Chemoenzymatic Synthesis of 3′-O-Acetal-Protected 2′-Deoxynucleosides as Building Blocks for Nucleic Acid Chemistry

Graphical Abstract

A simple and convenient chemoenzymatic strategy for the preparation of tetrahydropyranyl, 4-methoxytetrahydropyranyl, and tetrahydrofuranyl ethers of 2′-deoxynucleosides, which are useful building blocks for nucleic acid chemistry, has been developed. The three-step process is expected to enable the large-scale synthesis of protected nucleosides.

Abstract

We have developed a simple and convenient synthetic strategy for the preparation of tetrahydropyranyl, 4-methoxytetrahydropyranyl, and tetrahydrofuranyl ethers of 2′-deoxynucleosides, which are useful building blocks for nucleic acid chemistry. Enzymatic benzoylation provides an efficient alternative for protecting the 5′-hydroxy group of the parent nucleosides in a regioselective manner. Subsequently, tetrahydropyranylation and tetrahydrofuranylation of the 2′-deoxynucleosides at the 3′-hydroxy group were accomplished with p-toluensulfonic acid, MgBr₂, or camphorsulfonic acid as catalysts. Deprotection of the 5′-O-benzoyl group furnished 3′-O-acetal-protected 2′-deoxynucleosides. The three-step process is expected to enable the large-scale synthesis of protected nucleosides.