Synthesis of C-glycosides and C-disaccharides using Mukaiyama aldol reaction in aqueous media

Article abstract of DOI:10.1002/adsc.200606113

We describe here a new strategy for the preparation of C-glycosides and C-disaccharides in the aqueous phase using the Mukaiyama aldol reaction. We first studied the reaction between formyl-2,3,4,6-tetra-O-benzyl-β-D- glucopyranoside 1 and the trimethylsi

Full text of DOI:10.1002/adsc.200606113

FULL PAPERS
DOI: 10.1002/adsc.200606113
Synthesis of C-Glycosides and C-Disaccharides using Mukaiyama
Aldol Reaction in Aqueous Media
Jennifer Zeitouni,a StØphanie Norsikian,a,* Denis Merlet,b and AndrØ Lubineaua
a
Institut de Chimie MolØculaire et des MatØriauxd ’Orsay, UMR CNRS-UPS 8182, “Laboratoire de Chimie Organique
Multifonctionnelle” Bât. 420, UniversitØ Paris Sud, 91405 Orsay Cedex, France
Fax: ( +33)-1-69-15-47-15; e-mail: stephnorsikian@icmo.u-psud.fr
Institut de Chimie MolØculaire et des MatØriauxd ’Orsay, UMR CNRS-UPS 8182, “Laboratoire de RMN en Milieu
b
OrientØ” Bât. 410, UniversitØ Paris Sud, 91405 Orsay Cedex, France
Fax: ( +33)-1-69-15-81-05
Received: March 16, 2006; Accepted: June 19, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: We describe here a new strategy for the diastereoisomer but in a much lower yield (56%).
preparation of C-glycosides and C-disaccharides in The aldol reaction was then applied to the synthesis
the aqueous phase using the Mukaiyama aldol reac- of C-disaccharides using the trimethylsilyl enol ether
tion. We first studied the reaction between formyl- 10 derived from the functionalized ketone 9. In both
2,3,4,6-tetra-O-benzyl-b-d-glucopyranoside 1 and the the aqueous phase and in anhydrous THF, the reac-
trimethylsilyl enol ether 2 derived from acetophe- tion can be achieved in high yields giving in each
none. Using Yb(OTf)3 (10 mol%) as catalyst in a case only two aldol products out of the four possible
A
mixture of THF/water at room temperature, the enol diastereoisomers.
adducts were isolated in a high (90%) yield but with
a moderate diastereoselectivity. The reaction can Keywords: aldol reaction; chemistry in water; C-gly-
also be performed in pure THF leading to a single cosides; silyl enol ethers; ytterbium
Introduction
aqueous media between a 1-formyl-C-glycoside for
which we have recently reported a convenient ap-
C-Glycosides, in which the exo-anomeric oxygen atom proach[6] and a silyl enol ether. The aldol reaction
is replaced by a methylene group, have been the sub- using silyl enol ethers has been widely used for highly
[7]
ꢀ
ject of considerable interest in carbohydrate chemis- efficient and stereoselective C C bond formation.
try.[1] These carbohydrate mimetics, which possess an In organic solvents a variety of conditions, particulary
improved stability toward acid, base, and enzymatic the use of Lewis acids or high pressure, are known to
hydrolysis, may display interesting biological activity. promote the nucleophilic process. However, one of us
Indeed, they may serve as regulators of enzymes (gly- has shown several years ago that the reaction can be
cosidases and glycosyltransferases that are potential performed in water or mixed aqueous solvent without
anti-cancer, antiviral, or antidiabetic agents) or as ar- a catalyst, in totally neutral conditions but in moder-
tificial ligands that can be useful in probing cellular ate yields.[8] More recently, Kobayashi and co-workers
interactions. Moreover, despite structural investiga- have considerably improved the reaction[9] in aqueous
tions that revealed, most of the time, notable confor- conditions by showing that water-tolerant Lewis acids,
mational differences between the natural and unnatu- such as Sc
N
N
ral glycosides,[2] a number of studies has shown that salts of Fe(II), Cu(II), Zn(II) and Pb(II) are efficient
the biological properties of C-glycosides are retained catalysts and give, in some cases, near quantitative
and sometimes are even greater.[3] Consequently, a yields of aldol products.[10] The benefits gained by
wide variety of synthetic strategies has been devel- using such aqueous catalytic systems include easy re-
oped for the attachment of carbon-based groups to covery of the active Lewis acid catalyst,[11] decreased
the anomeric position, in particular in regard to the cost and increased safety. Moreover, water has unique
synthesis of C-disaccharides.[4,5] For our part, we en- physical and chemical properties such as a high die-
visaged a novel approach for the preparation of these lectric constant and a high energy density compared
compounds using the Mukaiyama aldol reaction in
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Mukaiyama Aldol Reaction in Aqueous Media
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with most organic solvents that allow one to obtain tested a few of the catalysts described for their effi-
different reactivity and selectivity.[12]
ciency in the Mukaiyama aldol reaction in aqueous
media. We first examined the reaction in pure water
and we tested Sc(DS)3 (DS: dodecyl sulfate),[13]
[14]
[15]
Results and Discussion
FeCl3
or InCl3
that are known to favorably
affect the Mukaiyama aldol reaction in this particular
solvent (entries 1, 2, 3). However, in all cases, only
traces of the desired aldol compounds were observed.
The boron enolate system reported recently by Ko-
Reaction with the Trimethylsilyl Enol Ether 2
Derived from Acetophenone
We examined first the reaction of the trimethylsilyl bayashi et al. was also tried.[16] With a catalytic
enol ether 2 derived from acetophenone with formyl- amount of diphenylborinic acid in the presence of a
2,3,4,6-tetra-O-benzyl-b-d-glucopyranoside 1[6] pre- surfactant (SDS) and a Brønsted acid (PhCO2H), the
pared in a few steps from d-glucose (50% overall reaction led to the aldol adducts in 5% yield
[9]
yield) (Scheme 1, Table 1). In a preliminary study, we (entry 4). We then tested Yb(OTf)3 in a mixture of
A
THF/water (4/1) (entry 5). The reaction was carried
out with 10 mol% of the catalyst at room tempera-
ture and two diastereoisomers 3a and 3b were isolat-
ed in a 65/35 ratio and in a moderate 42% yield. With
[11b]
Sc
A
similar results could be attained
(entry 6) but the reaction has to be carried out not
only at 658C but also with a high catalyst loading (20
mol%). We also examined CeCl3 in a mixture of i-
PrOH/water (19/1) as described by Juaristi et al.[17]
and the aldol adducts were obtained in a poor 18%
yield (entry 7).
From these results, we decided to optimize the re-
action conditions with Yb(OTf)3. As described in
A
entry 5, the reaction was carried out at room tempera-
ture with 10 mol% of the catalyst in THF/water. In
this case, the reaction was run at a concentration of
0.08M of aldehyde and a large excess of the enol
Scheme 1. Mukaiyama aldol condensation between aldehyde
1 and the trimethylsilyl enol ether 2.
Table 1. Mukaiyama aldol condensation between aldehyde 1 and enol ether 2 or 10 under various conditions.
Entry
Enol ether (equivs.)
Catalyst (mol%)
Solvent
T [8C],
[aldehyde] (mol·lꢀ1)
Yield [%][a]
dr[b]
AHCTREUNG
1
2
3
4
5
6
7
8
2 (10)
2 (10)
2 (3)
2 (10)
2 (5)
2 (5)
2 (10)
2 (5)
2 (5)
2 (3)
2 (2)
2 (3)
Sc(DS)3 (20)
FeCl3 (10)[d]
InCl3 (20)
H2O
H2O
H2O
H2O
THF/H2O
THF/H2O
iPrOH/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF
65, 0.08
65, 0.08
rt, 0.16
65, 0.16
rt, 0.08
65, 0.08
rt, 007
rt, 0.08
rt, 0.08
rt, 0.16
rt, 0.16
rt, 0.16
rt, 0.16
rt, 0.16
rt, 0.16
rt, 0.16
traces
traces
traces
5
42
42
18
54
68
90
–
–
–
Ph2BOH (10)[e]
63/37
65/35
65/35
63/37
68/32
67/33
60/40
65/35
63/37
>95/5
59/41
59/41
56/44
Yb
Sc(OTf)3 (20)
CeCl3 (20)
Yb(OTf)3 (20)
Yb(OTf)3 (30)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (5)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (20)
A
A
G
9
R
10
11
12
13
14
15
16
A
U
83
N
25
2 (3)
G
56[c]
55
10 (3)
10 (3)
10 (3)
R
THF/H2O
THF/H2O
THF
N
95
N
72[c]
[a]
Isolated yield following chromatography.
[b]
[c]
[d]
[e]
1
Determined by H and 13C NMR spectroscopy.
After acidic treatment.
The reaction was performed in the presence of sodium docecyl sulfate (10%) and NaOH (10%).
The reaction was performed in the presence of sodium docecyl sulfate (10%) and benzoic acid (1%).
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Jennifer Zeitouni et al.
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ether 2 (5 equivalents) was necessary to lead to 3a tween H-1’ and H-1. Moreover, for 5b the coupling
3
and 3b in a moderate yield (42%) that could not be constant J1’,1 =9.0 Hz indicates a trans diaxial orien-
improved at a higher temperature (658C) or by using tation between H-1ꢁ and H-1. This implies that the ab-
sonication.[8] However, a higher catalyst loading (en- solute configuration of C-1 for the major aldol adduct
tries 8 and 9) allowed us to reach yields of up to 3a is (R) and for the minor 3b, (S).
68%. The optimal conditions were found when the
The better diastereoselectivity observed in pure
reaction was carried out at a concentration of 0.16M THF may result from the Cram cyclic chelated model
of aldehyde (entry 10). In this case, 3 equivalents of showed in Figure 1.[7b–c,19] According to this model,
the enol ether 2 and 10 mol% of Yb(OTf)3 were re-
G
quired to lead to a mixture of 3a and 3b in a 60/40
ratio and 90% yield. The reaction carried out with 2
equivalents of 2 led also to a good 83% yield
(entry 11). However, with less catalyst (5 mol%,
entry 12) and 3 equivalents of 2, a poor 25% yield
was obtained. For comparison, the same reaction was
also performed in pure THF (entry 13). In this case,
using 10 mol% of the catalyst and 3 equivalents of 2,
the reaction led to 3a (in mixture with its O-silylated
Figure 1. The Cram chelated transition state.
form 4) as a single diastereoisomer (>95/5) that gave the ytterbium atom may coordinate the carbonyl
after acidic treatment pure 3a but in a much lower group and the endocyclic a-oxygen atom of the sugar
yield (56%).
moiety. Subsequent attack of the nucleophile from
In order to determine the absolute configuration of the sterically less hindered side of the carbonyl group
the newly formed stereocenter C-1 in 3a and in 3b, leads to the predominant formation of the (R) isomer
the two compounds were independently hydrogenated 3a. In contrast, the lower diastereoselectivity ob-
in the presence of palladium on charcoal in a mixture served in the aqueous reaction can presumably be ex-
of EtOH/EtOAc (Scheme 2). The two compounds ob- plained by the ratio of chelation-controlled to non-
chelation-controlled attack of the nucleophile.
Indeed, the presence of water, which is a stronger
donor solvent may interfere with the formation of the
chelate complex, which is a prerequisite for a high
chelation-controlled diastereoselection. In this case,
the formation of the minor adduct 3b may be explain
by the Felkin–Anh model depicted in Figure 2.
Figure 2. The non-chelated Felkin–Anh model.
Scheme 2. Determination of the absolute configuration of
the C-1 center in 3a and 3b. Reagents and conditions: a) H2,
Pd/C, EtOH/EtOAc. b) PhCH
55% for 2 steps, 5b, 77% for 2 steps).
A
Synthesis of C-Disaccharides
The Mukaiyama aldol reaction was then extended to
tained were then directly protected with benzylidene the trimethylsilyl enol ether 10 that should lead to the
groups using benzaldehyde dimethyl acetal in acetoni- synthesis of b-(1!4)-C-linked disaccharides. This
trile in the presence of a catalytic amount of p-tolu- enol ether 10 derived from ketone 9 can be synthe-
enesulfonic acid to give 5a and 5b. It is worth to be sized from the easily available methyl 2,6-di-O-
noticed that, under the conditions of the hydrogenoly- benzyl-b-d-galactopyranoside 6[20] (Scheme 3). The
sis step, the carbonyl function a to the phenyl group diol 6 was first treated with thionyl chloride and trie-
was also reduced.[18] The absolute configuration of thylamine in dichloromethane to furnish cyclic sulfites
the C-1 could therefore be deduced from an analysis as a mixture of diastereoisomers. This step was direct-
1
of the H NMR spectra. Indeed, for 5a, the coupling ly followed by the oxidation procedure described by
3
constant J1’,1 =5.0 Hz indicates a cis relationship be- Gao and Sharpless using the NaIO4-RuCl3·H2O
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Mukaiyama Aldol Reaction in Aqueous Media
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mol%) allowed us to obtain 11a and 11b in 95%
yield (entry 15). For comparison, the reaction was
also conducted in pure THF (entry 16). Using the
same conditions (20 mol% of Yb(OTf)3 and 3 equiva-
G
lents of 10), the two enol adducts were obtained in a
slightly decreased 72% yield. In this case, compared
with the use of water, a similar diastereoselectivity
was obtained in contrast to what was observed in the
previous case with enol ether 2.
As we could not separate the two diastereoisomers
at this stage, we were not able to determine directly
the absolute configuration of the two newly formed
stereocenters C-4 and C-1’ in 11a and 11b. This prob-
lem was resolved after treatment of these compounds
with sodium borohydride in MeOH at 08C that led to
a mixture of the three diols 12a, 12b and 12c in 94%
yield (Scheme 5). After flash chromatography, only
12c could be separated and was treated with benzal-
dehyde dimethyl acetal in acetonitrile in the presence
of a catalytic amount of p-toluenesulfonic acid to give
the benzylidene derivative 13c. The same reaction
was carried out with the mixture of 12a and 12b to
afford the desired separable benzylidene derivatives
13a and 13b.
Scheme 3. Synthesis of the enol ether 10. Reagents and con-
ditions: a) SOCl2, NEt3, CH2Cl2, 08C. b) RuCl3·H2O (cat.),
NaIO4, CH2Cl2/CH3CN/H2O (2/2/3) (7, 84% for 2 steps). c)
NaOH 10M, DMF, 708C. d) H2SO4 (9, 67%). e) LDA,
TMSCl, THF, ꢀ788C.
From these three compounds, we could deduce the
stereoselectivity of the Mukayiama aldol reaction be-
tween the formyl-2,3,4,6-tetra-O-benzyl-b-d-glucopyr-
anoside 1 and the trimethylsilyl enol ether 10 derived
system.[21] The 3,4-cyclic sulfate 7 obtained in 84% from ketone 9 (Figure 3). The stereochemistry of 13a
yield was then treated with aqueous sodium hydrox- was assigned on the basis of 3J values (3J4,1’ =10,
ide (10M) in DMF at 708C.[22] The elimination pro- 3J4,5 =10 and 3J4,3 =10 Hz) and strong NOE effects
cess that results from deprotonation at C-3 gave the between H-1’ and both H-3 and the hydrogen atom
vinylic sulfate 8 which was hydrolyzed to the corre- H-2’ of the benzylidene group. From these data, we
sponding ketone 9 in 67% yield. The kinetic enol can conclude that, for this compound, the alkylation
ether 10 was then obtained after reaction of LDA in at C-4 operated in an equatorial orientation with the
the presence of TMSCl at ꢀ788C in THF. After C-1’ (R) configuration. For 13b, the coupling con-
3
3
work-up, 10 was obtained quantitatively and was used stants J4,5 =10 Hz, 3J4,3 =2 Hz and J3,2 =2 Hz indi-
without further purification.
cate an axial H-4 and an equatorial H-3. Moreover,
3
We first carried out the aldol condensation between the coupling constant J4,1’ =0 Hz and a NOE effect
10 and 1 in aqueous phase using the best conditions observed between the hydrogen atom H-2’ of the ben-
that we found previously (Scheme 4, Table 1, zylidene group and H-3 but not with H-1’ indicate
entry 14). With 3 equivalents of the enol ether 10 and again that the alkylation at C-4 operated in an equa-
10 mol% of Yb(OTf)3, a mixture of only two aldol torial orientation with the C-1’ (R) configuration.
A
adducts 11a and 11b in a 59/41 ratio was obtained out These results show that 13a and 13b come from the
of the four possible diastereoisomers but in a moder- same aldol product 11a. However, for this compound
ate 55% yield. However, a higher catalyst loading (20 the reduction of the ketone function is not stereose-
Scheme 4. Synthesis of C-disaccharides using Mukaiyama aldol reaction in aqueous media.
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Jennifer Zeitouni et al.
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Scheme 5. Chemical modifications for the determination of the stereoselectivity of the Mukaiyama aldol reaction between 1
and 10. Reagents and conditions: a) NaBH4, MeOH (12a, 12b and 12c, 94%). b) PhCH
13a and 13b and 23% for 13c).
A
1
six-membered ring of 13c adopts an unusual C4 con-
formation having H-4 in an axial position and H-3 in
an equatorial one. In the six-membered ring formed
by the benzylidene derivative, the phenyl group and
the glycosyl group coming from the aldehyde, are in
equatorial positions. This is confirmed by a strong
NOE effect observed between the proton H-2’ of the
benzylidene group and both H-3 and H-1’ that indi-
cate that the absolute configuration of C-1’ is (R).
These results show that 13c comes from 11b, i.e., that
the alkylation at C-4 operated in an axial orientation.
For 11b, the reduction of the ketone by NaBH4 is ste-
reoselective, probably because the b face of the
ketone is more hindered due to the presence of an
axial substituent at C-4 and lead to the C-disaccharide
derivative [d-Glc-b-(1!4)-C-d-Gal] 12c.
In order to confirm the conformation found experi-
mentally for 13c, different molecular models have
been realized.[23] Whatever the level of calculation,
molecular mechanics or semi-empirical calculations,
1
the C4 conformation of the terminal six-membered
4
ring is much more stable than the C1 conformation
Figure 3. Selected 1H NMR data and NOEs for 13a, 13b
and 13c.
(10 kcal using MM+ force field). It is also worth
noting that the hH5C5C4H4i dihedral angle is smaller
than the other hHCCHi dihedral angles of this ring.
lective leading to the two C-disaccharide derivatives For example, with semi-empirical calculation using
[d-Glc-b-(1!4)-C-d-Glc] 12a and [d-Glc-b-(1!4)-C- the AM1 basis, hH5C5C4H4i dihedral angle was found
d-All] 12b in a 55/45 ratio that can be explain by simi- to be equal to 458 comparing to 568 for the
larly hindered faces of the ketone, flanked with two hH1’C1’C4H4i dihedral angle. This small value can
3
equatorial substituents at a-positions on both sides. therefore explain the unusual J4,5 =6 Hz obtained for
The stereochemisty of 13c was also assigned by an axial-equatorial coupling.
1H NMR analysis. According to the 3J values ob-
Concerning the selectivity of the Mukaiyama reac-
served (3J2,1 =2, 3J2,3 =3 and 3J4,3 =3 Hz), the terminal tion between the aldehyde 1 and the sterically hin-
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Mukaiyama Aldol Reaction in Aqueous Media
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formed using UV light and/or 5% sulfuric acid in ethanol,
followed by heating. Flash chromatography was performed
on silica gel 6–35 mm.
dered enol ether 10, in the aqueous phase as in anhy-
drous THF, in contrast to what happened with the
smaller enolate 2, the total selectivity at the C-1’
center may be explained by the chelated model de-
picted in Figure 1, which by far is less sterically de-
manding that the non-chelated model of Figure 2. In
contrast, a low degree of diastereoselection is ob-
served in the C-4 alkylation. This may be attributed
to a poor steric control induced by the substituents
next to the reactive center (at C-6 and C-2 positions).
Thus, the attack of the electrophile could not be pref-
erentially directed to one of the p-faces of the enolate
system and therefore yields both equatorial and axial
isomers in a 59/41 ratio.
Synthesis of 1(R)- and 1(S)-1-(2’,3’,4’,6’-Tetra-O-
benzyl-b-d-glucopyranosyl)-1-hydroxy-3-phenylpro-
pan-3-one (3a and 3b) using Mukaiyama Aldol
Condensation in the Aqueous Phase
To a solution of the aldehyde 1 (140 mg, 0.25 mmol) in a
mixture of H2O/THF (0.3/1.25 mL) was added ytterbium tri-
flate (15 mg, 0.025 mmol) and the silyl enol ether 2 of aceto-
phenone (450 mg, 0.75 mmol). After stirring for one week at
room temperature, THF was evaporated and water (10 mL)
was added. The aqueous phase was extracted with ethyl ace-
tate (3”10 mL). The combined organic layers were washed
with brine (2”10 mL), dried (MgSO4), filtered and concen-
trated. Flash chromatography of the crude residue on silica
gel (petroleum ether/ethyl acetate=8/2 to 7/3) gave 3a
(90 mg, 54%) and 3b (60 mg, 36%).
Conclusions
In this paper, we showed that the Mukaiyama aldol
reaction in the aqueous phase can be efficiently ap-
plied to the preparation of C-glycosides and C-disac-
charides starting from easily available formyl-2,3,4,6-
tetra-O-benzyl-b-d-glucopyranoside 1. A first study
was carried out with the trimethylsilyl enol ether 2 de-
rived from acetophenone. The best conditions were
1(R)-1-(2,3’,4’,6’-Tetra-O-benzyl-b-d-glucopyrano-
syl)-1-(trimethylsilyl)hydroxy-3-phenylpropan-3-one
(4)
To a solution of the aldehyde 1 (200 mg, 0.362 mmol) in
THF (2.25 mL) was added ytterbium triflate (22 mg,
0.0362 mmol) and the silyl enol ether 2 (209 mg, 1.09 mmol).
After stirring for 3 h at room temperature, saturated aque-
ous NaHCO3 solution (10 mL) was added and the aqueous
phase was extracted with ethyl acetate (3”10 mL). The
combined organic layers were dried (Na2SO4), filtered and
concentrated. Flash chromatography of the crude residue on
silica gel (petroleum ether/ethyl acetate=8/2 to 7/3) gave 4a
(100 mg, 37%) and 3a (46 mg, 19%).
found using Yb(OTf)3 (10 mol%) as catalyst in a mix-
G
ture of water/THF at room temperature leading to
the enol adducts in high yield (90%) but in a moder-
ate diastereoselectivity. The reaction can also be per-
formed in anhydrous THF affording only one diaste-
reoisomer but in a strongly decreased 56% yield. The
aldol reaction was then applied to the synthesis of C-
disaccharides using the trimethylsilyl enol ether 10 de-
rived from ketone 9. In this case, a higher catalyst
loading (20 mol%) is needed to reach a high 95%
yield and, in THF as in the aqueous phase, only two
enol adducts are obtained out of the four possible dia-
stereoisomers. After chemical modification, we deter-
mined the absolute configuration of these two adducts
and showed that there is a total selectivity for the nu-
cleophilic attack onto the aldehyde, and a lack of ste-
reoselectivity at the alkylated carbon of the enolate
system. With this methodology and after reduction
with sodium borohydride, we could access to the
three C-disaccharides derivatives [d-Glc-b-(1!4)-C-
1(R)-1,2’-O-Benzylidene-1-(4’,6’-O-benzylidene-b-d-
glucopyranosyl)-1-hydroxy-3-phenylpropane (5a)
To a solution of 3a (100 mg, 0.15 mmol) in a mixture of
ethyl acetate/ethanol (1/2, 1.5 mL) was added palladium on
charcoal (50 mg). The reaction mixture was stirred for 2 h
under a hydrogen atmosphere. After filtration on celite and
concentration, the crude residue was dissolved in acetoni-
trile (1 mL) and benzaldehyde dimethyl acetal (90 mL,
0.6 mmol) and a catalytic amount of para-toluenesulfonic
acid (3 mg) were added. After stirring for 1 h at room tem-
perature, the reaction mixture was neutralized with a satu-
rated aqueous NaHCO3 solution. After addition of water
d-Glc] 12a, [d-Glc-b-(1!4)-C-d-All] 12b and [d-Glc- (10 mL), the aqueous phase was extracted with ethyl acetate
(3”10 mL). The combined organic layers were dried
b-(1!4)-C-d-Gal] 12c. Work is currently in progress
(MgSO4), filtered and concentrated. The pure product 5a
in our laboratory to extend this methodology to other
(39 mg, 55%) was obtained after flash chromatography on
enol ethers derived from other sugar moieties.
silica gel (petroleum ether/ethyl acetate=8/2).
1(S)-1,2’-O-Benzylidene-1-(4’,6’-O-benzylidene-b-
Experimental Section
d-glucopyranosyl)-1-hydroxy-3-phenylpropane (5b)
All moisture-sensitive reactions were performed under
argon using oven-dried glassware. Whenever necessary, sol-
vents were dried and distilled prior to use. Reactions were
monitored on TLC (silica gel 60 F254). Detection was per-
To a solution of 3b (100 mg, 0.15 mmol) in a mixture of
ethyl acetate/ethanol (1/2, 1.5 mL) was added palladium on
charcoal (50 mg). After stirring for 2 h under a hydrogen at-
mosphere, the reaction mixture was filtered and concentrat-
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Jennifer Zeitouni et al.
FULL PAPERS
ed. To a solution of the crude residue in acetonitrile (1 mL)
were added benzaldehyde dimethyl acetal (90 mL, 0.6 mmol)
and a catalytic amount of para-toluenesulfonic acid (3 mg)
After stirring for 1 h at room temperature, the reaction mix-
ture was neutralized with a saturated aqueous NaHCO3 so-
lution. After addition of water (10 mL), the aqueous phase
was extracted with ethyl acetate (3”10 mL). The combined
organic layers were dried (MgSO4), filtered and concentrat-
ed. The pure product 5b (77%) was obtained after flash
chromatography on silica gel (petroleum ether/ethyl ace-
tate=8/2).
2.5 mmol) in THF (4 mL) were added. After stirring for
40 min at ꢀ788C, a saturated aqueous NaHCO3 (10 mL)
was added and the aqueous phase was extracted with pen-
tane (3”10 mL). The combined organic layers were washed
with brine (2”10 mL), then dried (MgSO4), filtered and
concentrated to afford crude enoxysilane 10, which was used
without further purification.
Methyl 2,6-Di-O-benzyl-4-deoxy-4-C-
[1’(R)-1’-(2’’,3’’,4’’,6’’-tetra-O-benzyl-b-d-glucopyrano-
syl)-1’-hydroxymethyl]-b-d-ribo-hexapyranosid-3-
ulose (11a) and Methyl 2,6-Di-O-benzyl-4-deoxy-4-C-
[1’(R)-1’-(2’’,3’’,4’’,6’’-tetra-O-benzyl-b-d-glucopyrano-
syl)-1’-hydroxymethyl]-b-d-xylo-hexapyranosid-3-
ulose (11b)
Methyl 2,6-Di-O-benzyl-3,4-sulfuryl-b-d-
galactopyranoside (7)
To a cooled (08C) solution of methyl 2,6-O-benzyl-b-d-gal-
actopyranoside (6; 7 g, 19 mmol) and triethylamine
(10.4 mL, 75 mmol) in dichloromethane (37 mL) was added
dropwise, over a period of 10 min, a solution of thionyl chlo-
ride (2 mL, 28 mmol) in dichloromethane (13 mL). After
stirring for 20 min at 08C, water (100 mL) was added and
the aqueous phase was extracted with dichloromethane (3”
100 mL). The combined organic layers were washed with
water (2”100 mL), brine (2”100 mL) and dried (MgSO4).
After filtration and concentration, the crude residue was dis-
solved in a mixture of CHCl3/CH3CN/H2O (1/1/1.5, 91 mL)
and the solution was cooled to 08C. Ruthenium trichloride
(80 mg, 0.4 mmol) and sodium periodate (8 g, 38 mmol)
were added and the solution was stirred for one hour at
08C. After dilution with dichloromethane (150 mL), the so-
lution was filtered on celite. Water (150 mL) was added and
the product was extracted with dichloromethane (3”
100 mL). The combined organic layers were washed with a
saturated aqueous NaHCO3 solution (150 mL), brine
(150 mL), then dried (MgSO4), filtered and concentrated.
After flash chromatography on silica gel (petroleum ether/
ethyl acetate=8/2), the pure product 7 (7 g, 84%) was ob-
tained as a white solid.
To a solution of aldehyde 1 (246 mg, 0.45 mmol) and ytterbi-
um triflate (56 mg, 0.09 mmol) in a mixture of H2O/THF
(0.26/1.1 mL) was added the enol ether 10 (579 mg,
1.35 mmol). After 4 days at room temperature, the THF was
evaporated and water (10 mL) was added. The aqueous
phase was extracted with ethyl acetate (3”10 mL) and the
combined organic layers were washed with brine, dried
(MgSO4), filtered and concentrated. The products 11a and
11b (390 mg, 95%) were obtained as a mixture of diastereo-
isomers after flash chromatography on silica gel (petroleum
ether/ethyl acetate=85/15 to 7/3).
Synthesis of Methyl 2,6-Di-O-benzyl-4-deoxy-4-C-
[1’(R)-1’-(2’’,3’’,4’’,6’’-tetra-O-benzyl-b-d-glucopyrano-
syl)-1’-hydroxymethyl]-b-d-glucopyranoside (12a),
Methyl 2,6-Di-O-benzyl-4-deoxy-4-C-
[1’(R)-1’-(2’’,3’’,4’’,6’’-tetra-O-benzyl-b-d-glucopyrano-
syl)-1’-hydroxymethyl]-b-d-allopyranoside (12b) and
Methyl 2,6-Di-O-benzyl-4-deoxy-4-C-
[1’(R)-1’-(2’’,3’’,4’’,6’’-tetra-O-benzyl-b-d-glucopyrano-
syl)-1’-hydroxymethyl]-b-d-galactopyranoside (12c)
Methyl 2,6-Di-O-benzyl-4-deoxy-b-
d-erythro-hexopyranosid-3-ulose (9)
To a cooled (08C) solution of the disaccharides 11a and 11b
(200 mg, 0.22 mmol) in methanol (4 mL) was added sodium
borohydride (18 mg, 0.44 mmol). After stirring overnight, an
aqueous solution of NH4Cl was added and the aqueous
phase was extracted with ethyl acetate (3”10 mL). The
combined organic layers were washed with brine (3”
10 mL), dried (MgSO4), filtered and concentrated before
purification by flash chromatography on silica gel (petro-
leum ether/ethyl acetate=8/2 to 7/3). Two fractions were
obtained, the first one containing 12a and 12b (55:45,
102 mg, 51%), the second containing only compound 12c
(87 mg, 43%).
To a solution of the cyclic sulfate 7 (3.7 g, 8.5 mmol) in
DMF (146 mL) was added aqueous NaOH (10M, 7.3 mL,
73 mmol). After stirring for 2 h at 708C, the reaction mix-
ture was cooled to 08C before addition of concentrated sul-
furic acid until pH 1. After stirring overnight, water
(100 mL) was added and the aqueous phase was extracted
with ethyl acetate (3”150 mL). The combined organic
layers were washed with water (3”150 mL), brine (3”
150 mL), then dried (MgSO4), filtered and concentrated.
The ketone 9 (2.02 g, 67%) was obtained as a colorless oil
after flash chromatography (petroleum ether/ethyl acetate=
8/2).
Methyl 2,6-Di-O-benzyl-1’,3-O-benzylidene-4-
deoxy-4-C-[1’(R)-1’-(2’’,3’’,4’’,6’’-tetra-O-benzyl-b-d-
glucopyranosyl)-1’-hydroxymethyl]-b-d-glucopyrano-
side (13a) and Methyl 2,6-Di-O-benzyl-1’,3-O-
benzylidene-4-deoxy-4-C-[1’(R)-1’-(2’’,3’’,4’’,6’’-te-
tra-O-benzyl-b-d-glucopyranosyl)-1’-hydroxyme-
thyl]-b-d-allopyranoside (13b)
Methyl 2,6-Di-O-benzyl-4-deoxy-3-trimethyl-
silyloxy-b-d-erythro-hex-3-enopyranoside (10)
To a solution of diisopropylamine (0.52 mL, 3.75 mmol) in
THF (7 mL) at 08C, was added dropwise nBuLi (1.6 N in
hexane, 2.5 mL, 3.75 mmol). After stirring for 30 min at
08C, the reaction mixture was cooled to ꢀ788C and TMSCl
(0.5 mL, 3.75 mmol) then a solution of ketone 9 (0.9 g,
To a solution of a mixture of disaccharides 12a and 12b
(32 mg, 0.035 mmol) in acetonitrile (1 mL) were added ben-
1668
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Adv. Synth. Catal. 2006, 348, 1662 – 1670

Mukaiyama Aldol Reaction in Aqueous Media
FULL PAPERS
zaldehyde dimethyl acetal (21 mL, 0.14 mmol) and a catalytic
amount of TsOH (1 mg). After stirring for 2 h, the solution
was neutralized with saturated aqueous NaHCO3 solution
and the aqueous phase was extracted with AcOEt (3”
10 mL). The combined organic layers were dried (Na2SO4),
filtered and concentrated. Flash chromatography of the resi-
due on silica gel (petroleum ether/ethyl acetate=9/1 to 7/3)
gave 13a (14 mg, 40%) and 13b (11 mg, 31%).
2002, 124, 14940–14951; f) J. Schmieg, G. Yang, R. W.
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Methyl 2,6-Di-O-benzyl-1’,3-O-benzylidene-4-
deoxy-4-C-[1’(R)-1’-(2’’,3’’,4’’,6’’-tetra-O-benzyl-b-d-
glucopyranosyl)-1’-hydroxymethyl]-b-d-galactopyra-
noside (13c)
[5] For recent synthesis of C-linked disaccharides, see:
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T. Skrydstrup, J. Org. Chem. 2002, 67, 6297–6308;
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To a solution of 12c (24 mg, 0.026 mmol) in acetonitrile
(1 mL) were added benzaldehyde dimethyl acetal (15 mL,
0.14 mmol) and a catalytic amount of TsOH (1 mg). After
stirring for 2 h, the solution was neutralized with saturated
aqueous NaHCO3 solution and the aqueous phase was ex-
tracted with AcOEt (3”10 mL). The combined organic
layers were dried (Na2SO4), filtered and concentrated. Flash
chromatography of the residue on silica gel (petroleum
ether/ethyl acetate=9/1 to 7/3) afforded 13c (6 mg, 23%).
Characterization data for all products are given in the
Supporting Information.
Acknowledgements
We thank the UniversitØ Paris Sud, the CNRS for funding as
well as the Minist›re de l’Education Nationale et de la Re-
cherche for a Ph.D. grant (J.Z.).
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