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

点击翻译按钮获取中文摘要

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.