Microwave-assisted palladium-catalyzed cross-coupling reactions between pyranoid glycals and aryl bromides. Synthesis of 2′-deoxy C-aryl-β-glycopyranosides

Article abstract of DOI:10.1016/j.tetlet.2009.06.116

Under microwave irradiation, perbenzylated pyranoid glycals were coupled with aryl bromides in the presence of 5% mol palladium(II) acetate in dimethylformamide to produce 2′,3′-unsaturated C-aryl-α-glycopyranosides in a rapid and stereospecific manner. T

Full text of DOI:10.1016/j.tetlet.2009.06.116

Tetrahedron Letters 50 (2009) 5135–5138
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted palladium-catalyzed cross-coupling reactions between
pyranoid glycals and aryl bromides. Synthesis of 20-deoxy
C-aryl-b-glycopyranosides
*
Ming Lei, Liang Gao, Jin-Song Yang
Key Laboratory of Drug Targeting, Ministry of Education, and Department of Chemistry of Medicinal Natural Products, School of Pharmacy,
Sichuan University, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Under microwave irradiation, perbenzylated pyranoid glycals were coupled with aryl bromides in the
presence of 5% mol palladium(II) acetate in dimethylformamide to produce 20,30-unsaturated C-aryl-
a-
Received 30 March 2009
Revised 7 May 2009
Accepted 26 June 2009
Available online 2 July 2009
glycopyranosides in a rapid and stereospecific manner. The synthetic applicability of the method was fur-
ther demonstrated by converting the resulting C-aryl glycosides to 20-deoxy C-aryl-b-glycopyranosides
through oxidation mediated by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and stereoselective
reduction.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Aryl C-glycoside
Microwave
Glycal
Aryl bromide
The C-aryl glycosides, part of the general C-glycoside family, are
structurally unique carbohydrates with an aromatic moiety di-
rectly bound to the anomeric carbon.1 These compounds display
diverse biological activities, such as antibacterial, antitumor, en-
zyme inhibitory effects, and inhibition of platelet aggregation,
and they are currently attracting significant synthetic interests.
In this context, a number of synthetic methodologies for assembly
of the C-aryl glycosidic linkages have been developed to date,2 and
they can be typically classified as (a) the transition metal-mediated
coupling of glycals (1,2-unsaturated sugars) with performed aro-
matic or heterocyclic aglycons,3 (b) the electrophilic aromatic sub-
stitution of activated glycosyl donors such as glycosyl halides and
glycosyl trichloroacetimidates with aromatic species,4 (c) the Le-
wis acid-promoted O?C glycoside rearrangements,5 and (d) the
de novo construction of C-aryl glycosidic scaffold from nonsaccha-
ride precursors through cycloaddition6 or ring-closure methasis7
reaction.
Of these methods for preparing C-aryl glycosides, we thought
that the palladium-catalyzed Heck cross-coupling reaction be-
tween glycals and halogenated aromatic coupling partners de-
served to be tried, because it permits direct introduction of the
aryl moiety to the anomeric center of carbohydrate substrate to
form the C-glycosidic bond and employs readily available glycals
and aryl halides as starting materials. Previously, Daves and co-
workers reported such Heck-type coupling of furanoid and pyra-
noid glycals with iodo aglycons for the synthesis of C-nucleosides
and C-glycoside antibiotics.8 Although the viability of the reaction
was demonstrated, the reported protocols suffered from the large
excess of glycals (up to 6 equiv), the moderate stereochemical out-
come (formation of a mixture of
a/b-anomers in some cases), the
prolonged reaction time (up to several days), and the limited reac-
tion examples of pyranoid glycals (only four examples). These dis-
advantages prompted us to find a more practical Heck C-aryl
glycosylation protocol that can proceed ideally in a fast and highly
stereocontrolled manner. In order to tackle this issue, we sought to
employ flash-heating by microwave irradiation which proved to be
useful for reducing reaction time and in some cases improving re-
gio- and/or chemoselectivity of Heck reactions.9 Herein, we de-
scribe a rapid and stereospecific Heck-type C-aryl glycosylation
under microwave irradiation. The process was mediated by a
high-temperature stable catalytic system consisting of palla-
dium(II) acetate, inorganic base potassium carbonate (K2CO3),
and quaternary ammonium salt tetra-n-butylammonium bromide
(TBAB) and effected cross-couplings between a range of pyranoid
glycals and aryl bromides with low palladium loadings
(0.05 equiv), fast reaction time (ca. 30 min), and complete
a-stere-
oselectivity, producing 20,30-unsaturated C-aryl-
a
-glycosides in
good yields. Furthermore, extension of the method to the prepara-
tion of 20-deoxy C-aryl-b-glycosides is also detailed.
First, the effectiveness of microwave irradiation on the cross-
coupling of glycal with aryl halide was tested by conducting the
model experiment of 3,4,6-tri-O-benzyl-
with phenyl bromide (0.15 mmol) in the presence of 10 mol %
D-glucal 1a (0.05 mmol)
* Corresponding author. Tel./fax: +86 28 85503723.
E-mail address: yjs@scu.edu.cn (J.-S. Yang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.116

5136
M. Lei et al. / Tetrahedron Letters 50 (2009) 5135–5138
palladium(II) acetate (1.1 mg) in anhydrous dimethylformamide
(DMF, 0.2 mL) containing sodium formate (0.15 mmol) as a base.
The reaction mixture was subjected to microwave irradiation until
1a was completely consumed as monitored by TLC analysis. As
illustrated in Table 1, the glycosylation proceeded fast in only
60 min and delivered 24% isolated yield of C-phenyl gluctopyrano-
1.0 equiv of PPh3 as ligand for palladium had no significant impact
on the reaction outcome (entry 6 vs 14).
Based on these results, we next explored the synthetic general-
ity of this microwave-assisted coupling protocol. Thus, a series of
representative perbenzyl-protected glycals, including
D-glucal 1a,
D
-galactal 1b, -rhamnal 1c, and -rhamnal 1d, all of which exist
D
L
side 2a as a single
a
-anomer (entry 1). The double-bond migrated
as common glycosidic components in many C-aryl glycoside anti-
biotics, were prepared and used for coupling with aryl bromides.
We were pleased to find that under the suitable conditions
(1.0 equiv of glycal, 3.0 equiv of aryl bromide, 0.05 equiv of
Pd(OAc)2, 1.0 equiv of TBAB, 3.0 equiv of K2CO3, and microwave-
heating, 30 min, DMF), as recognized in entry 7 (Table 1), C-aryl
glycosylations of the selected D- and L-series glycals afforded the
to 20,30-position of the pyranoid ring in a fashion similar to the car-
bon-Ferrier rearrangement.10
Following the initial promising result, we then turned our
attention to the optimization of the reaction conditions with
respect to salt additives, equivalents of glycal, base and catalyst
(Table 1). It was found that addition of 1.0 equiv of tetra-n-butyl-
ammonium bromide (TBAB) to the reaction medium exerted a use-
ful effect on the reaction outcome and consequently improved the
yield of 2a to 40% (Table 1, entry 2). On the other hand, the use of
tetra-n-butylammonium chloride was detrimental, resulting in the
generation of numerous side products and thus giving a reduced
yield (entry 3). A similar observation on enhancement of tetrabu-
tylammonium salts for the Pd-catalyzed C1-arylations of glycals
was noted as well by Daves and co-workers.8e As for the equiva-
lents of glycal, the decrease in the ratio of phenyl bromide to 1a
lowered the yield of 2a (entries 4 and 5). We also assessed the role
of base in the reaction yield and found that the combined use of
3.0 equiv of sodium hydride or potassium carbonate rather than
sodium formate with TBAB led to great improvements in both reac-
tion yields and rate (entries 6 and 7, respectively). In contrast, no
coupling was realized with either piperidine or triethylamine as
the base, and the starting 1a was largely recovered. Phenyl iodide
was much less reactive than phenyl bromide under these condi-
tions, providing 2a in only 25% yield (entry 10). As a palladium
source, Pd(OAc)2 proved to be the best choice of catalyst, while
zerovalent Pd2(dba)3 afforded a poor yield (entry 11), and none
of the desired product was detected when Pd(PPh3)4 or PdCl2
was used (entries 12 and 13). Furthermore, introduction of
expected products 2b–j in high yields (73–81%) with exclusive a-
stereoselectivity in all cases, which demonstrated that the proce-
dure is generally applicable for a rapid and stereospecific synthesis
of various 20,30-unsaturated C-aryl- -glycosides (Table 2).11 The
a
yield of the products appeared to be strongly related to the nature
of the starting bromoarenes. For example, reactions with phenyl
bromide (Table 2, entries 3, 5 and 8) gave substantially better
yields than those with more sterically hindered 1- and 2-naphthyl
bromides (entries 2, 4 and 7). Compared with the corresponding
unsubstituted analogues (entries 3, 5 and 8), bromoarenes possess-
ing para-substituted electron-donating groups (entries 1, 6 and 9)
gave lower yields. That was consistent with the previous observa-
tions on the couplings of glycal tin12 or indium13 reagents with aryl
halides. Moreover, the methoxy group and the acid-labile
methoxymethyl group remained stable under the reaction condi-
tions, which expanded the functional-group tolerance (entries 1,
6 and 9).
The configuration of C-10 in 2a–j was assigned on the basis of
NOE correlation between H-10and H-50as well as compared with
literature reports on similar compounds.14 For instance, irradiation
of the C-50 methine signal (dH 3.89 ppm) in 2a at 400 MHz (CDCl3)
showed no evidence of any NOE enhancement in the C-10 methine
signal (dH 5.03 ppm), which indicated an
a configuration at the
anomeric center.
Table 1
Survey of reaction conditions of microwave-assisted Pd-catalyzed coupling of 3,4,6-
Having obtained the C-aryl-a-glycosides 2a–j, we further inves-
tri-O-benzyl-D-glucal (1a) with phenyl bromidea
tigated their applications in the synthesis of 20-deoxy C-aryl glyco-
sides (Scheme 1). Thus, treatment of 2a–j with 1.2 equiv of
oxidizing agent 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in
wet dichloromethane (0.1 M for 2a–j) at room temperature for
2–4 h led to, respectively, the formation of the corresponding C1’-
arylated enones 3a–j in quantitative yields. Subsequent catalytic
hydrogenation of the resulting enones15 in the presence of 10% pal-
ladium on charcoal in basic ethanol stereoselectively generated the
desired 20-deoxy C-aryl-b-glycopyranosides 4a–j with free 30-hy-
droxyl groups in excellent yields (78–90%) after chromatographic
separation. These results are evidence of simultaneous reductions
OBn
O
Br
OBn
O
palladium catalyst
base, Bu4NX
microwave irradiation
170 ºC, DMF
BnO
BnO
BnO
BnO
1a
2a
Entry Amt. of phenyl
Catalyst
X in
Base
Reaction
Yield of
bromide/1a (equiv)
Bu4NX
time (min) 2ab (%)
1c
2
3
4
5
6
7
8
9
3
3
3
2
1
3
3
3
3
3
3
3
3
3
Pd(OAc)2
—
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
NaH
60
60
60
60
60
30
30
24
40
20
37
22
71
81
0
Pd(OAc)2 Br
Pd(OAc)2 Cl
Pd(OAc)2 Br
Pd(OAc)2 Br
Pd(OAc)2 Br
Pd(OAc)2 Br
Pd(OAc)2 Br
Pd(OAc)2 Br
Pd(OAc)2 Br
Pd2(dba)3 Br
Pd(PPh3)4 Br
of both C@C and C@O bonds from a-face of the enones.
The structures of the obtained 20-deoxy C-aryl glycosides were
unambiguously established on the basis of spectroscopic data.14b
The configurations at C-30 were determined by the values of J3 ,4
K2CO3
Piperidine 30
Et3N
NaH
0
0
coupling constants which were, respectively, in the range of 8.8–
9.6 Hz for 4a–c and 4f–j (axial–axial relationship), and 2.4–2.8 Hz
for 4d–e (axial-equatorial relationship). In the 1H NMR
(400 MHz) spectra, the H-10 signal was a characteristic doublet of
doublets with a large J1 ,2a constant (>10 Hz, e.g., 11.6 Hz for 4a),
revealing an axial–axial coupling relationship between H-10 and
H-2a0. These data are consistent with a b anomeric configuration
for all the compounds, and a 4C1(D) conformation for 4a–h and a
1C4(L) conformation for 4i–j. NOE experiments were further used
to confirm the configuration at the anomeric sites. Take compound
4a, irradiation of the H-10 (dH 4.49 ppm) showed an enhancement
of 10% of the H-50 signal at dH 3.60 ppm, which was in agreement
with a cis disposition of these two atoms.
30
60
30
30
30
30
0
10d
11
12
13
14e
25
27
0
0
74
K2CO3
K2CO3
K2CO3
NaH
PdCl2
Pd(OAc)2 Br
Br
0
0
a
Reactions were performed with palladium (0.05 equiv), tetrabutylammonium
salt (1.0 equiv) and base (3.0 equiv) under microwave irradiation (170 °C) in DMF
(C = 10 M), unless otherwise indicated.
b
Isolated yields based on 1a after purification by column chromatography on
silica gel.
c
0.1 equiv of Pd(OAc)2 was used.
Use of phenyl iodide rather than phenyl bromide as starting material.
In the presence of 1.0 equiv of PPh3.
d
e

M. Lei et al. / Tetrahedron Letters 50 (2009) 5135–5138
5137
Table 2
Pd(OAc)2-catalyzed glycal-aryl bromide cross-couplings promoted by microwave irradiationa
Entry
Glycal
Aryl bromide
Product
Yield (%)
OBn
O
BnO
BnO
OBn
O
1
BnO
BnO
p-Methoxyphenyl bromide
75
1a
OMe
2b
2c
OBn
O
BnO
BnO
2
1-Naphthyl bromide
78
OBn OBn
OBn
O
OBn
O
3
4
5
6
7
8
Phenyl bromide
81
73
79
76
74
80
75
BnO
BnO
1b
2d
OBn
OBn
O
BnO
2-Naphthyl bromide
2e
O
BnO
BnO
O
BnO
BnO
Phenyl bromide
1c
2f
O
BnO
BnO
p-Methoxyphenyl bromide
2-Naphthyl bromide
Phenyl bromide
OMe
2g
O
BnO
BnO
2h
2i
O
BnO
BnO
O
BnO
BnO
1d
OMOM
9
p-Methoxymethylphenyl bromide
O
BnO
BnO
2j
a
General conditions: glycal (1.0 equiv), aryl bromide (3.0 equiv), Pd(OAc)2 (0.05 equiv), TBAB (1.0 equiv), and K2CO3 (3.0 equiv) in DMF (C = 10 M), microwave-heating
(170 °C).
In summary, we have developed a microwave-assisted cross-
formation of structurally diverse 20,30-unsaturated C-aryl-
a-glyco-
coupling reaction of perbenzylated pyranoid glycals with aryl bro-
mides in the presence of catalytic amounts of palladium(II) acetate.
Compared with the known techniques, this high-yielding and
stereospecific procedure offers a more practical approach to the
pyranosides in a rapid and well-applicable way. Through DDQ-
mediated oxidation and stereoselective reduction, the obtained
C-glycosides can be further transformed into 20-deoxy C-aryl-b-
glycopyranosides. Thus, this sequence of reactions described con-

5138
M. Lei et al. / Tetrahedron Letters 50 (2009) 5135–5138
DDQ (1.2 eq.)
10% Pd/C, Et3N
References and notes
4
2
3
CH2Cl2/H2O, rt, 2-4 h
(y. quant.)
EtOH, 0 ºC, 6-12 h
(y. 78-90%)
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OBn
Ar
O
BnO
O
O
BnO
Ar
3i
3j
R1
O
Ar
O
Ar
O
R1 R2 Ar
Ar
3f phenyl
3a OBn
phenyl
p-methoxymethylphenyl
H
phenyl
p-mthoxyphenyl 3g
1-naphthyl
p-methoxyphenyl
2-naphthyl
3b
3c
3d
OBn H
3h
H
OBn
H
3e H
OBn phenyl
OBn 2-naphthyl
R2
OBn
O
Ar
O
O
R1
BnO
BnO
Ar
Ar
HO
HO
HO
R1 R2 Ar
Ar
Ar
4i phenyl
4j p-methoxymethylphenyl
p-methoxyphenyl
7. (a) Calimente, D.; Postema, M. H. D. J. Org. Chem. 1999, 64, 1770–1771; (b)
Schmidt, B. Org. Lett. 2000, 2, 791–794; (c) Hart, D. J.; Merriman, G. H.; Young,
D. G. J. Tetrahedron 1996, 52, 14437–14458.
4a
phenyl
-methoxyphenyl
4f phenyl
OBn H
4g
4h
4b
4c
4d
4e
H
p
OBn
8. (a) Zhang, H. -C.; Daves, G. D., Jr. J. Org. Chem. 1993, 58, 2557–2560; (b) Zhang,
H. -C.; Daves, G. D., Jr. J. Org. Chem. 1992, 57, 4690–4696; (c) Farr, R. N.; Kwok,
D. -I.; Daves, G. D., Jr. J. Org. Chem. 1992, 57, 2093–2100; (d) Kwok, D. -I.; Farr, R.
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Barge, A.; Tagliapietra, S.; Tei, L.; Cintas, P.; Cravotto, G. Curr. Org. Chem. 2008,
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1-naphthyl
OBn
H
H
2-naphthyl
H
OBn phenyl
OBn 2-naphthyl
Scheme 1. Conversion of C-aryl-
anosides 4a–j.
a
-glycosides 2a–j to 20-deoxy C-aryl-b-glycopyr-
10. (a) Ferrier, R. J. Chem. Soc. 1964, 5443–5449; (b) Ferrier, R.; Prasad, N. J. Chem.
Soc. C 1969, 570–575; (c) Toshima, K.; Miyamoto, N.; Matsuo, G.; Nakata, M.;
Matsumura, S. Chem. Commun. 1996, 1379–1380.
11. Typical experimental procedure for microwave-assisted cross-couplings between
pyranoid glycals and aryl bromides. An oven-dried round flask was charged with
glycal (1.0 equiv), Pd catalyst (0.05 equiv), TBAB (1.0 equiv), and K2CO3
(3.0 equiv). The aryl bromides (3.0 equiv) and anhydrous DMF (0.1 mL/mmol)
were successively added via syringe. Then the vessel was equipped with a
condensation tube and irradiated by microwave (400 W) without stirring
stitutes a new synthetic pathway to 20-deoxy b-C-glycosylarenes.
Further investigations are underway to apply this methodology
to the synthesis of biologically important natural products.
Acknowledgments
under
a nitrogen atmosphere until the starting glycal was completely
Financial supports from the National Natural Science Founda-
tion of China (Nos. 30300434 and 20672074) and the Outstanding
Youth Foundation of Sichuan Province, China (No. 08ZQ026-029)
are gratefully appreciated.
consumed as judged by TLC analysis. The reaction mixture was cooled to
room temperature and then diluted with water and dichloromethane. The
organic layer was separated, dried over anhydrous Na2SO4, and concentrated.
The crude material was purified by flash column chromatography on silica gel
eluted with petroleum ether/EtOAc to afford the 20,30-unsaturated C-aryl-
glycopyranosides 2a–j.
a-
12. Friesen, R. W.; Loo, R. W.; Sturino, C. F. Can. J. Chem. 1994, 74, 1262–1272.
13. Lehmann, U.; Awasthi, S.; Minehan, T. Org. Lett. 2003, 5, 2405–2408.
Supplementary data
14. (a) Danishefsky, S.; Kerwin, J. F., Jr. J. Org. Chem. 1982, 47, 3803–3805; (b)
Brakta, M.; Farr, R. N.; Chaguir, B.; Massiot, G.; Lavaud, C.; Anderson, W. R., Jr.;
Sinou, D.; Daves, G. D., Jr. J. Org. Chem. 1993, 58, 2992–2998.
Supplementary data (the optical rotation, 1H and 13C NMR spec-
troscopic data as well as results of HR ESI-MS for 4a–j) associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.06.116.
0
15. For a similar reduction of C1 -arylated enone acetates, see: Benhaddou, R.;
Czernecki, S.; Ville, G. J. Org. Chem. 1992, 57, 4612–4616.