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.

项目摘要/摘要 烯烃是许多行业（包括制药开发）依赖的丰富化学原料 以立体和调节方式准备必需的合成子。类似于烯烃的普遍性，硫酸 - 自上古以来，含有分子已在医学环境中使用，并继续代表大型 新的FDA批准的一部分。硫采用五种稳定氧化状态的能力进一步有助于 预测形成至关重要的C – S键的结构多样性。因此，化学和化学的发展 从烯烃中构建C – S键（即硫乙烯）的对映选择性方法将用作有用的合成 制备许多药物相关目标的工具。 尽管存在许多方法来准备硫代乙烯剂，但他们在经典上依靠硫酸盐的添加 到高反应性物种，例如烷基卤化物。这种方法的化学选择性差，因为 亲核添加可以在复杂体系结构内的许多地点发生，并且具有立体选择性 基于首先形成对映体酒精卤化物的基础。这两个因素很大程度限制了这一点的一般效用 方法并经常决定必须在目标合成中构建键的顺序。最后 十年来，硫醇 - 烯化学已成为构建烯烃键的有用工具。然而， 硫醇 - 烯化学以限制的区域选择性进行，因为它仅允许抗马科夫尼科夫 功能化，不会产生映射的产品。 该提案的目的是提供一种新的合成方法，以合成富含对映的硫代乙醇 来自广泛可用的功能化烯烃前体。使用铜（i）氢化物催化剂与A结合 基于亚磺胺的硫转移试剂将产生一种多功能方法，以构建对映体和对照的方法 线性硫化物。此外，制备的硫代乙烯剂将作为其他立体构焦硫的入口处 含有诸如亚氧化物和磺基酮等功能组。这种多功能方法将受益于 为了合成许多含硫的药物，从而证明了这一点的整体效用 方法。拟议的研究有望提供新颖的方法来应对长期存在的挑战 在使用CUH催化的情况下锻造C – S键。 麻省理工学院的布赫瓦尔德实验室是完成拟议的研究和培训的理想环境 为在学术界做好事业做准备的目标。在布赫瓦尔德小组中，我将在许多领域获得重要的培训 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 学习实验室。总的来说，所有这些因素使我选择MIT作为购买的最佳机构 我拥有成功的独立学术生涯的最终目标。