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

Krzysztof W. Pankiewicz, Jacek Krzeminski, Lech A. Ciszewski, Wu Yon Ren, Kyoichi A. Watanabe

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)553-559
Number of pages7
JournalJournal of Organic Chemistry
Volume57
Issue number2
DOIs
StatePublished - Jan 1 1992

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Hypoxanthine
Adenine
Hydroxyl Radical
Nucleosides
Fluorine
Fluorides
Sugars
Substitution reactions
Derivatives
diethylaminosulfur trifluoride
2-fluoroadenosine

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

@article{a68301b13fa448a794e95b6c5339d8ca,
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.",
author = "Pankiewicz, {Krzysztof W.} and Jacek Krzeminski and Ciszewski, {Lech A.} and Ren, {Wu Yon} and Watanabe, {Kyoichi A.}",
year = "1992",
month = "1",
day = "1",
doi = "10.1021/jo00028a030",
language = "English (US)",
volume = "57",
pages = "553--559",
journal = "Journal of Organic Chemistry",
issn = "0022-3263",
publisher = "American Chemical Society",
number = "2",

}

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. / Pankiewicz, Krzysztof W.; Krzeminski, Jacek; Ciszewski, Lech A.; Ren, Wu Yon; Watanabe, Kyoichi A.

In: Journal of Organic Chemistry, Vol. 57, No. 2, 01.01.1992, p. 553-559.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Pankiewicz, Krzysztof W.

AU - Krzeminski, Jacek

AU - Ciszewski, Lech A.

AU - Ren, Wu Yon

AU - Watanabe, Kyoichi A.

PY - 1992/1/1

Y1 - 1992/1/1

N2 - 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.

AB - 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.

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