What is the best spatial arrangement of a pair of reactive groups for bifunctional catalysis of a chemical transformation? The conformational versatility of proteins allows reactive group geometry to be explored and optimized via evolutionary selection, but it has been difficult for chemists to identify synthetic scaffolds that allow broad comparative evaluation among alternative reactive group geometries.
In work published in JACS, Zebediah Girvin, a member of the Samuel Gellman lab, show that a family of helices, adopted predictably by oligomers composed partially or exclusively of β-amino acid residues, enables us to explore a range of orientations for a pair of pyrrolidine units that must work in tandem to catalyze a crossed aldol reaction. Thus, the crossed aldol reaction serves as an assay of reactive diad efficacy.
Gellman and Girvin chose a test reaction free of stereochemical complexity in order to streamline their study of reactivity. The best geometry enhances the initial rate of product formation by two orders of magnitude. These findings raise the possibility that rudimentary catalysts involving an isolated secondary structure might have facilitated the development of prebiotic reaction networks.
Exploration of Diverse Reactive Diad Geometries for Bifunctional Catalysis via Foldamer Backbone Variation
Zebediah C. Girvin and Samuel H. Gellman
J. Am. Chem. Soc. 2018, 140, 12476-12483