Synthesis of homo-N-nucleoside with 1,2,4-triazole-3-carboxamide

Article abstract of DOI:10.1081/NCN-200059368

On the basis of potent biological activities of ribavirin and homo-N-nucleosides, a novel homo-N-1,2,4-triazole-3-carboxamide derivative 1 was synthesized starting from 2,3,5-tri-O-benzoyl-ribofuranosyl-1-acetate as a potential antiviral agent. Copyright

Full text of DOI:10.1081/NCN-200059368

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SYNTHESIS OF HOMO-N-NUCLEOSIDE WITH 1,2,4-
TRIAZOLE-3-CARBOXAMIDE
Moon Woo Chun a , Jin Hee Kim a , Myong Jung Kim a , Bo Ram Kim a & Lak Shin Jeong b
a Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National
University , Seoul, Korea
b College of Pharmacy, Ewha Womans University , Seoul, Korea
Published online: 15 Nov 2011.
To cite this article: Moon Woo Chun , Jin Hee Kim , Myong Jung Kim , Bo Ram Kim & Lak Shin Jeong (2005) SYNTHESIS OF
HOMO-N-NUCLEOSIDE WITH 1,2,4-TRIAZOLE-3-CARBOXAMIDE, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 979-981,
DOI: 10.1081/NCN-200059368
To link to this article: http://dx.doi.org/10.1081/NCN-200059368
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):979–981, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200059368
SYNTHESIS OF HOMO-N-NUCLEOSIDE WITH
1,2,4-TRIAZOLE-3-CARBOXAMIDE
5
Moon Woo Chun, Jin Hee Kim, Myong Jung Kim, and Bo Ram Kim
Research
Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul,
Korea
5
Lak Shin Jeong
College of Pharmacy, Ewha Womans University, Seoul, Korea
5
On the basis of potent biological activities of ribavirin and homo-N-nucleosides, a novel homo-N-
1,2,4-triazole-3-carboxamide derivative 1 was synthesized starting from 2,3,5-tri-O-benzoyl-
ribofuranosyl-1-acetate as a potential antiviral agent.
INTRODUCTION
A number of nucleoside analogues have been synthesized for the development
of antiviral and anticancer agents. Among them, 2’,3’-dideoxynucleosides such as
3’-azido-2’3’-dideoxythymidine (AZT), 2’,3’-diedoxycytidine (ddC), and 2’3’-die-
doxyinosine (ddI) have exhibited potent antiviral activity against HIV. However, in
their antiviral chemotherapy, toxicity and emergence of drug-resistant virus strains
have been major problems.[1] A number of structurally modified nucleosides have
been synthesized in order to overcome these drawbacks, among which homo-N-
nucleoside in which methylene (CH2) is inserted between the base and the glycosyl
donor, that are resistant to hydrolytic or enzymatic cleavage of glycosidic bond and
are also highly conformationally flexible because they have no anomeric center,[2,3]
compared to natural nucleosides. Among them, guanine and adenine derivatives
have shown potent antiviral activity against herpes simplex virus.[4,5]
Ribavirin[6] is a synthetic nucleoside analogue that shows broad spectrum
antiviral activity against a variety of both DNA and RNA viruses. It has been
suggested that ribavirin[1] monophosphate (RMP), the active form of ribavirin
inhibits IMP dehydrogenase, resulting in a decrease of the guanine nucleotide level
and inhibition of viral DNA and RNA synthesis.
Address correspondence to Moon Woo Chun, Research Institute of Pharmaceutical Sciences, College of
Pharmacy, Seoul National University, Seoul 151-742, Korea.
979
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980
M. W. Chun et al.
FIGURE 1 The rationale for the design of the target nucleosides.
Based on these findings, it was great interesting to synthesize 1’-home-N-
nucleoside with 1,2,4-triazole base moiety (1) for the development of novel antiviral
agents (Figure 1).
RESULTS AND DISCUSSION
Our synthetic strategy to the target homo-N-nucleoside 1 is to synthesize 1-C-
hydroxymethyl-ribofuranoside 7 as a key intermediate from 2,3,5-tri-O-benzoyl-
ribofuranosyl-1-acetate (2) and then to treat with methyl-1,2,4-triazole-3-carboxylate,
as shown in Scheme 1.
SCHEME 1 Reagents and conditions: (a) TMSCN, SnCl4, CH2Cl2, reflux, 3 h, 79%; (b) NaOMe/MeOH, Dowex
50H+, MeOH, H2O, rt, 5 h, 75%; (c) DMP, p-TsOH, acetone, rt, overnight, 65%; (d) TrCl, pyridine, rt, 2 d, 62%; (e) 1
M LAH in THF, THF, 0°C, 2 h, 96%; (f) TsCl, DMAP, CH2Cl2, rt, overnight, 77%; (g) methyl-1,2,4-triazole-3-
carboxylate, DBU, CH3CN, reflux, 56%; (h) NH3/MeOH, rt, 24 h, 96%; (i) TFA, THF, H2O, rt, 1 h, 67%.

M. W. Chun et al.
981
Commercially available starting material 2 was treated with trimethylsilyl
cyanide in dichloromethane in the presence of stannic chloride as a Lewis acid
catalyst to give the ribouranosyl cyanide 3. Compound 3[7] was converted to 1-C-
methoxycarbonyl ribose 4 by treating with sodium methoxide followed by treating
with Dowex 50 H+ resin in MeOH/H2O. Treatment of 4 with 2,2-dimethoxy-
propane in acetone gave its 2,3-O-acetonide derivative 5, in which primary
hydroxyl group was protected with trityl chloride to afford 6. Reduction of 6 with
lithium aluminum hydride (LAH) in THF yielded 1-C-hydroxymethyl derivative 7
as a key intermediate.
Treatment of compound 7 with p-toluenesulfonyl chloride gave the tosylate 8.
Direct nucleophilic displacement of 8 with a triazole anion derived from
deprotonation of methyl-1,2,4-triazole-3-carboxylate with DBU in acetonitrile
provided the desired triazole-homonucleside 9. Compound 9 was treated with
methanolic ammonia to give the amide 10, which was deprotected with
trifluoroacetic acid to yield the desired home-N-1,2,4-triazole-3-carboxamide
derivative 1.
In summary, we have completed the stereoselective, synthesis of novel homo-N-
nucleoside, starting from commercially available intermediate 2 via b-selective
anomeric cyanation as a key step. Biological evaluation of homo-N-nucleoside
derivative (1) is in progress and will be reported in due course.
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