Synthesis of 2′-β-Fluoro- and 3′-α-Fluoro-Substituted Guanine Nucleosides. Effects of Sugar Conformational Shifts on Nucleophilic Displacement of the 2′-Hydroxy and 3′-Hydroxy Group with DAST

Krzysztof W. Pankiewicz, Jacek Krzeminski, Kyoichi A. Watanabe

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Abstract

Tritylation of 2-N-acetyl-6-O-((4-nitrophenyl)ethyl)guanosine (4) with TrCl/DMAP followed by TrCl/AgNO3 afforded a mixture of isomeric 3′,5′-di-O-trityl and 2′,5′-di-O-trityl derivatives 6 and 7, which were separated on a silica gel column to give 6 and 7 in 40% and 50% yield, respectively. Upon treatment with DAST, 6 was converted into the corresponding 2′-β-fluoro nucleoside 8 in 43% yield. Deprotection of the 2-N-acetyl group occurred during the reaction. Removal of the 6-O-NPE group from 8 with DBU/pyridine, followed by detritylation with CF3COOH/CHCl3, gave F-ara-G (lb) in good yield. The same treatment of 7 with DAST did not lead to nucleophilic substitution with fluoride ion, but only decomposition took place. Treatment of the 2′,5′-di-O-trityl nucleoside 7 with CF3SO2Cl/DMAP in CH2Cl2, followed by PhCO2K/HMPA, afforded the corresponding xylofuranosyl derivative 16 along with 6-O-deprotected nucleoside 19. The 6-O-NPE group was completely removed in the reaction of triflate nucleoside 15 with CH3CO2Na/HMPA. The obtained diacetyl nucleoside 20 under hydrolysis with Et3N/MeOH/H2O gave 9-(2,5-di-O-trityl-β-D-xylofuranosyl)guanine (22). Upon reaction of derivative 22 with DAST no formation of the desired 3′-fluoro nucleoside 23 was observed, but only decomposition took place. When, however, the triflate nucleoside 15 was treated with CH3COONa in DMF instead of HMPA the corresponding diacetyl nucleoside 17 with intact 6-O-NPE group was obtained. This compound was hydrolyzed with Et3N/MeOH/H2O to give the 2-N-acetyl derivative 18, which was smoothly converted into the desired 3'-α-fluoro-substituted nucleoside 24 in 76% yield. Again, removal of the 2-N-acetyl group occurred during the reaction with DAST. Compound 24 was deprotected with DBU/pyridine followed by CF3COOH/CHCl3 to give 3′-fluoro-3′-deoxyguanosine in good yield (3b). In a similar manner the O2,O5,N6-tritrityladenosine (25) was converted into the corresponding 3′-deoxy-3′-fluoroadenosine (3a).

Original languageEnglish (US)
Pages (from-to)7315-7321
Number of pages7
JournalJournal of Organic Chemistry
Volume57
Issue number26
DOIs
StatePublished - Dec 1 1992

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Guanine
Nucleosides
Sugars
Hempa
Derivatives
Diacetyl
Decomposition
diethylaminosulfur trifluoride
Guanosine
Silica Gel
Fluorides
Hydrolysis
Substitution reactions
Ions

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

@article{39dc1de8fe714c0fb80da92cfddf53b4,
title = "Synthesis of 2′-β-Fluoro- and 3′-α-Fluoro-Substituted Guanine Nucleosides. Effects of Sugar Conformational Shifts on Nucleophilic Displacement of the 2′-Hydroxy and 3′-Hydroxy Group with DAST",
abstract = "Tritylation of 2-N-acetyl-6-O-((4-nitrophenyl)ethyl)guanosine (4) with TrCl/DMAP followed by TrCl/AgNO3 afforded a mixture of isomeric 3′,5′-di-O-trityl and 2′,5′-di-O-trityl derivatives 6 and 7, which were separated on a silica gel column to give 6 and 7 in 40{\%} and 50{\%} yield, respectively. Upon treatment with DAST, 6 was converted into the corresponding 2′-β-fluoro nucleoside 8 in 43{\%} yield. Deprotection of the 2-N-acetyl group occurred during the reaction. Removal of the 6-O-NPE group from 8 with DBU/pyridine, followed by detritylation with CF3COOH/CHCl3, gave F-ara-G (lb) in good yield. The same treatment of 7 with DAST did not lead to nucleophilic substitution with fluoride ion, but only decomposition took place. Treatment of the 2′,5′-di-O-trityl nucleoside 7 with CF3SO2Cl/DMAP in CH2Cl2, followed by PhCO2K/HMPA, afforded the corresponding xylofuranosyl derivative 16 along with 6-O-deprotected nucleoside 19. The 6-O-NPE group was completely removed in the reaction of triflate nucleoside 15 with CH3CO2Na/HMPA. The obtained diacetyl nucleoside 20 under hydrolysis with Et3N/MeOH/H2O gave 9-(2,5-di-O-trityl-β-D-xylofuranosyl)guanine (22). Upon reaction of derivative 22 with DAST no formation of the desired 3′-fluoro nucleoside 23 was observed, but only decomposition took place. When, however, the triflate nucleoside 15 was treated with CH3COONa in DMF instead of HMPA the corresponding diacetyl nucleoside 17 with intact 6-O-NPE group was obtained. This compound was hydrolyzed with Et3N/MeOH/H2O to give the 2-N-acetyl derivative 18, which was smoothly converted into the desired 3'-α-fluoro-substituted nucleoside 24 in 76{\%} yield. Again, removal of the 2-N-acetyl group occurred during the reaction with DAST. Compound 24 was deprotected with DBU/pyridine followed by CF3COOH/CHCl3 to give 3′-fluoro-3′-deoxyguanosine in good yield (3b). In a similar manner the O2,O5,N6-tritrityladenosine (25) was converted into the corresponding 3′-deoxy-3′-fluoroadenosine (3a).",
author = "Pankiewicz, {Krzysztof W.} and Jacek Krzeminski and Watanabe, {Kyoichi A.}",
year = "1992",
month = "12",
day = "1",
doi = "10.1021/jo00052a055",
language = "English (US)",
volume = "57",
pages = "7315--7321",
journal = "Journal of Organic Chemistry",
issn = "0022-3263",
publisher = "American Chemical Society",
number = "26",

}

TY - JOUR

T1 - Synthesis of 2′-β-Fluoro- and 3′-α-Fluoro-Substituted Guanine Nucleosides. Effects of Sugar Conformational Shifts on Nucleophilic Displacement of the 2′-Hydroxy and 3′-Hydroxy Group with DAST

AU - Pankiewicz, Krzysztof W.

AU - Krzeminski, Jacek

AU - Watanabe, Kyoichi A.

PY - 1992/12/1

Y1 - 1992/12/1

N2 - Tritylation of 2-N-acetyl-6-O-((4-nitrophenyl)ethyl)guanosine (4) with TrCl/DMAP followed by TrCl/AgNO3 afforded a mixture of isomeric 3′,5′-di-O-trityl and 2′,5′-di-O-trityl derivatives 6 and 7, which were separated on a silica gel column to give 6 and 7 in 40% and 50% yield, respectively. Upon treatment with DAST, 6 was converted into the corresponding 2′-β-fluoro nucleoside 8 in 43% yield. Deprotection of the 2-N-acetyl group occurred during the reaction. Removal of the 6-O-NPE group from 8 with DBU/pyridine, followed by detritylation with CF3COOH/CHCl3, gave F-ara-G (lb) in good yield. The same treatment of 7 with DAST did not lead to nucleophilic substitution with fluoride ion, but only decomposition took place. Treatment of the 2′,5′-di-O-trityl nucleoside 7 with CF3SO2Cl/DMAP in CH2Cl2, followed by PhCO2K/HMPA, afforded the corresponding xylofuranosyl derivative 16 along with 6-O-deprotected nucleoside 19. The 6-O-NPE group was completely removed in the reaction of triflate nucleoside 15 with CH3CO2Na/HMPA. The obtained diacetyl nucleoside 20 under hydrolysis with Et3N/MeOH/H2O gave 9-(2,5-di-O-trityl-β-D-xylofuranosyl)guanine (22). Upon reaction of derivative 22 with DAST no formation of the desired 3′-fluoro nucleoside 23 was observed, but only decomposition took place. When, however, the triflate nucleoside 15 was treated with CH3COONa in DMF instead of HMPA the corresponding diacetyl nucleoside 17 with intact 6-O-NPE group was obtained. This compound was hydrolyzed with Et3N/MeOH/H2O to give the 2-N-acetyl derivative 18, which was smoothly converted into the desired 3'-α-fluoro-substituted nucleoside 24 in 76% yield. Again, removal of the 2-N-acetyl group occurred during the reaction with DAST. Compound 24 was deprotected with DBU/pyridine followed by CF3COOH/CHCl3 to give 3′-fluoro-3′-deoxyguanosine in good yield (3b). In a similar manner the O2,O5,N6-tritrityladenosine (25) was converted into the corresponding 3′-deoxy-3′-fluoroadenosine (3a).

AB - Tritylation of 2-N-acetyl-6-O-((4-nitrophenyl)ethyl)guanosine (4) with TrCl/DMAP followed by TrCl/AgNO3 afforded a mixture of isomeric 3′,5′-di-O-trityl and 2′,5′-di-O-trityl derivatives 6 and 7, which were separated on a silica gel column to give 6 and 7 in 40% and 50% yield, respectively. Upon treatment with DAST, 6 was converted into the corresponding 2′-β-fluoro nucleoside 8 in 43% yield. Deprotection of the 2-N-acetyl group occurred during the reaction. Removal of the 6-O-NPE group from 8 with DBU/pyridine, followed by detritylation with CF3COOH/CHCl3, gave F-ara-G (lb) in good yield. The same treatment of 7 with DAST did not lead to nucleophilic substitution with fluoride ion, but only decomposition took place. Treatment of the 2′,5′-di-O-trityl nucleoside 7 with CF3SO2Cl/DMAP in CH2Cl2, followed by PhCO2K/HMPA, afforded the corresponding xylofuranosyl derivative 16 along with 6-O-deprotected nucleoside 19. The 6-O-NPE group was completely removed in the reaction of triflate nucleoside 15 with CH3CO2Na/HMPA. The obtained diacetyl nucleoside 20 under hydrolysis with Et3N/MeOH/H2O gave 9-(2,5-di-O-trityl-β-D-xylofuranosyl)guanine (22). Upon reaction of derivative 22 with DAST no formation of the desired 3′-fluoro nucleoside 23 was observed, but only decomposition took place. When, however, the triflate nucleoside 15 was treated with CH3COONa in DMF instead of HMPA the corresponding diacetyl nucleoside 17 with intact 6-O-NPE group was obtained. This compound was hydrolyzed with Et3N/MeOH/H2O to give the 2-N-acetyl derivative 18, which was smoothly converted into the desired 3'-α-fluoro-substituted nucleoside 24 in 76% yield. Again, removal of the 2-N-acetyl group occurred during the reaction with DAST. Compound 24 was deprotected with DBU/pyridine followed by CF3COOH/CHCl3 to give 3′-fluoro-3′-deoxyguanosine in good yield (3b). In a similar manner the O2,O5,N6-tritrityladenosine (25) was converted into the corresponding 3′-deoxy-3′-fluoroadenosine (3a).

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U2 - 10.1021/jo00052a055

DO - 10.1021/jo00052a055

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JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

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ER -