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-dinucleotide (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 difluoromethylenediphosphonate congener (5) have been synthesized. Adenosine 5'-difluoromethylenediphosphonate (8) was prepared from 5'-O-tosyladenosine (6) and tris(tetra-n-butylammonium)difluoromethylenediphosphonate (7) by a modified procedure of Poulter's. 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 isopropylidene-protected diadenosine tetraphosphonate 12. After deprotection of 11, the desired beta-difluoromethylene TAD (3) was separated by HPLC as the minor product. The diadenosine tetraphosphonate 12, an analogue of Ap4A, 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 analogue 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 N6-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 deacetylation afforded 9-(3-O-tetrahydropyranyl-5-O-trityl-beta-D- arabinofuranosyl)-N6-benzoyladenine (22), which was then treated with DAST. After deprotection of the product, 15 was obtained in good yield.
Zatorski
A
A
Laboratory of Organic Chemistry, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division of Graduate School of Medical Sciences, Cornell University, New York, NY 10021.
Lipka
P
P
Mollova
N
N
Schram
K H
KH
Goldstein
B M
BM
Watanabe
K A
KA
Pankiewicz
K W
KW
D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000241:Adenosine / Q000031:analogs & derivatives*; D005461:Fluorine; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
D000227:Adenine Nucleotides; D007202:Indicators and Reagents; D013844:Thiazoles; D005461:Fluorine; D000241:Adenosine