Screening for Generality in Asymmetric Catalysis

在化学系化学催化项目的支持下，哈佛大学的Eric Jacobsen教授正在研究发现广泛适用的催化过程的新方法，这些催化过程能够控制产物分子的三维结构。在不对称催化领域，工艺发现工作传统上集中在其初始阶段对单个转化的优化；因此，尽管几十年的工作和数以千计的出版物描述了新系统，相对较少的反应已经出现，显示出足够的普遍性，适用于真正的预测方式。这一特性对于新的不对称催化过程非常重要，因为它对经济和环境可持续的对社会有价值的化学品的生产产生了最深远的影响，例如药剂、农用化学品和先进的技术材料。为了加速发现能够提供尽可能广泛的增值产品的有效过程，资助的研究旨在推进“筛选的普遍性”概念，其中催化剂和反应条件被评估和优化，同时针对相对较大的和有意多样化的模型起始材料集。除了预计将为化学制造业带来的好处之外，该奖项更广泛的影响还包括为从事该研究的研究生提供教育和培训机会。这些人将在多学科研究中获得宝贵的经验，他们很可能继续成为国家未来STEM劳动力的高技能成员。大多数当代手性分子合成方法的可靠性和可预测性差，阻碍了化学和邻近领域的创新，并鼓励使用较老的、“已被证明”的反应，限制了该领域从业者可获得的化学空间的多样性。通过将立体选择性和一般性设置为催化剂发现和优化工作的主要标准，该资助的研究依赖于同时对多种底物的反应进行优化，旨在加速开发可获得最广泛手性化合物的方法。为了避免使用手性固定相色谱法与紫外（UV）检测来确定复杂混合物中多种组分的对映体选择性的不切实际，超临界流体手性（SFC）色谱法与质谱（MS）相结合作为检测方法正在被部署为实现快速和精确分析的工具。至关重要的是，通过这种技术组合，可以生成提取离子色谱图（EICs），即使它们与其他产物或残留反应组分共洗脱，也可以对不同质量的产物进行准确的对映体过量（e.e）测定。因此，优化筛选可以在广泛的基板上进行，不同的产品可以汇集在一起进行分析，大大加快了分析速度。基于sfc - ms的混合分析和新的峰反卷积计算方法，正在研究筛选一般概念的理论和实践发展，在各种有用的转化类型的背景下，包括：一个对映选择性picet - spengler反应，用于合成四氢- β -羰基化合物和一个氢键介导的氮杂啶打开，以提供有用的γ -氯胺构建块。如果这些方法完全实现，预计将得到广泛采用，并有助于将推动不对称催化领域研究的主要问题从“在反应中是否可以实现高e值”转变为“是否可以找到该反应的不对称催化的真实和一般解决方案？”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 Eric Jacobsen of Harvard University is studying new approaches for the discovery of broadly applicable catalytic processes that are capable of controlling the three-dimensional structure of product molecules. Within the field of asymmetric catalysis, process discovery efforts have traditionally focused in their initial stages on the optimization of a single transformation; accordingly, and despite decades of work and thousands of publications describing new systems, comparatively few reactions have emerged that display sufficient generality to be applicable in a truly predictive manner. This attribute is important for new asymmetric catalytic processes to most deeply impact the economical and environmentally sustainable manufacture of chemicals of value to society, such as, pharmaceutical agents, agrochemicals, and advanced materials for technology. To accelerate the discovery of efficient processes capable of delivering the widest possible range of value-added products, the funded research is directed at advancing a "screening for generality" concept wherein catalysts and reaction conditions are evaluated and optimized against relatively large and intentionally diverse sets of model starting materials simultaneously. Beyond the benefits that it is expected to offer to chemical manufacturing, the broader impacts of the award extend to the educational and training opportunities afforded to the graduate students who are conducting the research. These individuals will gain valuable experiences in multidisciplinary research and they are likely to go on to become highly skilled members of the national future STEM workforce.The poor reliability and predictability of most contemporary synthetic methods for chiral molecule synthesis hampers innovation in chemistry and adjacent fields and incentivizes the use of older, "proven" reactions, limiting the diversity of chemical space attainable by practitioners in the field. By enabling both stereoselectivity and generality to be set as primary criteria in catalyst discovery and optimization efforts, the funded research, which relies on performing optimization of reactions across multiple substrates at once, aims to accelerate the development of methods that provide access to the broadest range of chiral compounds. To avoid the impracticalities of using chiral stationary phase chromatography with ultraviolet (UV) detection to determine enantioselectivities for multiple components within complex mixtures, supercritical fluid chiral (SFC) chromatography in combination with mass spectrometry (MS) as the detection method is being deployed as a tool to enable rapid and precise analysis. Crucially, the generation of extracted ion chromatograms (EICs) made possible by this combination of techniques enables accurate enantiomeric excess (e.e.) determinations of products of different masses even when they co-elute with other products or residual reaction components. Optimization screens can therefore be performed on a broad set of substrates and the different products can be pooled and analyzed together, greatly accelerating the analysis. The theoretical and practical development of the screening for generality concept, including use of SFC-MS-based pooled analysis and new computational methods for peak deconvolution, is being studied in the context of a variety of useful transformation types, including: an enantioselective Pictet-Spengler reaction for the synthesis of tetrahydro-beta-carbolines and a hydrogen-bond-mediated opening of azetidines to furnish useful gamma-chloroamine building blocks. If brought fully to fruition, the approaches developed are anticipated to find broad adoption and they will help to shift the overarching question propelling research in the field of asymmetric catalysis from “is high e.e. achievable in a reaction?” to “can a true and general solution be found for asymmetric catalysis of this reaction?”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.