A convenient synthesis and biological evaluation of novel pseudonucleosides bearing a thiazolidin-4-one moiety by tandem Staudinger/aza-Wittig/cyclization

Article abstract of DOI:10.1002/ejoc.200900863

Novel pseudonucleosides 3 and 4 bearing a thiazolidin-4-one moiety were firstly synthesized by a one-pot, multicomponent, tandem Staudinger/aza-Wittig/ intermolecular nucleophilic addition/intramolecular cyclization process in good, yields of 43.8-88.0%.

Full text of DOI:10.1002/ejoc.200900863

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900863
A Convenient Synthesis and Biological Evaluation of Novel Pseudonucleosides
Bearing a Thiazolidin-4-one Moiety by Tandem
Staudinger/Aza-Wittig/Cyclization
Hua Chen,[a] Hongzhi Zhang,[a] Junna Feng,[a] Xiaoliu Li,*[a,b] Lingling Jiao,[a]
Zhanbin Qin,[a] Qingmei Yin,[a] and Jinchao Zhang[a]
Keywords: Pseudonucleosides / Heterocycles / Wittig reactions / Biological activity
Novel pseudonucleosides 3 and 4 bearing a thiazolidin-4-one
moiety were firstly synthesized by a one-pot, multicompo-
nent, tandem Staudinger/aza-Wittig/intermolecular nucleo-
philic addition/intramolecular cyclization process in good
yields of 43.8–88.0%. Deacetylation of 3 and 4 afforded com-
pounds 5 and 6, respectively. The structures of the new com-
pounds were determined on the basis of the X-ray crystal
structures of 3b and 3e and by 1H and 13C NMR spectroscopy
and high-resolution mass spectrometry. The antitumor ac-
tivity and the inhibitory activities against glycosidases and
HIV reverse transcriptase of 5 and 6 were also evaluated.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Analogues of natural nucleosides have been a growing
research topic in the last decade due to their highly poten-
tial value as therapeutic agents for the treatment of many
infectious diseases and tumors.[1] In the search for more ef-
fective anti-infective and antitumor agents, various chemi-
cal modifications of nucleosides have been proposed to im-
prove their biological activities. One of the successful ways
is to replace the natural pyrimidine or purine base with het-
erocycles that can form H-bonds with the natural nucleo-
side, such as thiazoles, imidazoles, triazoles, triazines, and
so on.[2] For instance, the compounds shown in Figure 1
have good antitumor and antiviral activities. These promis-
ing biological results demanded to synthesize such potent
pseudonucleosides and to meet the ever-growing require-
ments in the discovery of new drugs.
The thiazolidin-4-one ring is a core substructure in vari-
ous synthetic pharmaceuticals that are associated with di-
verse biological activities such as antibacterial, antifungal,
anticancer, antiviral, anti-inflammatory, and analgesic, cal-
cium antagonistic, and so on.[3] In the literature, most of
the synthetic thiazolidin-4-one derivatives contain aryl and/
Figure 1. Pseudonucleosides with good biological activities.
or alkyl substituents, and only a few examples bear a sugar
moiety such as pseudonucleosides have been reported.[4]
Considering the strong biological activities of thiazolidin-4-
[a] Key Laboratory of Chemical Biology of Hebei Province, Key ones, we envisaged to synthesize pseudonucleosides with a
thiazolidin-4-one moiety[4c] as a continuation of the synthe-
Laboratory of Medicinal Chemistry and Molecular Diagnosis,
Ministry of Education; College of Chemistry and
sis of functionalized glycomimics.[5]
Environmental Science,
Hebei University, Baoding 071002, China
Fax: +86-312-5971116,
E-mail: lixl@hbu.cn
Various protocols for preparing thiazolidin-4-one deriva-
tives have been developed.[3,6] Of the most conventional
methods, three-component reactions involving an amine, a
carbonyl compound, and mercaptoacetic acid have been
well documented[3,6] and have been improved by using a
condensation agent,[7] microwaves,[8] ion liquids,[8d] and
[b] State Key Laboratory of Natural and Biomimetic Drugs,
Peking University,
Beijing 100191, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900863.
6100
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6100–6103

Synthesis and Biological Evaluation of Novel Pseudonucleosides
Lewis acids or bases.[6a,8b] The three-component reaction
was carried out in a tandem process as shown in Scheme 1,
in which aldehyde IV was condensed with amine III to pro-
duce intermediate imine V, followed by intermolecular nu-
cleophilic addition with mercaptoacetic acid and then intra-
molecular cyclization via intermediate VII to afford thiazol-
idin-4-one product VIII.
Results and Discussion
Staudinger/aza-Wittig reactions are a powerful tool in
organic synthetic strategies toward constructing nitrogen-
containing heterocycles.[9] To the best of our knowledge,
there is no report of applying such reactions to the synthesis
of thiazolidin-4-one derivatives. On the basis of the success-
ful synthesis of the thiazolidin-4-one derivatives containing
a sugar moiety,[4c] we firstly investigated the one-pot tan-
dem synthesis by using methyl 6-azido-6-deoxy-2,3,4-O-tri-
acetyl-α--glucopyranoside (1)[10]and aromatic aldehydes
2a–h at room temperature. Our strategy in the one-pot syn-
thesis is in situ Staudinger/aza-Wittig reactions using an
azido sugar and aldehydes in the presence of triphenylphos-
phane, followed by the intermolecular nucleophilic addition
of mercaptoacetic acid and then intramolecular cyclization
as shown in Scheme 1. Thus, the synthesis was carried out
by stirring the mixture of sugar azide 1, triphenylphosphane
(Ph3P), and aldehyde 2 to generate the imine intermediate
via an iminophosphorane, followed by in situ reaction with
mercaptoacetic acid to afford the corresponding dia-
stereomeric thiazolidin-4-one derivatives containing a sugar
moiety, 3a–h and 4a–h, respectively, in good yields as shown
in Scheme 2 and Table 1. The results were similar to those
in a previous synthesis starting from an amino sugar by a
one-pot, three-component reaction at room temperature in
the presence of DCC;[4c] thus, this method provides a conve-
nient one-pot, multicomponent, tandem synthesis of thia-
zolidin-4-one derivatives directly from azides.
Scheme 1. One-pot tandem Staudinger/aza-Wittig reactions and
three-component synthesis of thiazolidin-4-one derivatives.
In our previous paper,[4c] we reported the synthesis of 2-
aryl-3-[5-deoxy-1,2-O-isopropylidene-α--xylofuranose-5-
C-yl]thiazolidin-4-ones by the three-component condensa-
tion of an amino sugar, an aromatic aldehyde, and mercap-
toacetic acid in the presence of N,NЈ-dicyclohexylcarbodi-
imide (DCC) and 4-dimethylaminopyridine (DMAP) at
room temperature. Because intermediate imine
V
(Scheme 1) could be conveniently prepared from azide and
aldehyde by a Staudinger/aza-Wittig reaction, which has
been successfully used in the constructions of C=N bonds
and nitrogenous heterocycles,[9] we conceived that it would
be more convenient to utilize the tandem Staudinger/aza-
Wittig reaction to generate key intermediate imine V di-
rectly from azidosugar I and aldehyde IV to give the thiazo-
lidin-4-one pseudonucleosides after intermolecular nucleo-
philic addition with mercaptoacetic acid and intramolecular
cyclization as depicted in Scheme 1. Herein we would like
to report the one-pot tandem Staudinger/aza-Wittig/inter-
molecular nucleophilic addition/intramolecular cyclization
process for the synthesis of novel thiazolidin-4-one deriva-
tives as pseudonucleosides starting from an azidosugar and
aromatic aldehydes (Scheme 2).
Table 1. Synthesis of novel pseudonucleosides bearing the thiazoli-
din-4-one moiety.
Yield [%]
Ratio of
Yield [%]
3
4
3 +4[a]
3/4[b]
5
6
a
b
c
d
e
f
31.0
31.2
36.5
27.7
25.5
45.7
43.8
30.2
25.7
22.1
26.6
16.1
34.5
27.8
44.2
32.4
56.7
53.5
63.1
43.8
60.0
73.5
88.0
62.6
1:0.8
1:0.7
1:0.7
1:0.6
1:1.4
1:0.6
1:1.0
1:1.1
88.7
96.6
84.0
99.0
68.8
89.0
90.3
79.3
83.6
70.0
74.9
98.1
71.9
81.2
95.3
98.9
g
h
1
[a] Isolated yield. [b] Determined by H NMR spectroscopy.
Scheme 2. Synthesis of 5 and 6. Reagents and conditions: (i) (a) 1 (1 equiv.), Ph3P (1.5 equiv.), 2 (1.5 equiv.), toluene (2 mL), r.t., 1.5 h;
(b) HSCH2COOH (2 equiv.), r.t., 2 h; (two steps); (ii) NaOMe/MeOH, r.t., 30 min.
Eur. J. Org. Chem. 2009, 6100–6103
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6101

H. Chen, H. Zhang, J. Feng, X. Li, L. Jiao, Z. Qin, Q. Yin, J. Zhang
SHORT COMMUNICATION
The deacetylation of diastereomers 3 and 4 was carried respectively, and the RT inhibitory activities of compounds
out effectively in sodium methoxide in methanol at room 5a–b, 6a–b, 5e, and 6e were evaluated by determining their
temperature, which provided corresponding products 5 and percentage inhibition of HIV-RT activity in HIV-RT kit by
6 in very good yields (Table 1), respectively.
comparison with AZT.[13] However, most of the tested com-
The structures of 3b and 3e were determined by single pounds did not show obvious activities. Compounds 5a and
X-ray crystallographic analysis[11] (Figure 2), which con- 5h showed weak inhibitory activity against glycosidases (9.5
firmed the new generated chiral carbon centers (C-2Ј) in and 15.9% in vitro at 25 µgmL–1 against α-amylase, respec-
both 3b and 3e to be of the (S) form. Consequently, dia- tively; 12.7 and 11.0% in vitro at 25 µgmL–1 against β-glu-
stereomers 4b and 4e should have the (R) form in the corre- cosidase, respectively), and compounds 5e and 6e showed
sponding C-2Ј. On the basis of these crystallographic struc- certain RT inhibitory activity (39.4 and 55.8% in vitro at
1
tures and by comparison of the chemical shifts in the H 25 µgmL–1, respectively). All tested compounds had no an-
NMR spectra of the protons at C-2Ј of compounds 3–6 titumor activities (IC50 Ͼ 300 µ).
(Table 2), the structures of the other compounds of 3, 5 and
4, 6 would be tentatively determined. In the NMR spectra,
the H-2Ј proton of 4 appeared upfield relative to those of
3, and the H-2Ј proton of its corresponding deacetylated
Conclusions
In conclusion, we synthesized a series of novel pseudonu-
cleosides bearing a thiazolidin-4-one moiety by a one-pot,
multicomponent tandem Staudinger/aza-Wittig/intermo-
lecular nucleophilic addition/intramolecular cyclization
process starting from azido sugars, aromatic aldehydes, and
mercaptoacetic acid at room temperature, providing a con-
venient method for constructing such thiazolidin-4-one de-
rivatives in good yields under very mild conditions. The
configurations of the diastereomers were determined by X-
ray crystallographic and NMR spectroscopic analyses. Pre-
liminary biological evaluation of the synthesized com-
pounds against glycosidases, HIV reverse transcriptase
(RT), and antitumor were carried out, and no significant
activity was observed. Further synthesis and biological
study of new pseudonucleosides with the thiazolidin-4-one
moiety are underway in this laboratory.
products 6 showed a similar chemical shift change relative
to those of 5, implying that compound 3 would have the
same (S) configuration at C-2Ј, and compound 4 would
have the (R) form. Accordingly, deacetylated products 5
and 6 should possess the (S) and (R) forms at C-2Ј, respec-
tively.
Supporting Information (see footnote on the first page of this arti-
cle): General procedures and spectroscopic data for compounds 3,
4, 5, and 6; procedures for glycosidases inhabitation, antitumor ac-
tivity assay, and in vitro HIV-RT kit assay.
Figure 2. X-ray crystallographic structures of 3b and 3e.
Table 2. The chemical shifts of H-2Ј of compounds 3, 4 and 5, 6.
δ of H-2Ј [ppm]
Acknowledgments
Financial support from the National Natural Science Foundations
of China (NSFC) (20472015 and 20672027), the Natural Science
Foundations of Hebei (2005000106 and B2008000588), the Re-
search Foundation from the Ministry of Education of China
(206013) and an open research fund of the State Key Laboratory
of Natural and Biomimetic Drugs, Peking University, is gratefully
acknowledged.
3(S)
4(R)
5(S)
6(R)
a
b
c
d
e
f
5.81
6.35
5.87
5.82
6.93
6.60
5.96
5.91
5.76
6.30
5.81
5.77
6.83
6.52
5.88
5.87
6.08
6.44
6.03
5.98
7.02
6.74
6.12
6.04
5.95
6.32
5.90
5.87
6.86
6.59
5.98
5.97
g
h
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