Solid phase synthesis of C2,N6-disubstituted adenosine analogues

Abstract

A 6-step solid phase sequence towards C2,N⁶-disubstituted adenosine analogues was developed, which was validated by the construction of a small combinatorial library. Attachment of the 5′-OH of readily available 2′,3′-methoxymethylidene protected 6-chloropurine ribonucleoside onto carboxypolystyrene furnished the immobilised 6-chloropurine ribonucleoside. Nitration on the solid phase resulted in the formation of the 2-nitro-6-chloropurine nucleoside, a highly reactive difunctionalised species. Amines were selectively introduced at the 6-position by 6-chloro displacement at room temperature without affecting the 2-nitro group. Subsequent substitution of the 2-nitro group by amines was achieved at 80–90 °C. Removal of the methoxymethylidene group under mildly acidic conditions, followed by cleavage of the nucleosides from the resin, yielded the C2,N⁶-disubstituted adenosine analogues.