantioselective method to construct C–S bonds (i.e., thioethers) from olefins would serve as a useful synthetic tool in the preparation of many pharmaceutically relevant targets. While many methods exist to prepare thioethers, they classically rely on the nucleophilic addition of thiolates to highly reactive species such as alkyl halides. This approach has poor chemo-selectivity, in that uncontrolled nucleophilic addition can occur at many sites within complex architectures, and has stereoselectivity that is predicated on first forming enantiopure alkyl halides. These two factors greatly limit the general utility of this approach and often dictate the order in which bonds must be constructed in targeted synthesis. Over the last decade, thiol-ene chemistry has emerged as a useful tool in constructing C–S bonds from olefins. However, thiol-ene chemistry proceeds with restricted regioselectivity, in that it only allows anti-Markovnikov functionalizations, and does not yield enantioenriched products. The object of this proposal is to provide a new synthetic approach to synthesize enantioenriched thioethers from widely available functionalized olefin precursors. Using copper(I) hydride catalysis in conjunction with a sulfenamide-based sulfur transfer reagent will yield a versatile method to construct both enantioenriched and linear thioethers. Furthermore, the prepared thioethers will serve as an entry point to other stereodefined sulfur- containing functional groups such as sulfoxides and sulfones. This versatile method will be beneficially adopted to the synthesis of many sulfur-containing pharmaceuticals, thereby demonstrating the overall utility of this approach. The proposed research is expected to provide novel approaches to tackle long-standing challenges in forging C–S bonds using CuH catalysis. The Buchwald laboratory at MIT is the ideal environment to accomplish the proposed research and training goals in preparation for a career in academia. In the Buchwald group, I will gain crucial training in many areas of organic chemistry including method development and physical organic chemistry. Furthermore, MIT will provide numerous opportunities to improve my skills as an educator and scientific mentor through the MIT Teaching and Learning Laboratory. Collectively, all of these factors led me to choose MIT as the optimal institution to pursue my ultimate goal of having a successful independent academic career.

项目概要/摘要 烯烃是丰富的化学原料，包括药物开发在内的许多行业都依赖于它 以立体和区域选择性方式制备必要的合成子。与普遍存在的烯烃类似，硫- 含有分子自古以来就被用于医学领域，并继续代表着大量 FDA 新批准的一部分。硫采用五种稳定氧化态的能力进一步有助于 结构多样性取决于形成关键的 C-S 键。因此，化学和 从烯烃构建C-S键（即硫醚）的对映选择性方法将作为一种有用的合成方法 制备许多药学相关靶标的工具。 虽然存在许多制备硫醚的方法，但它们通常依赖于硫醇盐的亲核加成 高活性物质，如烷基卤化物。这种方法的化学选择性较差，因为不受控制 亲核加成可以发生在复杂结构中的许多位点，并且具有立体选择性 基于首先形成对映体纯烷基卤化物。这两个因素极大地限制了这种方法的普遍实用性 方法并经常规定在目标合成中必须构建键的顺序。过去的 十年来，硫醇-烯化学已成为从烯烃构建 C-S 键的有用工具。然而， 硫醇-烯化学以有限的区域选择性进行，因为它只允许反马尔可夫尼科夫 功能化，并且不产生对映体富集的产物。 该提案的目的是提供一种新的合成方法来合成对映体富集的硫醚 来自广泛可用的官能化烯烃前体。使用氢化铜 (I) 催化与 基于次磺酰胺的硫转移试剂将产生一种通用的方法来构建对映体富集和 直链硫醚。此外，制备的硫醚将作为其他立体定义的硫的切入点。 含有亚砜、砜等官能团。这种多功能的方法将被有益地采用 许多含硫药物的合成，从而证明了这种方法的整体效用 方法。拟议的研究预计将为解决长期存在的挑战提供新方法 使用 CuH 催化形成 C-S 键。 麻省理工学院的布赫瓦尔德实验室是完成拟议研究和培训的理想环境 为学术界职业生涯做准备的目标。在布赫瓦尔德小组中，我将获得许多领域的重要培训 有机化学包括方法开发和物理有机化学。此外，麻省理工学院将提供 通过麻省理工学院的教学和培训，我有很多机会提高我作为教育家和科学导师的技能 学习实验室。总的来说，所有这些因素使我选择麻省理工学院作为我追求的最佳机构 我的最终目标是拥有成功的独立学术生涯。