DOI: 10.1002/chem.201403560
Communication
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Non-natural Nucleosides
Synthesis and Antiviral Properties of Spirocyclic [1,2,3]-
Triazolooxazine Nucleosides
Antonio Dell’Isola,[a] Matthew M. W. McLachlan,[b] Benjamin W. Neuman,[c] Hawaa M. N. Al-
Mullah,[c] Alexander W. D. Binks,[c] Warren Elvidge,[c] Kenneth Shankland,[a] and
Alexander J. A. Cobb*[a]
alone, but there are also examples whereby the nucleobase is
Abstract: An efficient synthesis of spirocyclic triazolooxa-
zine nucleosides is described. This was achieved by the
conversion of b-d-psicofuranose to the corresponding
azido-derivative, followed by alkylation of the primary al-
cohol with a range of propargyl bromides, obtained by
Sonogashira chemistry. The products of these reactions
underwent 1,3-dipolar addition smoothly to generate the
protected spirocyclic adducts. These were easily depro-
tected to give the corresponding ribose nucleosides. The
library of compounds obtained was investigated for its an-
tiviral activity using MHV (mouse hepatitis virus) as
a model wherein derivative 3 f showed the most promis-
ing activity and tolerability.
directly involved in the conformational restriction of the nu-
cleoside (so-called “cyclonucleosides”).[4] In this respect, we
have an interest in the synthesis and use of anomeric spironu-
cleosides, whereby the anomeric carbon belongs to both the
sugar moiety and the nucleobase (Figure 1). This fixes the nu-
cleobase in a specific orientation around the N-glycosidic
bond, imposing an altered flexibility on the sugar moiety.
Spiro-functionalised nucleosides have gained considerable in-
terest with the discovery of (+)-hydantocidin (1), a natural spi-
ronucleoside with potent herbicidal and plant growth regula-
tory activity.[5] However, to the best of our knowledge, synthet-
ic work in this field is limited, with the majority of anomeric
spirocycles being hydantoine or diketopiperazine analogues, or
simple pseudonucleosides with anchored purinic and pyrimi-
dinic bases.[6]
The design and synthesis of nucleoside analogues has been
a subject of great interest in the discovery of novel anticancer
and antiviral agents owing to the fact that they can be in-
volved in the disruption of nucleic acid biosynthesis and thus
inhibit cellular division and viral replication.[1] Additionally, they
have been utilised for various gene-silencing techniques as
constituents of antisense oligonucleotides, small interfering
RNAs (siRNAs) and microRNA-targeting oligonucleotides (anti-
miRNAs).[2]
In particular, conformationally restricted nucleosides such as
“locked nucleic acids” (LNAs), whereby the sugar moiety of the
nucleoside is locked in the bioactive C3’-endo (North) or C2’-
endo (South) conformations, represent an interesting class of
nucleoside inhibitor as they can show a dramatic improvement
in enzymatic recognition, as well as enhancing base stacking
and backbone pre-organisation.[3] Most of these systems are
locked by virtue of bridging groups on the furanose unit
Figure 1. Representation of a spironucleoside (where the shared carbon is at
the anomeric position), the spironucleoside hydantocidin, and the triazolyl
antiviral ribavirin.
As part of an on-going programme within our laboratories
on the synthesis of non-natural nucleic acids,[7] we aimed to
prepare a library of spiro-fuctionalised nucleosides, containing
a [1,2,3]-triazolyl moiety using a straightforward and highly ste-
reoselective route. It was felt that this class of spironucleoside
would make an interesting alternative to the [1,2,4]-triazolyl
class of nucleoside the biological activity of which is well
known, owing to their resemblance to ribavirin 2.[8] We there-
fore evaluated our resulting [1,2,3]-triazolospironucleosides for
their anti-HMV (mouse hepatitis virus) activity in vitro.
[a] A. Dell’Isola, Dr. K. Shankland, Dr. A. J. A. Cobb
School of Chemistry, Food and Pharmacy (SCFP)
University of Reading, Whiteknights, Reading, Berks RG6 6AD (UK)
[b] Dr. M. M. W. McLachlan
Syngenta, Jealott’s Hill International Research Centre
Bracknell, Berks RG42 6EY (UK)
As depicted in the retrosynthetic path (Scheme 1), the versa-
tility of the synthetic strategy towards novel anomeric spironu-
cleosides 3 lies in the strategic installation of azide and alkyne
moieties on the d-psicofuranose derivative 4, followed by an
intramolecular Huisgen 1,3-dipolar cycloaddition to generate
the spirocyclic [1,2,3]-triazolooxazine ring.[9]
[c] Dr. B. W. Neuman, H. M. N. Al-Mullah, A. W. D. Binks, W. Elvidge
School of Biological Sciences, University of Reading
Whiteknights, Reading, Berks RG6 6AJ (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403560.
Chem. Eur. J. 2014, 20, 1 – 6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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