Synthesis of 4(S)-(N-Boc-amino)-2(S/R)-(thymin-1-ylmethyl)-pyrrolidine-N-1-acetic acid: a novel cyclic PNA with constrained flexibility

Pyrrolidyl PNA has emerged as a result of our efforts to achieve optimum fine-tuning of the aminoethylglycyl PNA structure in binding to complementary nucleic acids. The two chiral centers in each unit can give rise to four diastereoisomers, leading to a library of PNA monomers and oligomers. The pyrrolidyl ring nitrogen atom is partially charged at physiological pH, leading to cationic PNA that also results in increased water-solubility. The constraint introduced by the pyrrolidyl ring could lead to pre-organization of the PNA structure and thus pose entropic advantages in binding to complementary nucleic acids. We report herein the synthesis of 4(S)-(N-Boc-amino)-2(S/R)-(thymin-1-ylmethyl)-pyrrolidine-N-1-acetic acids, their site-specific incorporation into PNA oligomers and their preliminary DNA binding properties.