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

美国国家科学基金会化学催化项目支持德克萨斯农工大学主校区Steven E. Wheeler教授合理设计用于芳香醛丙基化的高立体选择性催化剂的工作。这些设计工作是由一套计算工具的发展，以促进这些反应的立体选择性的快速和可靠的预测。该团队试图在24小时内准确预测给定催化剂所提供的立体选择性，从而可以相对快速地筛选潜在的新催化剂。丙基化催化剂的设计基于联吡啶n -氧化物催化烷基化反应的立体选择性主要由配体在六配位硅过渡态周围的手性排列决定的概念。值得注意的是，只有某些配体排列具有立体选择性，而催化剂被设计为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，丙基化催化剂预测具有高度立体选择性，由实验合作者，捷克布拉格查尔斯大学的Martin Kotara教授合成和测试。这种合作提供了有价值的反馈，同时也确保了新开发的催化剂立即应用于天然产物合成。这些不对称有机反应的无金属催化剂为重要的手性分子（包括天然产物和药物）提供了新的、更环保的途径，因此代表了可持续化学的重要努力。本研究的另一个成果是开发了用于预测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。美国国家科学基金会化学催化项目支持德克萨斯农工大学主校区的Steven E. Wheeler教授开发新的催化剂和改进现有的无金属催化剂，用于生产天然产品和药物的有价值和可持续的化学合成。新催化剂的开发需要详细了解潜在的反应机制和控制立体选择性的无数因素。计算化学，通过提供结构和能量信息，不仅是操作反应途径，而且是更高的过渡态，提供了关键的见解，立体选择性的起源这类有机催化反应。这项工作的重点是利用计算资源来制备无金属催化剂，从而使材料比以前的路线更环保。本科生和研究生在计算有机化学以及量子化学和电子结构理论方面接受广泛的实践训练。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的广泛主题，并教会他们清楚地将他们的结果传达给非计算听众。开发的计算方法在开源许可下免费分发，以便科学界的其他人可以受益。

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.