Development of Sulfur-Based Reactions with Translational Applications

硫基反应的发展及其转化应用

• 批准号: 10180743
• 负责人: Tian Qin
• 金额: $ 32.37万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10180743
• 关键词: Acids; Address; Adoption; Alkenes; Area; Belief; Biological; Boron; Boronic Acids; Chemicals; Chemistry; Collaborations; Complex; Coupling; Dehydration; Development; Drug Industry; Elements; Evaluation; Family; Fluorine; Goals; Laboratory Research; Libraries; Ligands; Literature; Mediating; Medical center; Metabolic; Metals; Methodology; Methods; Modernization; Pathway interactions; Pentas; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Property; Protocols documentation; Reaction; Reagent; Research; Seminal; Structure; Sulfoxide; Sulfur; Transition Elements; analog; base; catalyst; chemical bond; drug development; field study; industry partner; innovation; interest; novel; oxidation; preservation; programs; scaffold; small molecule libraries; synergism

Project Summary/Abstract Cross-coupling reactions provide the most reliable and modular means to diverse chemical space, enabling the discovery of novel pharmaceuticals and elucidation of critical biological pathways. Seminal efforts spanning the last century have led to the development of a variety of metal-catalyzed cross-coupling reactions that allow efficient chemical bonds formation. However, these powerful chemical transformations still have shortcomings. Endeavors in developing novel coupling methodologies could address the identified challenges in the chemical literature. More importantly, they can be deployed to rapidly synthesize structurally and topologically complex compounds from accessible starting materials. Our research laboratory is seeking to invent new synthetic approaches to address this identified gap in the cross-coupling literature, specifically focusing on methodology development with the nonmetal element sulfur, one of the most abundant and inexpensive starting materials with versatile oxidation states (–2 to +6). We propose high valent sulfur complexes can enable diverse coupling modes in either stoichiometric or catalytic fashions. This proposal is organized into three sections with the goal of addressing current limitations in synthetic methodology and affording the ability to rapidly generate diverse and complex small molecule libraries. The first portion of this proposal illustrates a plan for sulfurane-mediated hindered C(sp2) and C(sp3) coupling via S(IV) to S(II) reduction. The second section illustrates how nonmetal sulfur (S(VI) to S(IV)) can provide a general and practical solution to alkyl boronate synthesis, especially for unprotected alkyl boronic acids. The last part of this proposal argues that persulfuranes have the potential to mediate synthetically valuable C–F bond formation, even possibly in a catalytic manner (S(VI) ↔ S(IV)). These described methods will enable facile access to scaffolds of interest for medicinal chemistry and biological evaluation. The biological properties of several families of compounds will be further investigated through our already established collaborations. Taken together, these innovative new synthetic modes could address the synthesis of challenging and medicinally relevant chemical scaffolds.

项目总结/摘要 交叉偶联反应为多样化的化学空间提供了最可靠和模块化的手段，使其能够用于化学反应。 发现新的药物和阐明关键的生物途径。种子工作跨越 上世纪已经导致了各种金属催化的交叉偶联反应的发展 有效的化学键形成。然而，这些强大的化学转化仍然存在缺点。 努力开发新的偶联方法可以解决化学品中确定的挑战， 文学更重要的是，它们可以用于快速合成结构和拓扑复杂的 化合物从可获得的起始材料。我们的研究实验室正在寻求发明新的合成 解决交叉耦合文献中这一已确定差距的方法，特别是侧重于方法学 开发与非金属元素硫，其中一个最丰富和廉价的起始材料， 多种氧化态（-2至+6）。我们提出高价硫配合物可以实现多种偶联 以化学计量或催化方式的模式。本提案分为三个部分，其目标是 解决目前合成方法的局限性，并提供快速产生多种 和复杂的小分子文库。该提案的第一部分说明了一个计划， 通过S（IV）还原成S（II）的受阻C（sp2）和C（sp3）偶联。第二部分说明非金属如何 硫（S（VI）至S（IV））可以为烷基硼酸酯合成提供通用和实用的解决方案，特别是用于 未保护的烷基硼酸。该提案的最后一部分认为，全硫烷有可能 介导合成有价值的C-F键形成，甚至可能以催化方式（S（VI）Particles（IV））。这些 所描述的方法将使得能够容易地获得用于药物化学和生物学的感兴趣的支架 评价几个家族的化合物的生物学特性将通过我们的研究进一步研究。 已经建立的合作关系。总之，这些创新的新合成模式可以解决 具有挑战性和医学相关的化学支架的合成。