Regioselective 1-N-Alkylation and Rearrangement of Adenosine Derivatives

GRAPHICAL ABSTRACT

Abstract

Several methods for the preparation of some N⁶-substituted adenosines based on selective 1-N-alkylation with subsequent Dimroth rearrangement were developed. The proposed methods seem to be effective for the preparation of natural N⁶-isopentenyl- and N⁶-benzyladenosines, which are known to possess pronounced biological activities. Direct 1-N-alkylation of 2′,3′,5′-tri-O-acetyladenosine and 3′,5′-di-O-acetyl-2′-deoxyadenosine with alkyl halides in N,N-dimethylformamide (DMF) in the presence of BaCO₃ and KI gave 1-N-substituted derivatives with quantitative yields, whereas 1-N-alkylation of adenosine was accompanied by significant O-alkylation. Moreover, the reaction of trimethylsilyl derivatives of N⁶-acetyl-2′,3′,5′-tri-O-acetyladenosine and N⁶-acetyl-3′,5′-di-O-acetyl-2′-deoxyadenosine with alkyl halides leads to the formation of the stable 1-N-substituted adenosines. Dimroth rearrangement of 1-N-substituted adenosines in aqueous ammonia yields pure N⁶-substituted adenosines.

Keywords:

• 1-N-substituted adenosines
• N⁶-substituted adenosines
• alkylation
• regioselectivity
• Dimroth rearrangement
• TMS derivatives