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

开发药物发现、材料和生物质衍生平台化学品的脱羧和脱亚磺交叉偶联策略

• 批准号: RGPIN-2020-07211
• 负责人: Forgione, Pat
• 金额: $ 2.11万
• 依托单位: Concordia University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741664
• 关键词: Development; Decarboxylative; Desulfinative; Cross; Coupling

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.

我们的研究集中在脱羧和脱硫化交叉偶联的发展上，及其用于制备碳碳键的应用。在过去五年中，扎实的基础将使本研究能够向新的方向发展，以吸引新的和加强现有的学术和工业合作。我们的计划探索了强大的钯介导的交叉偶联方法，以构建具有重要应用的芳基芳基和杂芳基 - 亚芳基结构，这些结构是绝缘体/热导体作为药用化学，液晶和农业化学的“特权结构”。与更经典的，广泛使用的有机金属耦合伴侣相比，替补板/空气稳定的硫酸和羧酸的耦合是具有高度区域性反应的优势，而没有产生有毒的金属副产品。重要的是，我们已经证明了这些耦合可以在水和乙醇等环保溶剂中进行，这导致了有关硫酸盐交叉偶联的小型评论。我们已经开发了用于硫酸盐的可移动指导组的实践和有效合成。此外，该方法用于合成A螺旋模拟物的合成，这些模拟物已显示为淀粉样蛋白原纤维调节剂的希望。此外，我们还能够通过串联交叉耦合方法将脱羧的互羧化交叉耦合与C-H激活策略相结合，以在单盘过程中制备密集的功能化的硫代喹啉，这些方法证明了抗癌活性，用于对三个阴性乳腺癌的潜在治疗。该研究计划旨在逐步建立并扩展到我们在脱羧和脱硫化芳基方面的专业知识上的新方向，并通过利用其独特的反应性以及仔细控制RegioCoioChemistry的能力来专注于目标结构的应用。将探索吡啶基​​磺酮作为掩盖的硫酸盐，可以用作选择性氘掺入的指导组，扩展到一系列其他官能团，并准备在药物化学中应用1,2,5-三型吡咯骨。将利用高度区域选择性脱羧芳基化的使用来制备寡头碘的离散库并扩展以制备无缺陷的聚息烯。此外，将应用脱羧耦合，以生成下一代生物燃料和非传统的聚合物，这些聚合物可以从可再生生物量的衍生原料中制备。在所有情况下，该研究计划均设计为将由该DG资助的各种HQP水平（博士学位，MSC，本科生）。