Synthesis of achiral and chiral peptide nucleic acid (PNA) monomers using Mitsunobu reaction

Peptide nucleic acids (PNAs) are intensively studied DNA analogues. We elaborated an efficient procedure for the synthesis of N-, C-protected pseudodipeptides with a reduced peptide bond and then peptide nucleic acid (PNA) monomers, based on the Mitsunobu reaction of N-Boc-beta -amino alcohols with N-o-nitrobenzenesulfonyl-protected (oNBS-protected) amino acid esters. Using the new procedure, we obtained protected PNA monomer backbones with various amino acid side chains. The pseudodipeptide, secondary amine groups were then deprotected by thiolysis, and after appropriate work-up, acylated with thymin-1-ylacetic acid to give the protected monomers. The procedure seems to be of general applicability and allows various modifications of PNA structure by using diverse alcohols and amino acid esters. (C) 2001 Elsevier Science Ltd. All rights reserved.