Screening for Generality in Asymmetric Catalysis

Harvard University, Cambridge MA

Investigators

Abstract

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.