Synthesis of 3′-deoxy-3′-C-hydroxymethyl analogues of tiazofurin and ribavirin

Article abstract of DOI:10.1081/NCN-200059338

On the basis of potent biological activity of 3′-branched-3′- deoxynucleoside analogues, novel ribavirin and tiazofurin derivatives with 3′-C-hydroxymethyl substituent were synthesized, starting from D-xylose. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200059338

This article was downloaded by: [University of California Santa Cruz]
On: 25 November 2014, At: 16:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
SYNTHESIS OF 3′-DEOXY-3′-C-HYDROXYMETHYL
ANALOGUES OF TIAZOFURIN AND RIBAVIRIN
Moon Woo Chun a , Myong Jung Kim a , Ji Hye Shin 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 , Myong Jung Kim , Ji Hye Shin & Lak Shin Jeong (2005) SYNTHESIS OF 3′-DEOXY-3′-C-
HYDROXYMETHYL ANALOGUES OF TIAZOFURIN AND RIBAVIRIN, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 975-977,
DOI: 10.1081/NCN-200059338
To link to this article: http://dx.doi.org/10.1081/NCN-200059338
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):975–977, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200059338
SYNTHESIS OF 3’-DEOXY-3’-C-HYDROXYMETHYL ANALOGUES OF
TIAZOFURIN AND RIBAVIRIN
5
Moon Woo Chun, Myong Jung Kim, and Ji Hye Shin
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 activity of 3’-branched-3’-deoxynucleoside analogues, novel
ribavirin and tiazofurin derivatives with 3’-C-hydroxymethyl substituent were synthesized, starting
from D-xylose.
INTRODUCTION
Ribavirin[1] is a broad-spectrum antiviral agent through the inhibition of
IMPDH which catalyzes an essential step in the de novo biosynthesis of guanine
nucleotides, namely, the conversion of inosine-5’-monophosphate (IMP) to
xanthosine-5’-monophosphate (XMP) and currently used in combination with
interferon-a for the treatment of chronic hepatitis C virus infection. Tiazofurin[2]
inhibits the same enzyme after metabolic conversion into thiazole-4-carboxamide
adenine dinucleotide (TAD), an analogue of the cofactor NAD, and is currently
undergoing clinical trials as an antitumor agent.
The 3’-branched-3’-deoxy nucleoside analogues have received much attention
as potential chemotherapeutic agents and some of them have been shown to
display antiviral and anticancer activities. Also, it has been known that branched
nucleosides are biologically active due to greater recognition of these substrates by
DNA polymerase, compared to non-branched nucleoside substrates.[3]
Based on these findings, it was interesting to put the hydroxymethyl group at
the C3 position of tiazofurin and ribavirin, respectively, and to compare their
biological activities with those of parent nucleosides. Here, we wish to report the
asymmetric synthesis of the 3’-deoxy-3’-C-hydroxymethyl tiazofurin (1) and
ribavirin (2) derivatives, starting from D-xylose (Figure 1).
Address correspondence to Moon Woo Chun, Research Institute of Pharmaceutical Sciences, College of
Pharmacy, Seoul National University, Seoul 151-742, Korea.
975
Order reprints of this article at www.copyright.rightslink.com

976
M. W. Chun et al.
FIGURE 1 Structures of the target nucleosides.
RESULTS AND DISCUSSION
Our synthetic approach to the thiazole nucleoside 1 was fist to synthesize
ribofuranosyl cyanide as a key intermediate from D-xylose and then to cyclo-
condense with L-cysteine ethyl ester hydrochloride.
3-C-Hydroxymethyl derivative (3) was prepared from D-xylose by known
method.[4] Treatment of 3 with benzoyl chloride gave the dibenzoate 4, in which
1,2-acetonide was removed by acid-catalyzed methanolysis to give the methoxide 5.
Compound 5 was treated with benzoyl chloride to afford the tribenzoate 6, which
was treated with Ac2O/AcOH/c-H2SO4 to give the 1-O-acetyl derivative 7. 3-C-
Benzoyloxymethyl-3-deoxy-2,5-di-O-benzoylribofuranosyl cyanide (8) was prepared
by treating acetate 7 with cyanotrimethylsilane and SnCl4 in dichloromethane.
Cyanide 8 was treated with L-cystein ethyl ester hydrochloride in the presence of
triethylamine to give the thiazole 9, which was dehydrogenated by treatment with
bromotrichloromethane in combination with DBU to afford the thiazole 10.
Ammonolysis and debenzoylation of the ester 10 using methanolic ammonia
yielded 3’-C-hydroxymethyl substituted tiazofurin derivative 1 (Scheme 1).
SCHEME 1 Reagents and conditions: (a) BzCl, pyridine, RT, 16 h, 90%; (b) 1%HCl in MeOH, RT, 3 h, 89%;
(c) BzCl, pyridine, RT, 16 h, 90%; (d) AcOH/Ac2O/c-H2SO4, 0°C, 0.5 h, 95%; (e) TMSCN, SnCl4, CH2Cl2, reflux,
3 h, 81%; (f) L-cysteine ethyl ester hydrochloride, Et3N, MeOH, 2 h, 75%; (g) DBU, BrCCl3, CH2Cl2, 0°C, 16 h, 80%;
(h) NH3/MeOH, RT, 18 h, 80%.

M. W. Chun et al.
977
SCHEME 2 Reagents and conditions: (a) i. 85% HCO2H, 55°C, 2 h; ii. Ac2O, pyridine, RT, 18 h, 92%;
(b) silylated methyl-1,2,4-triazole-3-carboxylate, SnCl4, CH3CN, RT, 29 h, 45%; (c) NH3/MeOH, RT, 18 h, 80%.
Synthesis of 3’-deoxy-3’-C-hydroxymethylribavirin (2) is outlined in Scheme 2.
1,2-O-Isopropylidene group of 4 was hydrolyzed with 85% formic acid, followed by
acetylation to give the acetate 11. Condensation of glycosyl donor 11 with silylated
methyl-1,2,4-triazole-3-carboxylate in the presence of SnCl4 in acetonitrile gave the
protected nucleoside 12. Treatment of 12 with methanolic ammonia yielded the 3’-
C-hydroxymethyl substituted ribavirin derivative 2. In summary, we have accom-
plished the synthesis of novel 3’-deoxy-3’-C-hydroxymethyl analogues of tiazofurin
and ribavirin via cyclocondensation of ribofuranosyl cyanide 8 with L-cysteine ethyl
ester hydrochloride and condensation of glycosyl donor 11 with methyl-1,2,4-
triazole-3-carboxylate, respectively. The biological assay of the final nucleosides 1
and 2 is in progress in our laboratory and will be reported elsewhere.
REFERENCES
1. Wray, S.K.; Gilbert, B.E.; Noall, M.W.; Knight, V. Mode of action of ribavirin: effect of nucleotide pool
alterations on influenza virus ribonucleoprotein synthesis. Antiviral Res. 1985, 5, 29.
2. Weber, G.; Prajda, N.; Abonyi, M.; Look, K.Y.; Tricot, G. Tiazofurin: molecular and clinical action.
Anticancer Res. 1996, 16, 3313.
3. Acton, E.M.; Goerner, R.N.; Uh, H.S.; Ryan, K.J.; Henry, D.W. Improved antitumor effects in 3’-branched
homologues of 2’-deoxythioguanosine. Synthesis and evaluation of thioguanine nucleosides of 2,3-dideoxy-3-
(hydroxymethyl)-D-erythro-pentofuranose. J. Med. Chem. 1979, 22, 518.
4. Lin, T.-S.; Zhu, J.-L.; Dutschmann, G.E.; Cheng, Y.-C.; Prusoff, W.H. Syntheses and biological evaluations of
3’-deoxy-3’-C-branched-chain-substituted nucleosides. J. Med. Chem. 1993, 36, 353.