Concise synthesis of thiophene C -nucleoside analogues bearing sugar residues and aromatic residues through dimerization and sulfur heterocyclization of sugar alkynes and substituted iodoethynylbenzene

Article abstract of DOI:10.1039/c9ob02717c

The synthesis of thiophene C-nucleoside analogues bearing sugar residues (mono- and disaccharides) and aromatic residues has been achieved by symmetric dimerization of terminal sugar alkynes or unsymmetric dimerization of terminal sugar alkynes and substi

Full text of DOI:10.1039/c9ob02717c

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DOI: 10.1039/C9OB02717C
ARTICLE
Concise synthesis of thiophene C-nucleoside analogues
bearing sugar residue and aromatic residue through
dimerization and sulfur heterocyclization of sugar
alkynes and substituted iodoethynylbenzene
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Xiang Zhou,a Tongtong Jia,a Yang Luo,a Hong Liu,*a Fuyi Zhang,*a Yufen Zhaoa,b
The synthesis of thiophene C-nucleoside analogues bearing sugar residue (mono- and disaccharides) and
aromatic residue has been achieved by symmetric dimerization of terminal sugar alkynes or unsymmetric
dimerization of terminal sugar alkynes and substituted iodoethynylbenzene followed by sulfur heterocyclization in
one pot. Homocoupling of terminal sugar alkyne and subsequent sulfur heterocyclization produce thiophene C-
nucleoside analogues bearing disaccharides. Unsymmetric dimerization of terminal sugar alkyne and substituted
iodoethynylbenzene followed by sulfur heterocyclization give those bearing monosaccharide and aromatic
residue. This approach is concise, general and mild, which is suitable for structurally diversified pyranosides,
furanosides, and acyclic sugars. Thirty-two examples have been given and the corresponding products are
obtained in moderate to excellent yields.
derived respectively from 1 were found to be an inhibitor of
recombinant human inosine 5’-monophosphate dehydrogenase
(IMPDH) type I and II.7 Compound 2 showed remarkable inhibitory
activity against hSGLT2 (IC50 = 4.0 nM) and good rat UGE effect
(1381 mg/d).8
Introduction
The therapeutic effect of nucleoside analogues largely depends on
their stability in organism, because their catabolism usually includes
degradation of nucleosidic linkage. C-Nucleoside analogues
including “reversed” or “iso-” C-nucleoside ones with an aromatic or
heteroaromatic moiety directly attached to the carbohydrate through
a C-C bond, different from the usual N-nucleosides or O-glycosides,
result in better stability to both acidic and enzymatic hydrolysis,
while preserving excellent biological efficacy.1 These C-nucleoside
analogues exhibit interesting biological activities. They have proven
to be efficient antibiotics,2 antitumor agents,3 and inhibitors for
diabetes.4 Figure 1 shows two typical thiophene C-nucleoside
analogues. Thiophenfurin 15 is a good antitumor agent. It can inhibit
the growth of K562 human erythroid leukaemia and LoVo human
colon adenocarcinoma, and exhibits substantial activity in vivo
against L1210 leukaemia. Thiophenfurin also possesses good
selectivity towards tumour cells in vitro and high-level of conversion
to its dinucleotide form.6 Dinucleotides TFAD, FFAD, and SFAD
CONH2
Cl
HO
S
OH
O
S
O
HO
HO
OH
Et
OH
OH
2
1
Figure
1 Examples of thiophene C-nucleoside analogues
possessing biological activities.
Several thiophene C-nucleosides and their analogues were
obtained during the synthesis of aryl C-nucleosides or ary C-
glycosides (Figure 2). A mixture of thienyl α- and β-C-nucleosides
were obtained by the reaction of protected D-ribose with lithium salt
of thiophene followed by intramolecular cyclisation of the
corresponding 1,4-diols under Mitsunobu conditions,9 or catalyzed
a. X. Zhou, T.-T. Jia, Y. Luo, Prof. H. Liu, Prof. Dr. F. Zhang
College of Chemistry
The Key Lab of Chemical Biology and Organic Chemistry
Zhengzhou University
Zhengzhou, Henan 450052 (China)
E-mail: zhangfy@zzu.edu.cn
b. Prof. Dr. Y. Zhao
Institute of Drug Discovery Technology
Ningbo University
Ningbo 315211, China
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
10
by Yb(OTf)3 and p-TsOH11. Lemaire group synthesized 2-thienyl
β-D-glucopyranoside by the reaction of perpivaloylated
glucopyranosyl bromide with thienylzinc in toluene/n-dibutyl ether
during the synthesis of C-aryl glycosides,12 and later they
synthesized 2- and 3-thienyl α-D-glucopyranoside via syn opening of
perpivaloylated 1,2-anhydroglucal with thienylzinc.13 This group
prepared 2- and 3-thienyl β-isomers using perpivaloylated α-D-
glucopyranosyl bromide reacting with thienylzinc or thienylzinc
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ARTICLE
Journal Name
bromide, during the study of Friedel−Crafts fashion substitution of in one pot, thus affording thiophene C-nucleoside analogues having
View Article Online
glucoside bromide and arylzinc reagents.14 Lee and his coworkers two sugars. Sugar alkyne 3a (scheme 1) having two acidic sensitive
DOI: 10.1039/C9OB02717C
synthesized substituted thienyl β-C-glucopyranosides by lithium and sterically hindered isopropylidene was employed to explore this
halogen exchange of iodothiophene or bromothiophene derivatives synthetic method, and the conditions for dimerization of 3a and
followed by the addition of a lithiated thiophene derivatives to sulfur heterocyclization of 4a were optimized respectively. Initially,
gluconolactone to yield lactols, which were reduced by various reaction conditions for dimerization of 3a were examined.
Et3SiH/BF3·OEt2 and deprotected.15 Some compounds showed When the homocoupling of 3a was carried out under Eglington
inhibitory activities in vitro against SGLT2. Imamura16 and conditions in the presence of copper(II) acetate in pyridine (Table 1,
Migaud17 employed the similar strategy to synthesize 2-(4- entry 1),23 the disaccharides 1,3-butadiyne 4a was not obtained and
methoxybenzyl)-4-thienyl β-C-glucopyranoside and 2-cyano-5- most of starting material 3a was recovered except a small amount of
thienyl C-nucleoside from D-gluconolactone and D-ribonolactone, decomposition. When the Hay coupling conditions24 were applied to
respectively. Gagné also obtained a mixture of thienyl α- and β-D- 3a with O2 in the presence of catalytic amounts of bidentate ligand
glucopyranoside by Ni(COD)2/tBu-Terpy catalyzed coupling of TMEDA and copper(I) chloride (entry 2), yield of 4a was low and
acetyl protected α-D-glucopyranosyl bromide with thienylzinc many side products were present. The Sonogashira coupling
halide·LiCl (halide = Br, I).18 Recently, Molander reported the conditions were then used for this homocoupling.25 The influence of
general synthesis of “reverse” aryl C-glycosides and used this various factors on the homocoupling of 3a was investigated. When
method to synthesize
two “reverse” thiophene C-nucleoside the reaction was performed in CH3CN and Et2NH at rt using
analogues via Ni/photoredox dual catalysis and dihydropyridyl PdCl2(PPh3)2/CuI as catalysts, 4a was produced in 66% yield (entry
saccharide motifs as radical precursors.19 However, the available 3). The change of base Et2NH to Et3N improved the reaction(entries
methods and strategies are restricted to very few sugar substrates. 4-7). When the reaction was carried out in CH3CN and Et3N, 4a was
Thiophene C-nucleoside analogues remain sparse, and they were afforded in 73% yield (entry 4). THF is superior to CH3CN, giving
usually obtained incidentally in the synthesis of aryl C-glycosides. 4a in 85% yield (entry 5). The change of solvent to DMF largely
The development of a general, modular, and simple synthetic improved the dimerization. The dimer 4a was obtained in 93% yield
method remains an unsolved challenge, especially the methods that at rt in the presence of 2 mol% of PdCl2(PPh3)2 and CuI each in
would preserve the anomeric carbon to produce nonclassical, DMF and Et3N (entry 6). Increasing the temperature caused the
“reversed” or “iso-” C-nucleoside analogues are particularly scarce, decrease of the yield (entry 7).
although they may have increased enzymatic stability and exhibit
attractive biological properties. In continuation of our interest in the
O
O
syntheses of biologically active carbohydrate analogues20 and C-
O
O
O
Dimerization conditions
substituted sugar analogues,21 herein, we present the synthesis of
thiophene C-nucleoside analogues bearing sugar residue (mono- and
disaccharides) and aromatic residue through sequential reactions in
one pot.
O
O
O
O
O
O
O
O
O
3a
O
O
4a
generated in situ
O
O
O
Heterocyclization conditions
O
O
S
O
O
O
OPg
O
OPg
O
5aa
O
(1)
n
n
Li
1.
2.
S
11
Ref. 9
Scheme
bearing disaccharides 5aa
1 Synthesis of thiophene C-nucleoside analogues
OH
(2) PPh3/DEAD,
or [M] Cat., or p
TsOH (OPg)m
S
(OPg)m
OPg
O
OPg
O
OPg
O
Br
OPg
O
S
S
(1)
, n BnLi
S
O
14
Ref. 12
(2) [M] Cat.
m(PgO)
m(PgO)
Table 1 Dimerization of 3a to form 4aa
(OPg)m
m(PgO)
OPg
O
R
OPg
O
(1)
, base
n
n
3.
4.
S
17
Ref. 15
(2) Et3SiH
Dimerization conditions
O
(OPg)m
S
R
3a
(OPg)m
O
4a
Solvent
PgO
O
PgO
R
Entry
catalyst
Base
T
Yield
NiBr2, dme
Ligand
R
O
Ref. 19
O
+
O
(°C) (%)b
S
DHP
Br
S
O
1
2
3
Cu(OAc)2
CuCl
Pyridine
TMEDA acetone
60
50
rt
-
Figure 2 Previous methods for the synthesis of thiophene C-
48
66
nucleoside
analogues.
PdCl2(PPh3)2,
CuI
Et2NH
Et3N
Et3N
Et3N
Et3N
CH3CN
CH3CN
THF
4
5
6
7
PdCl2(PPh3)2,
CuI
rt
73
85
93
89
Results and discussion
PdCl2(PPh3)2,
CuI
rt
Because the coupling of terminal alkyne is a useful reaction and is
tolerant of many functional groups to construct molecules,22 we
envisioned the dimerization of the terminal sugar alkyne and
subsequent sulfur heterocyclization of the corresponding
disaccharides 1,3-butadiyne generated in situ to form thiophene ring
PdCl2(PPh3)2,
CuI
DMF
rt
PdCl2(PPh3)2,
DMF
60
2 | J. Name., 2012, 00, 1-3
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CuI
Nucleophilic attack of Na2S on 4a followed by absVtrieawctAiortincleoOfnlHine+
aReaction conditions: 0.6 mmol of 3a, 0.6 mmol of Cu(OAc)2, 3 ml of
Pyridine, 0.03 mmol of CuCl and TMDEA each, 5 ml of acetone, 0.012
mmol of PdCl2(PPh3)2 and CuI each, 3 ml of CH3CN and THF each, 1.5 ml of
DMF, 0.5 ml of Et2NH and Et3N each. bIsolated yield.
DOI: 10.1039/C9OB02717C
from H2O yields 7a. Intermediate 7a undergoes intramolecular
nucleophilic cyclisation reaction and then abstraction of H+ from
H2O to form the desired product 5aa.
PPh3
The next task was to explore the method for heterocyclization of
4a to 5aa. Cyclization of alkynes have been applied in the synthesis
of various heterocyclic compounds with high-atom efficiency,26 but
were usually performed in the presence of strong acid or lewis acid
at high temperature. These reaction conditions were unsuitable for
disaccharides 1,3-butadiynes due to their instability in acidic
medium, especially at high temperature. Therefore, heterocyclization
of disaccharides 1,3-butadiyne 4a using different types of sulfur
sources were examined in neutral or basic medium. When 4a was
treated by H2S gas/NaOH in MeOH, a trace of 5aa was produced
(Table 2, entry 1). NaHS and Na2S were then employed as sulfur
sources. The heterocyclization of 4a with NaHS didn’t produce 5aa
PdCl2(PPh3)2
Sugar
3a
+
+
Sugar
Et3N CuI
Cu
Sugar
Pd
Sugar
5a
PPh3
6a
Et3NHI
CuCl
S-
Sugar
OH
S2-
Sugar
HO
Sugar
Sugar
5aa
H
H
Pd(PPh3)2
7a
4a
Scheme 2 The proposed mechanism for the formation of 5aa
from 3a.
After finishing optimization studies, attempts to perform the
dimerization of 3a and sulfur heterocyclization of the intermediate
4a in one pot was successful. Specifically, when the dimerization of
3a was finished under optimal conditions, the mixture was filtered
by diatomaceous earth. The solution of mother liquid, Na2S·9H2O
and KOH was heated under optimal conditions to give 5aa in 88%
yield (Table 3, entry 1). This one-pot approach was also successfully
applied to the synthesis of thiophene C-nucleoside analogues bearing
monosaccharide by unsymmetric dimerization of terminal sugar
alkynes and iodides followed by sulfur heterocyclization. When 3a
was employed to couple with iodoethynylbenzene, 1-iodoethynyl-4-
methylbenzene, and 1-fluoro-4-iodoethynylbenzene followed by
sulfur heterocyclization, respectively, the corresponding products
5ab, 5ac, and 5ad were given in 73%, 80% and 70% yields (Table 3,
entry 1). The electron-donating CH3 is superior to the electron-
withdrawing F, giving 5ac in higher yield. The yields of the
compounds 5ab, 5ac, and 5ad having monosaccharide were lower
than 5aa bearing disaccharides due to the side reaction of
homocoupling of sugar alkyne 3a and homocoupling of iodides.
To examine the scope and generality of this synthetic method and
to synthesize more thiophene C-nucleoside analogues, the
structurally diversified terminal sugar alkynes were employed to
perform this one-pot procedure. The results were shown in Table 3.
The pyranosides 3a, 3b, and 3c gave the corresponding thiophene C-
nucleoside analogues in moderate to excellent yields (entries 1-3). 3c
afforded 5ca in 91% yield, which is higher than the products 5aa and
5ba, probably due to that the benzyl protected sugar is more stable
than the isopropylidene protected ones, thus resisting the
decomposition. Next, the scope of substrates was expanded to
furanosides such as 3d, 3e, 3f, and 3g. The corresponding products
were obtained in 65%-90% yields. 3g was superior to the other
furanosides, giving the corresponding products in higher yields.
When the scope was extended to acyclic sugars such as 3h and 3i,
the corresponding products were produced in 68-80% yields. In
general, the yields of thiophene C-nucleoside analogues bearing
disaccharides are higher than those of the ones having
0
in DMF at rt. Increasing the temperature to 80 C gave a trace of
product, but KOH promoted the reaction, giving 5aa in 55% yield
(entries 2-4). The change of solvent to DMSO and THF didn’t
improve the reaction (entries 5-6). When the heterocyclization with
Na2S·9H2O was carried out in DMF, no desired product 5aa was
obtained (entry 7), which is similar to the case of NaHS. However,
the presence of KOH led to 5aa in 90% yield (entry 8). The change
of solvent to DMSO gave the similar result (entry 9). The other
solvents such as Dioxane, THF, and MeOH are inferior to DMF or
DMSO, resulting in 5aa in 40-55% yields (entries 10-12).
Table 2 Sulfur heterocyclization of 4a to 5aa under various
conditionsa
Heterocyclization conditions
4a
5aa
Entry
sulfur
Base
Solvent
T (°C) Yield
(%)b
reagent
1
H2S gas
NaOH
MeOH
DMF
reflux
rt
trace
-
2
NaHS
3
NaHS
DMF
80
trace
55
50
45
-
4
NaHS
KOH
KOH
KOH
DMF
80
5
NaHS
DMSO
THF
80
6
NaHS
reflux
60
7
Na2S·9H2O
Na2S·9H2O
Na2S·9H2O
Na2S·9H2O
Na2S·9H2O
Na2S·9H2O
DMF
8
KOH
KOH
KOH
KOH
EtOH
DMF
60
90
85
40
53
55
9
DMSO
Dioxane
THF
60
10
11
12
60
60
MeOH
reflux
aReaction conditions: 0.40 mmol of 4a, 1.0 mmol of sulfur reagent (except
H2S gas), 0.80 mmol of NaOH, 0.12 mmol of KOH, 2 ml of solvent. bIsolated
yield.
A plausible mechanism for the formation of 5aa from 3a is
proposed as shown in Scheme 2. The reaction of 3a with CuI in the
presence of Et3N gives intermediate 5a. Then the substitution
reaction of Pd(Ⅱ) with 5a occurs to afford bis-(triphenylphosphine)
dialkynylpalladium 6a and CuCl. Intermediate 6a undergoes
reductive elimination to produce disaccharides 1,3-diyne 4a.
1
monosaccharides. All the products were characterized by H NMR,
13C NMR, DEPT-135, 2D NMR, HRMS, and IR.
Table 3 Synthesis of structurally diversified thiophene C-
nucleoside analogues bearing sugar residue (mono- and
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disaccharides) and aromatic residue a.
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OCH3
DOI: 10.1039/C9OB02717C
O
O
S
O
O
Sugar
3a 3i
O
Pd(PPh3)2Cl2, CuI, Et3N, DMF, rt,
then Na2S 9H2O, KOH, 60 0
O
-
C
OCH3
or
5ea
: 3.0 h, 70%
Sugar(Ar)
Sugar
S
Ar
Sugar
3a 3i
I
+
OCH3
O
5aa 5ib
-
-
5
O
S
O
O
R2
R1
Entry
Terminal sugar alkynes
Product, Time, Yieldb
O
O
OCH3
O
5eb
5ec
5ed
: R1 = H, R2 = H, 3.5 h, 66%
: R1 = CH3, R2 = H, 3.0 h, 70%
: R1 = H, R2 = F, 4.0 h, 65%
3e
O
O
O
O
O
S
O
O
O
O
5aa
: 2.5 h, 88%
O
O
O
O
O
S
O
O
O
O
O
OCH3
H3CO
O
5fa
O
S
1
: 2.5 h, 78%
O
O
O
O
3a
S
O
R
5ab
5ac
5ad
R2
: R = H, 3.5 h, 73%
O
O
6
O
O
: R = CH3, 3.0 h, 80%
: R = F, 4.0 h, 70%
O
R1
H3CO
OCH3
5fb
: R1 = R2 = H, 3.5 h, 68%
3f
O
5fc
5fd
5fe
: R1 = CH3, R2 = H, 3.0 h, 70%
: R1 = F, R2 = H, 3.5 h, 65%
: R1 = H, R2 = F, 3.5 h, 65%
O
O
O
S
O
O
O
O
O
O
2
BnO
O
O
5ba
: 2.5 h, 85%
O
OBn
S
O
O
O
O
O
O
O
5ga
O
O
: 2.5 h, 90%
O
3b
R2
R1
S
OBn
O
O
S
OBn
O
R2
7
O
O
O
O
5bb
5bc
5bd
: R1= R2 = H, 3.5 h, 69%
: R1 = CH3, R2 = H, 3.0 h, 75%
: R1 = H, R2 = F, 4.0 h, 69%
O
R1
O
3g
5gb
5gc
5gd
: R1 = R2 = H, 3.5 h, 72%
: R1 = F, R2 = H, 3.5 h, 70%
: R1 = H, R2 = F, 3.5 h, 70%
BnO
BnO
O
OCH3
OBn
OH
S
H
O
O
BnO
H3CO
BnO
O
BnO
O
O
3
BnO
BnO
5ca
: 2.5 h, 91%
S
O
O
BnO
O
H
OH
BnO
OCH3
OBn
H
3c
O
8
O
5ha
OH
S
: 3.0 h, 76%
O
BnO
OH
O
O
O
O
H
5cb
O
: 3.5 h, 75%
H3CO
3h
O
S
O
O
O
5hb
: 4.0 h, 68%
O
S
O
4
O
O
O
O
O
O
O
TrO
S
O
OH
OH
5da
: 3.0 h, 71%
O
O
9
3d
TrO
O
OH
5ia
: 3.0 h, 80%
S
O
R2
TrO
O
O
O
R1
S
3i
OH
O
5db
5dc
5dd
5de
: R1 = R2 = H, 3.5 h, 70%
O
: R1 = CH3, R2 = H, 3.0 h, 75%
: R1 = F, R2 = H, 4.0 h, 70%
: R1 = H, R2 = F, 4.0 h, 70%
5ib
: 4.0 h, 72%
TrO
aReaction condition: 0.60 mmol of sugar alkyne, 0.72 mmol of
iodoethynylbenzene, 0.012 mmol of PdCl2(PPh3)2 and CuI each, 0.5 ml of
Et3N, 1.5 ml of DMF, 1.5 mmol of Na2S·9H2O, 0.18 mmol of KOH.
bIsolated yield.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9OB02717C
Conclusions
Notes and references
In summary, we report the synthesis of thiophene C-nucleoside
analogues having sugar residue (mono- and disaccharides) and
aromatic residue by symmetric dimerization of terminal sugar alkyne
or unsymmetric dimerization of terminal sugar alkyne and iodode
followed by sulfur heterocyclization in one pot. Homocoupling of
terminal sugar alkyne and subsequent sulfur heterocyclization
produce thiophene C-nucleoside analogues with disaccharides.
Unsymmetric dimerization of terminal sugar alkyne and iodide
followed by sulfur heterocyclization gives thiophene C-nucleoside
analogues with monosaccharides. The synthetic approach was
concise, simple, and general. The structurally diversified substrates
which include pyranosides, furanosides, and acyclic sugars have
been examined. 32 examples have been given and the corresponding
products are given in moderate to excellent yields.
1
Selected reviews: (a) D. Lee, M. He, Curr. Top. Med. Chem.,
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Goyard, M. Tóth, J.-P. Praly, S. Vidal, L. Somsák, Chem. Rev.,
2017, 117, 1687-1764.
(a) U. Hacksell, G. D. Daves, Progress in Medicinal Chemistry,
Elsevier, Amsterdam, 1985, Vol. 22, 1–65; (b) J. G. Buchanan,
Progress in the Chemistry of Organic Natural Products,
Springer, New York, 1985, 44, 243-285.
Selected examples: (a) T. Hosoya, E. Takashiro, T. Matsumoto,
K. Suzuki, J. Am. Chem. Soc., 1994, 116, 1004–1015; (b) K. A.
Parker, Y. Koh, J. Am. Chem. Soc., 1994, 116, 11149–11150; (c)
X. Cai, K. Ng, H. Panesar, S.-J. Moon, M. Paredes, K. Ishida, C.
Hertweck, T. G. Minehan, Org. Lett., 2014, 16, 2962–2965.
(a) S. A. Jabbour, B. J. Goldstein, Int. J. Clin. Pract., 2008, 62,
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2
3
4
Experimental Section
General
Commercially available reagents were used without purification.
Commercially available solvents were dried by standard procedures
prior to use. Nuclear magnetic resonance spectra were recorded on a
400 MHz spectrometer, and the chemical shifts are reported in δ
units, parts per million (ppm), relative to residual chloroform (7.28
ppm) in the deuterated solvent. The following abbreviations were
used to describe peak splitting patterns when appropriate: s = singlet,
d = doublet, t = triplet, dd = doublet of doublets, and m = multiplet.
Coupling constants, J, are reported in hertz (Hz). The 13C NMR
spectra are reported in ppm relative to CDCl3 (77.0 ppm).
5
6
7
8
9
General procedure for the synthesis of 5aa-5ib:
A mixture of sugar alkyne (0.60 mmol), or sugar alkyne (0.60 mmol)
and iodoethynylbenzene (0.72 mmol), PdCl2(PPh3)2 (0.012 mmol),
CuI (0.012 mmol), Et3N (0.5 mL) and DMF (1.5 mL) was stirred
under air atmosphere at rt until TLC indicated the disappearance of
sugar alkyne. The mixture was filtered by diatomaceous earth.
Na2S·9H2O (1.5 mmol) and KOH (0.18 mmol) was added to the
mother liquid, and the solution was heated at 60 0C until TLC
showed the completion of the reaction. Then it was evaporated to
dryness and the residue was dissolved in EtOAc (25 mL), washed
with water (2×5 mL) and brine (5 mL), dried over Na2SO4 and
evaporated to dryness. The residue was purified by column
chromatography to give the desired products.
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Conflicts of interest
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There are no conflicts to declare.
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We gratefully acknowledge the National Natural Science Foundation
of China (No. 21772180, 21272219) for financial support.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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Organic & Biomolecular Chemistry
Concise synthesis of thiophene C-nucleoside analogues bearing sugar residue and aromatic residue througVhiew Article Online
DOI: 10.1039/C9OB02717C
dimerization and sulfur heterocyclization of sugar alkynes and substituted iodoethynylbenzene
Xiang Zhou, Tongtong Jia, Yang Luo, Hong Liu, Fuyi Zhang and Yufen Zhao
The synthesis of thiophene C-nucleoside analogues bearing mono- and disaccharides has been achieved by symmetric dimerization of
terminal sugar alkynes or unsymmetric dimerization of terminal sugar alkynes and substituted iodoethynylbenzene followed by sulfur
heterocyclization in one pot.
Pd(PPh3)2Cl2, CuI, Et3N, DMF, rt,
Sugar
then Na2S 9H2O, KOH, 60 0
C
or
Sugar(Ar)
Sugar
S
Sugar
Ar
I
+
broad substrate scope, 32 examples
mild conditions
good functionality compatibility