Synthesis of 5'-O-DMT-2'-O-TBS Mononucleosides Using an Organic Catalyst

Abstract

This unit describes a highly effective method to produce 5'-O-DMT-2'-O-TBS mononucleosides selectively using a small organic catalyst. This methodology avoids the tedious protection/deprotection strategy necessary to differentiate the 2'- and 3'-hydroxyl groups in a ribonucleoside. The catalyst was synthesized in two steps, starting from the condensation of valinol and cyclopentyl aldehyde, followed by anionic addition of N-methylimidazole. Ring closure of the amino alcohol with N,N-dimethylformamide dimethyl acetal in methanol furnishes the catalyst. All four 2'-O-TBS protected mono-nucleosides, U, A(Bz), G(Ib), and C(Ac), were produced in a single step using 10 to 20 mol% of the catalyst at room temperature with excellent yields and selectivity. Further transformation to phosphoramidite demonstrates the utility of this protocol in the preparation of monomers useful for automated synthesis of RNA.

Keywords: 2′-O-TBS ribonucleosides; organocatalyst; phosphoramidation; protection by site-selective functionalization.

Figure 1

Preparation of catalyst

Figure 2

Selective 2′-O-TBS protection

Figure 3

Preparation of 3′-O-phosphoramidite