Screening for Generality in Asymmetric Catalysis

不对称催化的通用性筛选

• 批准号: 2247494
• 负责人: Eric Jacobsen
• 金额: $ 57.5万
• 依托单位: Harvard University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2247494&HistoricalAwards=false
• 关键词: Screening; Generality; Asymmetric; Catalysis

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.

在化学催化计划中，哈佛大学的埃里克·雅各布森教授正在研究发现广泛适用的催化过程的新方法，这些方法能够控制产品分子的三维结构。在不对称催化的领域，过程发现工作传统上一直集中在其初始阶段上，以优化单个转换。因此，并且需要数十年的工作和数千本描述新系统的出版物，相对较少的反应显示出足够的一般性，以真正的预测方式适用。该属性对于新的不对称催化过程至关重要，最大程度地影响了对社会的价值化学品的经济和环境可持续性制造，例如药品，农业化学和技术的先进材料。为了加速能够提供能够提供最宽的增值产品范围的有效过程，资助的研究旨在推进“一般性筛查”概念的“筛选”概念，在该概念中，对相对较大且有意多样化的模型起始物质集对催化剂和反应条件进行了评估和优化。除了预期为化学制造提供的好处外，该奖项的更广泛影响范围扩展到了研究生提供的教育和培训机会。进行研究的学生。这些人将在多学科研究中获得宝贵的经验，并且他们可能会继续成为国家未来STEM劳动力的高技能成员。大多数当代合成方法的可靠性和可预测性使手性分子合成的可预测性阻碍了化学和邻近领域的创新。通过使立体选择性和通用性都可以作为催化剂发现和优化工作的主要标准，这项资助的研究依赖于同时对多个底物进行反应的优化，旨在加快提供最广泛的鼠标化合物的方法的开发。为了避免使用紫外线（UV）检测的手性固定相色谱法的不切实际，以确定复杂混合物中多个组件的对映选择性，将超临界流体性手性（SFC）色谱与质谱法（MS）结合使用，因为检测方法正在作为一种工具作为一种工具来启用快速分析。至关重要的是，通过这种技术组合，提取的离子色谱（EIC）的产生使得准确的对映体过量（E.E.）即使与其他产物或残留反应成分共同穿时，可以准确地测定不同质量的产物。因此，可以在广泛的底物上执行优化屏幕，并且可以将不同的产品汇总和分析在一起，从而大大加速了分析。在多种有用的转换类型的背景下，正在研究一般性概念筛查的理论和实际发展，包括使用基于SFC-MS的汇总分析和新的计算方法进行峰值反卷积的方法，包括：对映射的picket-picket-spenger反应，用于tetrahydro-beta-beta-beta-carboline for Hydrogen-sparitied odicied opbinied opbiniced oparied opbinied opinied opbinied opinied opbiniced opbiniced opinied opidied-se a ze γ-氯胺的构件。如果完全流动，则预计开发的方法会发现广泛的采用，它们将有助于转移总体问题在不对称催化领域的促进研究，从“在反应中可以实现的高E.E.”？要“可以找到真正的和一般的解决方案，以使该反应不对称催化？”该奖项反映了NSF的法定任务，并通过使用基金会的知识分子优点和更广泛的影响审查标准来评估被认为是宝贵的支持。