Design and Synthesis of Nucleoproline Amino Acids for the Straightforward Preparation of Chiral and Conformationally Constrained Nucleopeptides

A straightforward synthesis of orthogonally protected nucleoproline (Nup) amino acids and their coupling to oligomers are described. A key step is the attachment of alkynylated nucleobases to Fmoc-protected 4-azidoproline (Fmoc-Azp-OH) by a Cu-catalyzed 1,3-dipolar cycloaddition (click reaction). The developed protocol allows preparation of the nucleoprolines in scales of >30 g. Solid-phase peptide synthesis proved to be straightforward with these Nup amino acids. The resulting oligonucleoproline peptides adopt defined helices, are very well H2O soluble, and show comparable cell-penetrating properties as recently reported a-nucleoalanine peptides.