Development of Sulfur-Based Reactions with Translational Applications

项目摘要/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手段，使 新药物的发现和关键生物途径的阐明。跨越世界各地的开创性努力 上个世纪导致了各种金属催化的交叉偶联反应的发展，使得 高效的化学键形成。然而，这些强大的化学转化仍然有缺点。 开发新的耦合方法的努力可以解决该化学品中已确定的挑战 文学。更重要的是，它们可以被部署来快速合成结构和拓扑复杂的 从可获得的起始材料中提取化合物。我们的研究实验室正在努力发明新的合成材料 解决交叉耦合文献中确定的差距的方法，特别是侧重于方法论 非金属元素硫的开发，硫是资源最丰富、价格最便宜的原料之一 多种氧化态(-2至6)。我们认为高价硫络合物可以实现不同的偶联 模式的化学计量或催化方式。这项提案分为三个部分，目标是 解决目前合成方法中的局限性，并提供快速生成各种 和复杂的小分子文库。该提案的第一部分说明了一项以硫烷为媒介的计划。 抑制C(Sp2)和C(Sp3)通过S(IV)至S(II)还原。第二部分说明了非金属材料是如何 硫磺(S(VI)至S(IV))为烷基硼酸酯的合成提供了一种通用而实用的解决方案，特别是对 无保护的烷基硼酸。该提案的最后部分认为，过硫烷有可能 参与合成有价值的C-F键的形成，甚至可能以催化方式(S(VI)↔S(IV))。这些 所描述的方法将使人们能够方便地接触到药物化学和生物感兴趣的支架 评估。几个化合物家族的生物学特性将通过我们的 已经建立了合作关系。综上所述，这些创新的新合成模式可以解决 具有挑战性和药用相关的化学支架的合成。

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.