Selective Peptide-Based Oxidation Catalysts for Bioactive Molecule Synthesis

Yale University, New Haven CT

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): We wish to develop a new paradigm for the selective oxidation of complex molecules. Our approach will extend the development of the now-validated paradigm of aspartic acid catalysis. We will also develop additional catalysis paradigms based on catalytic ketones and metal complexes. All of the catalytic centers to be developed will be incorporated into peptides. The peptide-based scaffolds will provide the molecular environment that will be responsible for selectivity. Enantioselective reactions, as well as those that deal wih regio-, chemo- and site-selectivity will be explored. This project began with previously unknown catalytic cycles for olefin epoxidation and the Baeyer-Villiger oxidation, wherein a carboxylic acid functions as a catalytic moiety. We are now poised to explore this unique catalytic strategy for these two venerable processes, each of which engages an intermediate peracid moiety for a mechanistically distinct function: in epoxidation, the peracid functions as an electrophile; in the Baeyer-Villiger oxidation, the peracid functions as a nucleophile. Our specific goals include development of ever-more active and selective catalysts for each process. We intend to push the frontiers for epoxidations wherein venerable catalysts fail, including applications to problems involving remote olefin functionalization when several alkenes are present. We will also examine these catalysts for site- and enantioselective oxidations of conjugated polyenes, so commonly found in complex natural products. We will also continue our studies of selective epoxidations of highly substituted, electron-rich arenes, such as indoles, furans and pyrroles; the products of these reactions will be relevant to natural product synthesis, as well as for the synthesis of natural product analogs. We plan to expand greatly our study of enantioselective Baeyer-Villiger oxidations, a class of catalytic reactions that are truly under-developed from the standpoint of enantioselective catalysis. These studies will also lead to explorations of site-selective Baeyer-Villiger oxidations performed on natural products containing multiple ketone sites. This work will enable an aggressive set of applications involving the catalyst-dependent diversification of biologically active natural products. All the while, this work will be conducted in an environment where mechanistic studies will be performed to enhance our understanding of the selective reactions we discover. So too, collaborations and plans are in place so that the impact of our studies will extend beyond our own laboratory, assisting colleagues engaged in complex molecule synthesis, and in the biological evaluation of the new natural product analogs we obtain.