5'‐O‐(2‐Isopropoxyprop‐2‐yl)‐protected Phosphoramidite Building Blocks in the Liquid Phase Oligonucleotide Synthesis

Abstract

5´‐O‐(2‐isopropoxyprop‐2‐yl) (IIP)‐protection was introduced to 5’‐OH function of nucleosides in high yields by an acid‐catalysed transacetalization with 2,2‐diisopropoxypropane. The applicability of this temporal 5’‐O‐protecting group was demonstrated in the liquid phase oligonucleotide synthesis (LPOS) using the corresponding phosphoramidite building blocks (dA, dG, dC and dT) and a tetrapodal precipitative soluble support. Standard protecting groups were used on nucleobases. Tetrazole as an activator, followed by oxidation using m‐chloroperbenzoic acid, was used for the coupling. The IIP was shown to be a capable choice to the 5’‐O protection in solution phase synthesis. It could be readily removed with formic acid (t1/2 < 10s in 6% HCOOH in dichloromethane/methanol (2/1) at RT), resulting in volatile byproducts (acetone and isopropanol).

An Update on Protection of 5′‐Hydroxyl Functions of Nucleosides and Oligonucleotides

“…To make oligonucleotide manufacturing more sustainable and process compatible, liquid phase approaches have been recently explored using a small‐sized acetal (ketal) group for 5′‐ O‐ protection (Liang et al., 2023). The introduction of the 5′‐ O ‐(2‐isopropoxyprop‐2‐yl) (IIP) protection group was accomplished for four natural 2′‐deoxynucleosides that were transformed into corresponding amidites (Fig.…”