Development of Sulfur-Based Reactions with Translational Applications

硫基反应的发展及其转化应用

• 批准号: 10373112
• 负责人: Tian Qin
• 金额: $ 32.41万
• 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/10373112
• 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; 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; translational applications

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.

项目概要/摘要 交叉偶联反应为不同的化学空间提供了最可靠和模块化的方法，使 新型药物的发现和关键生物学途径的阐明。 上个世纪导致了各种金属催化交叉偶联反应的发展，这些反应允许 然而，这些强大的化学转变仍然存在缺点。 努力开发新颖的偶联方法可以解决化学领域已确定的挑战 更重要的是，它们可以用来快速合成结构和拓扑复杂的内容。 我们的研究实验室正在寻求发明新的合成材料。 解决交叉耦合文献中发现的这一差距的方法，特别关注方法论 非金属元素硫的开发，硫是最丰富、最便宜的原材料之一 我们提出高价硫络合物可以实现多种偶联。 该提案分为三个部分，其目标是化学计量或催化方式。 解决当前合成方法的局限性并提供快速生成多样化的能力 该提案的第一部分阐述了硫烷介导的计划。 通过 S(IV) 还原至 S(II) 受阻 C(sp2) 和 C(sp3) 耦合 第二部分说明了非金属如何进行。 硫（S（VI）至S（IV））可以为烷基硼酸酯的合成提供通用且实用的解决方案，特别是对于 该提案的最后部分认为，全硫烷有潜力。 介导具有合成价值的 C-F 键形成，甚至可能以催化方式 (S(VI) ↔ S(IV))。 所述方法将能够轻松获得药物化学和生物感兴趣的支架 几个化合物家族的生物学特性将通过我们的进一步研究 总而言之，这些创新的新合成模式可以解决这个问题。 具有挑战性和医学相关的化学支架的合成。