UNS: New Approaches to Catalyst Screening and Development

University Of Nebraska-Lincoln, Lincoln NE

Investigators

Abstract

PI: Stephen G DiMagno Proposal Number: 1500076 Catalysts are materials that promote chemical reactions for production of industrial chemicals, fuels, plastics, and pharmaceuticals from a wide variety of raw materials. A fundamental scientific challenge is to design the catalyst to be active for a specific type of reaction. In Nature, biological catalysts called enzymes have very specific catalyst functions. The overall goal of this project is to use enzymes to help guide the design of new catalyst materials. The key novelty is that the enzyme screening process reports if the catalyst candidate is capable of performing stereochemistry, which is fundamental to making many valuable compounds and pharmaceuticals. In this continuing effort, complex chemical reactions involving stereochemistry will be developed and studied. One possible target is a more efficient approach to synthesis of commercial drugs like Pregabalin. The educational activities of the project include training of graduate students and post-doctoral research associates at the interface of biology and chemistry, as well as high school student outreach through Chemistry Day. This proposed continuation of NSF-supported research focuses on the use enzymes to help identify catalysts of interest for synthetic organic chemistry through a process called In Situ Enzymatic Screening (ISES). The reporting enzymes used in ISES are chiral sensors that provide information the relative rate, stereoselectivity, and substrate scope of catalyst candidates. This renewal proposal will use ISES tools and previous discoveries from ISES screening outcomes to advance three Aims. The first Aim is to extend both the Rh- and Pd-mediated (pseudo) halometalation/carbocyclization transformations various ring sizes, explore competition between post-cyclization/cross-metathesis and ring-closing metathesis, examine other nucleophiles, and test mechanistic postulates, particularly regarding the stereochemical course of the carbocyclization step. The second Aim is develop the scope of the ISES method, with specific focus on developing viable enzyme couples for both the diethyl phosphate leaving group and for the acetate leaving group through a three enzyme couple. Towards this end, candidate dialkyl phosphatase reporting enzymes will be expressed from E. aerogenes, and this enzyme will be used, in tandem with an alcohol dehydrogenase, to screen for metal-ligand mediated allylic substitution directly that involves displacement of the diethyl phosphate. The third Aim seeks to identify viable catalytic combinations for the desymmetrization of 3-substituted oxetanes and N-protected azetidines via nucleophilic-opening. If successful, this chemistry would provide a fundamentally new entry into the asymmetric synthesis of beta(2)-amino acids (AAs) and of gamma(3)-AAs.