Saari Verneri, Eerola Aino, Ora Mikko, Gimenez Molina Alejandro, Horvath Andras, Sanghvi Yogesh S, Virta Pasi
Department of Chemistry, University of Turku, 20500 Turku, Finland.
Janssen Pharmaceutica N.V., 30 Turnhoutseweg, B-2340 Beerse, Belgium.
Org Lett. 2025 Aug 1;27(30):8251-8256. doi: 10.1021/acs.orglett.5c02400. Epub 2025 Jul 20.
A mixture of 2-methoxypropene and an acid catalyst in pyridine results in an efficient 5'--(methoxyisopropyl) (MIP) acetalization of nucleosides, including 2'-deoxy, 2'-OH, 2'--methyl, 2'--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'--MIP-acetal an attractive protecting group for the sustainable synthesis of nucleosides and oligonucleotides in solution.
2-甲氧基丙烯与酸催化剂在吡啶中的混合物能高效地将包括2'-脱氧、2'-羟基、2'-甲基、2'-甲氧基乙基（MOE）和2'-氟变体在内的核苷进行5'-（甲氧基异丙基）（MIP）缩醛化反应，分离产率为44-77%。对于反应机理，我们提出了一种吡啶鎓2-甲氧基丙-2-基预缔合络合物，它提高了对伯羟基（5'-OH）相对于仲羟基（2'-OH和3'-OH）的区域选择性。所开发的方法使5'-MIP-缩醛成为溶液中核苷和寡核苷酸可持续合成的有吸引力的保护基团。
