Fast, Solid‐Phase Synthesis of Chiral Peptide Nucleic Acids with a High Optical Purity by a Submonomeric Strategy

Abstract

AbstractThe solid‐phase synthesis of chiral peptide nucleic acids (PNAs) usually results in partial epimerization of the products, since the α‐nitrogen atom of the amino acid is involved in an amidic bond. It is also time‐consuming, since all the chiral monomers bearing different nucleobases have to be independently synthesized. In order to prevent racemization and to speed up the synthetic procedure we adopted a submonomeric approach by using a solid‐phase, Boc‐based PNA synthesis in which the chiral backbone orthogonally Nα‐Fmoc‐protected (submonomer) was first linked to the growing chain on the resin, followed by Fmoc‐deprotection and derivatization with the carboxymethylnucleobase. The submonomer bearing the D‐lysine residue was designed by protecting the Nα‐(aminoethyl)amino acid moiety with an Fmoc protecting group, compatible with standard Boc chemistry, and with the use of an MBHA‐PS resin, normally employed for PNA synthesis. Different synthetic pathways towards the desired submonomer were studied by using the amino acid D‐lysine as a chiral synthon, obtaining a fast method leading to a high yield and an excellent enantiomeric excess of the submonomer. The solid‐phase submonomeric reaction conditions were optimized for the synthesis of a thyminyl PNA dimer and then used to synthesize two different chiral PNAs. In this way two advantages were obtained: a lower degree of racemization in the coupling step during the solid‐phase synthesis and the possibility of using the same submonomer for every different nucleobase. All the D‐lysine‐based chiral PNAs were obtained in good yields and, as compared with PNAs synthesized by other coupling methods, showed the highest optical purity reported so far. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)