Avoiding pyran ring opening during palladium acetate catalyzed C-glycosidation of peracetylated glycals

Article abstract of DOI:10.1016/j.tetlet.2005.07.128

Palladium acetate catalyzed C-glycosidation of peracetylated glycals with arylboronic acids in acetonitrile (CH₃CN) yields the desired 1-substituted 2,3-unsaturated glycal as well as a byproduct corresponding to the ring-opened pyran, present in varying proportions depending on the reaction conditions used. The byproduct is not formed when toluene/EtOH is used as reaction solvent.

Full text of DOI:10.1016/j.tetlet.2005.07.128

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Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7271–7274
Avoiding pyran ring opening during palladium acetate catalyzed
C-glycosidation of peracetylated glycals
a
a
a
Natalia de la Figuera,a, Pilar Forns, Joan-Carles Fernandez, Sandra Fiol,
*
`
b
c
´
Dolors Fernandez-Forner and Fernando Albericio
aAlmirall Prodesfarma-Barcelona Science Park Unit, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain
bResearch Center, Almirall Prodesfarma, Cardener 68-74, 08024 Barcelona, Spain
cBarcelona Biomedical Research Institute, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain
Received 9 May 2005; revised 22 July 2005; accepted 25 July 2005
Available online 6 September 2005
Abstract—Palladium acetate catalyzed C-glycosidation of peracetylated glycals with arylboronic acids in acetonitrile (CH3CN)
yields the desired 1-substituted 2,3-unsaturated glycal as well as a byproduct corresponding to the ring-opened pyran, present in
varying proportions depending on the reaction conditions used. The byproduct is not formed when toluene/EtOH is used as reaction
solvent.
Ó 2005 Elsevier Ltd. All rights reserved.
C-Glycosides, natural products composed of a glycon
(usually furanosyl or pyranosyl) and an aglycon (aryl
or heterocyclic) linked via a C–C bond, have garnered
great interest in the past few years due to their pharma-
cological potential.1,2 Specifically, the C–C glycosylic
linkage in C-glycosides is resistant to hydrolytic or enzy-
matic cleavage, suggesting their utility as inhibitors of
carbohydrate-processing enzymes.3 Among C-glyco-
sides, C-arylglycopyranosides with a double bond in
the 2,3-position are useful synthetic intermediates, since
this unsaturation can be exploited for functionalization.
Many of the synthetic routes to such unsaturated com-
pounds are based on palladium-mediated coupling reac-
tions of 1,2-unsaturated carbohydrates.4 To date, three
methods exist for in situ formation of the aryl palladium
complex: treatment of an aryl iodide with palladium in
the presence of a base,5 treatment of an organomercury
compound with a palladium salt,6 and reaction of an
aromatic compound with palladium acetate in acetic
acid.7 However, these reactions suffer from low yields,
lack of regioselectivity, and instability of most of the
reagents to air and moisture; hence alternate strategies
are needed. Nucleophiles such as arylindiums8 or organo-
lithiums9 have recently been used to obtain 2,3-unsatur-
ated a-C-glycosides, although stereoselectivity is only
obtained via the organolithium route, which is long
and involves an epoxide intermediate.
The use of palladium acetate as a catalyst for formation
of C–C bond formation is well established, namely in
Heck-type reactions of aryl boronic acids with alkenes
to give arylated alkenes.10 Maddaford and co-workers11
investigated the use of boronic acids as nucleophiles,
which can undergo transmetalation with palladium salts
to yield the corresponding aryl palladium complex.
Boronic acids proved advantageous owing to their air
and moisture stability, broad commercial availability,
and low toxicity. The authors treated 3,4,6-tri-O-acetyl-
D-glucal 1 in CH3CN in the presence of 2 equiv of an
arylboronic acid and stoichiometric palladium acetate
to obtain the corresponding 2,3 dihydroarylglycopyrans
in good yields (Scheme 1).12
OH
B
OH
OAc
R
OAc
OAc
OAc
OAc
Pd(OAc)2
CH3CN
O
O
Keywords: C-Glycosidation; Arylboronic acids; Catalysis; Pyran ring
opening; Transacetylation; Palladium acetate; Solvent effects.
1
2
R
*
Corresponding author. Tel.: +34 93 403 4705; fax: +34 93 403
7109; e-mail: nfiguera@pcb.ub.es
Scheme 1. C-Glycosidation of 3,4,6-tri-O-acetyl-D-glucal.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.128

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N. de la Figuera et al. / Tetrahedron Letters 46 (2005) 7271–7274
Table 1. Yields for palladium acetate catalyzed C-glycosidation of tri-
O-acetyl-D-glucal 1 with arylboronic acids, as determined by column
chromatography (1) and HPLC (2)
OAc
O
OAc
AcOPd
Ar
OAc
OAc
OAc
OAc
OAc
2
3
ArPdOAc
4
1
5
6
OAc
OAc
OH
B
syn
Ar
O
O
OAc
OAc
OAc
OAc
OAc
OH
OAc
1
2
R
+
HO
O
O
Scheme 2. Mechanism of the palladium acetate catalyzed C-glycosi-
dation of 1 with arylboronic acids.
OAc
2
3
1
R
R
R
2 Yield (%)
3 Yield (%)
Ratio 2:3
The key steps of the reaction mechanism are the syn
insertion of the ArPdOAc and the antiperiplanar eli-
mination of the OAc and PdOAc to generate the p
bond (Scheme 2). The reaction is regio- and stereose-
lective. The regioselectivity stems from the fact that
the r-bond is formed by the electron deficient palla-
dium(II) and the electron rich b-carbon of the enol
ether. The stereochemistry of the reaction is determined
by the relative accessibility of the two respective faces
of the cyclic enol ether double bond to the organo-
palladium reagent for p-complex formation. In the case
of 1, only the a C-glycosil is obtained.
H1
80
77
27
34
22
51
48
51
49
nda
nda
53
59
23
37
32
26
25
—
—
2-Me2
4-iPrO2
4-MeO1
3-CF3O2
4-PhO2
3-F-4-BnO2
4-F2
0.5
0.6
1.0
1.4
1.5
2.0
2.0
3-Cl2
a nd = not detected.
The byproduct 4 was also isolated in different amounts,
and is a result of the acid-catalyzed transacetylation of 3
by the acidic reaction medium or the silica-gel used for
work-up (Scheme 3).
When we treated tri-O-acetyl-D-glucal in CH3CN with
2 equiv of the corresponding phenyl boronic acid deriva-
tive, in the presence of 0.1 M of palladium acetate, during
24 h, the expected product, 2, was obtained. How-
ever, aryl derivatives substituted with an electron-
donor group yielded two products: the expected
product, 2, and a byproduct, 3, in different yields
(Table 1).12
Based on the results, we concluded that pyran rings with
electron-donor substituents undergo ring opening during
the reaction. Electron-donor groups are responsible for
ring opening in acidic medium, due to mesomer effect,
as shown in Scheme 4.
Similar results were obtained with analogs having the S
configuration at C-4, such as tri-O-acetyl-D-galactal.
For instance, the ratios of 2:3 obtained for R = 4-PhO
and R = 3-F-4-BnO were 2.0 and 1.1, respectively.
C-Glycosylation was also carried out with heterocyclic
boronic acids instead of aryl boronic acids, in CH3CN
or THF at different temperatures. No reaction was
observed for 2-thiophen boronic acid in THF at any
temperature. On the other hand, using CH3CN instead
of THF gave the open product in 38% yield at tempera-
tures between 35 and 80 °C, while higher temperatures
led to decomposition of the product. The desired
The MS spectrum of the product 3 was similar to that of
2, but with an (MH+) that contained an extra AcOH
molecule. After purification of the crude by column
chromatography, product 3 was identified by NMR as
the ring-opened adduct. Upfield displacement of the
H-2 chemical shift as compared to that of 2 (5.45 vs
6.20 ppm) revealed that the double bond is in resonance
with the aryl group, leading to an increase in electronic
OAc
OAc
OAc
OAc
OH
H+
1
density in this position. Observation of a H NMR sig-
Ar
O
H
Ar
nal at 1.7 ppm corresponding to the hydroxyl, as well as
the presence of three signals corresponding to the acetyls,
AcO
OAc
3
4
1
seen in both the H NMR and in 13C NMR spectra of
Scheme 3. Transacetylation of the product 3 to give 4.
3, confirmed the structure.
OAc
OAc
OAc
OAc
OAc
AcOPd
OAc
OAc
OAc
OAc
AcOPd
OAc
OAc
4-MeOPhPdOAc
+
syn
O
O
H
O
H
O
OAc
H
O
O
+
3
O
Scheme 4. Proposed mechanism for the formation of the byproduct 3.

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N. de la Figuera et al. / Tetrahedron Letters 46 (2005) 7271–7274
7273
Table 4. Yields for the palladium(II) acetate catalyzed reaction of 3,4-
product was not detected for any of these conditions.
Similar results were obtained when 3-furan was used.
In this case the ring-opened adduct was obtained
in 61% yield in CH3CN at 35 °C. These results are not
surprising as the heterocycles used are p-excessive,
behaving in a similar way to the boronic acids that
contain an electron-donating group.
di-O-acetyl-6-deoxy-L-glucal
5
with arylboronic acids containing
electron-donating groups
OAc
OAc
OAc
OAc
OAc
O
+
HO
O
R
6
7
5
As the byproduct 3 is a result of the acidity of the reac-
tion medium, we thought that addition of base to the
reaction should prevent its formation. Thus, reaction
of tri-O-acetyl-D-glucal with 4-methoxyphenylboronic
acid in the presence of different organic and inorganic
bases was studied. Addition of an organic base such as
Et3N slightly increases the yield of the desired product
2, whereas inorganic bases prevented the reaction from
proceeding (Table 2).
R
R
6 Yield (%)a
4-iPrO
4-MeO
4-PhO
4-FBn
3-F-4-BnO
33
55
70
57
46
a The remainder is starting material.
Finally, solvent effects on the reaction were studied (Ta-
ble 3). In toluene/EtOH, the reaction gave product 2
exclusively. However, other solvents afforded mixtures
of 2 and 3. Thus, toluene/EtOH was found to be the sol-
vent of choice for this reaction.
rial remained for all cases. Low yields were interpreted
as a consequence of the reduction of the catalyst,
PdOAc2, to Pd0.
In summary, we have reported the formation of a
byproduct in the palladium(II) acetate catalyzed C-gly-
cosylation of peracetylated glycols with arylboronic
acids in CH3CN. The byproduct was identified as the
ring-opened adduct of the pyran, and a mechanism for
its formation has been suggested. When toluene/EtOH
is used as reaction solvent, the reaction proceeds in good
yield, regio- and stereoselectivity, and no byproduct is
formed. The reaction is currently being optimized, and
yields are expected to increase upon performing the
reaction in the presence of O2.
When the reaction was carried out using 3,4-di-O-acetyl-
6-deoxy-L-glucal (5) in toluene/EtOH, the corresponding
2,3 dihydroarylglycopyrans 6 was obtained exclusively.
In fact, no trace of the ring-opened adduct 7 could be
detected (Table 4). Large proportions of starting mate-
Table 2. Yields for C-glycosidation of tri-O-acetyl-D-glucal (1) with 4-
methoxyphenylboronic acid and palladium(II) acetate (0.1 equiv) in
the presence of different bases, as determined by HPLC
Base
Equiv
2 Yield (%)
3 Yield (%)
Acknowledgments
—
Et3N
—
1
34
39
59
40
This work was supported by Almirall Prodesfarma and
the Barcelona Science Park. The authors thank Dr. Gra-
ham Warrellow and Dr. Hamish Ryder for their
encouragement.
2
1
2
1
43
36
K3PO4
nda
nda
nda
nda
nda
nda
nda
nda
Na2CO3
2
a nd = not detected.
References and notes
1. Marquez, V. E.; Lim, M. I. Med. Res. Rev. 1986, 6, 1.
2. Subadolnik, R. J. Nucleoside Antibiotics; Wiley-Inter-
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Table 3. Solvent effects for the reaction of tri-O-acetyl-D-glucal 1 with
3-chlorophenyl boronic acid (R = 3-chloro) and palladium(II) acetate
(0.1 equiv)
3. Nicotra, F. Top. Curr. Chem. 1997, 187, 55.
4. (a) Kwork, D.-I.; Farr, R. N.; Daves, G. D., Jr. J. Org.
Chem. 1991, 56, 3711; (b) Czernecki, S.; Dechavanne,
V. Can. J. Chem. 1983, 61, 533; (c) Daves, G. D., Jr. Acc.
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Organometallics 1990, 9, 3151; (b) Levy, D. E.; Tang, C. In
The Chemistry of C-Glycosides. Tetrahedron Organic
Series; Pergamon Press, 1995; Vol. 13.
OAc
OAc
OH
B
OAc
OAc
OAc
OAc
OAc
OH
R
+
HO
O
O
OAc
2
3
1
R
R
Solvent
CH3CN
CH3CN/BuOH
THF
2 Yield (%)
3 Yield (%)
49
25
nda
27
nda
24
6. (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518; (b)
Heck, R. F. J. Am. Chem. Soc. 1979, 91, 6707.
7. (a) Moritani, I.; Fujiwara, Y. Synthesis 1973, 524; (b)
Bellosta, V.; Czernecki, S.; Avenel, D.; El Bahij, S.;
Toluene/EtOH (6:4)
60
nda
a nd = not detected.

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7274
N. de la Figuera et al. / Tetrahedron Letters 46 (2005) 7271–7274
Gillier-Pandraud, H. Can. J. Chem. 1990, 68, 1364; (c)
Czernecki, S.; Gruy, F. Tetrahedron Lett. 1981, 22, 437.
8. Price, S.; Edwards, S.; Wu, T.; Minehan, T. Tetrahedron
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Lett. 2003, 12, 2173.
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12. General procedure: To a solution of the 1,2-unsaturated
glycal (0.35 mmol) and arylboronic acid (0.7 mmol) in
CH3CN (2.5 mL) was added Pd(OAc)2 (0.035 mmol), and
the mixture was stirred at room temperature for 24 h. The
majority of the resulting Pd salt was then removed by
centrifugation. The supernatant was then concentrated,
taken up in CH2Cl2 and filtered through a BondElut
silica gel column. The filtrate was then concentrated to
dryness.