HClO4-silica-catalysed regioselective opening of benzylidene acetals and its application towards regioselective HO-4 glycosylation of benzylidene acetals in one-pot

Article abstract of DOI:10.1016/j.carres.2014.01.011

Here we report a high-yielding method for the regioselective reductive ring opening of 4,6-O-benzylidene acetals of hexapyranosides using inexpensive and robust HClO₄-SiO₂ as the acidic catalyst and triethylsilane as the hydride dono

Full text of DOI:10.1016/j.carres.2014.01.011

Accepted Manuscript
Note
HClO4-Silica-catalysed regioselective opening of benzylidene acetals and its
application towards regioselective HO-4 glycosylation of benzylidene acetals
in one-pot
Saidulu Dara, Varma Saikam, Mahipal Yadav, Parvinder Pal Singh, Ram A.
Vishwakarma
PII:
S0008-6215(14)00026-3
DOI:
http://dx.doi.org/10.1016/j.carres.2014.01.011
CAR 6651
Reference:
Carbohydrate Research
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 November 2013
11 January 2014
13 January 2014
Please cite this article as: Dara, S., Saikam, V., Yadav, M., Singh, P.P., Vishwakarma, R.A., HClO4-Silica-catalysed
regioselective opening of benzylidene acetals and its application towards regioselective HO-4 glycosylation of
benzylidene acetals in one-pot, Carbohydrate Research (2014), doi: http://dx.doi.org/10.1016/j.carres.2014.01.011
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HClO4-Silica-catalysed regioselective opening of benzylidene acetals and its
application towards regioselective HO-4 glycosylation of benzylidene acetals
in one-pot
Saidulu Dara,1,2 Varma Saikam,1,2 Mahipal Yadav,2 Parvinder Pal Singh2,*, and
Ram A. Vishwakarma1,2,3,
*
1Academy of Scientific and Innovative Research
2Medicinal Chemistry Division,
CSIR-Indian Institute of Integrative Medicine, Jammu 180 001, India
Tel.: +91-191-2569111, Fax: +91-191-2569333, e-mail: ram@iiim.res.in, ppsingh@iiim.res.in
IIIM Communication No. IIIM/1614/2013
Key-words: Regioselective, Reductive ring-opening, HClO4-SiO2, Glycosylation, One-pot

Abstract:
Here we report a high-yielding method for the regioselective reductive ring opening of 4,6-
O-benzylidene acetals of hexapyranosides using inexpensive and robust HClO4-SiO2 as the
acidic catalyst and triethylsilane as the hydride donor. Under the optimized condition, gluco- and
mannopyranosides give the respective 6-O-benzyl derivative in good to excellent yields while
the corresponding galactopyranoside gives the corresponding 6-O-benzyl derivative in lower
yield. As the optimized condition involves acidic catalyst, we also successfully developed further
application of the present method for the tandem regioselective opening and glycosylation in
one-pot.

Introduction:
Regioselective protection/deprotection methods play a key role in the synthesis of
complex oligosaccharide and glyco-conjugates1. In carbohydrates and polyol-containing natural
products, benzylidene acetals are commonly used for the protection of 1,2- and 1,3-diols because
of their easy installation and flexibility towards either complete removal or regioselective
opening of one of the two C-O bonds. The complete deprotection of 4,6-O-benzylidene acetals
was easily achieved under either hydrogenation or hydrolysis-conditions and a plethora of
reagents and conditions have been developed till date. Towards the regioselective opening of
4,6-O-benzylidene acetals either at the 4-O-position or the 6-O-position, various acids in the
presence of different hydride donors have been successfully employed.3-16 The reagents utilized
2
for the benzylidene acetal opening at 4-O-position are NaCNBH3-I2 , Me2EtSiH-Cu(OTf)2 ,
3
8
BH3.NMe3-TMSOTf4, Et3SiH-BF3.Et2O5, Et3SiH-TFA,6 NaCNBH3-HCl,7 DIBAL-H in CH2Cl2
and at 6-O-position are BH3.NMe3-BF3.Et2O,9 BH3.SMe3-BF3.Et2O,10 PHMS-AlCl3,11 BH3.THF-
16
V(O)(OTf)2,12 BH3.THF-Bu2BOTf,13 DIBAL-H in toluene,8,14 CoCl3-BH3.THF,15 TCT-NaBH4.
Most of these are either moisture sensitive or expensive or required in stiocheometric amounts
and therefore still there is a need for new, inexpensive and robust catalytic systems. In this
direction, silica-supported perchloric acid (HClO4-SiO2) has recently been introduced17 as a user
friendly acid catalyst (because of air stability, easy preparation and removal by simple filtration)
for various organic transformations.18-21 Recently, Agnihotri and Misra22 developed HClO4-SiO2
catalyzed method for the complete cleavage of benzylidene acetals and acetylation in one-pot.
Our continued interest in the development of HClO4-SiO2-catalyzed reaction,23,24 motivated us
towards the exploration of its application in the regioselective opening of 4,6-O-benzylidene
acetals (either at 4- or 6- position) in the presence of a hydride donor. Here, we have successfully

developed a HClO4-SiO2-catalyzed regioselective ring opening of 4,6-O-benzylidene acetals at
the 4-O-position.
Furthermore, many researchers have developed chemo-selective, orthogonal and iterative
glycosylation strategies by exploiting differential reactivities to synthesis oligosaccharides in
one-pot.25-27 As the present method involved acidic catalysis, we also successfully developed
tandem regioselective ring opening and glycosylation in one-pot by the sequential addition of the
appropriate glycosyl donor.
Result and Discussion:
To test this hypothesis, compound 1 was selected as the model substrate and HClO4-SiO2
as the acidic catalytic system in the presence of various hydride donors in CH2Cl2 for the
opening of the benzylidene ring (details given in Table 1). In the first experiment, treatment of 1
with 10 mol % of perchloric acid absorbed on silica (HClO4-SiO2) and 3 mol equivalent of
triethylsilane in CH2Cl2 gave a mixture of products 2 and 3 in 10 and 90% yield respectively
(Table 1, entry 1). To know the optimum amount of HClO4-SiO2 required for catalysis,
experiments with linearly decreased amount of HClO4-SiO2 from 10 mol% to 1 mol% were
performed (Table 1, entries 2-8) and the best result with 92% yield of 6-O-benzyl-containing
product 2 was obtained in the presence of 2.5 mol% of HClO4-SiO2 (Table 1, entry 7). The
decrease in the amount of triethylsilane (3 mol equivalent to 1.5 mol equivalent), lead to the loss
in the yield of expected 6-O-benzyl-containing product 2 (Table 1, entry 9-10). The change of
the hydride donor from triethylsilane to others such as Bu3SnH and NaCNBH3 drastically
decreased the yield of the desired product 2 (Table 1, entries 11-13). Further, the change of
solvent did not improve the yield of the desired product 2 (Table 1, entries 14-16). Based on this,
3 mol equivalent of triethylsilane as the hydride donor in the presence of 2.5 mol% of HClO4-

SiO2 as acid catalyst in CH2Cl2 was selected as the optimum condition for the regioselective
benzylidene ring opening at the 4-position.
Table 1: Optimization of reaction condition for the HClO4-SiO2 Catalyzed reductive ring
Opening of the 4,6-O-benzylidene acetal 1
R1O
R2O
BnO
O
O
O
BnO
x mol %
HClO4-SiO2
Ph
O
BnO
OMe
Hydride, Solvent
BnO
2: R1=Bn, R2 =H
3: R1=H, R2 =Bn
4: R1=H, R2=H
OMe
1
Yield %
3
x
Temp (0C)
Time (h)
Entry
Solvent Hydride (eq)
2
4
-
90
88
80
5
1
2
3
10
9
CH2Cl2 Et3SiH (3)
CH2Cl2 Et3SiH (3)
CH2Cl2 Et3SiH (3)
rt
rt
rt
1
1
1
10
12
20
35
-
-
7
-
CH2Cl2 Et3SiH (3)
CH2Cl2 Et3SiH (3)
CH2Cl2 Et3SiH (3)
4
5
6
rt
rt
0
1
5
2.5
2.5
3
56
45
44
55
-
-
12
7
8
2.5
1
CH2Cl2 Et3SiH (3)
CH2Cl2 Et3SiH (3)
CH2Cl2 Et3SiH (2.0)
CH2Cl2 Et3SiH (1.5)
CH2Cl2 Bu3SnH (3)
CH2Cl2 NaCNBH3 (3)
0-rt
0-rt
0-rt
0-rt
0-rt
0-rt
0-rt
0-rt
3
6
3
3
3
3
3
3
92
85
65
45
-
8
-
-
-
-
5
9
2.5
2.5
6
10
11
12
13
14
4
2.5
2.5
2.5
2.5
10
20
5
-
-
25
-
-
BH3.THF (3)
Et3SiH (3)
Et3SiH (3)
25
-
MeCN
THF
45
55
15
16
2.5
2.5
0-rt
0-rt
3
3
20
10
60
40
-
-
Toluene Et3SiH (3)
To investigate the compatibility of different protecting groups under the optimized
condition, we examined various substrates and the results are summarized in Table 2. The acetyl-
protected glucose derivative 5 gave the 4-OH-containing product 5a in 91% yield (Table 2, entry
1). Various methyl glucopyranosides 6, 7 and 8 having different protective groups at the 3-

position (Table 2, entries 2-4) successfully furnished the respective 4-OH-containing products
6a, 7a and 8a in 89%, 93% and 88% yields respectively. When we examined the phenyl 1-thio-
glucopyranosides 9 and 10 bearing acetyl/benzyl groups on O-2 and O-3 respectively, the
corresponding 6-O-benzyl derivatives 9a and 10a were obtained in 85 and 80% yields
respectively (Table 2, entries 5-6). Methyl mannopyranoside 11 underwent regioselective
benzylidene ring opening and furnished free 4-OH-containing product 11a with 80% yield
(Table 2, entry 7). Similarly phenyl-1-thio-2-azido-glucopyranoside 12 also gave the free 4-OH
product 12a in 77 % yield (Table 2, entry 8). Under the optimized condition, the p-
methoxybenzylidene-protected methyl glucopyranoside 13 did not give the expected 4-OH-
containing product but gave the hydrolytic product 13a (Table 2, entry 9). Furthermore, methyl
glucopyranosides bearing allyl and TBS groups 14 and 15 respectively also furnished the
corresponding 6-O-benzyl derivatives 14a and 15a with 92 and 87% yield (Table 2, entry 10 and
11). Phenyl 1-thio-galactoside-derived benzylidene acetal 16 and 17 gave corresponding 6-O-
benzyl derivatives 16a and 17a with comparatively lower yields 40 and 20% respectively. In the
case of Phenyl 1-thio-galactoside-derived benzylidene acetal 16 and 17, 4-O-benzyl derivatives
were also obtained along with complete hydrolytic product. When the optimized method was
tried for 4,6-benzlidene acetal-containing disaccharides such as cellobiose, lactose and pseudo-
disaccharide of GPI glycon core, we did not get the expected 6-O-benzyl-containing product.
To further explore the application of present method, we report here a strategy whereby a
regioselective opening of a benzylidene acetal and glycosylations are combined in a one-pot to
synthesized disaccharides (Scheme1). A few such methods have been reported wherein the
process of protection and glycosylation are achieved in one-pot.26,27 Trichloroacetimidate was
selected as glycosyl donor and its activation requires only catalytic amount of acids (such as

28
BF3.OEt2,28 TMSOTf,
and HClO4-SiO229,30) and therefore, it was anticipated that these
reaction conditions would be used for glycosylations. In this direction, when the
trichloroacetimidate glycosyl donor 18 was added after 3 h to the reaction mixture containing the
4,6-benzylidene acetal 2, HClO4-SiO2 and triethtylsilane in CH2Cl2, the β-glycosylated product
21 was obtained in 80% yield (Scheme 1). In order to further explore the functional group
compatibility of the optimized reaction condition, combination of other glycosyl acceptors
(generated in situ) and donors bearing different functional moieties such as azido- and thiopenyl
groups were also tried. The per-O-benzylated glycosyl donor 19 on reaction with the 4,6-O-
benzylidene acetal 2 under the optimized reaction condition gave the desired glycosylated
product 22 as a mixture of α and β (6:4) glycosides in 75%. The 2-azido-containing glycosyl
donor 20 also underwent glycosylation with in situ generated acceptor from 4,6-benzylidene
acetals 2 and gave the glycosylated product 23 in good yield as a mixture of α and β (8:2).
Thiophenyl containing 4,6-O-benzylidene acetal 10 also underwent tandem ring opening-
glycosylation with glycosyl donor 18 smoothly to give the β-glycosylated product 24 in 77%
yield. The stereochemistry of the newly formed glycosylated product was controlled by the
presence of the 2-O-acetyl group on the glcosyl donor substrate. The presence of participating
groups such as acetyl at 2-position favors the formation of steroselective β-isomer while the
presence of non-participating group such as azido and benzyl at 2-position gave a mixture of α-
and β-glycosylated products.

Table 2: HClO4-SiO2 catalyzed reductive ring opening of various benzylidene acetals
Entry
Substrate
Yield(%)
Product
BnO
HO
AcO
O
O
AcO
Ph
Ph
O
O
O
1
91
AcO
AcO
5a
OMe
OMe
OMe
5
BnO
HO
HO
O
O
HO
O
2
89
BzO
BzO
OMe
6a
6
BnO
HO
BzO
O
O
BzO
Ph
Ph
O
O
3
4
93
88
BzO
BzO
7
OMe
OMe
OMe
OMe
7a
BnO
HO
O
O
BnO
O
O
BnO
BzO
BzO
8a
8
BnO
HO
AcO
O
O
AcO
Ph
Ph
O
O
SPh
SPh
83
85
5
6
OAc
OAc
9a
9
BnO
HO
BnO
O
O
BnO
O
O
SPh
SPh
OBn
OBn
10
10a
OBn
O
OBn
O
BnO
HO
BnO
O
O
Ph
80
77
7
BnO
11a
OMe
OMe
11
BnO
HO
BnO
O
O
BnO
Ph
O
O
SPh
SPh
8
N3
N3
12
12a
O
O
BnO
HO
HO
BnO
PMP
O
O
9
81
92
BnO
BnO
OMe
OMe
13
13a
BnO
HO
AllylO
O
Ph
Ph
O
O
O
AllylO
10
11
AllylO
AllylO
OMe
OMe
14a
14
BnO
HO
TBSO
O
O
O
O
87
40
TBSO
15
Ph
BzO
BzO
OMe
OMe
15a
OBn
O
O
HO
AcO
O
12
O
SPh
SPh
AcO
16
OAc
OAc
16a
Ph
OBn
O
HO
BnO
O
20
13
O
O
SPh
SPh
BnO
17
OBn
OBn
17a
Reactions conditions: Benzylidene acetal (1 mol eq), Et3SiH (3 mol eq), HClO4-SiO2
(2.5 mol %), CH2Cl2, 3-4 h, 0 oC to rt.

Scheme 1: Synthesis of disaccharides by tandem benzylidene ring opening and
glycosylation in one pot.
O
O
BnO
O
O
BnO
Ph
O
Ph
SPh
O
OBn
BnO
OMe
NH
10
2
AcO
AcO
AcO
BnO
BnO
BnO
O
O
NH
O
O
OAc
OBn
19
CCl3
CCl3
18
AcO
AcO
AcO
O
NH
O
N3
CCl3
20
HClO4-SiO2
(2.5 mol%),
Et3SiH (3 eq),
0 oC-rt, 3 h
18 (1.5 eq)
0 oC-rt, 1 h
BnO
AcO
AcO
AcO
O
O
O
BnO
2
OAc
BnO
OMe
21 (80%)
HClO4-SiO2
(2.5 mol %),
Et3SiH (3 eq),
0 oC-rt, 3 h
19 (1.5 eq)
0 oC-rt, 1 h
BnO
BnO
BnO
O
BnO
O
O
2
OBn
BnO
BnO
OMe
22 (75%, α/β 6:4)
HClO4-SiO2
(2.5 mol %),
Et3SiH (3 eq),
0 oC-rt, 3 h
AcO
AcO
AcO
O
20 (1.5 eq)
0 oC-rt, 1 h
BnO
O
N3
O
BnO
2
BnO
OMe
23 (78%, α/β 8:2)
HClO4-SiO2
(2.5 mol %),
Et3SiH (3 eq),
0 oC-rt, 3 h
18 (1.5 eq)
0 oC-rt, 1 h
BnO
AcO
AcO
AcO
O
O
O
10
SPh
BnO
OAc
OBn
24 (77%)

Conclusion:
In conclusion, we have successfully developed a high yielding protocol for the
regioselective reductive ring opening of benzylidene acetals at 4-position using inexpensive and
robust HClO4-SiO2 as the acid catalyst and Et3SiH as the hydride donor. Under the optimized
condition, gluco- and mannopyranosides gave good to excellent yield. The optimized method
was successfully utilized for a tandem regio-selective ring opening and glycosylation in one-pot.
The efforts towards the application of the present method in the synthesis of intermediates of
several important oligosaccharides are under progress and will be published in due course.
Supplementary data
Supplementary data associated with this article can be found in online version, at--
Acknowledgement:
The financial support by CSIR research grant # BSC 0108 is gratefully acknowledged.
SD, VS and MY thank CSIR for Research Fellowship. Authors also thank the support from
Instrumentation Division of IIIM.
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Graphical Abstract
HClO4-Silica-catalysed regioselective opening of benzylidene acetals and its
application towards regioselective HO-4 glycosylation of benzylidene acetals
in one-pot
Saidulu Dara,1,2 Varma Saikam,1,2 Mahipal Yadav,2 Parvinder Pal Singh2,*, and
Ram A. Vishwakarma1,2,3,
*
Regioselective
benzylidene ring opening
Tandem regioselective
ring opening-glycosylation
RO
RO
RO
BnO
O
BnO
HO
O
O
O
O
Ph
O
O
RO
OR
RO
OP
RO
OP
OP
(4 examples)
(14 examples)

Highlights
• Regioselective reductive ring opening of 4,6-O-benzylidene acetals.
• Regioselective formation of 6-O-benzyl-gluco and mannopyranosides.
• Mild reaction condition, high yield and broad functional group compatibility.
• Tandem regioselective reductive ring opening and glycosylation in one-pot.