Ring-expanded analogues of natural oxetanocin: (+) and (-) hydroxymethyl isodideoxyadenosine

Article abstract of DOI:10.1081/NCN-200060036

New enantiomeric isonucleoside analogues related to natural oxetanocin have been synthesized from D-glucosamine and D-glucose. The structures of the target compounds were confirmed by NMR, HRMS, UV, single crystal X-ray, and optical rotation data. Stabili

Full text of DOI:10.1081/NCN-200060036

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RING-EXPANDED ANALOGUES OF NATURAL
OXETANOCIN: (+) AND (-) HYDROXYMETHYL
ISODIDEOXYADENOSINE
Byoung-Kwon Chun a , Jean John Vadakkan a & Vasu Nair a
a Department of Pharmaceutical and Biomedical Sciences , The University of Georgia ,
Athens, Georgia, USA
Published online: 15 Nov 2011.
To cite this article: Byoung-Kwon Chun , Jean John Vadakkan & Vasu Nair (2005) RING-EXPANDED ANALOGUES OF NATURAL
OXETANOCIN: (+) AND (-) HYDROXYMETHYL ISODIDEOXYADENOSINE, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7,
725-728, DOI: 10.1081/NCN-200060036
To link to this article: http://dx.doi.org/10.1081/NCN-200060036
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):725–728, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060036
RING-EXPANDED ANALOGUES OF NATURAL OXETANOCIN: (+) AND
(À) HYDROXYMETHYL ISODIDEOXYADENOSINE
5
Byoung-Kwon Chun, Jean John Vadakkan, and Vasu Nair
Department of
Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia 30602,
USA
5
New enantiomeric isonucleoside analogues related to natural oxetanocin have been synthesized from
D-glucosamine and D-glucose. The structures of the target compounds were confirmed by NMR, HRMS,
UV, single crystal X-ray, and optical rotation data. Stability studies with respect to purine nucleoside
phosphorylase and adenosine deaminase show that these compounds are not substrates. Antiviral results
are discussed.
Keywords Oxetanocin, Isonucleoside, Chiral Synthesis, Antiviral
INTRODUCTION
The anti-HIV active compound, oxetanocin 1 (Figure 1), isolated from bacteria
has a ring-contracted surrogate carbohydrate moiety.[1] In designing antiviral
analogues of oxetanocin with a tetrahydrofuran ring in place of an oxetane, we
combined some of the structural features of the surrogate carbohydrate moiety of
oxetanocin with that of a potent antiviral compound, 4(S)-(adenin-9-yl)-2(S)-
hydroxymethyltetrahydrofuran [(S,S)-isoddA] (2).[2–4] Compound 2 exhibits potent
anti-HIV activity against HIV-1, HIV-2, and HIV-resistant strains. (S,S)-IsoddA
triphosphate is among the strongest known inhibitors of HIV reverse transcrip-
tase.[2] In addition, another isomeric nucleoside related to oxetanocin and bearing a
tetrahydrofuranyl moiety shows antiviral activity against HSV-1 and HSV-2.[5] This
paper reports on the chemistry and biology of the enantiomeric isonucleosides 3
and 4 (Figure 1).
Received 1 October 2004, accepted 21 January 2005.
The project described was supported by Grant Number AI 32851 from the National Institutes of Health. Its
contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
We thank Dr. Erik De Clercq and Dr. Jan Balzarini for the anti-HIV screening.
Address correspondence to Vasu Nair, Department of Pharmaceutical and Biomedical Sciences, University
of Georgia, Room 320, R.C. Wilson PH, Athens, GA 30602, USA; E-mail: vnair@rx.uga.edu
725
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726
B.-K. Chun, J. J. Vadakkan, and V. Nair
FIGURE 1 Structures of compounds 1, 2, 3 and 4.
RESULTS AND DISCUSSION
Retrosynthetic analysis revealed that the (+) enantiomer would be accessible
through an epoxide[6–8] derived from D-glucosamine and the (À) enantiomer
through an intermediate accessible through a rearrangement reaction[9,10] from D-
glucose derivative (Figure 2).
The total synthesis of the (+) isomer is shown in Scheme 1.
Details of the synthesis of the (À) isomer are shown in Scheme 2.
The structures of the target compounds and intermediates were confirmed by
1
NMR, HRMS, UV spectral data. Compounds 3 and 4 gave identical H and 13C
NMR spectra except that compound 3 was dextrorotatory and compound 4 was
levorotatory with approximately the same magnitude of optical rotation. Final
confirmation of structure and stereochemistry came from the single crystal X-ray
data for compound 4.
Compounds 3 and 4 were not substrates for adenosine deaminase and purine
nucleoside phosphorylase. Anti-HIV evaluations showed that these compounds
were either devoid of anti-HIV activity or had low anti-HIV activity. Other antiviral
studies are in progress.
FIGURE 2 Retrosynthetic analysis.

B.-K. Chun, J. J. Vadakkan, and V. Nair
727
SCHEME 1 Synthesis of compound 3.
SCHEME 2 Synthesis of compound 4.
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