GOALI: CAS: Iron-Catalyzed Suzuki-Miyaura Cross Coupling Using Pseudohalide Alkyl Electrophiles

在化学系化学催化计划的支持下，波士顿学院的Jeffery Byers教授与赛诺菲制药公司的合作伙伴密切合作，正在研究一种组装与制药行业相关的复杂分子的新方法。新方法涉及易于获得的原材料和更丰富的铁基催化剂，与贵金属基催化剂（通常是钯基催化剂）相比，后者几乎总是用于目标反应。此外，该方法提供了对产物分子的三维结构的更好控制，这是大多数药物所需的至关重要的特征。为了补充该提案的科学目标，波士顿学院和赛诺菲之间的合作伙伴关系将被利用，通过市政厅会议和学生访问赛诺菲，教育公众关于可持续化学的价值及其在制药行业中的作用。波士顿学院的拜尔斯研究小组和他们在赛诺菲制药公司的合作者将致力于开发铃木-宫浦交叉，由铁基络合物催化的烷基拟卤化物与芳基硼酸酯和烷基硼酸酯和/或硼烷的偶联反应。Suzuki-Miyaura交叉偶联反应是在学术和工业化学中应用最广泛的C-C键形成反应之一。 然而，钯基催化剂与sp3杂化底物的反应性有限，这导致在药物化学界中研究平面分子作为治疗候选分子的代表性过高。人们希望通过引入铁基催化剂，更广泛的sp3杂化基板将是可访问的。在这些反应中用烷基拟卤化物代替烷基卤化物亲电试剂预期在制药工业中具有显著影响，因为烷基拟卤化物方便地由醇制备，由于其稳定性和低毒性，其在制药工业中的化合物库中有很好的代表性。该项目将利用赛诺菲的高通量和中通量仪器，用于开发芳基-烷基和烷基-烷基交叉偶联反应以及对映选择性和/或对映特异性交叉偶联反应。此外，反应的原位监测将有助于深入的机理研究，这是铁催化交叉偶联反应领域所缺乏的。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Jeffery Byers of Boston College, in close collaboration with partners at the Sanofi pharmaceutical company, is studying a new method to assemble complex molecules with relevance to the pharmaceutical industry. The new method involves readily available raw materials and more abundant, iron-based catalysts in contracts to the precious metal-based catalysts, typically palladium-based, that are almost always used for the targeted reactions. Additionally, the method provides greater control over the three-dimensional structure of the product molecules, a critically important characteristic desired in most drugs. To complement the scientific goals of the proposal, the partnership between Boston College and Sanofi will be leveraged to educate the general public about the values of sustainable chemistry and its role in the pharmaceutical industry through town hall meetings and student visits to Sanofi.Under this GOALI award, the Byers research group at Boston College and their collaborators at Sanofi Pharma will work to develop Suzuki-Miyaura cross-coupling reactions of alkyl pseudo-halides with aryl boronic and alkyl boronic esters and/or boranes catalyzed by iron-based complexes. The Suzuki-Miyaura cross coupling reaction is one of the most widely used C–C bond-forming reactions in academic and industrial chemistry. However, palladium-based catalysts have limited reactivity with sp3-hybridized substrates, which has resulted in an over-representation of flat molecules being investigated as therapeutic candidate molecules in pharmaceutical chemistry circles. It is hoped that by introducing Fe-based catalysts, a wider array of sp3-hybridized substrates will be accessible. Replacing the alkyl halide electrophile in these reactions with alkyl pseudo-halides is expected to have significant impact in the pharmaceutical industry as alkyl pseudo-halides are conveniently prepared from alcohols, which, due to their stability and low toxicity, are well represented in compound libraries in the pharmaceutical industry. The project will take advantage of the high and medium throughput instrumentation that is at Sanofi for the development of aryl-alkyl and alkyl-alkyl cross coupling reactions and enantioselective and/or enantiospecific cross coupling reactions. Moreover, in situ monitoring of reactions will facilitate in depth mechanistic investigations, which are lacking in the field of iron-catalyzed cross-coupling reactions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.