This project will continue the development of a family of highly practical chiral silane Lewis acids for asymmetric synthesis. The silanes activate acylhydrazones and other imines towards highly enantioselective attack by a wide variety of nucleophiles. Reactions under investigation include Pictet-Spengler and Friedel-Crafts reactions, Imine-Diene [4+2] cycloaddition and related cycloaddition reactions, tandem aza-Darzens/Friedel-Crafts reactions, and Mannich reactions. Mechanistic studies will guide the development of the chemistry into new realms of efficiency and practicality, as the development of a family of enabling reagents and catalysts for the rapid synthesis of a diverse array of medicinally relevant structures is pursued. Efforts to commercialize the technology will continue as well.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor James Leighton of the Department of Chemistry at Columbia University. Professor Leighton's research programs are directed towards the design of highly practical and useful synthetic methods for the preparation of a wide variety of compounds with relevance to medicinal chemistry. The chemistry in this proposal is based upon the use of silicon, and such reactions will contribute to the development of ever more efficient and environmentally benign methods in organic synthesis. Success will continue to make a strong impact in the pharmaceutical and agricultural industries, as chemists engaged in these arenas continue to adopt the methods for use in their own research projects.
- NSF Award CHE-08-09659; Leighton, PI Intellectual Merit. The accomplished work entails the discovery and development of a new family of silicon-based reagents and catalysts for the asymmetric synthesis of chiral carbinamines. The developed reagents spring from a deceptively simple concept: silanes, when constrained in a 5-membered ring by 1,2-diols, aminoalcohols, or diamines possess Lewis acidity sufficient for efficient yet mild, highly enantioselective organic transformations. Silanes have many desirable attributes in terms of practicality and sustainability, yet highly enantioselective reagents/catalysts based on silicon chemistry have proven rare, despite substantial effort from synthetic chemists. This work has expanded 1) the range of otherwise elusive asymmetric transformations made possible by these silane Lewis acids, 2) the boundaries in terms of the reactivity of the silane Lewis acids, and 3) our understanding of the mechanistic basis for the interesting and useful reactivity that the silanes display. Because use of a given method by other chemists is one particularly direct measure of impact, the reagents and catalysts have been developed so as to maximize their practicality and utility. Thus, they are readily and inexpensively prepared, they are isolable and stable to storage, they are environmentally benign, and their use requires no extraordinary techniques or procedures. To the extent that these goals have been met or exceeded, and to the extent that the reagents may be used to access medicinally important and otherwise difficult to access chiral carbinamine-containing structures, they may be expected to continue to enjoy widespread use. The intellectual challenge in devising methods that meet these criteria is formidable and has occasioned a deeper understanding of the reactivity of these silanes. Broader Impacts. While the project as outlined above has been driven by a fascination with mechanism and "pure" science, there can be no question that organic chemists engaged in reaction design also have an obligation to focus on issues of practicality, environmental impact, economic viability etc. One straightforward measure of true success in this regard is whether the reagents in question may be commercialized, and we are delighted to report that this program has had significant success in this regard. Commercialization has many broader benefits, besides the obvious potential for job creation. For example, medicinal chemists in the pharmaceutical industry are often hesitant to carry out time-consuming preparations of reagents and difficult procedures, and these considerations can affect the direction of the project. The ability simply to purchase a reliable, safe, and enantioselective reagent for any number of imine addition reactions, for example, could have a significant impact on the decisions made by these chemists. Indeed, there is significant evidence that this is already happening, including one case where one of the silane reagents developed during the course of this project was quite literally indispensable to the discovery, development, and large-scale synthesis of a melanoma drug candidate that is currently in Phase Ib trials. In addition, this project offers an excellent training ground for both graduate students and undergraduates. For the former, issues of reaction design, optimization, and mechanistic elucidation to guide the further development of the project must all be addressed successfully. As the project is firmly based on a unique mechanistic paradigm, there is a great opportunity for graduate students to directly impact the direction of the project by making their own creative contributions. This, of course, is the most important aspect of their training to become independent scientists ready to run their own research group either in academia or industry. For the latter, more focused smaller aspects of the individual projects can, have been, and will continue to be devoted to undergraduate participation in the research.
