Work

Selective Acetalization in Pyridine: A Sustainable 5′-O-(2-Methoxypropyl) Protecting Group in the Synthesis of Nucleic Acid Analogs

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide A mixture of 2-methoxypropene and an acid catalyst in pyridine results in an efficient 5′- O -(methoxyisopropyl) (MIP) acetalization of nucleosides, including 2′-deoxy, 2′-OH, 2′- O -methyl, 2′- O -methoxyethyl (MOE) and 2′-F-variants, in 44–77% isolated yields. For the reaction mechanism, we propose a pyridinium 2-methoxyprop-2-yl preassociation complex, which improves regioselectivity for the primary (5′-OH) over secondary (2′-OH and 3′-OH) hydroxy groups. The developed protocol makes the 5′- O -MIP-acetal an attractive protecting group for the sustainable synthesis of nucleosides and oligonucleotides in solution.

Source: Organic Letters

DOI: 10.1021/acs.orglett.5c02400