A simple, mild, and regioselective method for the benzylation of carbohydrate derivatives promoted by silver carbonate

Article abstract of DOI:10.1016/j.carres.2009.12.012

A simple, mild, and regioselective method has been developed for the selective benzylation and p-methoxybenzylation of carbohydrate derivatives in high yields using Ag₂CO₃ as the promoter. Benzylation of base-labile substrates, for w

Full text of DOI:10.1016/j.carres.2009.12.012

Carbohydrate Research 345 (2010) 559–564
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
A simple, mild, and regioselective method for the benzylation
of carbohydrate derivatives promoted by silver carbonate q
*
Satish Malik, Vaibhav A. Dixit, Prasad V. Bharatam, K. P. Ravindranathan Kartha
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 October 2009
Received in revised form 19 November 2009
Accepted 14 December 2009
Available online 14 January 2010
A simple, mild, and regioselective method has been developed for the selective benzylation and p-meth-
oxybenzylation of carbohydrate derivatives in high yields using Ag2CO3 as the promoter. Benzylation of
base-labile substrates, for which other reported methods are of little use, has been performed in high
yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Silver carbonate
Alkylation
Benzylation
Carbohydrate derivative
1. Introduction
as the promoter has been reported in good to excellent yield in
the case of symmetric diols, but this methodology has been unsuc-
Protection of the hydroxyl groups as ethers is an important
transformation used in synthetic organic chemistry, in particular,
synthetic carbohydrate chemistry. In this context, benzyl (Bn), tri-
tyl (Tr), t-butyldimethylsilyl (TBDMS), p-methoxybenzyl (PMBn),
and t-butyldiphenylsilyl (TBDPS) ethers are the most important
protecting groups. While highly efficient literature methods, taking
advantage of the bulkiness of the respective group to be intro-
duced, are available for the regioselective preparation of Tr,
TBDMS, and TBDPS ethers,2 the situation is far from satisfactory
for the regioselective Bn/PMBn-protection. The most frequently
used classical Williamson alkylation (and its variants) has been
of little synthetic use in this regard as the method involves the
use of strong alkali/base and therefore differential activation of a
particular OH group from among several of relatively close reactiv-
ity in a given carbohydrate is of limited success. For example, in an
cessful in the case of diols such as 1,2-propanediol.7
Regioselective alkylation/acylation of various alkyl 1-O-/S-/Se-
4,6-O-benzylidene-a-/b-D-glucopyranoside-derived dianions via
Cu(II)chloride-activationhasbeenreportedbyAvelaandHolmbom8
as well as by Gridley et al.9 Recently, the monoalkylation of non-car-
bohydrate-based 1,2-and 1,3-diols was reported using Cu(II)chlo-
ride, or alternatively, using certain boronic acids in the presence of
K2CO3.10 These reports, while meritorious, involve the use of alkali
and hence could prove incompatible when extended to partially
acylated sugar derivatives. Thus, although several alternative (indi-
rect) alkylation methods have been reported,11,12 there is a clear
need for methods that allow selective benzylations under mild con-
ditions, in particular, with substrates bearing base-labile substitu-
ents/protecting groups.
Thus an investigation was undertaken to evaluate the suitability
of Ag2CO3 for this purpose. These studies were motivated by the
fact that Ag2CO3 is insoluble in most of the common solvents used
for organic reactions, it is highly halophilic in nature, it is only mar-
ginally basic, and is widely accepted as a promoter for Koenigs–
Knorr glycosylations. In particular this reagent has proved highly
efficient in regioselective glycosylation of ‘naked’ galactosides
using glycosyl bromides as glycosyl donors.13 The observations of
Lichtenthaler et al. on the benzylation of 50-OH of 20,30-O-isopro-
pylidene-inosine under Koenigs–Knorr condition (Ag2CO3, BnBr
in MeNO2/CHCl3/benzene) leading to the alkylation of the nucleo-
side base moiety (instead of the desired 50-O-alkyl derivative) and
of Morel et al. on the alkylation of quinolones in the presence of
Ag2CO3 were also of interest.14 The results are presented herein.
attempted regioselective benzylation of methyl a-D-galactopyran-
oside under the above-mentioned conditions, Flowers obtained a
mixture of products, namely, the respective 2-O-, 3-O-, 4-O-, and
6-O-monobenzyl derivatives in 8%, 4%, 15%, and 23.5% yields,
respectively, from the monobenzyl ether fraction obtained in a
yield of 50%.3 Purdie alkylations using Ag(I) oxide, although milder,
are often limited by acyl migrations.4,5 Loss of acyl groups followed
by concomitant alkylation has also been reported under these
conditions.6 Selective monoalkylation of diols using Ag(I) oxide
q
See Ref. 1.
* Corresponding author. Fax: +91 172 2214692.
E-mail address: rkartha@niper.ac.in (K.P.R. Kartha).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.12.012

560
S. Malik et al. / Carbohydrate Research 345 (2010) 559–564
Selectively benzylated product 8 was obtained in 92% yield after
2. Result and discussion
chromatographic isolation. The retention of the acetate group in
8 was evident from its 1H NMR spectrum (d 2.15, s, 3H, COCH3)
as was the presence of the Bn group (d 7.50–7.56, m, 5H, ArH).
The reaction of ‘naked’ hexosides (tetraols) 11 and 13 with PMBnCl
led to the regioselelective protection of the primary OH group giv-
ing the desired products 12 and 14, respectively, in high yield (91%
and 94%, respectively, isolated).
When monotritylated glycerol 1a was treated with BnBr in tol-
uene in the presence of Ag2CO3 at rt in the dark for 10 h, complete
consumption of the diol took place and the monobenzylated prod-
uct 2a was obtained in 82% isolated yield (after chromatographic
purification, Scheme 1). The structure was confirmed by the char-
acteristic IR absorption band for the OH group and by 1H NMR
spectroscopy (d 7.43–7.23, m, 20H, ArH; 4.55, s, 2H, CH2Ph; 4.00,
s, 1H, CHOH). Upon acetylation, compound 2a gave a mono-O-ace-
tate for which the H-2 chemical shift showed the expected down-
field shift in its 1H NMR spectrum (d 5.28–5.23, q, 1H, J = 5.2 Hz,
CHOAc) thus confirming the structure of 2a. Selective monobenzy-
lation of propane-1,2-diol (1b, Scheme 1), a reaction that was
reportedly unsuccessful under the literature conditions,8 was sub-
sequently attempted as described above and the monobenzyl
ether 2b was obtained in 80% yield. The NMR spectral (1H and
13C) data obtained for 2b and its monoacetate [2-O-acetyl-1-O-
benzyl-propane-1,2-diol: cf. dH 5.16–5.10 (m, 1H, CHOAc; 2.07
(s, 3H, COCH3)] were in accordance with those expected for the
structure.
Inspired by this result we went on to examine the possibility of
achieving selective reactions with carbohydrate derivatives of
varying structural diversity and bearing more than one free OH
group. Thus, the hexose-derived diols 3, 5, 7, and 9, when treated
with BnBr in the presence of Ag2CO3, were selectively benzylated
to produce the respective 6-O-benzylated derivatives 4, 6, 8, and
10 in high yields in all cases. The selective benzylation of the par-
tially acetylated furanose derivative 7 was of particular interest be-
cause of the presence of the base-labile acetate group in it.
HO
HO
OR'
O
R'O
HO
OR
O
OR
O
O
O
SPh
O
OR
O
OH
OH
48 h,
11 R = Oct, R' = H
12 R = Oct, R' = PMBn
3 R = Bn, R' = H
9 R = H
10 R = Bn
24 h,
67%
14 h, 88%
91%
4 R = Bn, R' = Bn
5 R = Me, R' = H
6 R = Me, R' = Bn
7 R = Ac, R' = H
8 R = Ac, R' = Bn
13
R = SE, R' = H
18 h,
94%
16 h, 90%
16 h, 92%
14 R = SE, R' = PMBn
SE = 2-(trimethylsilyl)ethyl
Successful regioselective benzylation of the partially acetylated
7 to give 8 in high yield with retention of the O-Ac group prompted
us to study the scope and limitations of this reaction. Thus, while
the partially protected base-labile (6-O-Bz substituent) galactoside
derivative 15 was found to be unreactive at rt in the presence of
BnBr, the reaction proceeded with ease when carried out at 60 °C
giving a 65% isolated yield of the corresponding 2-O-Bn ether 16
in 3 h. Reaction of BnBr with the hemiacetal 17 was, however,
found to react smoothly at rt to provide the corresponding benzyl
b-D-galactoside 18 in 90% yield in 12 h. Neither the loss nor the
migration of the acetyl group was observed during the reaction.
OMe
AcO
AcO
O
OAc
OBz
RO
AcO
O
O
O
OMe
O
O
OR
O
AcO
OR
15 R = H
3 h, 60 ºC, 65%
17 R = H
24 h, no
reaction
24 h,
no
reaction 21
19
R = H
16
R = Bn
12 h, 90%, only β-
18
R = Bn
20 R = Bn
R = PMBn
OAc
OR'
CH OAc
OR
2
OAc
O
O
H
AcO
H
OAc
H
XMe
RO
AcO
OAc
OAc
AcO
OAc
OAc
18 h,
55%
18 h,
60%
22 X = O, R = H, R' = Ac
23 X = O, R = Bn,R' = Ac
24 X = S, R = Ac, R' = H
25 X = S, R = Ac, R' = Bn
H
26 R = H
27 R = Bn
24 h,
no reaction
CH OR
2
28 R = H
24 h, no reaction
both at 60 ºC
29
R = Bn
Ag2CO3 (3 mol equiv)
BnBr (2 mol equiv)
R
OH
R
OBn
OH
1a/b
OH
Toluene, rt, 10 h, 80-82%
2a/b
a R = OTr
b R = H
Scheme 1. Regioselective benzylation of polyols promoted by silver carbonate.

S. Malik et al. / Carbohydrate Research 345 (2010) 559–564
561
HBr
or
HCl
R1
O
H
MeBr
or
MeCl
R1
O
R1
O
+
+
or
O
R2
O
O
CH3
R2
R2
H3C
1o Substitution
2o Substitution
1b R1 = H, R2 = H
32
30 R1 = H, R2 = H
33 R1 = H, R2 = Ac
31 R1 = H, R2 = H
R1 = H, R2 = Ac
34 R1 = OH, R2 = H
37 R1 = OH, R2 = Ac
39 R1 = OAc, R2 = H
35
36
R1 = OH, R2= H
R1 = OH, R2 = H
38 R1 = OH, R2 = Ac
40 R1 = OAc, R2 = H
41 R1 = OAc, R2 = H
Scheme 2. Hypothetical model methylations used for the calculation of the heat of formation.
From the well-known ‘disarming’ nature of the 2-O-acyl sub-
stituents toward glycosylation reactions under electrophilic acti-
vation of hexosyl donors, we expected that the reactivity of OH
groups toward benzylation in partially protected hexoses may
be influenced by the O-Ac groups on the neighboring C atoms
in the molecule. Benzylation of 19 (5-O-acetylated 5) was there-
fore examined under the above-mentioned conditions. Indeed
while the diol 5 gave the 6-O-benzylated product 6 in 90% (iso-
lated) yield in 12 h at rt, compound 19 was proved to be unreac-
tive toward both benzylation and p-methoxybenzylation (using
BnBr and PMBnCl, respectively) at rt as well as at 60 °C for up
to 24 h. Thus, the deactivating effect of the 5-O-Ac group in 19
on the benzylation reaction became evident. Other compounds
investigated in this context included the galactosyl derivatives
22, 24, and 26 as well as the hexitol derivative 28. As expected
they also proved to be either sluggish or unreactive toward the
benzylation reaction.
We have observed that although primary OH groups in polyols
bearing both primary and secondary OH groups are known to be
generally more reactive, no theoretical estimates supporting this
view have been reported to date. Hence, in the light of the obser-
vations noted above, we set out to determine qualitative estimates
of the reactivity differences between OH groups in certain diols
and triols with and without an acetoxy substituent. Thus, using
propylene glycol 1b and its 2-O-acetate 32 as the model substrates
and with O-methylation as the model reaction using MeBr and
MeCl as the halide donor reagents, the heat of formation for the
respective products were calculated using the GAUSSIAN0315 soft-
ware package (Scheme 2; Table 1). The results (Table 1, entries
1–3) clearly show that methylation at the primary OH group in diol
1b is thermodynamically more favored by 7.56 kcal molꢀ1 and that
the introduction of an Ac group on O-2 renders the neighboring
primary OH less reactive toward methyl halide by a margin of
1.16–1.17 kcal molꢀ1 (entries 1 and 3). In the case of glycerol 34,
the primary OH was shown to be considerably more reactive to-
ward the methylation reaction (Table 1, entries 4 and 5). Again,
the energy estimates obtained for the formation of 38 as well as
40 and 41, respectively, from the mono-O-acetates 37 and 39 have
revealed the decreasing influence of the substituent group with
increasing distance from the reaction site (Table 1, entries 6–8).
Thus, the computational data noted above not only accounts for
the observed reactivity differences between the primary and sec-
ondary hydroxyls but also provides theoretical proof for the long
known deactivating/disarming effect of neighboring acetyl substit-
uents in carbohydrates.16
To further validate the above-mentioned results, Natural Bond
Orbital (NBO) analysis and Molecular Electrostatic Potential
(MESP) calculations on model systems utilizing the GAUSSIAN03
and SPARTAN-Pro software,18 respectively, were carried out.
NBO-based charge analysis at B3LYP/6-31+G(d) level revealed a
moderate drop in the negative charge at O-1 and the group charge
at the OH-1 in the 2-O-acetyl-propanediol 32, 2-O-acetyl-glycerol
37, and 1-O-acetyl-glycerol 39, respectively. These findings were
also supported by the MESP maps generated at the same level of
theory (see Supplementary data). The effect of the proximity of
the acetate was revealed by a similar analysis on glycerol 34,
where the acetyl-substitution at O-1 decreases the electron density
at O-3; however, the effect was marginal.
Finally, the method developed above was successfully applied
to the benzylation of the disaccharide derivative 42 to give the gly-
cosyl donor 43, a key donor in the oligosaccharide synthesis cur-
rently underway in our laboratory.
OBz
O
BzO
BzO
O
BzO
O
O
SPh
O
RO
Table 1
42 R = H
43 R = Bn
3h, 60 ºC, 75%
Reaction enthalpies (ZPE corrected) for methylation estimated using B3LYP/6-
31+G(d) method under the gas phase conditionsa
Entry no.
Substrate
Product
D
H (kcal molꢀ1
)
In conclusion, we have developed a novel strategy to achieve
regioselective benzylation and p-methoxybenzylation of carbohy-
drates that has not been possible by current literature methods.
The mild nature of the method allows application to substrates
bearing base-labile substituents. Benzylation/p-methoxybenzyla-
tion of isolated secondary OH groups has also been possible. These
reactions have been found to be particularly facile when the sub-
strates are devoid of any electron-withdrawing acyl substituents
on the neighboring position. The data obtained for thermodynamic
and NBO charge analyses along with MESP calculations, obtained
for the first time, are in accord with the experimental findings.
From MeBr
From MeCl
1
2
3
4
5
6
7
8
1b
30
31
33
35
36
38
40
41
4.20
11.76
5.37
7.58
11.71
7.28
1.86
9.42
3.02
5.23
9.37
4.93
2.62
10.16
32
34
37
39
4.97
12.50
a
The ZPE corrected values have been estimated by performing frequency cal-
culations on the optimized geometries and scaled by a factor of 0.9806.17

562
S. Malik et al. / Carbohydrate Research 345 (2010) 559–564
Theoretical studies on the transition state are currently in progress
in our laboratory and will be forthcoming. We hope that the meth-
od will find wide application in synthetic carbohydrate chemistry.
3.4. Synthesis of 1-(benzyloxy)-propan-2-ol (2b)8
Compound 2b was synthesized from 1b using the general pro-
cedure as described above (yield, 80%). 1H NMR (400 MHz, CDCl3,
dH) 7.39–7.27 (m, 5H, Ar–H), 4.69 (d, 1H, J = 4.2 Hz, OH), 4.57 (s,
2H, CH2Ph), 4.04–3.98 (m, 1H, CHOH), 3.48 and 3.30 (2 dd, 1H each,
J = 3.1 Hz; 9.4 Hz and J = 8.0 Hz; 9.4 Hz, respectively, CH2OBn), 1.16
(d, 3H, J = 6.4 Hz, CH3); NMR (100 MHz, CDCl3, dC) 128.54, 127.80,
126.97, 75.83, 73.33, 66.52, 18.63. MS (APCI): 166.27.
3. Experimental section
3.1. General experimental methods
All the reagents were used as purchased without purification.
Solvents used for reactions were dried according to standard meth-
ods.19 Reactions were monitored by TLC, which was performed
with 0.2 mm Merck pre-coated Silica Gel 60 F254 aluminum
sheets. Compounds were detected by dipping the TLC plates in
an ethanolic solution of sulfuric acid (5% v/v) and thereafter heat-
ing them. Melting points were determined on a Buchi melting
point apparatus. Specific rotations were recorded on a Rudolph
Research Autopol IV Polarimeter at room temperature (approxi-
mately 20–25 °C). NMR spectra were recorded on a Bruker Avance
DPX (300 or 400 MHz) spectrometer. 1H NMR and 13C NMR spectra
were referenced using either residual solvent signals20 or tetra-
methylsilane in the respective deuterated solvents. Coupling con-
stants (J) are reported in hertz. Mass spectra were recorded on a
MALDI (Bruker Daltonics, Ultraflex TOF/TOF) spectrometer. Physi-
cal constants and spectral data obtained for previously reported
compounds were in agreement with the literature. Although the
identification of the partially protected disaccharide 42 that served
as the precursor for compound 43 has been described below, its
synthesis has not been reported in this article.
3.5. 53,6-Di-O-benzyl-1,2-O-isopropylidene-a-D-glucofuranose
(4)22
Compound 4 was synthesized from 3 using the same general
procedure as described above (yield, 88%). 1H NMR (400 MHz,
CDCl3, dH) 7.32 (s, 10H, Ar–H), 5.92–5.91 (d, 1H, J1,2 = 3.7 Hz,
H-1), 4.68–4.50 (m, 5H, PhCH2, H-2), 4.14–4.03 (m, 3H, H-4, H-3,
H-5), 3.75–3.72 (dd, 1H, J = 3.7 Hz, J = 12.8 Hz, H-6a), 3.62–3.57
(dd, 1H, J = 5.6 Hz, J = 9.7 Hz, H-6b), 1.48 (s, 3H, C(CH3)2), 1.31 (s,
3H, C(CH3)2); 13C NMR (100 MHz, CDCl3, dC) 138.57, 137.93,
129.12–127.52, 112.30, 105.71, 82.85, 82.64, 80.38, 74.07, 72.90,
72.66, 68.60, 65.85, 59.86, 27.36, 26.85; MALDI-TOF MS: m/z calcu-
lated for C23H28O6: 400.465. Found: 423.550 [M+Na]+, 439.540
[M+K]+.
3.6. 6-O-Benzyl-1,2-O-isopropylidene-3-O-methyl-a-D-glucofu-
ranose (6)23
Compound 6 was synthesized from 5 using the same general
procedure (yield, 90%). 1H NMR (300 MHz, CDCl3, dH) 7.25–7.20
(m, 5H, Ar–H), 5.82–5.81 (d, 1H, J1,2 = 3.15 Hz, H-1), 5.09–4.45
(m, 3H, H-2, PhCH2), 4.05 (s, 2H, PhCH2), 3.84–3.74 (m, 2H, H-5,
H-4), 3.67–3.53 (m, 2H, H-6a, H-6b), 3.33 (s, 3H, OCH3), 3.31 (s,
1H, H-3), 2.82 (br s, 1H, OH), 1.41 (s, 3H, C(CH3)2), 1.24 (s, 3H,
C(CH3)2.); 13C NMR (75 MHz, CDCl3, dC) 136.99, 126.74, 110.78,
103.99, 83.28, 82.48, 78.56, 72.78, 71.03, 66.99, 56.95, 25.73,
25.22; MALDI-TOF MS: m/z calculated for C17H24O6: 324.369.
Found: 347.56 [M+Na]+, 363.545 [M+K]+.
3.2. General procedure for alkylation
To a mixture of the sugar (1 mmol) and Ag2CO3 (3 mmol) in dry
toluene (1–2 mL/100 mg) in the dark was added BnBr (2 mmol),
and the mixture was stirred at rt or 60 °C in the dark until TLC
showed completion of reaction. After completion of the reaction,
excess of the BnBr was quenched by the addition of Et3N followed
by dilution of the reaction mixture with CH2Cl2 (20 mL) and filtra-
tion through a Celite-bed. The organic layer was then washed suc-
cessively with dilute aqueous HCl, dilute aqueous NaHCO3, and
distilled water. It was then dried (Na2SO4), concentrated to dryness
under reduced pressure, and was purified by column chromatogra-
phy (silica gel; EtOAc–hexane) to yield pure product.
3.7. 3-O-Acetyl-6-O-benzyl-1,2-O-isopropylidene-a-D-
glucofuranose (8)24
Compound 8 was synthesized from 7 using the general proce-
dure described above (yield, 92%). 1H NMR (300 MHz, CDCl3, dH)
7.50–7.56 (m, 5H, Ar–H), 6.06–6.05 (d, 1H, J1,2 = 2.97 Hz, H-1),
5.49–5.48 (d, 1H, J3,4 = 1.68 Hz, H-3), 4.79–4.64 (m, 3H, H-2,
PhCH2), 4.42–4.39 (m, 1H, H-4), 4.08–4.04 (m, 1H, H-5), 3.95–
3.93 (m, 1H, H-6a) 3.80–3.75 (m, 1H, H-6b), 2.26 (s, 3H, COCH3),
1.66 (s, 3H, C(CH3)2), 1.47 (s, 3H, C(CH3)2.); 13C NMR (75 MHz,
CDCl3, dC) 169.30, 136.86, 126.75, 111.24, 103.88, 82.09, 77.69,
75.24, 72.91, 70.61, 69.49, 66.52, 25.74, 25.62, 19.8; MALDI-TOF
MS: m/z calculated for C18H24O7: 352.379. Found: 375.465
[M+Na]+, 391.485 [M+K]+.
3.3. Typical procedure: synthesis of 1-(benzyloxy)-3-(trityloxy)-
propan-2-ol (2a)21
To a mixture of Ag2CO3 (827 mg, 3 mmol) and 1a (334 mg,
1 mmol) in dry toluene (10 mL) in the dark was added BnBr
(0.24 mL, 2 mmol), and the mixture was stirred at rt in the dark un-
til TLC (EtOAc–hexane, 2:3) showed completion of the reaction
(10 h). Excess of the BnBr was quenched by the addition of Et3N
followed by dilution of the reaction mixture with CH2Cl2 (20 mL)
and filtration through a Celite-bed. The organic layer was then
washed successively with dilute aqueous HCl, dilute aqueous NaH-
CO3, and distilled water. It was then dried (Na2SO4), concentrated
to dryness under reduced pressure, and was purified by column
chromatography (silica gel; EtOAc–hexane, 2:3) to yield 2a as a
colorless syrup (336 mg, 82%). 1H NMR (400 MHz, CDCl3, dH)
7.43–7.23 (m, 20H, Ar–H), 4.55 (s, 2H, CH2Ph), 4.00 (s, 1H, CHOH),
3.64–3.55 (m, 2H, CH2OBn), 3.28–3.20(m, 2H, CH2OTr); 13C NMR
(100 MHz, CDCl3, dC) 143.83, 137.99, 128.67, 128.58, 128.40,
127.93, 127.84, 127.68, 86.67, 73.37, 71.54, 69.94, 64.56; MALDI-
TOF MS: m/z calculated for C29H28O3: 424.531. Found: 447.802
[M+Na]+.
3.8. Phenyl 6-O-benzyl-3,4-O-isopropylidene-1-thio-b-D-
galactopyranoside (10)
Compound 10 was synthesized from 9 using the general proce-
dure described above (yield, 67%). [
2.4 (c 0.25, CH2Cl2); 1H
a]
D
NMR (400 MHz, CDCl3, dH) 7.57–7.25 (m, 10H, Ar–H), 4.66–4.63 (d,
1H, J = 12.0 Hz, CH2Ph), 4.58–4.55 (d, 1H, J = 12.0, CH2Ph), 4.47–
4.45 (d, 1H, J1,2 = 10.0 Hz, H-1), 4.22–4.20 (dd, 1H, J2,3 = 5.2 Hz,
J3,4 = 2.0 Hz, H-3), 4.09–4.06 (dd, 1H, J1,2 = 6.8 Hz, J2,3 = 5.2 Hz, H-2),
4.0–3.97 (m, 1H, H-5), 3.86–3.77 (m, 2H, H-4, H-6a), 3.59–3.55 (dd,
1H, J = 6.8 Hz, J = 10.4 Hz, H-6b), 1.42, 1.34 (2s, 6H, (CH3)2C); 13C
NMR (100 MHz, CDCl3, dC) 138.18, 132.51, 132.20, 128.98, 128.38,

S. Malik et al. / Carbohydrate Research 345 (2010) 559–564
563
128.01, 127.66, 127.63, 110.27, 88.01, 79.00, 76.07, 73.75, 73.55,
71.60, 69.58, 29.35, 29.69; MALDI-TOF MS: m/z calculated for
C22H26O5S: 402.504. Found: 425.634 [M+Na]+, 441.628 [M+K]+.
COCH3); 13C NMR (75 MHz, CDCl3, dC) 169.28, 135.68, 126.99,
98.75, 69.98, 69.67, 67.81, 66.03, 60.30, 19.68, 19.57; MALDI-TOF
MS: m/z calculated for C21H26O10
: 438.425. Found: 461.56
[M+Na]+, 477.62 [M+K]+.
3.9. Octyl 6-O-p-methoxybenzyl-b-D-galactopyranoside, (12)
3.13. Methyl 2,4,6-tri-O-acetyl-3-O-benzyl-b-D-galactopyrano-
Compound 12 was synthesized from 11 using the general pro-
side (23)27
cedure described above. It was obtained as a low melting solid
(yield, 91%). [
a
]
D ꢀ22.4 (c 0.25, CH2Cl2); 1H NMR (300 MHz, CDCl3,
Compound 23 was prepared from 22 by the same general pro-
cedure as described above except that the reaction mixture was
stirred at 60 °C instead of room temperature (yield 55%). 1H NMR
(400 MHz, CDCl3, dH) 7.39–7.26 (m, 5H, Ar–H), 5.37–5.36 (dd,1H,
J = 0.8 Hz, J = 3.44 Hz, H-4), 5.00–4.96 (dd, 1H, J = 3.44 Hz,
J = 10.2 Hz, H-3), 4.88–4.85 (d, 1H, J = 11.7 Hz, CH2Ph), 4.64–4.61
(d, 1H, J = 11.7 Hz, CH2Ph), 4.41–4.39 (d, 1H, J = 7.7 Hz, H-1),
4.22–4.17 (dd,1H, J = 6.5, J = 11.2, H-6a), 4.14–4.09 (dd, 1H,
J = 6.96 Hz, J = 11.2 Hz, H-6b), 3.89–3.86 (dt, 1H, J = 0.9, J = 6.8 Hz,
H-5), 3.64–3.59 (m, 4H, H-2, OCH3), 2.17 (s, 3H, COCH3), 2.05 (s,
3H, COCH3), 1.96 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3, dC)
170.43, 170.19, 170.09, 138.29, 128.47, 127.91, 127.70, 127.66,
104.79, 77.23, 76.48, 74.75, 72.21, 70.37, 67.41, 61.37, 57.37,
20.68; MALDI-TOF MS: m/z calculated for C20H26O9: 410.415.
Found: 433.817 [M+Na]+, 449.844 [M+K]+.
dH) 7.30–7.34 (d, 2H, J = 8.24 Hz, Ar–H), 6.88–6.85 (d, 2H,
J = 8.24 Hz, Ar–H), 4.50 (s, 2H, OCH2PhOCH3), 4.22–4.19 (d, 1H,
J1,2 = 7.45 Hz, H-1), 3.96 (br s, 1H, H-4), 3.92–3.84 (m, 1H, H-3),
3.79 (s, 3H, OCH2PhOCH3), 3.74–3.46 (m, 4H, H-5, H-2, H-6a, H-
6b), 1.63–1.59 (m, 2H, OCH2CH2(CH2)5CH3), 1.25 [bs, 10H,
OCH2CH2(CH2)5CH3], 0.89–0.85 [m, 3H, OCH2CH2(CH2)5CH3]; 13C
NMR (75 MHz, CDCl3, dC) 159.85, 129.96, 114.49, 103.55, 74.07,
73.87, 72.35, 70.74, 69.76, 69.59, 55.80, 32.36, 30.14, 29.95,
29.80, 26.71, 26.48, 23.20, 14.64; MALDI-TOF MS: m/z calculated
for C22H36O7: 412.517. Found: 435.780 [M+Na]+, 451.778 [M+K]+.
3.10. 2-(Trimethylsilyl)ethyl 6-O-p-methoxybenzyl-b-D-
galactopyranoside (14)25
Compound 14 was synthesized from 13 using the general pro-
cedure described above and was obtained as a colorless viscous
3.14. Methyl 2,3,4-tri-O-acetyl-6-O-benzyl-1-thio-b-D-galactopy-
compound (yield, 94%).
[
a]
ꢀ21.1 (c 1, CHCl3); 1H NMR
ranoside (25)28
D
(400 MHz, CDCl3, dH) 7.25–7.24 (d, 2H, J = 8.64 Hz, Ar–H), 6.87–
6.85 (d, 2H, J = 8.64 Hz, Ar–H), 4.40 (s, 2H, OCH2PhOCH3), 4.23–
4.21 (d, 1H, J1,2 = 7.68, H-1), 4.00–3.95 (m, 2H, H-3, H-4), 3.78 (s,
3H, OCH2PhOCH3), 3.76–3.57 (m, 6H, H-5, H-2, H-6a, H-6b,
OCH2CH2SiMe3), 1.04–1.00 (m, 2H, OCH2CH2SiMe3); 13C NMR
(100 MHz, CDCl3, dC) 158.95, 129.64, 129.44, 129.08, 113.59,
113.51, 113.44, 102.20, 73.30, 73.23, 72.97, 71.38, 68.92, 68.78,
67.06, 66.75, 54.93, 17.96, -1.09; MALDI-TOF MS: m/z calculated
for C19H32O7Si: 400.539. Found: 423.680 [M+Na]+, 439.678 [M+K]+.
Compound 25 was prepared from 24 by the same general pro-
cedure as described above except that the reaction mixture was
stirred at 60 °C instead of room temperature (yield, 60%). 1H
NMR (400 MHz, CDCl3, dH) 7.39–7.26 (m, 5H, Ar–H), 5.53–5.52
(dd, 1H, J = 0.8 Hz, J = 3.28 Hz, H-4), 5.27–5.22 (t, 1H, J = 9.82 Hz,
H-2), 5.08–5.04 (dd,1H, J = 3.36 Hz, J = 10.04 Hz, H-3), 4.58–4.55
(d, 1H, J = 12.0 Hz, CH2Ph), 4.44–4.41 (d, 1H, J = 12.0 Hz, CH2Ph),
4.40–4.38 (d, 1H, J = 9.8 Hz, H-1), 3.92–3.88 (t, 1H, J = 6.0, H-5),
3.60–3.56 (dd, 1H, J = 5.92 Hz, J = 9.52 Hz, H-6a), 3.48–3.44 (dd,
1H, J = 7.0 Hz, J = 9.52 Hz, H-6b), 2.28 (s, 3H, SCH3), 2.08 (s, 3H,
COCH3), 2.06(s, 3H, COCH3), 1.99 (s, 3H, COCH3); 13C NMR
(100 MHz, CDCl3, dC) 170.28, 170.17, 169.85, 140.88, 137.46,
128.57, 128.49, 128.31, 127.99, 127.92, 127.65, 127.01, 83.52,
77.27, 75.87, 73.55, 72.10, 67.80, 67.39, 66.89, 20.83, 20.67,
20.65, 11.62; MALDI-TOF MS: m/z calculated for C20H26O8S:
426.481. Found: 449.719 [M+Na]+, 465.726 [M+K]+.
3.11. Methyl 6-O-benzoyl-2-O-benzyl-3,4-O-isopropylidene-b-D-
galactopyranoside (16)
Compound 16 was prepared from 15 by the same general pro-
cedure as described above except that instead of room temperature
the reaction mixture was stirred at 60 °C. The product was ob-
tained in 65% yield as a colorless solid. Mp 61.1–62.7 °C; [a]
D
31.4 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3, dH) 8.06–8.04 (m,
2H, Ar–H), 7.57–7.25 (m, 8H, Ar–H), 4.84–4.81 (d, 1H,
J = 11.62 Hz, CH2Ph), 4.79–4.77 (d, 1H, J = 11.62 Hz, CH2Ph), 4.63–
4.56 (m, 2H, H-6a, H-6b), 4.26–4.24 (1H, d, J1,2 = 8.0 Hz, H-1),
4.20–4.19 (m, 2H, H-4, H-3), 4.10–4.06 (m, 1H, H-5), 3.54 (s, 3H,
OMe), 3.43–3.40 (m, 1H, H-2), 1.37, 1.34 (2s, 6H, (CH3)2C); 13C
NMR (100 MHz, CDCl3, dC) 166.33, 138.19, 133.14, 129.94,
129.64, 128.43, 128.33, 128.24, 128.18, 127.58, 110.23, 103.80,
79.38, 78.99, 77.21, 73.57, 73.53, 70.80, 63.83, 56.74, 27.67,
26.33; MALDI-TOF MS: m/z calculated for C24H28O7: 428.475.
Found: 451.939 [M+Na]+, 467.950 [M+K]+.
3.15. Phenyl 6-O-(2,3,4,6-tetra-O-benzoyl-b-
D
-glucopyranosyl)-
2-O-benzyl 3,4-O-isopropylidene-1-thio-b-D-galactopyranoside
(43)
Compound 43 was prepared from 42 by the same general proce-
dure as described above except that instead of room temperature the
reaction mixture was stirred at 60 °C. It was obtained in 75% yield as a
colorless solid. Mp 157.1–160 °C; [
a
]
24.4 (c 1, CHCl3); 1H NMR
D
(400 MHz, CDCl3, dH) 8.05–7.83 (m, 8H, Ar–H), 7.52–7.27 (m, 22H,
3.12. Benzyl 2,3,4,6-tetra-O-acetyl-b-D
-galactopyranoside (18)26
Malik, S.; Kartha, K. P. R. Unpublished Results. Compound 42, colorless solid; mp
86.3–88.1 °C; [a
]D 23.4 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3, dH) 8.03–7.82 (4d,
8H, J = 6.8 Hz, Ar–H), 7.54–7.26 (m, 17H, Ar–H), 5.90–5.86 (t, 1H, J = 9.6 Hz, H-30)
5.71–5.67 (t, 1H, J = 9.6 Hz, H-40), 5.57–5.52 (dd, 1H, J1,2 = 8.0 Hz, J2,3 = 9.6 Hz, H-20)
5.00–4.99 (d, 1H, J1,2 = 7.6 Hz, H-10), 4.67–4.64 (dd, 1H, J = 12.0 Hz, J = 3.2 Hz, H-60a),
4.51–4.47 (dd, 1H, J = 4.8 Hz, J = 12.4 Hz, H-60b), 4.30–4.27 (d, 1H, J1,2 = 10.0 Hz, H-1),
4.14–3.89 (m, 6H, H-50, H-6a, H-6b, H-3, H-4, H-5), 3.49–3.45 (dd, 1H, J = 6.8 Hz,
J = 10.0 Hz, H-2), 1.36, 1.25 (2s, 6H, (CH3)2C); 13C NMR (100 MHz, CDCl3, dC) 166.13,
165.79, 165.20, 165.15, 133.45, 133.17, 133.63, 131.87, 129.83, 129.79, 129.16,
128.83, 128.79, 128.42, 128.40, 128.32, 128.30, 128.21, 110.33, 101.21, 87.86, 78.75,
77.21, 76.15, 73.63, 72.93, 72.95, 72.25, 71.85, 71.25, 69.71, 68.94, 62.99, 27.96, 26.23;
MALDI-TOF MS: m/z calculated for C49H46O14S: 890.946. Found 929.932 [M+K]+,
913.942 [M+Na]+.
Compound 18 was synthesized from 17 using the general pro-
cedure as described above (yield, 90%). [
ꢀ25.2 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3, dH) 7.31–7.20 (m, 5H, Ar–H), 5.32–5.31
(d, 1H, J4,5 = 3.11 Hz, H-4), 5.24–5.18 (dd, 1H, J1,2 = 8.02 Hz, J2,3
10.37 Hz, H-2), 4.93–4.89 (dd, 1H, J3,4 = 3.34 Hz, J3,2 = 10.43 Hz, H-
3), 4.86–4.82 (d, 1H, J = 12.33 Hz, CH2Ph), 4.58–4.53 (d, 1H,
J = 12.32 Hz, CH2Ph), 4.46–4.43 (d, 1H, J1,2 = 7.98 Hz, H-1), 4.17–
4.01 (m, 2H, H-6a, H-6b), 3.84–3.79 (m, 1H, H-5), 2.08 (s, 3H,
COCH3), 1.99 (s, 3H, COCH3), 1.94 (s, 3H, COCH3), 1.90 (s, 3H,
a
]
D
=

564
S. Malik et al. / Carbohydrate Research 345 (2010) 559–564
Ar–H), 5.84 (t, 1H, J = 9.6 Hz, H-30), 5.67 (t, 1H, J = 9.6 Hz, H-40), 5.53–
5.49 (dd, 1H, J1,2 = 8.0 Hz, J2,3 = 9.6 Hz, H-20), 4.94 (d, 1H, J1,2 = 7.8 Hz,
H-10), 4.75 (d, 1H, J = 11.2 Hz, CH2Ph), 4.66–4.61 (m, 2H, CH2Ph, H-
60a), 4.57 (d, 1H, J1,2 = 8.8 Hz, H-1), 4.50–4.46 (dd, 1H, J = 4.8 Hz,
J = 12.0 Hz, H-60b), 4.12 (t, 1H, J = 6.0 Hz, H-50), 4.07–4.00 (m, 4H, H-
3, H-4, H-6a, H-6b), 3.88–3.86 (m, 1H, H-5), 3.49–3.45 (dd, 1H,
J = 6.4 Hz, J = 9.2 Hz, H-2), 1.36, 1.27 (2s, 6H, (CH3)2C); 13C NMR
(100 MHz, CDCl3, dC) 166.13, 165.78, 165.19, 165.13, 137.76, 133.68,
133.43, 133.19, 133.11, 132.0, 129.82, 129.76, 129.60, 129.21,
129.01, 128.87, 128.84, 128.42, 128.37, 128.33, 128.28, 128.16,
127.74, 127.67, 126.98, 110.14, 100.89, 85.98, 79.08, 77.77, 77.21,
75.94, 73.68, 73.26, 72.95, 72.15, 71.92, 69.73, 68.63, 63.04, 27.60,
26.16; MALDI-TOF MS C56H52O14S [M]+ calculated m/z 981.069, found
m/z 1004.164 [M+Na]+ and 1020.086 [M+K]+.
7. Bauzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945–5948.
8. Avela, E.; Holmbom, B. Acta Acad. Abstr., Ser. B 1971, 31, 1–14.
9. Gridley, J. J.; Osborn, H. M. I.; Suthers, W. G. Tetrahedron Lett. 1999, 40, 6991–
6994.
10. Maki, T.; Ushijima, N.; Matsumura, Y.; Onomura, O. Tetrahedron Lett. 2009, 50,
1466–1468.
11. Petit, J.-M.; Jacquine, J.-C.; Sinay, P. Carbohydr. Res. 1980, 82, 130–134.
12. Ogawa, T.; Matsui, M. Carbohydr. Res. 1978, 62, C1–C4; Ogawa, T.; Nukada, T.;
Matsui, M. Carbohydr. Res. 1982, 101, 263–270; Kumar, H. M. S.; Reddy, B. V. S.;
Mohanty, P. K.; Yadav, J. S. Tetrahedron Lett. 1997, 38, 3619–3622; Eby, R.;
Webster, K. T.; Schuerch, C. Carbohydr. Res. 1984, 129, 111–120; Auge, C.;
David, S.; Veyrières, A. J. Chem. Soc., Chem. Commun. 1976, 375–376; David, S.;
Thieffry, A.; Veyrières, A. J. Chem. Soc., Perkin Trans. I 1981, 1796–1801; Gelas, J.
Adv. Carbohydr. Chem. Biochem. 1981, 39, 71–156. and the references cited
therein; Garegg, P. J.; Hultberg, H. Carbohydr. Res. 1981, 93, C10–C12; Garegg, P.
J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97–101; Johansson, R.;
Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1984, 2371–2374; Bessodes, M.;
Boukarim, C. Synlett 1996, 1119–1120; Wessel, H.-P.; Iversion, T.; Bundle, D. R.
J. Chem. Soc., Perkin Trans. 1 1985, 2247–2250; Nakajima, N.; Horita, K.; Abe, R.;
Yonemitsu, O. Tetrahedron Lett. 1988, 29, 4139–4142.
3.16. Computational details
13. Kartha, K. P. R.; Kiso, M.; Hasegawa, A.; Jennings, H. J. J. Chem. Soc., Perkin Trans.
1 1995, 3023–3026.
14. Lichtenthaler, F. W.; Kitahara, K.; Riess, W. Nucleic Acids Res. 1978, 4, s115;
Morel, A. F.; Larghi, E. L.; Selvero, M. M. Synlett 2005, 2755–2758.
15. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G. Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Laham, A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
GAUSSIAN03, suite of programs, Gaussian, Inc.: Pittsburgh, PA, 2003.
16. Veeneman, G. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31, 275–278;
Konradsson, P.; Udodong, U. E.; Fraser-Reid, B. Tetrahedron Lett. 1990, 31,
4313–4316; Kartha, K. P. R.; Field, R. A. Tetrahedron Lett. 1997, 38, 8233–8236.
17. Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502–16513.
All the structures were drawn using the GAUSSVIEW03 programme
and the initial geometry was minimized using the AM1 method
followed by optimization and NBO analysis (see Fig. 1, Supplemen-
tary data) at the B3LYP/6-31+G(d) level. The GAUSSIAN output geom-
etries were used for MESP calculations (see Fig. 2, Supplementary
data) directly at the same level of theory. Results of the thermody-
namic analysis are given in the table in Supplementary data.
Acknowledgments
Satish Malik sincerely thanks the University Grants Commis-
sion, New Delhi for a Senior Research Fellowship and Vaibhav A.
Dixit acknowledges NIPER, S.A.S. Nagar for providing the financial
support.
Supplementary data
18. Hehre, W. J.
A Guide to Molecular Mechanics and Quantum Chemical
Calculations, Wavefunction: Irvine, 2001.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2009.12.012.
19. Perrin, D. D.; Amarego, W. L.; Perrin, D. R. Purification of Laboratory Chemicals;
Pergamon: London, 1966.
20. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512–7515.
21. Brard, M. J. Org. Chem. 2007, 72, 8267–8279.
References
22. Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989, 54, 1346–1353.
23. Mocerino, M.; Stick, R. V. Tetrahedron Lett. 1990, 31, 3051–3054.
24. Falck, J. R.; Barma, D. K.; Venkataraman, S. K.; Baati, R.; Mioskowski, C.
Tetrahedron Lett. 2002, 43, 963–966.
25. Kartha, K. P. R.; Field, R. A. Tetrahedron 1997, 53, 11753–11766.
26. Lehtila, R. L.; Lehtila, J. O.; Roslund, M. U.; Leino, R. Tetrahedron 2004, 60, 3653–
3661.
27. Pei, Z.; Dong, H.; Caraballo, R.; Ramstrom, O. Eur. J. Org. Chem. 2007, 29, 4927–
4934.
28. Dekany, G.; Wright, K.; Toth, I. J. Carbohydr. Chem. 1997, 16, 983–999.
1. Novel selectivity in carbohydrate-reactions V. For Part IV see: Gadakh, B. K.;
Patil, P. R.; Malik, S.; Kartha, K. P. R. Synth. Commun. 2009, 39, 2430–2438.
2. Patil, P. R.; Kartha, K. P. R. J. Carbohydr. Chem. 2008, 27, 279–293.
3. Flowers, H. M. Carbohydr. Res. 1982, 100, 418–423; Also see: Warren, C. D.;
Jeanloz, R. W. Carbohydr. Res. 1977, 53, 67–84.
4. Haines, A. H. Adv. Carbohydr. Chem. Biochem. 1976, 33, 11–109.
5. Deng, S.; Chang, C.-W. T. Synlett 2006, 756–760.
6. Sashidhar, M. S. ARKIVOC 2002, 63–75.