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

Andrzej Zatorski, Pawell Lipla, Nevena Mollova, Karl H. Schram, Barry M. Goldstein, Kyoichi A. Watanabe, Krzysztof W. Pankiewicz

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11 Scopus citations


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 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 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 N6-benzoyl-3′-O-tetrahydropyranyladenosine (18), which was converted into 3′-O-tetrahydropyranyl-2′-O-triflyl-5′-O-trityladenosi ne (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)-N6 -benzoyladenine (22), which was then treated with DAST. After deprotection of the product, 15 was obtained in good yield.

Original languageEnglish (US)
Pages (from-to)95-108
Number of pages14
JournalCarbohydrate Research
Issue number1
StatePublished - Oct 18 1993

Bibliographical note

Funding Information:
This investigationw as supported by grants from National Cancer Institute and from National Institute of General Medical Sciences,N ational Institutes of Health, U.S., Department of Health and Human Services Grants Nos. CA-33907 (KAW), CA-45145 (BMG), and GM-42010 (KWP). We thank Mr. Marvin Olsen of this Institute for recording NMR spectra.


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