Synthesis and biological evaluation of pyrimidine nucleosides fused with 3′,4′-tetrahydrofuran ring

Article abstract of DOI:10.1081/NCN-120022618

Pyrimidine nucleosides fused with 3′,4′-tetrahydrofuran ring were synthesized, starting from 1,2;5,6-di-O-isopropylidene-D-glucose and assayed for antiviral activities. Thymine analogue 1 and its corresponding 2′-deoxy analogue 3 exhibited high cytotoxici

Full text of DOI:10.1081/NCN-120022618

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Synthesis and Biological Evaluation of Pyrimidine
Nucleosides Fused with 3′,4′-Tetrahydrofuran Ring
Moon Woo Chun a f , Myong Jung Kim a , Hea Ok Kim b , Hyung Ryong Moon e , Hee-Doo Kim c
, Joong Hyup Kim d & Lak Shin Jeong e
a College of Pharmacy , Seoul National University , Seoul, Korea
b Division of Chemistry and Molecular Engineering , Seoul National University , Seoul, Korea
c College of Pharmacy, Sookmyung Women's University , Seoul, Korea
d Korea Institute of Science and Technology , Seoul, Korea
e College of Pharmacy, Ewha Womans University , Seoul, Korea
f Seoul National University , 56-1 Shinrim-dong San, Kwanak-gu, 151-742, Seoul, Korea
Published online: 31 Aug 2006.
To cite this article: Moon Woo Chun , Myong Jung Kim , Hea Ok Kim , Hyung Ryong Moon , Hee-Doo Kim , Joong Hyup Kim &
Lak Shin Jeong (2003) Synthesis and Biological Evaluation of Pyrimidine Nucleosides Fused with 3′,4′-Tetrahydrofuran Ring,
Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 719-721, DOI: 10.1081/NCN-120022618
To link to this article: http://dx.doi.org/10.1081/NCN-120022618
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 719–721, 2003
Synthesis and Biological Evaluation of Pyrimidine
Nucleosides Fused with 30,40-Tetrahydrofuran Ring
1
2
Moon Woo Chun,1, Myong Jung Kim, Hea Ok Kim,
*
Hyung Ryong Moon,5 Hee-Doo Kim,3 Joong Hyup Kim,4
and Lak Shin Jeong5
1College of Pharmacy and
2Division of Chemistry and Molecular Engineering,
Seoul National University, Seoul, Korea
3College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
4Korea Institute of Science and Technology, Seoul, Korea
5College of Pharmacy, Ewha Womans University, Seoul, Korea
ABSTRACT
Pyrimidine nucleosides fused with 30,40-tetrahydrofuran ring were synthesized,
starting from 1,2;5,6-di-O-isopropylidene-D-glucose and assayed for antiviral
activities. Thymine analogue 1 and its corresponding 20-deoxy analogue 3 exhi-
bited high cytotoxicity instead of giving antiviral activities.
A number of 20,30-dideoxy nucleosides have been discovered to possess signif-
icant antiviral activity against HIV-1 and other viruses. Since it has been sug-
gested that proper conformation of the dideoxynucleosides is required for them
to exhibit antiviral activity,[1] bicyclic nucleoside analogues like the fused oxetanyl
or cyclopropanyl derivatives of thymidine[2,3] have been synthesized and reported
*Correspondence: Moon Woo Chun, Seoul National University, 56-1 Shinrim-dong San,
Kwanak-gu, 151-742 Seoul, Korea; Fax: +82 2 888 0649; E-mail: mwchun@snu.ac.kr.
719
DOI: 10.1081/NCN-120022618
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

720
Chun et al.
Scheme 1.
to inhibit HIV replication. However, 30,40-cyclopentane fused pyrimidine nucleo-
sides did not show antiviral activity.[4] Based on these findings, we report the
synthesis of pyrimidine nucleosides fused with 30,40-tetrahydrofuran ring starting
from 1,2;5,6-di-O-isopropylidene-D-glucose as potential antiviral agents to obtain
further information regarding the correlation between sugar ring conformation
and antiviral activity.
1,2;5,6-Di-O-isopropylidene-D-glucose (4) was oxidized with PDC and Wittig
reaction of the resulting ketone gave the olefin 5. Hydroboration-oxidation of 5
followed by benzylation of the resulting hydroxyl group yielded the benzyl ether
6. Selective removal of 5,6-O-isopropylidene of 6 using 75% acetic acid followed
by oxidative cleavage of the diol with NaIO4 afforded the aldehyde. Aldol reaction
of the aldehyde using 37% aqueous formaldehyde and NaOH and then in situ
Cannizzarro reaction produced diol 7 in good yield.
Mesylation of 7 followed by catalytic hydrogenolysis afforded 8, which under-
went intramolecular cyclization in the presence of NaH and hydrolysis of the sulfo-
nate using aqueous NaOH to give 9. Treatment of 9 with acetic anhydride gave the
acetate which was hydrolyzed with 85% aqueous formic acid and then successively
acetylated to give glycosyl donor 10. Condensation of 10 with silylated thymine
and N4-benzoylcytosine gave the protected nucleosides 11a and 11b, respectively.
Deacylation of 11a and 11b gave the desired nucleosides 1 and 2, respectively. Regio-
selective protection of primary hydroxyl group of 1 as a TBDPS ether followed by
treatment with phenyl chlorothionoformate and then tributyltin hydride in the pre-
sence of AIBN furnished 20-deoxy derivative 13. Deblocking of 50-silyl group of 13
afforded the final 20-deoxy analogue 3.
The final nucleosides 1, 2 and 3 were assayed for antiviral activities
against HIV-1, VSV and HCMV, among which thymine analogue 1 and its corre-
sponding 20-deoxy analogue 3 exhibited high cytotoxicity without antiviral
activities.

Nucleosides Fused with 30,40-Tetrahydrofuran Ring
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721
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