A new route to 2-C- And 4-C-branched sugars by palladium-indium bromide-mediated carbonyl allylation

Article abstract of DOI:10.1039/b510811j

Palladium-catalysed carbonyl allylations can be effectively applied to the regio- and diastereoselective synthesis of 2-C- and 4-C-branched sugars from allylic esters or carbonates via the formation of π-allylpalladium(II) intermediates and their reductiv

Full text of DOI:10.1039/b510811j

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A R T I C L E
A new route to 2-C- and 4-C-branched sugars by palladium–indium
bromide-mediated carbonyl allylation
Ste´phanie Norsikian* and Andre´ Lubineau
Laboratoire de Chimie Organique Multifonctionnelle, UMR CNRS-UPS 8614
“Glycochimie Mole´culaire” Baˆt. 420, Universite´ Paris Sud, 91405, Orsay Cedex, France.
E-mail: stephnorsikian@icmo.u-psud.fr; Fax: + 33 1 69154715; Tel: + 33 1 69156836
Received 1st August 2005, Accepted 6th September 2005
First published as an Advance Article on the web 5th October 2005
Palladium-catalysed carbonyl allylations can be effectively applied to the regio- and diastereoselective synthesis of
2-C- and 4-C-branched sugars from allylic esters or carbonates via the formation of p-allylpalladium(II)
intermediates and their reductive transmetalation with indium(I) bromide.
preparing C-branched sugars in organic solvents as well as in
Introduction
aqueous media. Indeed, this avoids the preparation of bromide
derivatives that are less accessible than hydroxyl groups naturally
present in sugars.
The allylation reaction has received a great deal of attention as an
important C–C bond forming reaction. In particular indium has
emerged as the reagent of choice to mediate the reaction between
an allyl halide and a carbonyl compound because of its environ-
mentally benign properties allied with a high degree of chemo-,
regio- and diastereoselectivity especially in aqueous media.1 This
methodology has been widely studied from a mechanistic point
of view2 and also for various synthetic applications.3 For exam-
ple, we recently reported the synthesis of C-branched sugars and
C-disaccharides under indium promoted Barbier-type allyla-
tions in aqueous media.4 In particular, starting with 4-bromo-2-
enopyranosides, we could access different 2-C-branched sugars
and 4-C-branched sugars as well as C-disaccharides.4a,b The
preparation of the allylic indium reagent was also reported
by reductive transmetalation of p-allylpalladium(II) complexes
obtained from a large variety of allylic substrates with in-
dium salts in various solvents.5 This umpolung methodology
was successfully extended to vinyloxiranes,6 vinylaziridines,7
N-acylnitroso Diels–Alder cycloadducts,8 or p-allylpalladium
species obtained from aryl iodides and allenes in the presence
of palladium.9 The higher availability of usable allylic acetates
prompted us to examine the use of this methodology for
Results and discussion
We started our investigation by studying the reactivity of com-
pounds 3a–d, which were readily available from 110 (Scheme 1).
After deacetylation (NaOMe/MeOH) and selective benzylation
at O-6, the allylic alcohol 211 was obtained in 85% yield in two
steps. Adequate protection of the hydroxyl group under standard
conditions furnished 3a–d in nearly quantitative yields.
We then tested the allylation reaction of benzaldehyde with
these substrates using indium(I) bromide and palladium(0) in
anhydrous THF as the solvent (Scheme 2). As shown in Table 1,
the yield in allylation compounds is dependant on the nature of
the leaving group. Indeed, when the reaction was carried out with
3a or 3b, which possess an acetate or a benzoate leaving group,
poor yields of coupling adducts were obtained even with heating
and a high catalyst loading (20 mol% of Pd(PPh3)4) (entries 1
and 2). The yields of coupling products were greatly increased
when carbonate or trifluoroacetate were used as leaving groups.
Scheme 1 Reagents and conditions for synthesis of compounds 3a–d and 4b and 4c.
Scheme 2 Palladium-catalysed carbonyl allylation of allylic substrates with benzaldehyde.
T h i s j o u r n a l i s T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5 O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 8 9 – 4 0 9 4
4 0 8 9
©

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Table 1 Palladium-catalysed allylation of benzaldehyde with indium bromide and allylic substrates 3a–d and 4b and 4c under various conditions
Entrya
3 or 4
Pd(0) (mol%)
Conditions
Yieldb (%)
5/6c
1
2
3
3a
3b
3c
3c
3c
3c
3c
3d
3d
3d
3d
3d
4b
4b
4c
Pd(PPh3)4 (20)
Pd(PPh3)4 (20)
Pd(PPh3)4 (20)
Pd(PPh3)4 (10)
Pd(OAc)2 (10) 3PPh3
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (20)
Pd(PPh3)4 (10)
Pd(OAc)2 (10) 3PPh3
Pd(OAc)2 (5) 3PPh3
Pd(OAc)2 (2) 5PPh3
Pd(PPh3)4 (20)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
60 ◦C, 36 h
60 ◦C, 48 h
r.t., 18 h
r.t., 12 h
r.t., 12 h
r.t., 12 h
r.t., 6 h
r.t., 3 h
r.t., 3 h
r.t., 3 h
r.t., 3 h
8
31
96
80
82
82
65
93
77
90
86
76
95
40
51
100/0
100/0
37/63
36/64
44/56
99/1
66/34
100/0
100/0
100/0
100/0
100/0
50/50
0/100
0/100
4
5
6e
7d
8
9
10
11
12
13
14e
15
r.t., 12 h
r.t., 6 h
r.t., 12 h
r.t., 4 h
a The reactions were carried out in a Barbier-type manner with InBr/allylic substrate/PhCHO (2/2/1) in THF (unless specified). b Isolated yield
following chromatography. c Determined by 1H NMR spectroscopy. d THF/H2O (2/1). e 2 equivalents of LiCl were added.
Indeed, with the carbonate 3c (R = OEt), the reaction was
carried out at room temperature with 20 mol% of Pd(PPh3)4 and
led to a mixture of regioisomers 5 and 6 in a 37/63 ratio and 96%
yield (entry 3). The reaction was highly stereoselective since for
each regioisomer, a single stereoisomer was observed. The yields
were slightly decreased using 10 mol% of catalyst (entries 4 and
5). For the trifluoroacetate 3d, the 2-C-axial diastereoisomer
5 was the sole product obtained in high yield even with only
2 mol% of catalyst (entries 8–12). In this case, it was found that
Pd(OAc)2 used in combination with PPh3 gave better results than
Pd(PPh3)4 contrary to what was observed with the carbonate 3c
(entries 9 and 10 versus 4 and 5).
The reaction was also carried out with 3c in aqueous media
using a mixture of THF/H2O (2/1) to produce compounds 5
and 6 in a 66/34 ratio and 65% yield (entry 7). This decreasing
yield was due to the competitive hydrolysis of the carbonate
compound leading back to compound 2. Using these aqueous
conditions, the trifluoroacetate 3d was found to be too labile and
no coupling adduct was obtained. We also tried the Pd(OAc)2–
TPPTS catalyst that was described recently by our group to
favourably affect the generation of p-allylpalladium species and
their aqueous transmetalation with indium salts.5c However, this
system was found to be ineffective with these two substrates.
The allylation reaction with compounds 4b and 4c with
the leaving group in the axial position was also tested. They
were readily synthesized from 2 by a Mitsunobu reaction
giving 4a11 in 83% yield. After removal of the benzoate group
(MeONa/MeOH), the corresponding alcohol was protected to
give 4b or 4c in high yields (Scheme 1).
The carbonate 4b (R = OEt) was then submitted to similar
conditions involving Pd(0)/InBr and provided the same cou-
pling adducts 5 and 6 in a 50/50 ratio and 95% yield (entry
13). On the other hand, the reaction with the trifluoroacetate 4c
(R = CF3) led to the 4-C-equatorial adduct 6 as the sole product
but in a modest 51% yield due to a partial degradation of the
starting material (entry 15).
Inspection of the regio- and stereochemistry for these 2-C- and
4-C-branched sugars derived from allylindium reactions has led
to a postulated mechanism depicted in Scheme 3. In the catalytic
process, Pd(0) complexes may react with alkenes 3 or 4 to form
Scheme 3 Rationalisation of the formation of 5 and 6.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 8 9 – 4 0 9 4
4 0 9 0

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p-allyl species with inversion of configuration of the carbon
bearing the leaving group.12 The resulting p-allylpalladium(II)
complexes 7 or 10 are then reductively transmetalated with
indium(I) salts to give allylindium(III) species, which react with
benzaldehyde. As was recently confirmed by our group, InBr
approaches from the same face as the palladium leading to a
reductive transmetalation with retention of configuration.5c
Starting from the trifluoroacetate 3d (R = CF3), the two
possible allylindium(III) regioisomers 8 and 9 can be formed.
However, the allylindium species 8 is probably preferred because
of a possible chelation operating between the indium and
the oxygen on the C-6 position of the sugar moiety. Then,
the reaction of the allylindium 8 and benzaldehyde led to
the formation of compound 5 probably through the currently
accepted six-membered cyclic transition state 13 between the
carbonyl compound and the allylindium.1–4 In this transition
state, the preferential equatorial position of the phenyl group of
benzaldehyde affords 5 as a single diastereoisomer with C-7 (S)
configuration.13
In opposition, when starting from the carbonate 3c (R =
OEt), we observed, along with the expected 5, the formation
of compound 6. This derivative must result from intermediate
12, which reacts with benzaldehyde through a six-membered-
ring transition state 14, which requires the inversion of the
pyranosidic ring leading to indium in the axial position. In
this transition state, the phenyl group is still preferentially in
an equatorial position, which led to the 4-C-equatorial adduct
6 as a single diasteroisomer with C-7 (S) configuration.13 The
intermediate allylindium species 12 can probably result from
an isomerisation of the p-allylpalladium(II) complex 7 to 10 by
Pd(0).14 After reductive transmetalation of 10 with indium(I)
salts, a mixture of 11 and 12 can be obtained. However, 12 is
probably favored by stabilisation of the anionic charge in the C-2
position due to the neighbouring electrophilic anomeric centre
in the absence of a possible chelation between the indium and
the oxygen on the C-6 position of intermediate 11.
exchange Br/In takes place with retention of stereochemistry
and that the alkylation occurs at the c position, one can deduce
that 5 comes from 8 after a stereospecific 1,3 indium migration of
9. This result provides strong evidence in favour of the assertion
that the allylindium(III) species 9 do not epimerise to 12 under
the reaction conditions.
In order to increase regioselectivity with the carbonate 3c, the
InBr/Pd(0)-mediated carbonyl allylation was carried out in the
presence of 2 equivalents of LiCl, which is known for having
an influence on the reactivity and selectivity of Pd-catalysed
allylic substitution reactions (Table 1, entry 6).17 In this case, the
chloride anion has a beneficial effect on the regiochemistry and
the coupling adducts 5 and 6 were obtained in a 99/1 ratio and
82% yield.
In the case of the axial derivatives, starting from the
trifluoroacetate 4c, the resulting p-allylpalladium(II) complex
10 is reductively transmetalated with indium(I) salts to give
preferentially the allylindium(III) species 12, which allylates
benzaldehyde and gives 6 as the sole coupling product. For this
substrate, the allylation step is less favorable since a change in the
conformation of the sugar moiety is needed so that the reaction
occurs. However, with the carbonate 4b (R = OEt), isomerisation
of the p-allylpalladium(II) complex 10 takes place leading to a
mixture of 5 and 6. In this case, the regioselectivity can also be
controlled by the addition of lithium chloride17 in the reaction
mixture furnishing only 6 but in a modest 40% yield (Table 1,
entry 14).
In conclusion, the above results show that 2-C- and 4-
C-branched sugars are effectively obtainable from readily
available allylic esters or carbonates via the formation of p-
allylpalladium(II) intermediates and their reductive transmet-
alation with indium(I) bromide. Work is currently in progress in
our laboratory to extend this methodology to pyranosides that
contain allylic esters or carbonates in other positions.
In order to verify our hypothesis that inversion occurs at
the p-allylpalladium stage and not at the allylindium one
(equilibration between 9 and 12), we synthesised 2-bromo-
4-enopyranoside 20 with the bromide atom in an axial C-2
position. This compound was prepared by selective protection of
1515 by a benzoate group at the O-2 position16 then the cleavage
of the 4,6-O-benzylidene group with NaBH3CN and HCl affords
the 6-O-benzyl derivative 17. Treated with PPh3, CHI3 and
imidazole in refluxing toluene,16 this later led to the allylic
benzoate 18 in 84% yield. After removal of the 2-O protecting
group and treatment of the resulting alcohol 19 with PPh3 and
CBr4 in CH2Cl2, the desired allylic bromide 20 was obtained.
This was then submitted to a Barbier-type allylation reaction
with benzaldehyde and indium bromide in THF (Scheme 4). In
this case, the reaction does not proceed at room temperature
Experimental
General
All moisture-sensitive reactions requiring anhydrous conditions
were conducted in oven-dried apparatus under an atmosphere
of argon. If necessary, solvents were dried and distilled prior
to use. External reaction temperatures are reported unless
stated otherwise. Reactions were monitored on silica gel 60
F254. Detection was performed using UV light and/or 5%
sulfuric acid in ethanol, followed by heating. Flash chromatogra-
phies were performed on silica gel 6–35 lm. [a]D Values (in
deg cm3 g−1 dm−1) were measured on an Electronic Digital Jasco
DIP-370 Polarimeter. IR spectra were recorded as thin films
unless stated otherwise. NMR spectra were recorded in CDCl3
unless stated otherwise with Bruker AC 200, 250 or Bruker AM
400 spectrometers. 1H NMR chemical shifts are reported relative
to CHCl3 (dH 7.26), 13C NMR chemical shifts are reported
◦
but at 60 C. After 36 hours, the only coupling adduct was 5,
which was obtained in a poor yield of 35%. Considering that the
Scheme 4 Reagents and conditions for the synthesis of compound 20. Barbier-type allylation of 20 with benzaldehyde and InBr.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 8 9 – 4 0 9 4
4 0 9 1

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relative to CDCl3 (dC [central line of three] 77.0). Coupling
constants (J) are given in Hz. Mass spectra were recorded in
positive mode on a Finnigan MAT 95 S spectrometer using
electrospray ionization. Elemental analyses were performed at
the Service Central de Microanalyses du CNRS (Gif-sur-Yvette,
France).
(EI) 391 ([M + Na]+, 100%); HRMS (EI high resolution): m/z
391.152240. C22H24NaO5 requires 391.152143.
Ethyl 6-O-benzyl-4-O-(ethylcarbonate)-2,3-dideoxyhex-2-
enopyranoside 3c
Compound 2 (0.66 g, 2.5 mmol) was dissolved in CH2Cl2.
Pyridine (1.4 mL, 12.5 mmol), DMAP (15 mg, 0.12 mmol)
and ClCO2Et (0.66 mL, 6.8 mmol) were added successively at
Ethyl 6-O-benzyl-2,3-dideoxyhex-2-enopyranoside 2
To a solution of 1 (10 g, 38.8 mmol) in MeOH (300 mL) at
room temperature was added sodium methanolate (105 mg,
1.94 mmol). After 2 hours, the solvent was removed under
reduced pressure and the crude residue was dissolved in toluene
(150 mL). Bu2SnO (10.6 g, 42.6 mmol) was added and the
reaction mixture was refluxed while water was continuously
removed by means of a Dean Stark trap. After 4 h, nBu4NBr
(14.1 g, 43.8 mmol) and BnBr were added and the reaction was
then allowed to warm at 115 ◦C for 18 hours. The temperature
of the reaction was cooled to room temperature before addition
of ethyl acetate (200 mL) and water (100 mL). The two phases
were separated and the organic one was washed with a saturated
aqueous solution of NaHCO3 (100 mL) and then with brine
(100 mL). The organic phase was dried over MgSO4, filtered and
concentrated. Flash chromatography of the crude residue (SiO2,
petroleum ether (40–65 ◦C)/ethyl acetate = 8/2) gave allylic
alcohol 2 as a colourless oil (8.7 g g, 85%). Data consistent with
the literature.11
0
◦C. After 12 hours at room temperature, solvents were co-
evaporated with toluene and the residue was diluted with ethyl
acetate (20 mL) and H2O (10 mL). The aqueous phase was
extracted with ethyl acetate (3 × 15 mL) and the combined
organic phases were washed with a saturated aqueous solution
of NaHCO3 (2 × 10 mL) and then with brine (10 mL). The
organic phase was dried over MgSO4, filtered and concentrated.
Flash chromatography of the crude residue (SiO2, petroleum
◦
ether (40–65 C)/ethyl acetate = 85/15) gave allylic carbonate
3c (0.8 g, 95%) as a colourless oil (Found: C, 64.29; H, 7.11; O,
28.51. C18H24O6 requires C, 64.27; H, 7.19; O, 28.54%); [a]D25 102
(c 0.7 in CHCl3); tmax/cm−1 3032, 2979, 2902, 1747, 1525, 1450,
1373, 1257, 1103, 1050, 1015; dH (250 MHz, CDCl3) 7.40–7.20
(5H, m), 5.97 (1H, d, J 10), 5.84 (1H, td, J 2, 10), 5.32 (1H,
dd, J 2, 9), 5.12–5.04 (1H, m), 4.68 (1H, d, J 12), 4.53 (1H, d,
J 12), 4.21 (1H, dd, J 2, 7), 4.14 (1H, dd, J 2, 7), 4.07 (1H,
td, J 3, 9), 3.85 (1H, qd, J 7, 10), 3.7–3.43 (3H, m), 1.33–1.18
(6H, m); dC (62.5 MHz, CDCl3) 154.8, 138.4, 129.2, 128.7, 128.6,
128.0, 127.9, 94.6, 73.7, 69.3, 69.1, 68.1, 64.6, 64.5, 15.7, 14.5;
MS (EI) 359 ([M + Na]+, 100%); HRMS (EI high resolution):
m/z 359.1472. C18H24NaO6 requires 359.1465.
Ethyl 4-O-acetyl-6-O-benzyl 2,3-dideoxyhex-2-enopyranoside 3a
Compound 2 (0.95 g, 3.6 mmol) was dissolved in pyridine (2 mL)
and acetic anhydride (0.7 mL, 7.2 mmol) was added. After
12 hours at room temperature, solvents were co-evaporated with
toluene and the residue was purified by flash chromatography
Ethyl 6-O-benzyl-4-O-trifluoroacetyl-2,3-dideoxyhex-2-
enopyranoside 3d
◦
(SiO2, petroleum ether (40–65 C)/AcOEt = 85/15) to afford
To a solution of 2 (0.66 g, 2.5 mmol) in CH2Cl2 (10 mL) was
added successively at 0 ◦C 2,6-lutidine (0.3 mL, 2.6 mmol),
DMAP (30 mg, 0.25 mmol) and trifluoroacetic anhydride
(0.4 mL, 2.6 mmol). After 3 hours at room temperature, H2O
(15 mL) was added and the aqueous phase was extracted with
ethyl acetate (3 × 20 mL). The combined organic phases were
washed with a saturated aqueous solution of K2HPO4 (2 ×
15 mL) and then with brine (15 mL). The organic phase was dried
over Na2SO4, filtered and concentrated. Flash chromatography
of the crude residue (SiO2, petroleum ether (40–65 ◦C)/ethyl
acetate = 85/15) gave allylic trifluoroacetate 3d (0.83 g, 92%) as
a colourless oil (Found: C, 57.05; H, 5.38. C17H19F3O5 requires
C, 56.67; H, 5.31; F, 15.82; O, 22.20.%); [a]D25 90 (c 0.5 in CHCl3);
tmax/cm−1 2978, 2899, 1787, 1454, 1372, 1223, 1160, 1109, 1050,
1018, 734; dH (250 MHz, CDCl3) 7.45–7.20 (5H, m), 6.0–5.91
(1H, m), 5.89 (1H, d, J 11), 5.69 (1H, d, J 10), 5.13–5.08 (1H,
m), 4.69 (1H, d, J 12), 4.48 (1H, d, J 12), 4.16 (1H, dt, J 3,
9), 3.86 (1H, dq, J 7, 10), 3.68–3.52 (3H, m), 1.26 (3H, t, J 7);
dC (62.5 MHz, CDCl3) 150.0, 137.3, 129.6, 128.4, 127.8, 126.7,
94.1, 73.5, 69.3, 67.8, 67.0, 64.5, 15.2; MS (EI) 287 (100%); 383
([M + Na]+, 40%).
3a (1.1 g, 100%) as a colourless oil (Found: C, 66.55; H, 7.09; O,
25
25.95. C17H22O5 requires C, 66.65; H, 7.24; O, 26.11%); [a]D
−
122.4 (c 0.5 in CHCl3); tmax/cm−1 2976, 2896, 1741, 1455, 1372,
1234, 1103, 1045, 907, 738, 699; dH (250 MHz, CDCl3) 7.50–7.25
(5H, m), 5.90 (1H, dd, J 3, 12), 5.83 (1H, dt, J 2, 12), 5.44 (1H,
dd, J 2, 10), 5.15–5.05 (1H, m), 4.67 (1H, d, J 12), 4.51 (1H, d, J
12), 4.15–4.05 (1H, m), 3.87 (1H, dq, J 7, 10), 3.7–3.5 (3H, m),
1.97 (3H, s), 1.25 (3H, t J 7); dC (62.5 MHz, CDCl3) 170.0, 152.0,
129.0, 128.0, 127.6, 127.4, 127.3, 93.9, 73.0, 68.3, 67.6, 65.3, 63.8,
20.6, 15.0; MS (EI) 329 ([M + Na]+, 100%); HRMS (EI high
resolution): m/z 329.136310. C17H22NaO5 requires 329.136493.
Ethyl 4-O-benzoyl-6-O-benzyl-2,3-dideoxyhex-2-
enopyranoside 3b
Compound 2 (0.66 g, 2.5 mmol) was dissolved in pyridine
(2.8 mL). DMAP (15 mg, 0.12 mmol) and benzoyl choride
((0.6 mL, 5 mmol) were added and the reaction mixture
was stirred 4 hours at room temperature. Solvents were co-
evaporated with toluene and the residue was diluted with ethyl
acetate (20 mL). The organic phase was washed with a saturated
aqueous solution of NaHCO3 (2 × 10 mL) and then with brine
(10 mL). The organic phase was dried over MgSO4, filtered and
concentrated. Flash chromatography of the crude residue (SiO2,
petroleum ether (40–65 ◦C)/ethyl acetate = 9/1) gave allylic
benzoate 3b (0.87 g, 94%) as a colourless oil (Found: C, 71.81;
H, 6.55; O, 21.6. C22H24O5 requires C, 71.72; H, 6.57; O, 21.71%);
Ethyl 4-O-benzoyl-6-O-benzyl-2,3-dideoxyhex-2-
enopyranoside 4a
To a solution of 2 (1.3 g, 4.9 mmol) in anhydrous THF (12 mL)
were added triphenylphosphine (2.3 g, 8.8 mmol), benzoic acid
(1.1 g, 9 mmol) and DIAD (1.8 mL, 9.1 mmol). The reaction
mixture was stirred for 2 hours at room temperature and EtOAc
(30 mL) was added to the residue. The organic phase was washed
with a saturated aqueous solution of NaHCO3 (3 × 15 mL) and
then with brine (15 mL). The organic phase was dried over
MgSO4, filtered and concentrated. Flash chromatography of the
crude residue (SiO2, petroleum ether (40–65 ◦C)/ethyl acetate =
95/5) gave the allylic benzoate 4a as a colourless oil (1.5 g, 83%).
Data consistent with the literature.11
25
[a]D 178 (c 0.6 in CHCl3); tmax/cm−1 3062, 3031, 2975, 2895,
1721, 1496, 1316, 1267, 1108, 1050, 1026, 736, 713; dH (200 MHz,
CDCl3) 7.97 (2H, d, J 8), 7.60–7.10 (8H, m), 6.03 (1H, d, J 12),
5.88 (1H, dt, J 2, 12), 5.70 (1H, dd, J 2, 9), 5.16–5.09 (1H, m),
4.64 (1H, d, J 12), 4.53 (1H, d, J 12), 4.32–4.20 (1H, m), 3.98
(1H, dq, J 7, 9), 3.7–3.5 (3H, m), 1.29 (3H, t J 6); dC (62.5 MHz,
CDCl3) 165.7, 152.6, 137.8, 133.1, 129.6, 129.4, 128.2, 128.1,
127.9, 127.4, 127.3, 94.2, 73.2, 68.7, 68.1, 65.9, 64.1, 15.2; MS
4 0 9 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 8 9 – 4 0 9 4

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Ethyl 6-O-benzyl-4-O-(ethylcarbonate)-2,3-dideoxyhex-2-
enopyranoside 4b
Ethyl
6-O-benzyl-2-C-[(S)-1-phenyl-1-hydroxymethyl]-3,4-
dideoxy-a-D-threo-hex-3-enopyranoside 5. Rf = 0.27 (SiO2,
petroleum ether (40–65 ◦C)/ethyl acetate = 9/1); Found: C,
74.36; H, 7.49; O, 18.31. C22H26O4 requires C, 74.55; H, 7.39; O,
To a solution of 4a (0.87 g, 2.36 mmol) in MeOH (10 mL)
at room temperature was added sodium methanolate (6 mg,
0.118 mmol). After 12 hours at room temperature, the solvent
was removed under reduced pressure and the crude residue was
dissolved in CH2Cl2 (15 mL). Pyridine (1.4 mL, 12.5 mmol),
DMAP (30 mg, 0.25 mmol) and ClCO2Et (1.3 mL, 13.8 mmol)
were added successively at 0 ◦C. After 2 hours at room
temperature, H2O (20 mL) was added and the aqueous phase
was extracted with CH2Cl2 (3 × 20 mL). The combined organic
phases were washed with a saturated aqueous solution of
NaHCO3 (15 mL) and then with brine (10 mL), dried over
MgSO4, filtered and concentrated. Flash chromatography of the
crude residue (SiO2, petroleum ether (40–65 ◦C)/ethyl acetate =
95/5 to 9/1) gave allylic carbonate 4b (0.7 g, 89%) as a colourless
oil (Found: C, 63.63; H, 7.03; O, 29.25. C18H24O6 requires C,
25
18.06%); [a]D 66 (c 0.6 in CHCl3); tmax/cm−1 3446, 3062, 3031,
2974, 2863, 1495, 1454, 1363, 1311, 1186, 1116, 1066, 1022,
920, 845, 766, 734, 700; dH (250 MHz, CDCl3) 7.50–7.20 (10H,
m, Ph), 5.80 (1H, dt, J 1, 12, H-3), 5.48 (1H, dt, J 2, 12, H-4),
5.11 (1H, bs, H-1), 4.69 (1H, d, J 7, H-7), 4.64 (2H, s, CH2Ph),
4.42–4.32 (1H, m, H-5), 3.82 (1H, dq, J 7, 10, CH2CH3), 3.61
(2H, dd, J 1, 4, H-6 and H-6ꢀ), 3.53 (1H, dq, J 7, 10, CH2CH3),
2.95–2.75 (1H, bs, OH), 2.55–2.45 (1H, m, H-2), 1.20 (3H,
t J 7, CH2CH3); dC (62.5 MHz, CDCl3) 142.4, 137.9, 128.2,
128.1, 127.7, 127.6, 127.5, 127.4, 124.3, 96.7, 74.7, 73.2, 71.9,
67.6, 63.3, 46.0, 15.0; MS (EI) 377 ([M + Na]+, 100%); HRMS
(EI high resolution): m/z 377.172879. C22H26NaO4 requires
377.173120.
64.27; H, 7.19; O, 28.54%; [a]D −146 (c 0.4 in CHCl3); tmax/cm−1
25
Ethyl
6-O-benzyl-4-C-[(S)-1-phenyl-1-hydroxymethyl]-2,3-
2978, 2876, 1742, 1455, 1372, 1259, 1101, 1050, 1009, 739; dH
(250 MHz, CDCl3) 7.40–7.20 (5H, m), 6.19 (1H, dd, J 5, 10),
6.05 (1H, dd, J 3, 10), 5.08 (1H, d, J 2), 4.90 (1H, dd, J 2, 5), 4.62
(1H, d, J 12), 4.54 (1H, d, J 12), 4.38 (1H, td, J 2, 7), 4.2 (1H, dd,
J 1, 7), 4.14 (1H, dd, J 1, 7), 3.86 (1H, dq, J 7, 9), 3.71 (2H, d,
J 7), 3.56 (1H, dq, J 7, 9), 1.28 (3H, t, J 7, CH2CH3), 1.23 (3H,
t, J 7); dC (62.5 MHz, CDCl3) 154.6, 138.0, 131.1, 128.7, 128.6,
128.0, 124.7, 93.5, 73.2, 68.6, 67.4, 65.8, 64.0, 63.6, 15.1, 14.0;
MS (EI) 359 ([M + Na]+, 100%); HRMS (EI high resolution):
m/z 359.147820. C18H24NaO6 requires 359.147058.
dideoxy-a-D-erythro-hex-2-enopyranoside 6. Rf = 0.24 (SiO2,
petroleum ether (40–65 ◦C)/ethyl acetate = 9/1); Found: C,
73.87; H, 7.56; O, 17.99. C22H26O4 requires C, 74.55; H, 7.39; O,
18.06%); [a]D25 3.6 (c 0.3 in CHCl3); tmax/cm−1 3450, 3087, 3032,
2976, 2927, 2876, 1495, 1453, 1266, 1089, 1050, 1012, 737, 702;
dH (250 MHz, CDCl3) 7.50–7.20 (10H, m, Ph), 5.75 (1H, dt, J
3, 10, H-3), 5.51 (1H, dd, J 2, 10, H-2), 4.97 (1H, bs, H-1), 4.61
(1H, d, J 12, CH2Ph), 4.53 (1H, dd, J 3, 8, H-7), 4.51 (1H, d, J
12, CH2Ph), 4.04 (1H, td, J 4, 8, H-5), 3.90–3.74 (2H, m, H-6
and CH2CH3), 3.68 (1H, dd, J 4, 10, H-6ꢀ), 3.52 (1H, qd, J 7,
10, CH2CH3), 3.14 (1H, d, J 3, OH), 2.82 (1H, m, H-4), 1.22
(3H, t, J 7); dC (62.5 MHz, CDCl3) 142.6, 138.2, 130.4, 128.9,
128.8, 128.3, 128.2, 128.1, 127.3, 127.2, 94.0, 75.9, 73.8, 72.8,
69.6, 63.9, 44.4, 15.8; MS (EI) 377 ([M + Na]+, 100%); HRMS
(EI high resolution): m/z 377.17225. C22H26NaO4 requires
377.1723.
Ethyl 6-O-benzyl-4-O-trifluoroacetyl-2,3-dideoxyhex-2-
enopyranoside 4c
To a solution of 4a (1.5 g, 4.08 mmol) in MeOH (20 mL) at room
temperature was added sodium methanolate (11 mg, 0.2 mmol).
After 12 hours at room temperature, the solvent was removed
under reduced pressure and the crude residue was purified by
Ethyl 4,6-benzylidene-2-O-benzoyl-a-D-glucopyranoside 16
◦
flash chromatography (SiO2, petroleum ether (40–65 C)/ethyl
acetate = 8/2 to 7/3) to afford allylic alcohol as a colourless
oil (0.88 g, 81%). The latter (0.88 g, 3.3 mmol) was dissolved in
CH2Cl2 (15 mL) and 2,6-lutidine (0.42 mL, 3.63 mmol), DMAP
(40 mg, 0.33 mmol) and trifluoroacetic anhydride (0.5 mL,
3.63 mmol) were added successively at 0 ◦C. After 3 hours at
room temperature, H2O (15 mL) was added and the aqueous
phase was extracted with CH2Cl2 (3 × 20 mL). The combined
organic phases were washed with a saturated aqueous solution of
K2HPO4 (2 × 15 mL) and then with brine (15 mL). The organic
phase was dried over Na2SO4, filtered and concentrated. Flash
chromatography of the crude residue (SiO2, petroleum ether
(40–65 ◦C)/ethyl acetate = 9/1) gave allylic trifluoroacetate 4c
(1.18 g, 99%) as a colourless oil (Found: C, 56.39; H, 5.28.
C17H19F3O5 requires C, 56.67; H, 5.31; F, 15.82; O, 22.20%);
To a solution of 15 (1.5 g, 5.1 mmol) in dry MeOH (20 mL) was
added Bu2SnO (1.24 g, 5 mmol) and the reaction mixture was
refluxed for 1 hour after which the solution became completely
clear. The solvents were removed under reduced pressure and
the crude residue was diluted in dry dioxane (37.5 mL). NEt3
(0.8 mL, 5.5 mmol) and benzoyl chloride (0.64 mL, 5.5 mmol)
were then added and the reaction mixture was stirred for 1 hour
at room temperature. The reaction mixture was filtered over
Celite and the solvents were evaporated under reduced pressure.
Flash chromatography of the crude residue (SiO2, petroleum
ether (40–65 ◦C)/ethyl acetate = 85/15 to 8/2) gave 16 (1. 8 g,
90%) as a colourless oil (Found: C, 66.13; H, 6.15; O, 27.84.
25
C22H24O7 requires C, 65.99; H, 6.04; O, 27.84%); [a]D 10.7 (c
0.6 in CHCl3); tmax/cm−1 3450, 3066, 3038, 2977, 2927, 2870,
1720, 1630, 1524, 1453, 1380, 1334, 1277, 1097, 1031, 988, 758,
710; dH (250 MHz, CDCl3) 8.13 (2H, d, J 7), 7.65–7.35 (8H, m),
5.59 (1H, s), 5.22 (1H, d, J 4), 5.05 (1H, dd, J 4, 9), 4.45–4.30
(2H, m), 3.97 (1H, dd, J 4, 9), 3.82–3.75 (2H, m), 3.64 (1H, t,
J 9), 3.51 (1H, qd, J 7,10), 2.90–2.75 (1H, bs), 2.70–2.62 (1H,
bs), 1.22 (3H, t J 7); dC (62.5 MHz, CDCl3) 166.2, 137.0, 133.2,
129.8, 129.2, 128.3, 128.2, 126.3, 126.2, 101.9, 96.4, 81.4, 74.0,
68.8, 68.7, 63.9, 62.1, 14.9; MS (EI) 423 ([M + Na]+, 100%).
25
[a]D −171 (c 0.9 in CHCl3); tmax/cm−1; dH (250 MHz, CDCl3)
7.50–7.20 (5H, m), 6.15–6.10 (2H, m), 5.24–5.18 (1H, m), 5.09–
5.05 (1H, m), 4.55–4.35 (3H, m), 3.82 (1H, dq, J 7, 9), 3.71–3.47
(3H, m), 1.22 (3H, t, J 7), 1.23 (3H, t, J 7); dC (62.5 MHz, CDCl3)
154.0, 137.5, 132.9, 128.4, 127.8, 127.6, 122.9, 93.4, 73.5, 67.9,
67.1, 66.6, 64.1, 15.1; MS (EI) 287 (100%); 383 ([M + Na]+, 80%).
General procedure for palladium–indium bromide mediated
carbonyl allylation
Ethyl 6-O-benzyl-2-O-benzoyl-a-D-glucopyranoside 17
To a solution of 3a–d or 4b, c (0.5 mmol) in dry THF (1.5 mL)
was added Pd0 under argon at room temperature. The reaction
mixture was stirred for 5 min before addition of benzaldehyde
(26 lL, 0.25 mmol) and indium bromide (97 mg, 0.5 mmol).
After completion of the reaction, the solvents were evaporated
under reduced pressure and the crude residue was purified by
To a solution of 16 (2.38 g, 5.95 mmol) in dry THF (60 mL)
˚
was added powdered molecular sieves (4 A, 3.2 g), orange
methyl and NaBH3CN (3.2 g, 50.8 mmol). After 15 min at
room temperature, the yellow solution was cooled to 0 ◦C
and a saturated solution of HCl in ether was added until the
solution turned to pink. The reaction mixture was then added
to a cold saturated aqueous solution of NaHCO3 (100 mL) and
the aqueous phase was extracted with Et2O (3 × 100 mL). The
◦
flash chromatography (SiO2, petroleum ether (40–65 C)/ethyl
acetate = 9/1 to 8/2) to afford to 5 and/or 6 as a colourless
oil.13
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 8 9 – 4 0 9 4
4 0 9 3

View Article Online
combined organic layers were washed with H2O (3 × 10 mL)
and then with brine (100 mL). The organic phase was dried over
Na2SO4, filtered and concentrated. Flash chromatography of the
crude residue (SiO2, petroleum ether (40–65 ◦C)/ethyl acetate =
6/4) gave compound 17 (2.1 g, 87%) as a white solid (Found:
C, 65.51; H, 6.53; O, 27.62. C22H26O7 requires C, 65.66; H, 6.51;
Acknowledgements
This work was supported by the CNRS and the Ministe`re de
l’Education Nationale de l’Enseignement Superieur et de la
Recherche.
25
O, 27.83%); [a]D − 109 (c 0.5 in CHCl3); tmax/cm−1 3484, 3351,
References and notes
3089, 3066, 3037, 2983, 2864, 1712, 1603, 1584, 1496, 1452,
1316, 1288, 1158, 1115, 1046, 705; dH (250 MHz, CDCl3) 8.08
(2H, d, J 7), 7.65–7.25 (8H, m), 5.15 (1H, d, J 3), 4.94 (1H, dd,
J 3, 10), 4.66 (1H, d, J 12), 4.47 (1H, d, J 12), 4.22–4.10 (1H,
m), 3.92–3.65 (5H, m), 3.49 (1H, dd, J 7, 10), 3.00–2.92 (1H,
bs), 2.70–2.62 (1H, bs), 1.19 (3H, t J 7); dC (62.5 MHz, CDCl3)
166.4, 137.8, 133.1, 129.8, 129.6, 128.3, 128.2, 127.6, 95.8, 73.7,
73.5, 71.7, 71.6, 69.8, 69.5, 63.6, 14.9; MS (EI) 425 ([M + Na]+,
100%).
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Tetrahedron, 2001, 57, 4139–4146; (k) P. Bernardelli, O. M. Moradei,
D. Friedrich, J. Yang, F. Gallou, B. P. Dyck, R. W. Doskotch, T.
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3206–3210; (b) A. Lubineau, Y. Canac and N. Le Goff, Adv. Synth.
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Org. Lett., 2000, 2, 847–849; (b) T. S. Jang, G. Keum, S. B. Kang,
B. Y. Chung and Y. Kim, Synthesis, 2003, 5, 775–779; (c) G. Fontana,
A. Lubineau and M.-C. Scherrmann, Org. Biomol. Chem., 2005, 3,
1375–1380.
Ethyl 2-O-benzoyl-6-O-benzyl-3,4-dideoxyhex-3-
enopyranoside 18
To a solution of 17 (0.125 g, 0.31 mmol) in toluene (10 mL) was
added successively PPh3 (0.33 g, 1.3 mmol), imidazole (43 mg,
0.635 mmol) and CHI3 (0.244 g, 0.62 mmol) and the reaction
mixture was allowed to warm to reflux for 45 min. The solution
was cooled and diluted with ethyl acetate. The organic layer
was washed with a saturated aqueous solution of NaHCO3 (2 ×
20 mL), dried over Na2SO4, filtered and concentrated. Flash
chromatography of the crude residue (SiO2, petroleum ether
(40–65 ◦C)/ethyl acetate = 9/1) gave compound 18 (95 mg,
84%) as a colourless oil (Found: C, 71.99; H, 6.66; O, 21.82.
25
C22H24O5 requires C, 71.72; H, 6.57; O, 21.71%); [a]D − 31 (c
0.3 in CHCl3); tmax/cm−1 3063, 3031, 2975, 2863, 1718, 1452,
1319, 1267, 1099, 714; dH (250 MHz, CDCl3) 8.08 (2H, d, J 7),
7.55–7.20 (8H, m), 5.99 (1H, dt, J 2, 10), 5.87 (1H, d, J 10),
5.62–5.55 (1H, m), 5.39 (1H, d, J 4), 4.65 (2H, s), 4.52–4.42 (1H,
m), 3.87 (1H, dq, J 7, 10), 3.72–3.51 (3H, m), 1.22 (3H, t J 7);
dC (62.5 MHz, CDCl3) 165.7, 137.6, 132.8, 129.4, 129.2, 128.1,
128.0, 127.3, 123.1, 94.3, 73.1, 71.6, 67.4, 66.9, 63.8, 14.8; MS
(EI) 391 ([M + Na]+, 100%); HRMS (EI high resolution): m/z
391.15215. C22H24NaO5 requires 391.152143.
6 (a) S. Araki, K. Kameda, T. Hirashita, H. Yamamura and M. Kawai,
J. Org. Chem., 2001, 66, 7919–7921; (b) S. Araki, S. Kambe, K.
Kameda and T. Hirashita, Synthesis, 2003, 5, 751–754.
7 M. Anzai, R. Yanada, F. Nobutaka, H. Ohno, T. Ibuka and Y.
Takemoto, Tetrahedron, 2002, 58, 5231–5239.
8 W. Lee, K. H. Kim, M. D. Surman and M. J. Miller, J. Org. Chem.,
2003, 68, 139–149.
9 L. A. T. Cleghorn, I. R. Cooper, R. Grigg, W. S. Maclachlan and V.
Sridharan, Tetrahedron Lett., 2003, 44, 7969–7973.
10 R. J. Ferrier and N. Prasad, J. Chem. Soc. C, 1969, 570–575.
11 V. Pedretti, J.-M. Mallet and P. Sinay, Carbohydr. Res., 1993, 244,
247–258.
Ethyl 6-O-benzyl-2-bromo-3,4-dideoxyhex-3-enopyranoside 20
To a solution of 18 (0.86 g, 2.3 mmol) in MeOH (10 mL) was
added sodium methanolate (6 mg, 0.115 mmol). After 2 days
at room temperature, the solvent was removed under reduced
pressure and the crude residue was diluted in ethyl acetate. The
organic layer was washed with a saturated aqueous solution
of NaHCO3 (20 mL), brine (20 mL) then dried over Na2SO4,
filtered and concentrated. The crude residue was diluted in
CH2Cl2 (10 mL) and PPh3 (0.9 g, 3.45 mmol) and CBr4 (0.84 g,
2.5 mmol) were successively added at −10 ◦C. After 2 hours at
12 T. Hayashi, T. Hagihara, M. Konishi and M. Kumada, J. Am. Chem.
Soc., 1983, 105, 7767–7768.
13 The structure and the absolute configurations were determined by
chemical correlation (benzylation at O-6) starting from compounds
described in references 4a and/or 4b for which the structures were
fully elucidated. Indeed, the Pd(0)/InBr mediated carbonyl allylation
of benzaldehyde gives the same coupling adducts as those obtained
from the allylic bromide derivatives.
◦
0 C then 12 hours at room temperature, a saturated aqueous
solution of NaHCO3 (10 mL) was added and the aqueous phase
was extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were washed with brine (25 mL), dried over Na2SO4,
filtered and concentrated. Flash chromatography of the crude
residue (SiO2, petroleum ether (40–65 ◦C)/ethyl acetate = 95/5)
afforded compound 20 (0.46 g mg, 61% for two steps) as a
14 (a) J. E. Ba¨ckvall, J. O. Va˚gberg, C. Zercher, J. P. Geneˆt and A.
Denis, J. Org. Chem., 1987, 52, 5430–5435; (b) M. Moreno-Man˜as,
J. Ribas and A. Virgili, J. Org. Chem., 1988, 53, 5328–5435; (c) S.-I.
Murahashi, Y. Taniguchi, Y. Imada and Y. Tanigawa, J. Org. Chem.,
1989, 54, 3292–3303; (d) J. E. Ba¨ckvall, K. L. Granberg and A.
Heumann, Isr. J. Chem., 2001, 31, 17–24.
colorless oil. [a]D 232 (c 0.4 in CHCl3); tmax/cm−1 3030, 2976,
25
15 C. Bosso, J. Defaye, A. Gadelle and J. Ulrich, Org. Mass Spectrom.,
1977, 12, 493–499.
2865, 1496, 1363, 1335, 1187, 1112, 1062, 761; dH (400 MHz,
CDCl3) 7.45–7.20 (5H, m), 6.01 (1H, dd, J 5, 10), 5.88 (1H,
dd, J 2, 10), 5.19 (1H, s), 4.62 (2H, s), 4.54–4.48 (1H, m), 3.83
(1H, dq, J 7, 10), 3.69 (1H, dd, J 6, 10), 3.61 (1H, dq, J 7,
10), 3.58 (1H, dd, J 6, 10), 1.21 (3H, t J 7); dC (62.5 MHz,
CDCl3) 138.0, 129.4, 129.4, 128.3, 127.7, 127.6, 124.5, 99.2, 73.5,
71.7, 67.4, 64.1, 42.7, 15.0; MS (EI) 349 ([M + Na]+, 98%), 351
([M + Na]+, 100%); HRMS (EI high resolution): m/z 349.04132.
C15H19NaBrO3 requires 349.041537.
16 A. G. Wee and L. Zhang, Synth. Commun., 1993, 23, 325–334.
˚
17 (a) S. Hansson, P.-O. Norrby, M. P. T. Sjo¨gren, B. Akermark,
M. E. Cucciolito, F. Giordano and A. Vitagliano, Organometallics,
1993, 12, 4940–4948; (b) M. Bovens, A. Togni and L. M. Venanzi,
J. Organomet. Chem., 1993, 451, C28–C31; (c) C. Amatore, A. Jutand,
M. A. M’Barki, G. Meyer and L. Mottier, Eur. J. Inorg. Chem., 2001,
873–880; (d) G. Malaise´, L. Barloy, J. A. Osborn and N. Kyritsakas,
C. R. Chim., 2002, 5, 289–296; (e) T. Cantat, E. Ge´nin, C. Giroud,
G. Meyer and A. Jutand, J. Organomet. Chem., 2003, 687, 365–376.
4 0 9 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 8 9 – 4 0 9 4