A synthesis of 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine and hypoxanthine. An effect of C3′-endo to C2′-endo conformational shift on the reaction course of 2′-hydroxyl group with DAST Journal Article
| Authors: | Pankiewicz, K. W.; Krzeminski, J.; Ciszewski, L. A.; Ren, W. Y.; Watanabe, K. A. |
| Article Title: | A synthesis of 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine and hypoxanthine. An effect of C3′-endo to C2′-endo conformational shift on the reaction course of 2′-hydroxyl group with DAST |
| Abstract: | O3′,O5′,N6-Tritrityladenosine (6), 3′,5′-di-O-trityl-N1-benzylinosine (15), and 3′,5′-di-O-tritylinosine (18) were prepared and subjected to nucleophilic reaction with DAST. Thus, 6 afforded 2′-β-fluorine-substituted nucleoside 11 along with the isomeric 2-deoxy-2-(N-trityladenin-3-yl)-3,5-di-O-trityl-α-d-arabinofuranosyl fluoride (12). Nucleoside 15, under the same treatment with DAST, gave the desired 2′-fluoroarabino derivative 16 exclusively in high yield. Although 18 was converted into the 2′-β-fluoro product 19 under the similar conditions, the yield was low. A plausible mechanism of formation of 12 is discussed. Deprotection of 11 and 16 afforded the desired 9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine (1) and -hypoxanthine (2), respectively, in high yield. The conformational influence of sugar protecting groups on the rate of nucleophilic substitution against elimination is discussed. Treatment of O3′,O5′,N1-benzylinosine (20) with DAST afforded only the elimination products 9-(3′,5′-di-O-benzyl-β-d-erythro-pent-2-enofuranosyl)-1-benzylhypoxanthine (22) and 3-(benzyloxy)-2-[(benzyloxy) methyl]furan (23). On the other hand, 9-(3,5-di-O-trityl-β-d-arabinofuranosyl)adenine (26) (prepared from 6 by triflyation followed by NaOAc treatment and deacetylation) afforded a mixture from which 2′-deoxy-2′-fluoroadenosine (27) and 9-(2-deoxy-3,5-di-O-trityl-d-erythro-pent-1-enofuranosyl)-N6-trityladenine (28) were isolated in 60 and 30% yield, respectively. O2′,O5′,N6-Tritrityladenosine (7) was selectively detritylated with HCO2H/Et2O to give O2′,N6-ditrityladenosine (30), which, upon treatment with benzyl chloride/KOH, afforded 3′.5′-di-O-benzyl-O2′,N6-ditrityladenosine (31). 9-(3,5-Di-O-benzyl-β-d-arabinofuranosyl)adenine (35) was prepared from 31 by further detritylation with CF3CO2H/CHCl3 and triflylation followed by NaOAc treatment and deacetylation of the product. Treatment of 35 with DAST followed by hydrogenolytic debenzylation afforded 2′-deoxy-2′-fluoroadenosine (3) in high yield. The three-step synthesis described herein, albeit about 10% overall yield, is far superior to the currently available multistep procedures which give the desired 2′-fluoroarabinosylpurines in much less overall yields. © 1992, American Chemical Society. All rights reserved. |
| Keywords: | unclassified drug; reaction analysis; synthesis; stereochemistry; adenosine derivative; article; 2' deoxy 2' fluoroadenosine; 2' deoxy 2' fluorovidarabine; 2' fluoro 2' deoxyhypoxanthine arabinoside |
| Journal Title: | Journal of Organic Chemistry |
| Volume: | 57 |
| Issue: | 2 |
| ISSN: | 0022-3263 |
| Publisher: | American Chemical Society |
| Date Published: | 1992-01-01 |
| Start Page: | 553 |
| End Page: | 559 |
| Language: | English |
| DOI: | 10.1021/jo00028a030 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Author Wu-Yen Ren's first name is misspelled on the original publication -- Source: Scopus |
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