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教授正在研究新的方法，以发现能够控制产物分子三维结构的广泛适用的催化过程。在不对称催化领域内，过程发现工作传统上在其初始阶段集中在单一转化的优化上;因此，尽管数十年的工作和数千篇描述新系统的出版物，但相对较少的反应已经出现，其显示出足够的普遍性以真正的预测方式适用。该属性对于新的不对称催化方法是重要的，以最深刻地影响对社会有价值的化学品的经济和环境可持续的制造，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工艺，资助的研究旨在推进“通用性筛选”概念，其中对催化剂和反应条件进行评估和优化，同时针对相对较大和故意不同的模型起始材料。除了预期为化学制造业带来的好处外，该奖项的更广泛影响还延伸到为进行研究的研究生提供的教育和培训机会。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劳动力中的高技能成员。大多数当代手性分子合成方法的可靠性和可预测性较差，阻碍了化学和邻近领域的创新，并鼓励使用较旧的，“经过验证的”反应，限制了本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定为催化剂发现和优化工作的主要标准，资助的研究依赖于同时在多个底物上进行反应优化，旨在加速提供最广泛手性化合物的方法的开发。为了避免使用具有紫外（UV）检测的手性固定相色谱来确定复杂混合物中的多个组分的对映体选择性的不切实际性，超临界流体手性（SFC）色谱与质谱（MS）组合作为检测方法被部署为能够进行快速和精确分析的工具。至关重要的是，通过这种技术组合产生的提取离子色谱图（EIC）能够实现准确的对映体过量（e.e.）不同质量的产物的测定，即使它们与其他产物或残留反应组分共混。因此，优化筛选可以在广泛的底物上进行，不同的产物可以合并在一起进行分析，大大加快了分析速度。筛选的一般性概念的理论和实践发展，包括使用基于SFC-MS的合并分析和新的计算方法的峰去卷积，正在研究的背景下，各种有用的转换类型，包括：一个对映选择性的Pictet-Spengler反应的合成四氢-β-咔啉和氢键介导的氮杂环丁烷的开放，以提供有用的γ-氯胺积木。如果完全实现，预计开发的方法将得到广泛采用，它们将有助于将推动不对称催化领域研究的首要问题从“高e. e.在反应中实现？”到“能为这个反应的不对称催化找到一个真正的和普遍的解决方案吗？”该奖项反映了NSF的法定使命，并被认为是值得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的支持。

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.