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.

我们的研究主要集中在脱羧型和脱硫型交叉偶联的开发及其在制备碳-碳键方面的应用。过去五年奠定的坚实基础将使目前的研究能够朝着新的方向发展，目的是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来构建芳基-芳基和杂芳基-芳基结构，这些结构在药物化学、液晶和农业化学中具有作为绝缘体/导热材料的重要应用。与更经典的、广泛使用的有机金属偶合伙伴相比，BASE/空气稳定的亚硫酸盐和羧酸进行偶联反应具有区域选择性高的优点，不会产生有毒的金属副产品。重要的是，我们已经证明了这些偶联可以在环境友好的溶剂中进行，如水和乙醇，这导致了对亚硫酸盐交叉偶联的邀请小型审查。我们开发了一种实用而高效的亚硫酸盐可移除导向基团的合成方法。此外，该方法被应用于a-螺旋模拟物的合成，这些模拟物已显示出作为淀粉样原纤维调节剂的前景。此外，我们已经能够将脱羧基交叉偶联与C-H活化策略相结合，通过串联交叉偶联方法在一锅工艺中制备密集官能化的硫代异喹啉，该方法已显示出抗癌活性，用于三阴性乳腺癌的潜在治疗。这项研究计划旨在以我们在脱羧基和脱硫基芳基化方面的专业知识为基础，逐步建立和扩展到新的方向，并通过利用目标结构的独特反应性和仔细控制区域化学的能力来专注于应用于目标结构。将探索使用吡啶基磺酸作为掩蔽的亚硫酸盐，作为选择性掺氢的导向基团，扩展到一系列额外的官能团，以及制备1，2，5-三芳基吡咯及其在药物化学中的应用。使用高区域选择性的脱羧基芳基化将被用来制备低聚硫吩离散库，并扩展到制备无缺陷的聚噻吩类。此外，脱羧化偶联将用于生产下一代生物燃料，并用于可从可再生生物质来源的原料制备的非传统聚合物。在所有情况下，研究计划都被设计成适合由该DG资助的各种HQP水平(博士、硕士、本科生)。