Palladium catalyzed stereoselective C-glycosylation of glycals with enol triflates

Article abstract of DOI:10.1021/ol202368n

An efficient palladium catalyzed C-glycosylation of glycals with enol triflates has been established. The coupling reactions took place on the anomeric carbon, and the coupling products gave exclusively α isomers. The flexibility of the reaction was exemp

Full text of DOI:10.1021/ol202368n

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5648–5651
Palladium Catalyzed Stereoselective
C-Glycosylation of Glycals with
Enol Triflates
Yaguang Bai, Minli Leow, Jing Zeng, and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371
xuewei@ntu.edu.sg
Received September 1, 2011
ABSTRACT
An efficient palladium catalyzed C-glycosylation of glycals with enol triflates has been established. The coupling reactions took place on the
anomeric carbon, and the coupling products gave exclusively R isomers. The flexibility of the reaction was exemplified by the broad spectra of
substrate scope, constituted of glycals protected with good leaving groups as well as an assortment of enol triflates.
C-Glycosides are a unique class of carbohydrate ana-
logues possessing a CꢀC bond between the anomeric carbon
and the aglycon. Research has been intensively conducted
on C-glycosides in past decades due to their importance in
enzymatic and metabolic chemistry.1 In addition, they are
also found in a wide range of naturally occurring products
such as ambruticin S,2 aspergilllide C,3 and (þ)-varitriol.4
The presence of multiple chiral centers on carbohydrates
renders C-glycosides as important building blocks5 for the
construction of these natural products.
pharmacological properties. The most commonly used
method to synthesize 2,3-unsaturated C-glycosides is the
Lewis acid promoted Ferrier rearrangement. To date, a
large number of Lewis acids have been explored to achieve
high yields and stereoselectivities. However, various draw-
backs such as limited nucleophilic reagents, high catalyst
loadings, and moderate stereoselectivities restrict the ap-
plication of this type of reaction.
More recently, the efficiency of transition metal cata-
lyzed reactions has stimulated chemists to investigate the
applicability of transition metals, especially palladium, in
carbohydrate chemistry. Given the vinyl feature of gly-
cals, C-glycosylation reactions producing 2,3-unsaturated
C-glycosides via a palladium-catalyzed Heck type reactions
have been intensively studied. Active nucleophilic reagents
such as mercury salts,6 aryl boronic acid,7 and aryl iodide8
were introduced to couple with glycal compounds. All the
reported Heck type C-glycosylations have given exclu-
sively R-selectivity due to steric hindrance from the C3
protecting group.8 After addition of the aryl palladium
Among the many diverse C-glycosides that exist, 2,3-
unsaturated C-glycosides are a unique class of carbohy-
drate analogues which are synthetically versatile for the
preparation of a variety of compounds with important
(1) (a) Bililign, T.; Griffith, B. R.; Thorson, J. S. Nat. Prod. Rep 2005,
22, 742. (b) Hultin, P. G. Curr. Top. Med. Chem. 2005, 5, 1299. (c) Wei,
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Lett. 2001, 3, 2013.
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(c) Nagasawa, T.; Kuwahara, S. Org. Lett. 2009, 11, 761. (d) Nishikawa,
T.; Koide, Y.; Kanakubo, A.; Yoshimura, H.; Isobe, M. Org. Biomol.
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r
10.1021/ol202368n
Published on Web 09/28/2011
2011 American Chemical Society

species, the palladium atom attached to the C2 carbon
potentially has two elimination pathways to follow
(Scheme 1). One gives the syn-β-hydride elimination pro-
ducts, the other gives the anti-β-heteroatom elimination
products.
Table 1. Palladium Catalyzed Ferrier Type C-Glycosylation
with Glycal and Cyclohexenyl Trifluoromethanesulfonatea
Scheme 1. Pd Elimination Pathways of Heck Type C-Glycosy-
lation
entry
catalyst
additive solvent temp (°C) yield (%)b
1c
2c
3c
4b
5
Pd(OAc)2
Pd(TFA)2
N.A.
N.A.
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
0
80
0
Pd(PhCN)2Cl2 N.A.
PdCl2(PPh3)2 N.A.
PdCl2(PPh3)2 N.A.
PdCl2(PPh3)2 dpped
PdCl2(PPh3)2 dpppd
PdCl2(PPh3)2 dpppend
PdCl2(PPh3)2 nBu4NCl
80
0
80
32%
46%
0
80
6
80
7
80
53%
0
8
80
9
80
62%
51%
46%
30%
65%
78%
69%
45%
12%
56%
23%
However, almost all of the existing palladium-catalyzed
methods focus on the formation of a CꢀC bond between
the anomeric carbon and the aryl group. To the best of our
knowledge, few palladium catalyzed coupling reactions of
glycals and alkyl groups have been reported. The use of
enol triflates with olefins, in Heck reactions, shows their
potential efficiency as coupling reagents and highlights
their underlying potential in a reaction with glycals.9 In
continuation of our interest in functionalized sugar pyra-
nose, especially glycals,10 herein we report a highly stereo-
selective palladium catalyzed C-glycosylation between gly-
cals and enol triflates.
Initially, the reaction of glucal (1a) and cyclohexenyl
triflate (2a) with palladium acetate as catalyst was carried
out in 1 equiv of triethylamine in dimethylformamide
(DMF) at 80 °C (Table 1, entry 1). Unfortunately, this
reaction could not afford any desired product after 48 h.
Upon screening different palladium catalysts, PdCl2(PPh3)2
was found to give the Ferrier type product (3a) in poor yield
(entry 4) while a catalyst such as Pd(OAc)2 (entry 1),
Pd(TFA)2 (entry 2), or Pd(PhCN)2Cl2 (entry 3) was found
to be ineffective.
10 PdCl2(PPh3)2 nBu4NBr
11 PdCl2(PPh3)2 nBu4NI
80
80
12 PdCl2(PPh3)2 nBu4NOAc DMF
80
13 PdCl2(PPh3)2 nBu4NCl
14 PdCl2(PPh3)2 nBu4NCl
15 PdCl2(PPh3)2 nBu4NCl
16 PdCl2(PPh3)2 nBu4NCl
17 PdCl2(PPh3)2 nBu4NCl
18 PdCl2(PPh3)2 nBu4NCl
19 PdCl2(PPh3)2 nBu4NCl
DMF
DMF
DMF
DMSO
ACN
100
120
135
120
100
120
110
NMP
toluene
a Unless otherwise specified, reactions were carried out with 1 equiv of
1a, 1.5 equiv of 2a, 10% catalyst, 150% additives, and 3 equiv of
triethylamine in a sealed tube for 36 h. b Isolated yield. c 1 equiv of base.
d Ligand added in 40 mol %. dppe: 1,2-diphenylphosphinoethene; dppp:
1,3-diphenylphosphinopropane; dpppen: 1,5-diphenylphosphenopentane.
was not necessary (entries 6ꢀ8) but a tetrabutylammo-
nium salt could enhance the yield significantly.12 Tetra-
butylammonium salts with different anions were further
tested, and it was found that tetrabutylammonium chlo-
ride afforded the desired product in the highest yield (entries
9ꢀ12). Gratifyingly, increasing the reaction temperatures
to 120 °C (entries 13ꢀ14) led to the Ferrier type product
exclusively in good yield within an acceptable period of
time. However, any further increase of temperature low-
ered the yield (entry 15). Several solvents were tested, but
DMF was found to afford the desired product with the
highest yield (entries 14, 16ꢀ18).
Next, we proceeded to screen various organic and
inorganic bases, and triethylamine was found to be the
most effective for mediating this process.11 In addition, 3
equiv of base were found to give a much higher yield of
product 3a (entry 5). Investigation of various additives and
ligands revealed that addition of ligands to the reaction
With the optimal reaction conditions identified, we
studied the substrate scope of this reaction, and the results
are summarized in Table 2. First, glycals with different
protecting groups were tested for their reactivities toward
the cyclohexenyl triflate. Among the protecting groups
surveyed, only good leaving groups such as acetyl (3a, 3d),
pivaloyl (3c, 3f) and ethoxycarbonyloxyl (3b, 3e) were
found to be reactive under standard conditions. Among
them, ethoxycarbonyl-protected glycals gave the desired
(9) (a) Vallin, K. S. A.; Larhed, M.; Johansson, K.; Hallberg, A. J.
Org. Chem. 2000, 65, 4537. (b) Scott, W. J.; Pena, M. R.; Sward, K.;
Stoessel, S. J.; Stille, J. K. J. Org. Chem. 1985, 50, 2302. (c) Kaukoranta,
€
€
P.; Kallstrom, K.; Andersson, P. G. Adv. Synth. Catal. 2007, 349, 2595.
ꢀ
ꢁ
(d) Mata, Y.; Pamies, O.; Dieguez, M. Chem.;Eur. J. 2007, 13, 3296.
(10) (a) Gorityala, B. K.; Lorpitthaya, R.; Bai, Y. G.; Liu, X.-W.
Tetrahedron 2009, 65, 5844. (b) Lorpitthaya, R.; Xie, Z. Z.; Sophy, K. B.;
Kuo, J. L.; Liu, X.-W. Chem.;Eur. J. 2010, 16, 588. (c) Ma, J. M.; Zhao,
Y. Y.; Ng, S.; Zhang, J.; Zeng, J.; Than, A.; Chen, P.; Liu, X.-W.
Chem.;Eur. J. 2010, 16, 4533. (d) Cai, S.; Kishan Gorityala, B.; Ma, J.;
Leow, M. L.; Liu, X.-W. Org. Lett. 2011, 13, 1072. (e) Lorpitthaya, R.;
Xie, Z.-Z.; Kuo, J.-L.; Liu, X.-W. Chem.;Eur. J. 2008, 14, 1561. (e)
Gorityala, B. K.; Cai, S.; Lorpitthaya, R.; Ma, J.; Pasunooti, K. K.; Liu,
X.-W. Tetrahedron Lett. 2009, 50, 676.
(12) (a) Liu, Y.; Yao, B.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G.; Li,
J.-H. Org. Lett. 2011, 13, 1126. (b) Mariampillai, B.; Herse, C.; Lautens,
M. Org. Lett. 2005, 7, 4745.
(11) For the selection of base, see Supporting Information.
Org. Lett., Vol. 13, No. 20, 2011
5649

Table 2. C-Glycosylation Coupling Reaction of Glycals and
Cyclohexenyl Triflatea
Table 3. C-Glycosylation Coupling Reactions of Glycals and
Enol Triflatea
a Reactions were carried out with 1 equiv of glycal, 1.5 equiv of enol
triflate, 10% catalyst, 150% nBu4NCl, and 3 equiv of triethylamine in a
sealed tube for 36 h. b Isolated yields.
reactivities of glycals prepared from different carbohy-
drates. It was found that glycals prepared from galactose
(3dꢀ3f), L-6-deoxyglucose (3g), ribose (3h), and disaccha-
ride (3i) also reacted with enol triflate (2a) to provide the
corresponding C-glycosides in moderate to high yields.
The structure of the coupling product (3d) was confirmed
by X-ray crystallography (Figure 1). It is notable that
glycals derived from galactose generally gave higher yields
as compared with their glucose equivalents.
a Reactions were carried out with 1 equiv of glycal, 1.5 equiv of enol
triflate, 10% catalyst, 150% nBu4NCl, and 3 equiv of triethylamine in a
sealed tube for 36 h. b Isolated yields.
The reactivities of enol triflates were further tested
(Table 3). Cyclohexenyl triflates with substituents such as
4-methyl (3j, 3k), 4-tert-butyl (3l, 3m), and 2-methyl (3n)
product in high yields while pivaloyl protected glycals were
shown to be less efficient. Next, we moved on to test the
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Org. Lett., Vol. 13, No. 20, 2011

Scheme 2. Plausible Mechanism of the Heck Type C-Glycosyl-
ation Reaction Observed
Figure 1. X-ray structure of compound 3d.
gave the corresponding products. However, when efforts
were made to change the ring size of the enol triflate, the
results were not promising. Both cycloheptenyl and cy-
cloocatenyl triflates were synthesized and tested under
standard conditions. However, only cycloheptenyl triflate
and D-galactal afforded the desired product (3o) in poor
yield while glucal, on the other hand, failed to give any
desired product. Conversely, other cyclo-derivatives like
cyclopentenyl triflate were not synthesized due to their
low-boiling points. In addition, cyclooctenyl triflate and
aliphatic enol triflate such as octyl triflate also failed to
afford any product with glucal or galactal.
A plausible mechanism for the process described is
proposed in Scheme 2. After the reduction of Pd(II) to
Pd(0), oxidative addition takes place to form the alkyl-Pd
cation complex. This complex is then added to the double
bond on glycal, which results in the formation of a Pd-
glycal complex. Next, anti-β-elimination of the acetyl
group with Pd takes place to give the final R-C glycosides
and Pd(II) species.13 Pd(II) is assumed to be reduced to
Pd(0) by amine,14 and the active catalyst Pd(0) is generated
to start a new catalytic cycle. In this case, the tetrabutyl-
ammonium salt acts as a phase transfer agent, and a
halogen anion promotes the anti-β-OAc-elimination.15
In conclusion, an efficient palladium catalyzed method
for C-glycosylation of glycals and enol triflates has been
established. The cross-coupling reactions proceed with
high regioselectivity and stereoselectivity. The substrate
scope includes glycals with good leaving groups and
various enol triflates. In addition, the cyclohexenyl and
cycloheptenyl groups on the productsprovide the potential
for further transformations to other functionalities.
Acknowledgment. Wethank Dr. Yong-Xin Li for X-ray
analyses. Wegratefully acknowledgeNanyang Technolog-
ical University (RG50/08) and the Ministry of Education,
Singapore (MOE 2009-T2-1-030) for the financial support
of this research.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Zhu, G.; Lu, X. Organometallics 1995, 14, 4899.
(14) Liu, Y.; Yao, B.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G.; Li, J.-
H. Org. Lett. 2011, 13, 2184.
(15) Zhang, Z.; Lu, X.; Xu, Z.; Zhang, Q.; Han, X. Organometallics
2001, 20, 3724.
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