Palladium-catalyzed oxidation of benzylated aldose hemiacetals to lactones

Article abstract of DOI:10.1016/j.carres.2004.02.014

Benzyl protected sugar hemiacetals are oxidized to the corresponding lactones in excellent yields using bromobenzene, K₂CO₃ and the Pd(OAc)₂/PPh₃ catalytic system.

Full text of DOI:10.1016/j.carres.2004.02.014

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 1377–1380
Note
Palladium-catalyzed oxidation of benzylated aldose
hemiacetals to lactones
*
ꢀ
Alla Bessmertnykh, Francoise Henin and Jacques Muzart
ß
Unitꢀe Mixte de Recherche ‘Rꢀeactions Sꢀelectives et Applications’, CNRS––Universitꢀe de Reims Champagne-Ardenne,
BP 1039, F-51687 Reims, France
Received 22 October 2003; received in revised form 10 February 2004; accepted 16 February 2004
Available online 15 April 2004
Abstract—Benzyl protected sugar hemiacetals are oxidized to the corresponding lactones in excellent yields using bromobenzene,
K2CO3 and the Pd(OAc)2/PPh3 catalytic system.
Ó 2004 Elsevier Ltd. All rights reserved.
Keywords: Oxidation; Catalysis; Palladium; Sugar hemiacetals; Sugar lactones; Bromobenzene
Metal-catalyzed oxidation appears to be advantageous
from economical and environmental points of view.
Nevertheless, oxidation of the anomeric hydroxyl group
of carbohydrates is still mainly carried out using clas-
sical stoichiometric oxidants although various catalytic
processes have been proposed.1–7 Pursuing our studies of
palladium-catalyzed oxidations of alcohols,6 we now
report the highly efficient oxidation of benzyl protected
sugar hemiacetals using the Yoshidaꢀs methodology,6;8;9
which has also been developed by Choudary and
co-workers.10;11 This process, which involves PdII as
catalyst and an aryl halide as hydrogen acceptor, has
allowed the oxidation of various alcohols but to our
knowledge has never been used for the oxidation of
sugar compounds.
The oxidation of 2,3,5-tri-O-benzyl-b-D-arabinofura-
nose (1) was chosen for the optimization of the reaction
conditions (Eq 1, Table 1).
When 1 was treated with 4-bromobiphenylꢁ (2 equiv),
t-BuONa (2 equiv), Pd(OAc)2 (0.1 equiv) and PPh3
(0.2 equiv) in refluxing dioxane for 1 h, lactones 212–14
and 314;15 were isolated in 44% and 17% yield, respec-
tively; only 21% of the substrate was recovered indi-
cating some decomposition reaction (run 1). The
formation of 3 was ascribed to a base-mediated elimi-
nation reaction from 2.14;15 The conversion yield was
greatly diminished in modifying the Pd(OAc)2/PPh3
ratio (runs 2 and 3). To overcome undesirable decom-
position and elimination reactions, the oxidation was
carried out using other bases and at reflux of THF
O
O
O
OH
O
O
Pd catalyst
ArBr, base
BnO
BnO
BnO
+
(1)
BnO
OBn
OBn
OBn
BnO
1
2
3
*Corresponding author. Tel.: +33-26-91-32-37; fax: +33-3-26-91-31-66; e-mail: jacques.muzart@univ-reims.fr
ꢁ
This aromatic halide was chosen for initial studies because we expected that the presence of the p-phenyl substituent could facilitate the insertion of
the reduced Pd species into the C–Br bond.
0008-6215/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.02.014

1378
A. Bessmertnykh et al. / Carbohydrate Research 339 (2004) 1377–1380
-arabinofuranose (1)a
Table 1. Optimization of reaction conditions in the oxidation of 2,3,4-tri-O-benzyl-b-
D
Run
Pd catalyst (mol %)
Ligand (equiv/Pd)
Aryl halide
1 equiv/1
Base
2 equiv/1
Solvent
Time, h Conv., %b
2, %b
3, %b
1
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(PPh3)4 (5)
Pd2(dba)3ÆCHCl3 (5)
Pd(acac)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (2)
Pd(OAc)2 (1)
Pd(OAc)2 (0.5)
PPh3 (2)
PPh3 (4)
PPh3 (1)
PPh3 (2)
PPh3 (2)
PPh3 (2)
PPh3 (2)
PPh3 (2)
PPh3 (2)
––
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
Ph–PhBr
PhBr
t-BuONa
t-BuONa
t-BuONa
NaOAc
NEt2(i-Pr)
DBU
Dioxane
Dioxane
Dioxane
THF
1
79
10
44c
17c
2
4
Trace
Trace
Trace
Trace
3
4
10
0
4
4
5
THF
THF
4
0
6
4
0
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
THF
2
4.5
100
100
100
65
100
85
0
15
90
50
8
9
THF
THF
48
10
15
10
11
12
13
14
15
16
17
18
19
20
4
4
PPh3 (2)
PPh3 (2)
PPh3 (2)
PPh3 (2)
P(o-tol)3 (2)
(R)-BINAP (2)
PPh3 (2)
PPh3 (2)
PPh3 (2)
PPh3 (2)
THF
THF
0
4
0
THF
THF
4
100
100
100
100
100
100
100
50
100
100
100
100
100
95c
0
0
0
0
0
20
4
THF
THF
2
THF
THF
2
PhBr
PhBr
PhBr
6
THF
THF
6
40
100
25
0
25
aAll reactions were carried out at reflux under Ar with 0.5 mmol of 1 and 4 mL of solvent. The course of the reaction was monitored by TLC.
bEstimated by 1H NMR analysis.
cIsolated yield.
instead of dioxane. Screening of the base indicated that
the nature of the base play a key role, sodium acetate,
diethyl(i-propyl)amine and DBU being ineffective (runs
4–6) while the use of 2 equiv of Cs2CO3 with 0.1 equiv of
Pd(OAc)2 and 0.2 equiv of PPh3 led to a complete and
selective consumption of 1 to 2 in 2 h (run 7). However,
decreasing the amount of catalyst increased the reaction
time to reach a complete reaction; this resulted in a
lower selectivity and the butenolide could become the
main compound (runs 8 and 9). The use of Pd(PPh3)4,
Pd2(dba)3ÆCHCl3/PPh3 or Pd(acac)2/PPh3 as catalytic
system was either less or not effective (runs 10–12).
Switching from Cs2CO3 to K2CO3 was of great interest
because 2 was selectively obtained even after a pro-
longed reaction time (runs 13 and 14). Associated to
Pd(OAc)2, the sterically hindered tris(o-tolyl)phosphine
and the bidentate phosphine, (R)-BINAP, were also
excellent ligands for this reaction (runs 15 and 16).
Interestingly, replacing 4-bromobiphenyl by bromo-
benzene provided 2 quantitatively through a fast reac-
tion (run 17). Bromobenzene is more convenient than
4-bromobiphenyl as hydrogen acceptor; indeed, it is
much cheaper and allows an easier product separation
since it produces benzene instead of biphenyl. Thus, an
aqueous work-up followed by evaporation of volatiles at
70 °C under diminished pressure led to a crude white-
solid product, which could be used without additional
purification in a multistep synthesis since only minute
amounts of phosphorus compounds were detected as
impurities by NMR analysis. Furthermore, 2 and even
1 mol % of the catalyst also provided 2 quantitatively, a
longer reaction time being however necessary (runs 18
and 19). A further decrease of the amount of catalyst to
0.5 mol % reduced both conversion and selectivity (run
20).
We then examined the scope of this process using the
-glucopyranose 4, D-xylopyranose 6 and D-galacto-
D
pyranose 8 analogues and the Pd(OAc)2/PPh3/PhBr/
K2CO3 system in refluxing THF (Table 2). With 1 mol %
of Pd(OAc)2, the oxidation of the D-glucose derivative 4
(entry 1) was neither efficient nor selective, the 1H NMR
analysis of the crude reaction mixture after heating for
8 h showing the presence of lactol 4, lactone 514;16–18 and
2,4,6-tri-O-benzyl-3-deoxy-D-erythro-hex-2-enono-1,5-
lactone17 (the elimination reaction product) in the ratio
2:5:1. Fortunately, increasing the amount of Pd(OAc)2
to 2 mol % resulted in the complete conversion of 4 in 4 h
leading to 5 in 98% isolated yield. Under such experi-
mental conditions,
D D-galac-
-xylose derivative 619 and
tose derivative 8 afforded the corresponding lactones 720
and 9,16 respectively, with excellent yields (entries 2 and
3). In contrast, an acetyl protected sugar hemiacetal
such as 2,3,4-tri-O-acetyl-D-xylopyranose was almost
quantitatively recovered under the above oxidation
conditions. A possible explanation for this reluctance to
oxidation could be the ability of the alcohol substrate or
the lactone product to chelate too strongly the palla-
dium thus inhibiting the oxidation as already proposed
for other unreactive alcohols.6;21;22
In conclusion, we have developed a mild process for
the oxidation of benzyl protected sugar hemiacetals into
lactones with high yields. Owing to the great importance
of the benzyl-protecting group in carbohydrate chemis-
try,23 this efficient catalytic oxidation method, which

A. Bessmertnykh et al. / Carbohydrate Research 339 (2004) 1377–1380
1379
Table 2. Palladium-catalyzed oxidation of benzyl protected sugar hemiacetals to d-lactonesa
Entry
Substrate
Product
Time, h
Isolated yield, %
BnO
BnO
O
O
O
8b
4d
56c
98
BnO
BnO
OH
OBn
BnO
BnO
O
1
OBn
4
6
5
7
O
BnO
BnO
BnO
BnO
BnO
OH
OBn
BnO
BnO
BnO
BnO
BnO
O
2
3
7d
94
94
OBn
O
O
6d
OH
OBn
O
OBn
8
9
aReaction conditions: carbohydrate (0.5 mmol), PhBr (1.0 mmol), K2CO3 (1.0 mmol), Pd(OAc)2/2PPh3 (cat.), THF (5 mL), heating to reflux under
Ar. After conventional work-up, the products were purified by flash chromatography (9:1 petroleum ether/EtOAc).
bPd(OAc)2: 1 mol %, PPh3: 2 mol %.
c
1H NMR yield.
dPd(OAc)2: 2 mol %, PPh3: 4 mol %.
requires only commercial reagents, can be of practical
use for glyconolactone synthesis.
lization from petroleum ether/EtOAc gave 2 as a white
solid (856 mg, 82%); mp 70–70.5 °C, ½aꢀ +6.3° (c 1.56,
D
CHCl3); lit.13 mp 67.5–68.5 °C, ½aꢀ +6.6° (c 1.65,
D
CHCl3).
1. Experimental
1.1. General
Acknowledgements
This work was supported by the ꢂContrat de plan Etat-
NMR spectra were determined in CDCl3 with a Bruker
AC 250 spectrometer (1H: 250 MHz, 13C: 62MHz). E.
Merck Silica Gel 60 F254 (0.25 mm plates) was employed
for analytical TLC. THF was distilled over sodium/ben-
zophenone prior to use. Substrates 1, 4 and 8 were com-
mercial compounds from SIGMA, FLUKA and
ACROS, respectively, and used as received; 619 was pre-
ꢀ
Regionꢀ (Glycoval program). We are grateful to ꢂFon-
dation du Site Paris-Reimsꢀ for a fellowship to A.B. and
to a referee for fruitful advice.
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