The 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.

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

CIAVARDELLI, DOMENICO;
2003

Abstract

The 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11387/10568
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