pKa Modulation of Pyrrolidine-Based Catalytic Polymers Used for the Preparation of Glycosyl Hydrazides at Physiological pH and Temperature

Inspired by the ability of enzymes to use the surrounding hydrophobic and/or polarizable groups to modulate the pK of a given amino acid, we designed a series of soluble polymers able to decrease the basicity of pyrrolidine (from 11.2 to 8.6 pK units), which clearly increases its aminocatalytic activity at physiological pH in C═N bond formation reactions via ion iminium activation. Other parameters such as charge density, hydrophobic/hydrophilic balance, and aggregation state have been studied as important factors in the catalytic activity of the polymers for a given substrate. To demonstrate the utility of our approach, an optimal pyrrolidine-based catalytic polymer has been used for the formation of C-N bonds between hydrazides and free sugars as the model system for the preparation of glycoconjugates.We thank the undergraduate student Elena Y. García for some preliminary experiments and Laura Lagartera Ortiz for her help with the Isothermal Titration Calorimetry (ITC) experiments. E. L. Vargas thanks the University of Costa Rica for a PhD scholarship. We acknowledge the Spanish Government (CTQ2016-78779-R, RTI2018-096328-B-I00, and MAT2015-65184-C2-2-R) for financial support