Facilitating the solid-phase synthesis of oligonucleotides and peptides.

Abstract

Oligonucleotides and peptides are important chemical entities in pharmaceutical and material industries. The synthesis of both is carried out using the solid-phase approach first developed by Merrifield for peptides. Briefly, protected monomers (nucleotides or amino acids) are incorporated into a solid support through a linker, then a protecting group is removed, and the next monomers are incorporated sequentially. At the end, the oligonucleotide or the peptide is detached from the linker-solid support. In the present thesis, we describe the synthesis of base labile linker (4-((2hydroxyethyl)sulfonyl)benzamide) and its application in solid phase synthesis of a 3’ phosphorylated oligonucleotide. The new linker is compatible with phosphoramidite chemistry and enables obtaining the desired 3’ phosphate oligonucleotides in excellent yields. Secondly, we reported the synthesis of ((2-oxopyridin-1(2H)-yl)oxy)tri(pyrrolidin-1-yl)phosphonium (PyHOPO) coupling reagent for solid phase peptide synthesis (SPPS) application and racemization study. PyHOPO was produced in excellent yield, and it enabled peptide synthesis with high purity and no detectable racemization. Furthermore, the crystal structure of PyHOPO, which is a bidentate molecule, has been solved, which has allowed to determine univocally its structure.