SYNTHESIS OF THIAZOLE-4-CARBOXAMIDE-ADENINE DIFLUOROMETHYLENEDIPHOSPHONATES SUBSTITUTED WITH FLUORINE AT C-2' OF THE ADENOSINE

Synthesis of an analogue 3 of thiazole-4-carboxamide adenine-dinucleot ide (TAD) in which the beta-oxygen atom of the pyrophosphate bridge is replaced by a difluoromethylene group has been achieved. Likewise, 2' -deoxy-2'-fluoroadenosine containing analogues of TAD (4) and its difl uoromethylenediphosphonate congener (5) have been synthesized. Adenosi ne 5'-difluoromethylenediphosphonate (8) was prepared from 5'-O-tosyla denosine (6) and tra-n-butylammonium)difluoromethylenediphosphonate (7 ) by a modified procedure of Poulter's.2 Compound 8 was converted into the 2',3'-cyclic carbonate 9 by treatment with triethyl orthoformate. Treatment of 9 with 2',3'-O-isopropylidenetiazofurin (10) in pyridine in the presence of DCC gave a mixture of dinucleotide 11 and the isop ropylidene-protected diadenosine tetraphosphonate 12. After deprotecti on of 11, the desired beta-difluoromethylene TAD (3) was separated by HPLC as the minor product. The diadenosine tetraphosphonate 12, an ana logue of Ap4A, was obtained as the major component. Alternatively, 2', 3'-O-isopropylidenetiazofurin (10) was tosylated, and the product 13 w as further converted into the corresponding difluoromethylenediphospho nate 14 by coupling with 7. DCC-catalyzed coupling of 14 with 2'-deoxy -2'-fluoroadenosine (15) followed by deisopropylidenation afforded the analogue 5. Again the corresponding tetraphosphonate analogue of tiaz ofurin 17 was the predominant product. Dinucleotide 4 was obtained by coupling of the carbonyldiimidazole-activated tiazofurin 5'-monophosph ate with 2'-deoxy-2'-fluoroadenosine 5'-monophosphate. 2'-Deoxy-2'-flu oroadenosine (15) was prepared efficiently from the known N6-benzoyl-3 '-O-tetrahydropyranyladenosine (18), which was converted into etrahydr opyranyl-2'-O-triflyl-5'-O-trityladenosine (20) by tritylation and tri flation. Treatment of 20 with sodium acetate in hexamethylphosphoric t riamide, followed by deacetylation afforded -trityl-beta-D-arabinofura nosyl)-N6-benzoyladenine (22), which was then treated with DAST. After deprotection of the product, 15 was obtained in good yield.