Synthesis of thiazole-4-carboxamide-adenine difluoromethylenediphosphonates substituted with fluorine at C-2′ of the adenosine

Abstract

Synthesis of an analogue 3 of thiazole-4-carboxamide adenine-dinucleotide (TAD) in which the α-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 difluoromethylenediphosphonate congener ( 5 have been synthesized. Adenosine 5′-difluoromethylenediphosphonate ( 8) was prepared from 5′- O-tosyladenosine ( 6) and tris-tetra- n-butylammonium)difluoromethylene-diphosphonate ( 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-isopro-pylidenetiazofurin ( 10) in pyridine in the presence of DCC gave a mixture of dinucleotide 11 and the isopropylidene-protected diadenosine tetraphosphonate 12. After deprotection of 11, the desired β-difluoromethylene TAD ( 3_ was separated by HPLC as the minor product. The diadenosine tetraphosphonate 12, an analogue of Ap 4A, was obtained as the major component. Alternatively, 2′-3′- O-isopropylidenetiazofurin ( 10) was tosylated, and the product 13 was further converted into the corresponding difluoromethylenediphosphonate 14 by coupling with 7. DCC-catalyzed coupling of 14 with 2′-deoxy-2′-fluoroadenosine ( 15) followed by deisopropylidenation afforded the anlogue 5. Again the corresponding tetraphosphonate analogue of tiazofurin 17 was the predominant product. Dinucleotide 4 was obtained by coupling of the carbonyldiimidazole-activated tiazofurin 5′-monophosphate with 2′-deoxy-2′-fluoroadenosine 5′-monophosphate. 2′-Deoxy-2′-fluoroadenosine (′15) was prepared efficiently from the known N 6-benzoyl-3′- O-tetrahydropyranyladenosine ( 18), which was converted into 3′- O-tetrahydropyranyl-2′- O-triflyl-5′- O-trityladenosine ( 20) by tritylation and triflation. Treatment of 20 with sodium acetate in hexamethylphosphoric triamide, followed by deaceltylation afforded 9-(3- O-tetrahydropyranyl-5- O-trityl-β- d-arabinofuranosyl)- N 6-benzoyladenine ( 22), which was then treated with DAST. After deprotection of the product, 15 was obtained in good yield.