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 r eaction of equimolar amounts of 2-(4-nitrophenyl)ethyl alcohol and met hylenebis(phosphonyl) tetrachloride in the presence of tetrazole. Comp ound 6 was further converted into the corresponding 4-nitrophenylethyl trisanhydride intermediate 7 by dehydration with diisopropylcarbodiim ide (DIC). Reaction of 7 with either 2',3'-O-isopropylideneadenosine ( 8a) or 2',3'-O-isopropylideneguanosine (8b) afforded, after hydrolysis , the desired ropylideneadenosin-5'-yl)methylenebis(phosphonate) (9a) and guanosine analogue 9b, respectively. A similar treatment of interm ediate 7 with 3'-O-acetylthymidine (12a), 3'-O-acetyl-2'-deoxy-N-4-ben zoylcytidine (12b), 3'-O-acetyl-2'-deoxy-N-6-benzoyladenosine (12c), a nd 3'-O-acetyl-2'-deoxy-N-2-isobutyrylguanosine (12d) gave the corresp onding 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]und ec-7-ene (DBU) which caused elimination of the 2-(4-nitrophenyl)ethyl group. The base labile 3'-O-acetyl, N-4-acetyl, N-6-benzoyl, and N-2-i sobutyryl groups of 12a-d were also removed during the DBU treatment. Thus, the 5'-methylenebis(phosphonate)s of 2',3'-O-isopropylideneadeno sine (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 1 0b afforded adenosine 5'-methylenebis(phosphonate) (11a) and guanosine 5'-methylenebis(phosphonate) (11b), respectively.