EAPSI: Development of New Methods for the Synthesis of Organic Compounds

Bartlett Samuel L, Chapel Hill NC

Investigators

Abstract

The synthesis of organic compounds in enantiopure form is of premiere importance to the discovery and production of new pharmaceuticals. Enantiomers are a set of organic compounds unique because they are non-superimposable mirror images of one another (similar to the way a right-hand and left-hand glove cannot be superimposed on one another). Single-enantiomer therapeutics account for sales of over 200 billion dollars, and comprise a significant portion of pharmaceutical sales worldwide. The increasing dominance of single-enantiomer drugs is partially due to increased awareness of their enhanced biological properties, in addition to regulatory guidelines. Thus, the preparation of organic compounds in enantiopure form directly impacts human health. The most strategic, straightforward method to produce medicinally important organic compounds in enantiopure form is through a process called enantioselective catalysis. In collaboration with Dr. Mikiko Sodeoka, a known expert in the field of asymmetric catalysis, at the RIKEN Institute in Japan, this research will study a method for the synthesis of a specific class of organic compounds that exhibit medicinal potential but lack a direct method for their enantioselective synthesis. The information produced in this study is expected to have broad impact and will contribute to the development of other catalytic asymmetric transformations as well. Specifically, a novel transition metal-catalyzed cycloaddition reaction between alpha-keto esters and nitrile oxides will be investigated. It is anticipated that chiral nickel-diamine complexes will be uniquely effective catalysts in this cycloaddition process due to their proven ability to enolize relatively weakly acidic alpha-keto esters. Initially the effect of solvent, temperature, ligand structure, and counterion identity on rate of conversion and stereoselectivity will be investigated. Next, an array of differentially substituted alpha-keto ester and nitrile oxide substrates, readily synthesized from cheap feedstock chemicals, will be tested under the optimized reaction conditions to evaluate the scope and utility of the proposed method. This NSF EAPSI award is funded in collaboration with the Japan Society for the Promotion of Science.