Catalytic Asymmetric Hydration of Nitriles with Chiral Platinum-Secondary Phosphine Oxide (SPO) Complexes

Dartmouth College, Hanover NH

Investigators

Abstract

With funding from the Chemical Catalysis Program of the Chemistry Division, Professor David Glueck of Dartmouth College will develop catalysts for the asymmetric hydration of nitriles to yield amides. Right- or left-handed molecules, called enantiomers, differ in their interactions with biological receptors. Often, one enantiomer of a drug molecule produces the desired therapeutic effect and the other is inactive, or, even worse, is harmful, so an important challenge for the pharmaceutical industry is the selective synthesis of drugs as single enantiomers. In this project, Professor David Glueck and his team will develop catalysts for this type of process, involving the addition of water to a carbon-nitrogen triple bond in a nitrile to form carbon-oxygen and nitrogen-hydrogen bonds in the amide product. This project will provide training for graduate and undergraduate student researchers, includes outreach activities, and broaden the participation of underrepresented groups, especially Native Americans, in chemistry education and research. In this project, Professor Glueck and his team will develop catalysts for the asymmetric hydration of nitriles to yield amides.Chiral nitriles and amides are important drugs and pharmaceutical intermediates. Asymmetric nitrile hydration is a green and atom economic route to these functional groups, but there are few synthetic catalysts for this process. This project will use mechanistic analysis to design and prepare chiral bifunctional catalysts for asymmetric nitrile hydration. These platinum complexes of secondary phosphine oxide (SPO) ligands feature cooperative behavior of the Pt–PR2OH group; the Pt electrophile binds the nitrile substrate, and the P-OH nucleophile attacks it to make a metallacycle, followed by amide formation and regeneration of the catalyst with water. The modular synthesis of [Pt(diphos*)(PR2OH)][X]2 catalyst precursors will enable independent variation of the chiral bis(phosphine), the SPO, and the anion. To test the hypothesis that SPO ligands control the rate and selectivity of nitrile binding, metallacycle formation and hydrolysis, three types of derivatives will be investigated, including SPOs which are (a) C-stereogenic or axially chiral (b) P-stereogenic, and (c) trifunctional, bearing pendant amines. Amine-SPOs and chiral anions X* will promote proton transfer and engage in hydrogen bonding with P-OH and water nucleophiles, while diphos* ligands with large bite angles and ion-paired X* anions will increase selectivity by maximizing catalyst-substrate interactions. 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.