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

在化学系化学催化项目的支持下，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，正在研究一种与制药工业相关的组装复杂分子的新方法。新方法涉及到现成的原材料和更丰富的铁基催化剂，而不是贵金属基催化剂，通常是钯基催化剂，后者几乎总是用于目标反应。此外，该方法可以更好地控制产物分子的三维结构，这是大多数药物所需的一个至关重要的特性。为了实现该提案的科学目标，波士顿学院和赛诺菲之间的合作伙伴关系将通过市政厅会议和学生参观赛诺菲，向公众宣传可持续化学的价值及其在制药行业中的作用。根据该GOALI奖，波士顿学院拜尔斯研究小组及其在赛诺菲制药的合作者将致力于开发由铁基配合物催化的烷基伪卤化物与芳基硼和烷基硼酯和/或硼烷的Suzuki-Miyaura交叉偶联反应。Suzuki-Miyaura交叉偶联反应是学术界和工业化学中应用最广泛的C-C成键反应之一。然而，钯基催化剂与sp3杂化底物的反应性有限，这导致了在药物化学圈中，扁平分子作为治疗候选分子被研究的过度代表。希望通过引入铁基催化剂，可以获得更广泛的sp3杂化底物。用烷基假卤化物代替这些反应中的亲电试剂烷基卤化物有望对制药工业产生重大影响，因为烷基假卤化物是由醇制备的，由于其稳定性和低毒性，在制药工业的化合物库中很有代表性。该项目将利用赛诺菲的高通量和中通量仪器来开发芳基-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，对反应的现场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。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.