Regio- and stereoselective synthesis of 2-deoxy-C-aryl glycosides via palladium catalyzed decarboxylative reactions

Article abstract of DOI:10.1021/ol201820m

An efficient and versatile approach for the synthesis of 2-deoxy-C-aryl glycosides is reported. This strategy is based on a palladium-catalyzed decarboxylative Heck coupling reaction of benzoic acids and glycals. A wide variety of glycals and benzoic acid

Full text of DOI:10.1021/ol201820m

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4608–4611
Regio- and Stereoselective Synthesis of
2-Deoxy-C-aryl Glycosides via Palladium
Catalyzed Decarboxylative Reactions
Shaohua Xiang, Shuting Cai, Jing Zeng, and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
xuewei@ntu.edu.sg
Received July 6, 2011
ABSTRACT
An efficient and versatile approach for the synthesis of 2-deoxy-C-aryl glycosides is reported. This strategy is based on a palladium-catalyzed
decarboxylative Heck coupling reaction of benzoic acids and glycals. A wide variety of glycals and benzoic acids have been screened, and all
these reactions could afford the desired C-aryl glycoside products in moderate to good yields with exclusive regio- and stereoselectivities.
Expansive attention and growing interest surrounding
C-glycosides, especially C-aryl glycosides, could be attrib-
uted to their prevalence in the composition of many
natural products with important biological properties1
(Figure 1). In addition, they are versatile chiral building
blocks in pharmaceutics and have the potential to act as
enzyme inhibitors and stable sugar mimics.2 Among all the
natural products containing C-aryl glycosides, 2-deoxy-
C-aryl glycoside structures are particularly recognized due
to their ubiquity.3 Therefore, the synthesis of C-aryl 2-deoxy
glycoside is of great interest. Until now, a variety of syn-
thetic methods have been reported for the synthesis of this
kind of compound.4À6 Among these methods, two strate-
gies remain the most widely used by researchers. One is the
cross-coupling of aryl halides with stannylated glycals,4
another is the cross-coupling of organometallic reagents
and glycal derivatives.5 A further method is the palladium-
catalyzed coupling of glycals with arylboronic acids.7
(1) (a) Subadolnik, R. J. Nucleoside Antibiotics; Wiley-Interscience:
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D. J. Nat. Prod. Rep. 2000, 17, 7.
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1986, 5, 1753. (c) Cheng, J. C. Y.; Hacksell, U.; Daves, G. D., Jr. J. Org.
Chem. 1986, 51, 3093. (d) Daves, G. D., Jr. Acc. Chem. Res. 1990, 23,
201. (e) Friesen, R. W.; Loo, R. W. J. Org. Chem. 1991, 56, 4821.
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123, 6937. (h) Steinhuebel, D. P.; Fleming, J. J.; Dubois, J. Org. Lett.
2002, 4, 293. (i) Chen, C.-L.; Martin, S. F. Org. Lett. 2004, 6, 3581.
(j) Chen, C.-L.; Martin, S. F. J. Org. Chem. 2006, 71, 4810.
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(b) Benhaddou, R.; Czernecki, S.; Ville, G. J. Org. Chem. 1992, 57, 4612.
(c) Calimente, D.; Postema, M. H. D. J. Org. Chem. 1999, 64, 1770.
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Gao, L.; Yang, J. -S. Tetrahedron Lett. 2009, 50, 5135. (f) Moral, J. A.;
Moon, S.-J.; Rodriguez-Torres, S.; Minehan, T. Org. Lett. 2009, 11,
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22, 742.
(4) (a) Dubois, E.; Beau, J. M. Tetrahedron Lett. 1990, 31, 5165.
(b) Dubois, E.; Beau, J. M. J. Chem. Soc., Chem. Commun. 1990, 1191.
(c) Friesen, R. W.; Sturino, C. F. J. Org. Chem. 1990, 55, 2572.
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A.; Beddoes, R. L.; Conway, J. C.; Quayle, P.; Urch, C. J. Synlett 1995,
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Lett. 2001, 3, 2013. (b) Ramnauth, J.; Poulin, O.; Bratovanov, S. S.;
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ꢀ
ꢁ
Frons, P.; Fernandez, J.; Fiol, S.; Forner-Fernandez, D.; Albericio, F.
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r
10.1021/ol201820m
Published on Web 08/04/2011
2011 American Chemical Society

In contrast to the former two strategies, the third strategy
is more attractive, owing to the air and moisture stability
of the reagents, their availability, and their low toxicity.
However, the dependenceofthe product on the stereogenic
center and the protecting group at C-3 limits the appli-
cation of this method.7d,8 Hence, it is still necessary to
develop more flexible and efficient strategies.
diverse C-glycosides. Herein, we describe our results for
the preparation of the 2-deoxy-C-aryl glycosides via this
method.
Table 1. Optimization of the Decarboxylative Coupling
Reactiona
temp
time
(h)
yield
(%)b
entry
catalyst
ligand
none
(°C)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
80
80
60
70
80
80
80
80
80
80
80
80
80
12
4
4
4
4
4
4
4
4
4
4
4
4
50
2
none
59
Figure 1. Biologically active natural products containing C-aryl
glycosides.
3
none
trace
<5
54
4
none
5
none
Currently, transition-metal-catalyzed decarboxylative
cross-coupling reactions offer efficient synthetic methods
for forming carbonÀcarbon bonds. They are attractive
since they use ubiquitous carboxylic acids as alternative
reagents to organometallic compounds.9À11 Pioneering
work by Myers9 and Goossen10 demonstrated that, in a
number of Heck-type reactions, ortho-substituted arene
carboxylic acids could be used as synthetic equivalents of
aryl halides in the presence of palladium catalysts and
stoichiometric amounts of silver or copper additives at
high temperatures. This type of reaction proceeded very
well with different kinds of olefins in air and even with
small amounts of water.9a Inspired by the successful im-
plementation of decarboxylative coupling and our group’s
continuing efforts at extending the synthetic methodolo-
gies of carbohydrates,12 we envisioned that this protocol
could be made to work effectively with glycals to give
6
Pd(TFA)2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
none
<5
<10
79
7
none
8
PPh3
9
R-monophos
X-phos
S-phos
Xantphos
(2-MeOPh)3P
77
10
11
12
13
63
46
28
10
a Reaction conditions: 3,4,6-tri-O-acetyl-D-glucal 0.2 mmol, 2,
6-dimethoxybenzoic acid 0.4 mmol (2.0 equiv), Ag2CO3 0.6 mmol
(3.0 equiv), catalyst 0.02 mmol (0.1 equiv), ligand 0.08 mmol (0.4 equiv),
DMF/DMSO = 2 mL/0.1 mL. b Isolated yields.
Our initial aim was to achieve coupling of commer-
cially available 3,4,6-tri-O-acetyl-D-glucal (1a) with 2,
6-dimethoxybenzoic acid (2a). Treatment of 1a with 2a at
80 °C in the presence of Ag2CO3 and catalytic Pd(OAc)2 in
DMSO/DMF (1:20) for 12 h afforded the corresponding
C-glycoside product 3a as a single diastereomer in 50%
yield. Encouraged by this result, different reaction times,
temperatures, and a variety of palladium catalysts with
different ligands were screened to optimize the reaction
conditions. As shown in Table 1, when the reaction time
was reduced to 4 h (entry 2) at 80 °C, the reaction did not
complete, and 29% of the starting material was recovered.
However, the yield was improved to 59%, demonstrating
the product’s instability to high temperatures. Attempts to
reduce the temperature were unsuccessful as only trace
amounts of the coupling product at 60 °C and less than 5%
coupling product at 70 °C were isolated (entries 3, 4). Fur-
ther investigations were conducted on the catalysts, and
the results demonstrated that this reaction proceeded when
PdCl2 was employed instead of Pd(OAc)2, albeit in a
slightly lower yield (entry 5). On the other hand, other
palladium catalysts such as Pd(TFA)2 and Pd(PPh3)2Cl2
did not perform well in this reaction (entries 6, 7). Inter-
estingly, subsequent examination of the ligand effect re-
vealed their significant influence on this reaction. Based on
the results, it was observed that while some ligands aid
(8) Cheng, J. C. Y.; Daves, G. D., Jr. J. Org. Chem. 1987, 52, 3083.
(9) (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250. (b) Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
(c) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005,
127, 10323.
(10) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
(b) Goossen, L. J.; Rodrı
L. M. J. Am. Chem. Soc. 2007, 129, 4824. (c) Goossen, L. J.; Rudolphi,
F.; Oppel, C.; Rodrıguez, N. Angew. Chem., Int. Ed. 2008, 47, 3043.
´
guez, N.; Melzer, B.; Linder, C.; Deng, J.; Levy,
´
(11) For other recent examples, see: (a) Forgione, P.; Brochu, M. C.;
Miguel, S. O.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem.
Soc. 2006, 128, 11350. (b) Becht, J. M.; Catala, C.; Drian, C. L.; Wagner,
A. Org. Lett. 2007, 9, 1781. (c) Wang, C.-Y.; Piel, I.; Glorius, F. J. Am.
Chem. Soc. 2009, 131, 4194. (d) Shang, R.; Fu, Y.; Li, J.-B.; Zhang, S.-L.;
Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2009, 131, 5738. (e) Hu, P.; Kan,
J.; Su, W.-P.; Hong, M.-C. Org. Lett. 2009, 11, 2341. (f) Lindh, J.;
€
Sjoberg, P. J. R.; Larhed, M. Angew. Chem., Int. Ed. 2010, 49, 7733.
(g) Wang, C.-Y.; Rakshit, S.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
14006. (h) Shang, R.; Yang, Z.-W.; Wang, Y.; Zhang, S.-L.; Liu, L.
J. Am. Chem. Soc. 2010, 132, 14391.
(12) (a) Lorpitthaya, R.; Xie, Z.-Z.; Kuo, J.-L.; Liu, X.-W. Chem.;
Eur. J. 2008, 14, 1561. (b) Sudibya, H. G.; Ma, J.-M.; Dong, X.; Ng, S.;
Li, L.-J.; Liu, X.-W.; Chen, P. Angew. Chem., Int. Ed. 2009, 48, 2723.
(c) Zeng, J.; Vedachalam, S.; Xiang, S.-H.; Liu, X.-W. Org. Lett. 2011,
13, 42. (d) Ding, F.-Q.; William, R.; Wang, F.; Ma, J.-M.; Ji, L.; Liu
X.-W. Org. Lett. 2011, 13, 652. (e) Gorityala, B. K.; Ma, J.-M.;
Pasunooti, K. K.; Cai, S.-T.; Liu, X.-W. Green Chem. 2011, 13, 573.
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Org. Biomol. Chem. 2011, 9, 3929.
Org. Lett., Vol. 13, No. 17, 2011
4609

substantially in increasing the yield of this reaction (entries
8À10), others were detrimental to the reaction (entries
11À13). Among the ligands examined, PPh3 was found to
bethe mostefficient ligandfor thisreaction(entry 8). Thus,
consolidating the results of our optimization, we con-
cluded that the reaction between 1a (1.0 equiv) and 2a
(2.0 equiv) using Pd(OAc)2 (0.1 equiv), Ag2CO3 (3.0
equiv), and PPh3 (0.4 equiv) in a DMSO/DMF (1:20)
solvent mixture at80°C for 4 h representsthe mostsuitable
set of conditions for the formation of C-aryl glycoside (3a).
glucals, regardless of whether they possess electron-donat-
ing (3b, 3c, 3f) or electron-withdrawing protecting groups
(3d, 3e), the reaction progresses smoothly. Their versatility
in the reaction could be further demonstrated by the fact
that glucals equipped with sterically hindered protecting
groups engaged in this reaction as well (3cÀ3e). In addi-
tion, glucal substrates with conformationally rigid struc-
tures could be converted to the desired C-aryl glycoside
product in 73% yield (3g) and glucal derivatives with an
ester group at the C-5 position could also couple effectively
with 2a, furnishing the product in 63% yield (3h). Various
galactals were then screened in this reaction and, similarly,
gave good results (3iÀ3l). Furthermore, glycals derived
from rhamnose and ribose were subsequently examined
and the corresponding C-aryl glycosides were afforded
in 72% and 58% yields (3m, 3n) respectively. It is note-
worthy that the reaction with a disaccharide also ad-
vanced smoothly to give the coupling product in mode-
rate yield (3o).
Table 2. Decarboxylative Coupling of 2,6-Dimethoxybenzoic
Acid with Different Kinds of GlycalsaÀc
Scheme 1. Decarboxylative Coupling of Glycals with Different
Benzoic Acid Derivativesa,b
a Isolated yields. bOnly one anomer was obtained for each
reaction.
To expand the scope of our methodology, we employed
our catalytic system in the decarboxylative coupling of
glycals with other benzoic acid derivatives. As shown in
Scheme 1, a variety of benzoic acid derivatives could be
used for the synthesis of various types of C-aryl glycosides
and all the reactions gave reasonable yields. The reaction
time was found to be sensitive to the aryl substituent posi-
tion and the overall electron density of the aryl group.
The reactivities of 2,4-disubstituted benzoic acids were
lower than those of the 2,6-disubstituted benzoic acids;
hence, longer reaction times were needed (4a, 4b, 4e, 4f).
a Isolated yields. b Only one single anomer was obtained for each
reaction. c Compound 3f is unstable in CDCl3.
With these optimized conditions in hand, we proceeded
to examine the substrate scope of the glycals. The results
are presented in Table 2. It was found that a variety of
glycals could afford the desired C-glycoside products in
moderate to good yields with complete stereocontrol. For
4610
Org. Lett., Vol. 13, No. 17, 2011

In addition, benzoic acid substrates with a more electron-
donating group exhibited greater activities, and conse-
quently, shorter reaction times were needed (4c, 4g, 4h).
Aryl substrates bearing a bromide substituent could also
be used as a coupling partner for this reaction, and the
products were generated in moderate yields (4d, 4i). De-
spite attempts to test the reaction with other benzoic acid
derivatives such as 2,3-dimethoxybenzoic acid, 2-bromo-
4,5-dimethoxybenzoic acid, 2-naphthoic acid, 2-bromo-
4-methoxybenzoic acid, 3,5-dimethoxybenzoic acid, and
6-methylpicolinic acid, the results obtained were not satis-
factory. Therefore, we deduce that the reaction would
proceed smoothly in the presence of benzoic acids sub-
stituted with strong electron-donating groups at the 2,4 or
2,6 position.
Scheme 2. Plausible Reaction Mechanism
an additional oxidation step by silver carbonate, Pd0 was
converted to the PdII species a and the catalytic cycle was
completed. This mechanism indicated that the product’s
anomeric stereochemistry adopted a contrasting config-
uration from the C-3 substituent of the glycal and this
coincided with the structure of the products confirmed by
X-ray crystallographic analysis.
In summary, we have developed the first metal-cata-
lyzed method for decarboxylative C-glycosylative cou-
pling. This strategy is based on a palladium-catalyzed
decarboxylative Heck coupling reaction of benzoic acids
and glycals and provides an efficient and versatile ap-
proach to the synthesis of various useful 2-deoxy-C-aryl
glycosides. A wide variety of glycals and benzoic acids
have been screened, and all the reactions afforded the
desired C-aryl glycoside products in moderate to good
yields with high regio- and stereoselectivities. Further
stereoselective functionalization of the enol ether double
bond of these products could readily afford different
kinds of aryl 2-deoxy-C-glycoside, which are compo-
nents of many natural products.
Figure 2. X-ray structures of compounds 4d and 4i.
Noteworthy, excellent anomeric stereoselectivities were
observed in all reactions. The stereochemistry was further
elucidated to be R-selective by X-ray crystallographic
analysis of both glucal C-aryl glycoside 4d and galactal
C-aryl glycoside 4i (Figure 2).
Based on our work and the previous results on the
palladium-catalyzed Heck decarboxylative reaction,6a,8,9c
we proposed the mechanism to be as shown in Scheme 2.
Beginning with a PdII species a, the Pd complex b is formed
by a salt change. A subsequent decarboxylative reaction of
complex b generates an aryl PdII species c. Carbopallada-
tion of the glycals would then give the intermediate d.
In this step, the PdII species would attack from the bottom
face, as the C-3 substituent created steric hindrance for
addition on the top face. The intermediate d would subse-
quently convert to the relatively more stable chair con-
formation e, with the C-3 substituent and the aryl group
in an anti configuration. The desired 2-deoxy-C-aryl glyco-
side and Pd0 species f were then formed by the syn-
β-hydrogen elimination. After elimination of HOAc and
Acknowledgment. The authors thank Dr. Yong-Xin Li
for X-ray analyses and gratefully acknowledge Nanyang
Technological University (RG50/08) and Ministry of Edu-
cation (MOE 2009-T2-1-030), Singapore for funding this
research.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
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