N²,3-Etheno-2′-deoxyguanosine [8,9-Dihydro-9-oxo-2′-deoxy-3-β-d-ribofuranosylimidazo[2,1-b]purine]: A Practical Synthesis and Characterization

The literature methods for the syntheses of N²,3-etheno-2′-deoxyguanosine (1a) and its 5′-O-phosphate are associated with very low overall yields. We now describe a route starting in the riboside series that permits the production of 1a in practical quantities and has allowed its complete chemical characterization for the first time. O⁶-Benzylguanosine (6b) when treated with bromoacetaldehyde under conditions of continuous buffering gives the N²3-etheno derivative 7b in 48% yield. The 3′,5′-O-(1, 1,3,3-tetraisopropyldisiloxa-1,3-diyl) derivative (8b, 89% yield) of 7b when allowed to react with phenyl chlorothionoformate led to the corresponding 2′ ester (10, 50%). 2′-Deoxygenation of 10 by the Barton procedure then afforded 65% of 11, and deprotection of the latter (Bu₄N+F−) gave 12 quantitatively. Catalytic hydrogenation of 12 then produced pure 1a in 86% yield. Stability studies on la have confirmed its exquisite sensitivity to acid and demonstrated its relative stability to alkali and the other reagents used in automated DNA synthesis (phosphoramidate method).