Linear and convergent approaches to 2-substituted adenosine-5′-N-alkylcarboxamides

Herein we report both linear and convergent pathways for the preparation of 2-alkynyl substituted adenosine-5′-N-ethylcarboxamides via the versatile synthetic intermediate, 2-iodoadenosine-5′-N-ethylcarboxamide (13). The linear approach afforded 13 in an overall yield of 30% from guanosine over eight synthetic steps. The convergent approach was shorter, but proceeded in lower yield (five steps, 20% yield). Both approaches compare favourably with previously reported syntheses of 13, which has been prepared in 15% yield from guanosine over nine steps. 2-Iodoadenosine-5′-N-ethylcarboxamide (13) was subsequently converted to HENECA (2) and PHPNECA (3) to exemplify the utility of this approach for the preparation of potent A2A adenosine receptor agonists. The linear approach was also amenable to the synthesis of 2-fluoropurine ribosides, which were subsequently elaborated into 2-alkylaminoadenosine-5′-N-ethylcarboxamides. Furthermore, both of these synthetic approaches are readily amenable to the synthesis of adenosine analogues with varied 2-, 6- and 5′-substitution patterns.

Graphical abstractNew linear and convergent pathways to 2-alkynyl substituted adenosine-5′-N-ethylcarboxamides via the versatile synthetic intermediate, 2-iodoadenosine-5′-N-ethylcarboxamide (13) have been developed.Download full-size image