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: 10616488
• 负责人: Michael Strauss
• 金额: $ 6.91万
• 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/10616488
• 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; Medicine; Mentors; Methods; Modeling; Natural Source; Organic Chemistry; Pattern; Petroleum; Pharmacologic Substance; Preparation; Prevalence; Procedures; Process; Reaction; Reagent; Research; Scheme; Silanes; Site; Source; Styrenes; Sulfones; Sulfoxide; Sulfur; Surveys; System; Therapeutic; Thiazines; Training; 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.

项目摘要/摘要 烯烃是丰富的化学原料，许多行业，包括制药开发， 以立体选择性和区域选择性的方式制备必需的配体。与烯烃的普遍存在类似，硫- 自古代以来，含有分子的药物就一直用于医学领域，并且仍然代表着大量的药物。 新FDA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硫的氧化。 结构多样性取决于形成关键的C-S键。因此，发展一种化疗和 构建C-S键的对映选择性方法（即，硫醚）将用作有用的合成 这是制备许多药物相关靶点的工具。 虽然存在许多制备硫醚的方法，但它们经典地依赖于硫醇盐的亲核加成 转化为高反应性物质如烷基卤化物。这种方法具有差的化学选择性，因为不受控制地 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， 其基于首先形成对映体纯的烷基卤化物。这两个因素极大地限制了它的普遍效用。 方法，并且通常规定在靶向合成中必须构建键的顺序。在过去 十年来，硫醇-烯化学已经成为从烯烃构建C-S键的有用工具。然而，在这方面， 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 因此，该方法不需要官能化，并且不产生对映体富集的产物。 本研究的目的是提供一种合成对映体富集硫醚的新方法 由广泛可得的官能化烯烃前体制得。使用氢化铜（I）催化剂结合 基于次磺酰胺的硫转移试剂将产生构建对映体富集和 线性硫醚。此外，所制备的硫醚将用作其它立体限定的硫醚的入口点。 含有官能团如亚砜和砜。这种通用的方法将被有益地采用 许多含硫药物的合成，从而证明了这一点的整体效用 approach.预计拟议的研究将提供新的方法来应对长期存在的挑战 使用CuH催化形成C-S键。 麻省理工学院的Buchwald实验室是完成拟议研究和培训的理想环境 为学术生涯做准备的目标。在Buchwald小组，我将获得许多领域的关键培训， 有机化学，包括方法开发和物理有机化学。此外，MIT将提供 无数的机会，以提高我的技能，作为一个教育工作者和科学导师通过麻省理工学院的教学和 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追求的最佳机构 我的最终目标是有一个成功的独立的学术生涯。