2-(4-Nitrophenyl)ethyl Methylenebis(phosphonate): A Versatile Reagent for the Synthesis of Nucleoside 5′-Methylenebis(phosphonate)s

2-(4-Nitrophenyl)ethyl methylenebis(phosphonate) (6) was prepared by reaction of equimolar amounts of 2-(4-nitrophenyl)ethyl alcohol and methylenebis(phosphonyl) tetrachloride in the presence of tetrazole. Compound 6 was further converted into the corresponding 4-nitrophenylethyl trisanhydride intermediate 7 by dehydration with diisopropylcarbodiimide (DIC). Reaction of 7 with either 2′,3′-O-isopropylideneadenosine (8a) or 2′,3′-O-isopropylideneguanosine (8b) afforded, after hydrolysis, the desired P ¹-[2-(4-nitrophenyl)ethyl]-F2-(2′,3′-O- isopropylideneadenosin-5′-yl) methylenebis(phosphonate) (9a) and guanosine analogue 9b, respectively. A similar treatment of intermediate 7 with 3′-O-acetylthymidine (12a), 3′-O-acetyl-2′-deoxy-N⁴-benzoylcytidine (12b), 3′O-acetyl-2′-deoxy-N⁶-benzoyladenosine (12c), and 3′-O-acetyl-2′-deoxy-N²-isobutyrylguanosine (12d) gave the corresponding 2-(4-nitrophenyl)ethyl methylenebis(phosphonate)s 13a-d. These compounds as well as 9a,b were treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) which caused elimination of the 2-(4-nitrophenyl)ethyl group. The base labile 3′-O-acetyl, N⁴-acetyl, N⁶-benzoyl, and N²-isobutyryl groups of 12a-d were also removed during the DBU treatment. Thus, the 5′methylenebis(phosphonate)s of 2′,3′-O-isopropylideneadenosine (10a), 2′,3′-O-isopropylideneguanosine (10b), thymidine (14a), 2′-deoxycytidine (14b), 2′-deoxyadenosine (14c), and 2′deoxyguanosine (14d) were prepared in good yield. De-O-isopropylidenation of 10a and 10b afforded adenosine 5′-methylenebis(phosphonate) (11a) and guanosine 5′-methylenebis(phosphonate) (11b), respectively.