Development of Decarboxylative and Desulfinative Cross-Coupling Strategies Towards Drug-Discovery, Materials and Biomass-Derived Platform Chemicals

我们的研究主要集中在发展脱羧和脱羧交叉偶联及其在制备碳-碳键中的应用。在过去五年中奠定的坚实基础将使目前的研究朝着新的方向发展，旨在吸引新的和加强现有的学术和工业合作。我们的项目探索了强大的钯介导的交叉偶联方法，以构建芳基-芳基和杂芳基-芳基结构，这些结构在医药化学，液晶和农业化学中作为绝缘体/热导体作为“特权结构”具有重要的应用。工作台/空气稳定的亚磺酸盐和羧酸进行偶联，其提供了与更经典的、广泛使用的有机金属偶联配偶体相比是高度区域选择性反应的优点，而不产生有毒的金属副产物。重要的是，我们已经证明，这些耦合可以在环境友好的溶剂，如水和乙醇中进行，并导致邀请对亚磺酸酯交叉耦合的小型审查。我们开发了一种实用而有效的合成亚磺酸酯的可去除导向基团的方法。此外，该方法被应用于合成α-螺旋模拟物，其已显示出作为淀粉样蛋白原纤维调节剂的前景。此外，我们已经能够将脱羧交叉偶联与C-H活化策略结合联合收割机，以通过串联交叉偶联方法在一锅法中制备密集官能化的噻吩异喹啉，其已经证明了用于三阴性乳腺癌的潜在治疗的抗癌活性。该研究计划旨在逐步建立并扩展到我们在脱羧和脱羧芳基化方面的专业知识的新方向，并专注于通过利用其独特的反应性和仔细控制区域化学的能力来应用于目标结构。将探索使用吡啶砜作为掩蔽的亚磺酸酯，其可以作为选择性氘掺入的指导基团，扩展到一系列额外的官能团和制备1，2，5-三芳基吡咯在药物化学中的应用。高度区域选择性的脱羧芳基化的使用将被利用来制备寡聚噻吩的离散库，并扩展到制备无缺陷的聚噻吩。此外，脱羧偶联将用于生产下一代生物燃料，以及可以从可再生生物质衍生原料制备的非传统聚合物。在所有情况下，研究计划的设计都适合于由本DG资助的各种HQP级别（博士，硕士，本科生）。

Our research has focused on the development of decarboxylative and desulfinative cross-couplings and their applications for the preparation of carbon-carbon bonds. The solid foundation laid in the last five years will allow the present research to build towards new directions with the aim of attracting new and strengthening existing academic and industrial collaborations. Our program has explored the powerful palladium-mediated cross-coupling method to build both aryl-aryl and heteroaryl-aryl structures that have important applications as insulators/heat conductors as "privileged structures" in medicinal chemistry, liquid crystals , and agrochemistry. The bench/air stable sulfinates and carboxylic acids undergo couplings that provide the advantage of being highly regioselective reactions compared to more classical, widely used organometallic coupling partners, without generating toxic, metallic by-products. Importantly, we have demonstrated that these couplings can be conducted in environmentally friendly solvents such as water and ethanol and that led to an invited mini-review on sulfinate cross-couplings. We have developed a practical and efficient synthesis of a removable directing group for the sulfinates. Further, the method was applied towards the synthesis of a-helix mimics that have shown promise as amyloid fibril modulators. Additionally, we have been able to combine the decarboxylative cross-couplings with C-H activation strategies to prepare densely functionalized thienisoquinolines in a one-pot process via a tandem cross-coupling method that have demonstrated anti-cancer activity for the potential treatment of triple-negative breast cancer. This research program aims to build both incremementally and extend into new directions on our expertise in decarboxylative and desulfinative arylations and focus on the application to target structures by capitalizing on their unique reactivity and the ability to carefully control regiochemistry. The use of pyridylsulfones as masked sulfinates that can act as directing groups for selective deuterium incorporation, extension to a range of additional functional groups and the preparation of 1,2,5-triarylpyrroles with applications in medicinal chemistry will be explored. The use of highly regioselective decarboxylative arylations will be exploited to prepare discrete libraries of oligothiophenes and extended to prepare defect-free polythiophenes. Additionally, decarboxylative coupling will be applied to generate next-generation biofuels and towards non-traditional polymers that can be prepared from renewable biomass-derived feedstocks. In all cases, the research program have been designed to be appropriate for a variety of HQP levels (PhD, MSc, undergraduates) that will be funded by this DG.