In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Jonathan Ellman of the Department of Chemistry at Yale University will develop methods for the asymmetric synthesis of amine-containing compounds using tert-butanesulfinamide. Powerful new methods for the efficient asymmetric synthesis of alpha-branched amines will be developed through the highly functional group compatible addition of organozinc and organoboron reagents to N-tert-butanesulfinyl imines. New sulfinamide-based organocatalysts will also be developed as a general new class of catalysts for the highly efficient synthesis of amine-containing compounds applicable to the production of bioactive drugs and agrochemicals.
The proposed work has broad impact because more than 80% of all drugs and drug candidates contain amine functionality, and many of these amine-containing compounds are also chiral. tert-Butanesulfinamide chemistry, developed in Professor Ellman's lab largely with NSF support, is one of the most extensively used methods for the preparation of amine containing compounds in the pharmaceutical, biotechnology and agrochemical industries as well as in academic chemical biology research. The research proposed here could further enhance the utility of this chemistry and consequently accelerate scientific advances, including the discovery of new drugs to treat unmet medical conditions. Moreover, the proposed work will involve training undergraduate and graduate students, including those from groups currently underrepresented in the sciences.
Project Outcome: Researchers in my lab have broadly developed a new chemical reagent, abbreviated TBS, for the more rapid, general and cost effective preparation of amine containing compounds. This research is of considerable importance because amines are present in a large majority of drugs and drug candidates and many biologically active natural products. Potential drug structures that were previously very difficult to prepare can now be made much more efficiently, rapidly, and reliably. Impact & Benefit: The reagent, TBS, has now extensively been used by most pharmaceutical companies and many biotechnology companies for the preparation of thousands of potential drug structures for biological testing. TBS has also been used for the production of large quantities of numerous drug candidates for preclinical evaluation and for clinical trials. The impact of the reagent is clearly indicated by the more than 800 patent applications/patents filed by companies where TBS was cited as a key reagent for the preparation or large scale production of potential drug candidates. Worldwide, many academic and government research laboratories also now extensively use the reagent. More than 100 chemical supply companies sell the reagent due to its importance to the pharmaceutical, agrochemical, and biotechnology industries. Background & Explanation: The Chemical Synthesis section in the Division of Chemistry of the National Science Foundation has provided the primary support for research on TBS for more than a decade. Funding from the NSF enabled development of methods to prepare TBS in large quantities, characterization and exploration of the chemical reactivity of TBS, and ultimately development of TBS based chemical synthesis methods that are so extensively used today.