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

A mixture of 2-methoxypropene and an acid catalyst in pyridine results in an efficient 5'-<i>O</i>-(methoxyisopropyl) (MIP) acetalization of nucleosides, including 2'-deoxy, 2'-OH, 2'-<i>O</i>-methyl, 2'-<i>O</i>-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'-<i>O</i>-MIP-acetal an attractive protecting group for the sustainable synthesis of nucleosides and oligonucleotides in solution.