SusChEM: Rational Design of Chiral Bipyridine N-Oxides for the Catalytic Propargylation of Aromatic Aldehydes

NSF化学催化计划支持德克萨斯A&M大学主校区的Steven E.Wheeler教授为芳香醛的丙烯酰化反应合理设计高立体选择性催化剂的努力。这些设计工作是通过开发一套计算工具来快速和可靠地预测这些反应的立体选择性而促进的。该团队寻求在24小时内准确预测给定催化剂提供的立体选择性，从而相对快速地筛选潜在的新催化剂。联吡啶-N-氧化物催化的烷基化反应的立体选择性主要由配体在六面体硅过渡态周围的手性排列决定，这一概念被设计成丙烯酰化催化剂。值得注意的是，只有某些配体排列是立体选择性的，而催化剂被设计成采用这些固有的立体选择性构型。为了最大限度地发挥这些研究的影响并验证计算预测，预测具有高度立体选择性的丙烯酰化催化剂被合成并由实验合作者、捷克共和国布拉格查尔斯大学的马丁·科塔拉教授进行测试。这种合作提供了宝贵的反馈，同时也确保了开发的新催化剂立即应用于天然产物合成。这些用于不对称有机反应的无金属催化剂有望为重要的手性分子提供新的、更环保的路线，包括天然产品和药物，因此代表着可持续化学的重要努力。这项研究的另一个成果是开发了一个用于预测N-氧化物烷基化催化剂立体选择性的计算工具包。该项目为计算催化剂设计的通用工具包奠定了基础，该工具包在开源许可下免费分发。NSF化学催化计划支持德克萨斯农工大学主校区的Steven E.Wheeler教授的努力，开发新的催化剂并改进现有的无金属催化剂，用于生产天然产品和药品中有价值的和可持续的化学合成。开发新的催化剂需要对潜在的反应机理和控制立体选择性的各种因素有详细的了解。计算化学不仅提供了操作反应途径的结构和能量信息，而且还提供了更高级别的过渡态的信息，为这类有机催化反应的立体选择性的起源提供了关键的见解。这项工作的重点是利用计算资源制备无金属催化剂，从而使材料比以前的路线更环保。本科生和研究生接受广泛的计算有机化学实践培训，以及更正规的量子化学和电子结构理论培训。与合成有机合作者的密切合作使学生接触到现代有机化学中的广泛主题，并教会他们向非计算受众清楚地传达他们的结果。开发的计算方法是在开源许可下免费分发的，这样科学界的其他人就可以受益。

The NSF Chemical Catalysis Program supports the efforts of Professor Steven E. Wheeler of Texas A&M University Main Campus to rationally design highly stereoselective catalysts for the propargylation of aromatic aldehydes. These design efforts are facilitated by the development of a set of computational tools for the rapid and reliable prediction of the stereoselectivities of these reactions. The team seeks to accurately predict the stereoselectivity provided by a given catalyst within a 24-hour time frame, which allows for the relatively rapid screening of potential new catalysts. Propargylation catalysts are designed based on the concept that the stereoselectivities of bipyridine N-oxide catalyzed alkylation reactions are dictated primarily by the chiral arrangement of ligands around a hexacoordinate silicon transition state. Notably, only certain ligand arrangements are stereoselective, and catalysts are designed to adopt these inherently stereoselective configurations. To maximize the impact of these studies and to validate the computational predictions, propargylation catalysts predicted to be highly stereoselective are synthesized and tested by an experimental collaborator, Professor Martin Kotara of Charles University in Prague, Czech Republic. This collaboration provides valuable feedback while also ensuring that new catalysts developed are immediately applied in natural product syntheses. These metal-free catalysts for asymmetric organic reactions promise new, more environmentally friendly routes to important chiral molecules, including natural products and pharmaceuticals and thus, represent important efforts in sustainable chemistry. An additional outcome of this research is the development of a computational toolkit for the prediction of stereoselectivities of N-oxide alkylation catalysts. This project lays the foundation for a general toolkit for computational catalyst design, which is distributed freely under an open-source license.The NSF Chemical Catalysis Program supports the efforts of Professor Steven E. Wheeler of Texas A&M University Main Campus to develop new catalysts and improve existing metal-free catalysts for valuable and sustainable chemical syntheses used in producing natural products and pharmaceuticals. The development of new catalysts requires a detailed understanding of the underlying reaction mechanisms and the myriad of factors that control stereoselectivity. Computational chemistry, by providing structural and energetic information about not only the operative reaction pathway but also higher-lying transition states, provides key insights into the origin of stereoselectivity of such organocatalyzed reactions. This effort focuses on the use of computational resources for the preparation of metal-free catalysts thereby making the materials more environmentally friendly than previous routes. Undergraduate and graduate students receive extensive hands-on training in computational organic chemistry as well as more formal training in quantum chemistry and electronic structure theory. Close collaborations with a synthetic organic collaborator exposes the students to a broad range of topics in modern organic chemistry and teaches them to clearly communicate their results to a non-computational audience. The computational methods that are developed are freely distributed under an open-source license so that others in the scientific community may benefit.