Enantioselective Thioetherification of Olefins Guided by CuH Catalysis

项目摘要/摘要 烯烃是一种丰富的化工原料，包括制药开发在内的许多行业都依赖于它。 以立体声和区域选择性的方式准备必要的合成子。类似于普遍存在的烯烃，硫磺- 含有分子自古以来就被用于医药领域，并继续代表着一种 FDA新批准的一部分。硫以五种稳定的氧化态存在的能力进一步有助于 结构多样性的前提是形成关键的C-S债券。因此，化疗的发展-和 由烯烃构筑C-S键(即硫醚)的不对称方法将是一种有用的合成方法 在许多药物相关靶点的制备过程中使用了这一工具。 虽然有许多制备硫醚的方法，但它们通常依赖于硫醇酸盐的亲核加成。 到高活性物种，如烷基卤化物。这种方法的化学选择性很差，因为不受控制 亲核加成可以发生在复杂建筑中的许多位置，并具有立体选择性，即 以首次生成对映异构烷基卤化物为基础。这两个因素极大地限制了这种方法的普遍应用。 方法，并经常规定在定向合成中键的构建顺序。在过去的几年里 十年来，硫醇-烯化学已成为从烯烃构筑C-S键的有用工具。然而， 硫醇-烯化学具有有限的区域选择性，因为它只允许反马尔科夫尼科夫 官能化，不产生对映体富集化的产品。 本建议的目的是提供一种新的合成方法来合成对映体富集硫醚 从广泛可用的官能化烯烃前体中提取。将铜(I)氢化物催化与 基于亚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型和 线型硫醚。此外，所制备的硫醚将作为其他立体定义的硫的入口点- 含有亚硫醚和亚砜等官能团的。这种多才多艺的方法将得到有益的采纳。 许多含硫药物的合成，从而展示了这一技术的总体用途 接近。预计拟议的研究将提供新的方法来应对长期存在的挑战 利用CuH催化锻造C-S键。 麻省理工学院的布赫瓦尔德实验室是完成拟议研究和培训的理想环境。 为在学术界的职业生涯做准备的目标。在布赫瓦尔德小组，我将在以下许多领域获得至关重要的培训 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科学指导，无数次机会提高我作为教育工作者和科学导师的技能 学习实验室。总而言之，所有这些因素促使我选择麻省理工学院作为我追求的最佳院校 我的最终目标是拥有一个成功的独立学术生涯。

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.