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 4 A, 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.