Design and synthesis of a nucleoside and a phosphonate analogue constructed on a branched-threo-tetrofuranose skeleton

Article abstract of DOI:10.1016/j.tetlet.2013.05.062

The synthesis of a novel nucleoside phosphonate constructed on a branched-threo-tetrofuranose scaffold, as a potential antiviral agent, is described. The pseudosugar moiety served as the nucleoside skeleton was produced starting from 2-butyne-1,4-diol in

Full text of DOI:10.1016/j.tetlet.2013.05.062

Accepted Manuscript
Design and Synthesis of A Nucleoside and A Phosphonate Analogue Construc‐
ted on A Branched-threo-tetrofuranose Skeleton
Y.B. Kiran, Hideaki Wakamatsu, Yoshihiro Natori, Hiroki Takahata, Yuichi
Yoshimura
PII:
S0040-4039(13)00830-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.062
TETL 42962
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 April 2013
11 May 2013
14 May 2013
Please cite this article as: Kiran, Y.B., Wakamatsu, H., Natori, Y., Takahata, H., Yoshimura, Y., Design and
Synthesis of A Nucleoside and A Phosphonate Analogue Constructed on A Branched-threo-tetrofuranose Skeleton,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.062
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Design and Synthesis of A Nucleoside and A
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Y. B. Kiran, Hideaki Wakamatsu, Yoshihiro Natori, Hiroki Takahata* and Yuichi Yoshimura*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Design and Synthesis of A Nucleoside and A Phosphonate Analogue Constructed on
A Branched-threo-tetrofuranose Skeleton
Y. B. Kirana , Hideaki Wakamatsu a , Yoshihiro Natori a , Hiroki Takahata a,  and Yuichi Yoshimura a, 
aFaculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University
4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of a novel nucleoside phosphonate constructed on a branched-threo-tetrofuranose
scaffold, as a potential antiviral agent, is described. The pseudosugar moiety served as the
nucleoside skeleton was produced starting from 2-butyne-1,4-diol in 10 steps. Glycosylation
with the pseudosugar involved stereoselective neighboring group participation of p-anisyl group
and gave the nucleoside derivative in 94% yield. After manipulating the protecting group and
introduction of a methylenephosphate unit, the synthesis of the target novel cytidine
phosphonate was achieved. The resulting nucleoside, a synthetic intermediate of the nucleoside
phosphonate, would also be expected to serve as a useful building block for the synthesis of
novel antisense/antigene derivatives.
Available online
Keywords:
nucleoside
nucleoside phosphonate
nucleotide
glycosylation
antiviral
2009 Elsevier Ltd. All rights reserved.
Drug development based on nucleosides/nucleotides has resulted in
the development of various medicines, the most typical examples of
which are antimetabolites for use in combatting cancer and viruses.
To date, a wide variety of antitumor, antiherpes and anti-HIV drugs
based on nucleoside analogues are approved and used in the clinic.1
Also drug development focused on antisence, antigene, aptamer and
RNAi has long been a subject of interest. These “nucleic acid
medicines” are highly attractive since they can directly suppress or
block transcription and the action of proteins that cause diseases.2
However, many problems remain to be solved before the widespread
use of nucleic acid medicines is to be achieved. This impedes the
development of nucleic acid medicines. As a result, only a few
nucleic acid-based drugs have been approved and their uses are
limited to topical treatment.3 One such problem to be overcome is
the instability of oligo(deoxy)nucleotides (ONs) in serum due to the
nuclease-catalyzed hydrolysis of the phosphodiester linkage. To
avoid this problem, ONs containing modified nucleotide units are
frequently used.4 From these points of view, it is obvious that a study
of the synthesis of nucleoside derivatives with emphasis on structural
novelty would greatly contribute to the development of nucleic acid
medicines as well as nucleoside antimetabolites. As part of our
ongoing studies related to the synthesis of nucleoside derivatives,5
we were prompted to consider a nucleoside phosphonate constructed
on a novel nucleoside skeleton. Nucleoside phosphonates are
promising as antiviral agents. They can bypass the conversion of
nucleosides to active triphosphate forms since nucleoside
phosphonate derivatives are able to skip the first phosphorylation
step. An alkylphosphate unit in their structure mimics a phosphate
moiety, which permits them to act as a nucleoside monophosphate.6
In this study, we report on the synthesis of a nucleoside derivative 1
bearing a branched-threo-tetrofuranose scaffold as a pseudosugar
moiety and a nucleoside phosphonate derivative 2 obtained from 1.
The nucleoside phosphonate 2 is promising as an anti-HIV agent
since it is structurally similar to PMDTA,7 a known anti-HIV
nucleoside phosphonate. In addition, the nucleoside derivative 1 has
primary and secondary hydroxyl groups in appropriate positions of
Figure 1: Structures of nucleoside 1 constructed on a branched-
threo-tetrofuranose scaffold and nucleoside phosphonate 2.
———
 Corresponding author. Tel.: +81-22-727-0145; fax: +81-22-275-2013; e-mail: yoshimura@tohoku-pharm.ac.jp

2
Tetrahedron
the sugar moiety and might serve as a useful building block, e.g. 3,
bis(trimethylsilyl)uracil in the presence of TMSOTf gave a mixture
of 12a and 12b in 53% yield as an anomeric mixture in a ratio of
10:1 to 12a : 12b (Scheme 1).
to create a novel antisense and antigene ONs (Figure 1). This
characteristic structure of nucleoside phosphonate 2 is also unique as
a mimic of cidofovir, an anti-HCMV drug (vide infra).
Our first attempt to synthesize a nucleoside derivative 1 having a
branched-threo-tetrofuranose skeleton started from 2-butyne-1,4-diol
(4) and was intended to produce 1 as a racemic mixture. The
reduction of 4 with lithium aluminum hydride under standard
conditions8 gave the (E)-butenediol 5 which was silylated at one
primary hydroxyl group to give a mono alcohol 6. The epoxidation
of 6 by treatment with mCPBA afforded the epoxide 7 in good yield.
To construct the pseudosugar skeleton, it was necessary to introduce
a C1 unit equivalent to an aldehyde into 7. This was achieved by
The fact that the glycosylation gave a mixture of products in
moderate yield prompted us to modify the synthetic route to the
target nucleoside in order to find a more efficient glycosylation
reaction. To complete this task, we intended to introduce a more
electron-donating acyl group at the primary hydroxyl group of the
pseudosugar donor, by which the effect of neighboring group
participation would be enhanced to stabilize the intermediate for the
glycosylation reaction11 (vide infra). Compound 8 was selectively
acylated with a p-anisyl group at the primary hydroxyl group to give
the p-anisyl derivative 13. Following the synthetic scheme described
above, the p-anisyl derivative 13 was converted into the pseudosugar
donor 16 in 4 steps. The glycosylation of 16 using the Vorbrüggen
method10 gave the nucleoside derivative 17 as a single isomer in 94%
yield (Scheme 2).12 It is noteworthy that yield and selectivity were
both improved as we expected.
nucleophilic
attack
of
an
anion
generated
from
di(thiophenyl)methane. Lithiation of di(thiophenyl)methane by
treatment with n-butyllithium produced the corresponding anion
which, on reaction with 7, gave the diol derivative 8 in 57%. The
nucleophilic attack of the anion occurred selectively from the less
hindered side and gave 8 as a single isomer. The diol portion of 8
was protected by introducing a benzoyl group and the resulting crude
Scheme 2: Modified synthesis of
a nucleoside derivative
constructed on a branched-threo-tetrofuranose scaffold.
From the results mentioned above, a proposed mechanism for the
glycosylation reaction is shown in Scheme 3. In both of the reaction
from the pseudosugar donors 11 and 16, the reaction with TMSOTf
generates the oxocarbenium ion 18. In addition, the neighboring
Scheme 1: Synthesis of a nucleoside derivative constructed on
a branched-threo-tetrofuranose scaffold.
product was subsequently treated with p-TsOH to remove the TBS
group giving the dibenzoate 9. Conversion of the
di(thiophenyl)methyl unit to an aldehyde was achieved by reacting 9
with NBS9 to spontaneously form a hemiacetal structure giving 10 in
excellent yield. Acetylation of 10 in pyridine gave the pseudosugar
donor 11 which was subjected to the glycosylation reaction under
Scheme 3: Postulated reaction mechanism of glycosylation
reaction.
Vorbrüggen
conditions.10
Treatment
of
11
with

3
group participation of the acyl group would form the cyclic
acyloxonium ion 19. It is clear that 18 and 19 are in equilibrium with
each other and that 19 would be the more stabilized form.11 When
silylated uracil only reacts with 18, the reaction gives a mixture of
anomers. On the other hand, the reaction of 19 with silylated uracil
This unstable intermediate was quickly treated with sodium
ethoxide to give the deprotected 4-ethoxypyrimidone derivative 20.
After again protecting the primary hydroxyl group with a TBDPS
group, the resulting 21 was assembled by the reaction with diethyl
[(trifluoromethanesulfonyl)oxy]methanephosphonate and LHMDS14
to give the phosphonate 22 in 86% yield. After deprotection of the
silyl group, the conversion of 22 to a cytosine derivative via reacting
it with methanolic ammonia at 100 ºC in a sealed tube gave
compound 24, one ethyl group of which was unexpectedly
deprotected. Finally, deprotection of remaining ethyl group by
treatment with TMSI gave the desired cytidine phosphonate 25 in
good yield (Scheme 4).
would exclusively give one isomer having
a
1’,2’-trans
stereochemistry. In the case of 11, the reaction predominantly gave
12a with only minor amounts of 12b being formed. This result
suggests that the oxocarbenium ion 18 partly contributes, although
most of the reaction proceeds through 19. To realize a further shift in
the equilibrium toward 19, the more electron-donating p-anisyl group
was introduced, as described above. Indeed, the reaction of 16 gave
the nucleoside 17 as the sole product, which is consistent with our
proposed mechanism (Scheme 3).
In conclusion, we report on the design and synthesis of a novel
nucleoside constructed on a branched-threo-tetrofuranose skeleton
which has the potential to serve as a useful nucleotide building block
for synthesizing novel ONs for antisense and antigene applications.
As a demonstration of its synthetic usefulness, we also synthesized a
new cytidine phosphonate 25 from the obtained nucleoside. It is
interesting to note that the cytidine phosphonate 25 has a unique
structure that is analogous to cidofovir15 as well as PMDTA7 and
would be expected to have promise for use as an antiviral agent.
Biological evaluations of 25 are currently in progress and the results
will be reported elsewhere.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research (No. 24590143, Y.Y.) from JSPS and by a grant of
Strategic Research Foundation Grant-aided Project for Private
Universities from Ministry of Education, Culture, Sport, Science,
and Technology, Japan (MEXT), 2010-2014.
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Scheme 4: Synthesis of nucleoside phosphonate 25.
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a 4-ethoxypyrimidone derivative in
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4
Tetrahedron
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