Synthesis of Alkyne-Functionalized Helical Polycarbodiimides and their Ligation to Small Molecules using ‘Click’ and Sonogashira Reactions

Abstract

New terminal alkyne side chain functionalized polycarbodiimides, have been synthesized and “alkyne” ligation tools—“click” (copper-catalyzed Huisgen 1,3-dipolar cycloaddition reaction) and Sonogashira couplings—were utilized to create functional polymers in one step postpolymerization modifications. Polycarbodiimides are interesting synthetic, helical, nanodimensional scaffolds that are capable of presenting a variety of functional groups in highly regular periodic fashion. Herein, we report the synthesis of the first alkyne substituted polycarbodiimides, Poly-1, Poly-2, and Poly-3 and the quantitative coupling of functional azides to the alkyne repeat units of these polymers, as evidenced by IR and 1H NMR and 13C NMR spectra. We are able to couple benzyl azide, carboxylic acid azide, and N-Boc amine azide by “click” and N-Boc-l-phenylalanine by Sonogashira reactions to the alkyne side chain of Poly 1 to provide Poly-1a, -1b, -1c and -1phe, respectively. Poly-1b and Poly-1c provide peptide-coupling sites and are precursors for synthetic helical polymer-peptide conjugates. This was demonstrated by coupling l-alanine methylester to Poly-1b with excellent conversion. Aliphatic-terminal alkyne functionalized polymer, Poly-2 with the flexible methylene linker to the backbone provides more degrees of steric freedom for the incorporated groups, fixes the groups closer to the chiral, helical backbone, and reduces the hydrophobic nature of the polymer. However, Poly-3 offers all of these advantages and with two clickable handles per repeat unit doubles the functional sites along the polymer backbone.