The Chemical Catalysis Program supports Professor David S. Glueck at Dartmouth College for a project that describes a plan for further development of a recently reported new reaction, platinum-catalyzed asymmetric phosphination. The plan is to understand the process in which a chiral metal catalyst couples a racemic secondary phosphine PHR(R') with a benzyl halide ArCH2X to give an enantioenriched tertiary phosphine PR(R')(CH2Ar) via metal-mediated stereocontrol at phosphorus. The development of such P-stereogenic chiral ligands has been relatively slow because of a lack of general synthetic methods. Asymmetric phosphination is a new and potentially useful approach to this problem. This reaction will be applied to the asymmetric synthesis of novel C2-symmetric bidentate diphosphines (the most common ligand class for industrial applications) and to analogous C3-symmetric tridentate triphosphines, which are virtually unexplored. In both cases, catalyst control may lead to asymmetric amplification and very high enantiomeric excess in the desired product, which may be separated from unwanted diastereomers. Chiral phosphines are particularly useful in asymmetric catalysis, which is commonly employed in the pharmaceutical industry to make single-enantiomer drugs.
With the support of the Chemical Catalysis Program in the Chemistry Division at the National Science Foundation, Professor David S. Glueck will develop a better understanding of metal-catalyzed asymmetric phosphination and new chiral phosphines, valuable ligands in asymmetric catalysis that have potential applications in the pharmaceutical industry. Studies of catalyst and substrate control of selectivity and the effect of catalyst symmetry on chiral recognition and reactivity will be broadly useful in homogeneous catalysis. Graduate and undergraduate students will receive training in synthesis and characterization of inorganic, organometallic, and organic compounds, mechanistic studies of their reactions, and in catalysis, and will have an opportunity to present their work to other scientists and to the public. The results will be disseminated broadly in publications and conference presentations. They will be integrated into Dartmouth courses and in presentations to local middle school students. This project will also continue to broaden the participation of underrepresented groups, especially women, in research at the graduate and undergraduate levels.
Your two hands are non-superimposable mirror images. "Chiral" molecules with similar symmetry properties are called enantiomers; right- or left-handed ones differ in their interactions with biological receptors, which are themselves chiral. Often, one enantiomer produces the desired therapeutic effect and the other is inactive, or, even worse, is harmful, so the FDA now requires new drugs to be produced and sold as single enantiomers. You can make a mixture of enantiomers and separate it, but this is often difficult and expensive, and wastes half the material. It would be better to make only one enantiomer selectively. But chirality cannot be created from scratch; it arises only from other chiral materials. The most efficient approach is asymmetric catalysis, where a chiral catalyst selectively forms one enantiomer of the desired product over and over again, thus amplifying a little chiral catalyst into a large amount of a chiral product. Therefore, a common area of research and applications in the pharmaceutical industry is design, synthesis and use of chiral catalysts, as recognized by the 2001 Nobel Prize in chemistry. Chiral organophosphorus molecules are a common component of these catalysts. Developing new chiral phosphines and new methods to make them should yield more efficient and broadly useful catalysts, which is the long-term goal of this project. Its societal importance and the fundamental significance of the concepts in catalysis which are involved makes the research potentially of broad impact, and ensures its intellectual merit. We used metal-catalyzed asymmetric phosphination to prepare C2-symmetric bis(phosphines), the most commonly used ligand class in industry, and investigated cooperativity (the effect of one chiral center on another) in these syntheses. We also prepared a rare C3-symmetric triphosphine and several of its metal complexes. This award supported the development of human resources in science, by enabling the training of many graduate and undergraduate students, who learned to carry out research and to communicate their results. Several are now employed in science and technology, or continuing their education in these fields.
