The Chemical Catalysis Program of the Chemistry Division supports Professor David S. Glueck at Dartmouth College for research on new methods to prepare phosphines with a chiral phosphorus stereocenter. Such chiral phosphines are useful in asymmetric catalysis, which is commonly employed in the pharmaceutical industry to make single-enantiomer drugs. However, the development of chiral phosphines ligands has been relatively slow because of a lack of general synthetic methods. This project further improved the methods to form phosphorus-carbon and phosphorus-phosphorus bonds, providing new and potentially useful synthetic approaches to this problem. This project also provides training for graduate and undergraduate student researchers, and broadens the participation of underrepresented groups, especially Native Americans, in chemistry, education and research. The results are disseminated broadly in publications and conference presentations, and are integrated into outreach programs.
Metal-catalyzed asymmetric synthesis, useful in the preparation of single-enantiomer drugs, often requires chiral phosphine ligands. Many are known, but their limited structural diversity and ligand-dependent selectivity in catalysis makes new types of chiral phosphines and new routes to them valuable. This award focuses on P-stereogenic phosphines, which despite their commercial success have been relatively unexplored because of a lack of general synthetic methods. Chiral phosphines are usually prepared either by resolution or by using a stoichiometric amount of a chiral auxiliary. Catalytic asymmetric synthesis allows more economical use of expensive chiral reagents. Expanding the scope and improving the selectivity of such processes make this unusual approach to a class of industrially important compounds more valuable. The research addresses these problems while investigating two fundamental topics in catalysis: (1) use of earth-abundant metals and (2) positive cooperativity. The targets are P-stereogenic heterocycles, which are useful both as ligands and as building blocks for other P-stereogenic phosphines. Catalytic asymmetric synthesis of P-stereogenic phosphines has been reported using platinum group metals, which induce rapid pyramidal inversion in the metal-phosphido groups and makes them nucleophilic. Professor Glueck and his group hypothesize that precious metals are not required and instead use copper catalysts. Their weaker metal-ligand bonds may result in faster ligand substitution and turnover. To prepare P-stereogenic heterocycles, they hypothesize that intramolecular processes to make bonds between two stereocenters result in higher selectivity via positive cooperativity. The carbon stereocenter in chiral epoxides are used for dynamic P-stereocontrol in synthesis of phosphiranes by P-C bond formation. The configurations of two P-stereocenters are controlled simultaneously as they are connected to make P-stereogenic diphosphines. Students who carry out the research receive training in synthesis and characterization of inorganic, organometallic, and organic compounds, mechanistic studies of their reactions, in catalysis, and in the presentation of their results both to other scientists and to the public.
