Highly efficient and mild method for regioselective de-O-benzylation of saccharides by Co2(CO)8-Et3SiH-CO reagent system

Article abstract of DOI:10.1021/ol902717y

[Chemical equation presented] A highly efficient and mild method for the de-O-benzylation of protected saccharides was developed by transforming terminal benzyl ethers Into silyl ethers using Co₂(CO)₈-Et ₃SIH under 1 atm of CO. The method was successfully used for the de-O-benzylatlon of perbenzylated monosaccharides with various anomerlc protecting groups, as well as natural disaccharldes and trisaccharides such as sucrose, raffinose, and melezltose In good yields (>80%).

Full text of DOI:10.1021/ol902717y

ORGANIC
LETTERS
2010
Vol. 12, No. 3
536-539
Highly Efficient and Mild Method for
Regioselective De-O-benzylation of
Saccharides by Co2(CO)8-Et3SiH-CO
Reagent System
Zhao-Jun Yin, Bo Wang, Yang-Bing Li, Xiang-Bao Meng, and Zhong-Jun Li*
The State Key Laboratory of Natural and Biomimetic of Drugs, School of
Pharmaceutical Sciences, Peking UniVersity, Beijing 100191, P. R. China
zjli@bjmu.edu.cn
Received November 25, 2009
ABSTRACT
A highly efficient and mild method for the de-O-benzylation of protected saccharides was developed by transforming terminal benzyl ethers
into silyl ethers using Co2(CO)8-Et3SiH under 1 atm of CO. The method was successfully used for the de-O-benzylation of perbenzylated
monosaccharides with various anomeric protecting groups, as well as natural disaccharides and trisaccharides such as sucrose, raffinose,
and melezitose in good yields (>80%).
The selective protection and deprotection of hydroxyl groups
plays a key role in carbohydrate chemistry owing to the
universal presence of multiple hydroxyl groups and the need
for controlled unmasking in the multistep chemical synthesis
of complex oligosaccharides. The benzyl ether is one of the
most widely used hydroxyl protecting groups because of its
easy formation, inherent stability, and the large number of
deprotection methods available.1 Various methods have been
developed to regioselectively introduce benzyl protecting
groups, including the controlled selective benzylation of
hydroxyl groups in carbohydrates2 and the regioselective
opening of benzylidene acetal derivatives.3 Alternatively, an
attractive route for the selective benzylation of carbohydrates
is provided by the regioselective de-O-benzylation of easily
available perbenzylated precursors.
Several selective de-O-benzylation methods have been
studied for monosaccharides, which include acetolysis,4
catalytic hydrogenolysis,5 catalytic transfer hydrogenolysis,6
Lewis acid deprotection (such as TiCl4 and SnCl4,7 BCl3,8
CrCl2/LiI,9 TMSI10), TIBAL/DIBAL-H,11 or halogenation
with NIS.12 Note that thioglycosides, which are the most
(3) For recent examples, see: (a) Kumar, P. S.; Baskaran, S. Tetrahedron
Lett. 2009, 50, 3489–3492. (b) Daragics, K.; Fu¨gedi, P. Tetrahedron Lett.
2009, 50, 2914–2916. (c) Kumar, P. S.; Kumar, G. D. K.; Baskaran, S.
Eur. J. Org. Chem. 2008, 6063–6067. (d) Johnsson, R.; Olsson, D.; Ellervik,
U. J. Org. Chem. 2008, 73, 5226–5232. (e) Tani, S.; Sawadi, S.; Kojima,
M.; Akai, S.; Sato, K. Tetrahedron Lett. 2007, 48, 3103–3104.
(1) Greene, T. W.; Wuts, P. G. M. Greene’s ProtectiVe Groups in
Organic Synthesis, 4th ed.; John Wiley & Sons: Hoboken, NJ, 2007; pp
102-120.
(2) (a) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643–663. (b)
Hanessian, S. PreparatiVe Carbohydrate Chemistry; Marcel Dekker: New
York, 1997; pp 69-83. (c) Bouzide, A.; Sauve´, G. Tetrahedron Lett. 1997,
38, 5945–5948. (d) Grice, P.; Ley, S. V.; Pietruszka, J.; Priepke, H. W. M.;
Warriner, S. L. J. Chem. Soc., Perkin Trans. 1 1997, 351–363. (e) Classon,
B.; Garegg, P. J.; Oscarson, S.; Tide´n, A. K. Carbohydr. Res. 1991, 216,
187–196. (f) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Fan, H.-F.; Pai, C.-L.;
Yang, W.-C.; Lu, L.-D.; Hung, S.-C. Angew. Chem., Int. Ed. 2002, 41,
2360–2362.
(4) (a) Allerton, R.; Fletcher, H. G., Jr. J. Am. Chem. Soc. 1954, 76,
1757–1760. (b) Eby, R.; Sondheimer, S. J.; Schuerch, C. Carbohydr. Res.
1979, 73, 273–276. (c) Sakai, J.-I.; Takeda, T.; Ogihara, Y. Carbohydr.
Res. 1981, 95, 125–131. (d) Angibeaud, P.; Utille, J.-P. Synthesis 1991,
737–738. (e) Yang, G.; Ding, X.; Kong, F. Tetrahedron Lett. 1997, 38,
6725–6728. (f) Ganem, B.; Small, V. R., Jr. J. Org. Chem. 1974, 39, 3728–
3730. (g) Brar, A.; Vankar, Y. D. Tetrahedron Lett. 2006, 47, 5207–5210.
10.1021/ol902717y  2010 American Chemical Society
Published on Web 01/08/2010

popular building blocks in carbohydrate chemistry, are rarely
utilized with the above methods because the sulfur is prone
to trap the strong electrophilic reagents.4g In addition, for
most methods, careful manipulations are needed to obtain
good selectivity and yield. Furthermore, there are few
methods for selective debenzylation of complex saccha-
rides.11 The difficulty obviously arises from the presence of
more benzyl ethers with similar reactivity. As a consequence,
development of mild methods that are compatible with
various anomeric protecting groups and that can achieve high
selectivity and good yields is necessary.
of Et3SiH in CH2Cl2 at room temperature under 1 atm CO,
perbenzylated methyl mannoside 1a (Table 1) was converted
Table 1. Regioselective De-O-benzylation of Perbenzylated
Monosaccharidesa
Natural disaccharides or trisaccharides, such as sucrose,
raffinose, and melezitose, have attracted considerable interest
in the chemical, biological, and material fields due to their
easy availability in large quantities and special properties.13
For example, sucrose can be used for the preparation of
biodegradable polymers and surfactants;13b,14 derivatives of
sucrose and raffinose modified at terminal positions possess
interesting biological properties;15 melezitose possesses
unique physiological activity and is often used in Chinese
medicine.16 Thus, great efforts have been made to synthesize
selectively O-benzylated intermediates for the preparation
of multifunctional derivatives with tunable properties. How-
ever, results are not satisfactory because of the presence of
many similar hydroxyl groups and the acid labile properties
of glycosidic bonds.17 Herein we described an efficient
method for the selective de-O-benzylation of protected sugars
that involves transforming the benzyl ethers into silyl ethers,
which can be used for the preparation of monosaccharides,
natural disaccharides, and trisaccharides with free primary
hydroxyl groups (Scheme 1).
Scheme 1
.
Regioselective De-O-benzylation of Saccharides by
Co2(CO)8-Et3SiH-CO Reagent System
During our experiments with siloxymethylation of glyco-
sides according to Murai’s protocol,18 we accidentally found
that when treated with 1.5 equiv of Co2(CO)8 and 6.0 equiv
(5) (a) Beaupe`re, D.; Boutbaia, I.; Wadouachi, A.; Fre´chou, C.; Demailly,
G.; Uzan, R. New J. Chem. 1992, 16, 405–411. (b) Maryanoff, B. E.; Reitz,
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a Reaction condition: Co2(CO)8 (1.5 equiv), Et3SiH (6 equiv), CO (1
atm), benzene, 50 °C. b Isolated yields.
(8) Xie, J.; Me´nand, M.; Vale´ry, J.-M. Carbohydr. Res. 2005, 340, 481–
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smoothly to the silylated product 1b (Table 1) in 48 h in a
yield of 75%. The reaction rate was greatly improved by
carrying out the reaction in benzene at 50 °C while selectivity
Org. Lett., Vol. 12, No. 3, 2010
537

was not influenced (Table 1, entry 1). Under these conditions,
all the entries (Table 1) gave excellent yields within 24 h,
except that 3a, 8a, and 10a (Table 1, entries 3, 8, and 10)
needed longer reaction time. We found that even if excess
of reagents were used, the selectivity was not affected but
reaction time is shortened.
After the successful application of our procedure to
monosaccharides, we investigated the potential selective de-
O-benzylation of perbenzylated disaccharides (Table 2).
anomeric protecting groups may have a great influence on
the reactivity of the 6-OBn. Then we carried out this selective
reaction in more complex substrates. Under the same
condition, the perbenzylated sucrose 12a19 afforded 6′-O-
TES derivative 12b in 85% yield. With additional reagents,
6,6′-di-O-TES product12c was obtained in 80% yield under
prolonged time (Table 2, entry 2). The TES group in 12b
and 12c could be readily cleaved to afford 6′-OH and 6,6′-
diol derivatives, which are very important versatile building
blocks in sucrose chemistry.20 The traditional approach to
6′-OH compound was achieved by selective protection of
the 6′-OH of sucrose with bulky ether-forming reagents,
benzylation, and selective deprotection of the bulky
ether.13c,21 The main difficulty comes from the complexity
of hydroxyl groups in sucrose. For example, a 49-85% yield
of the 6′-O-TBDPS derivative was obtained by treatment of
sucrose with 1.1 equiv of TBDPSCl, while equal amount of
6′-O-Tr and 6-O-Tr derivatives were formed in yield of 20%
when 1.2 equiv TrCl was used. The use of excess of reagents
will lead to multiple protection and it was reported that 1,6′,6-
triprotected derivative was obtained with about 4 equiv of
reagents.20h,22 In addition, perbenzylation of TBDPS-
protected sucrose requires a large amount of base and a long
reaction time, and a small fraction of TBDPS is usually
cleaved because it is slightly unstable under the basic reaction
condition.20h Moreover, the deprotection of Tr is a delicate
process because of the high sensitivity of the glycosidic bond
in acidic media. For the preparation of 6,6′-diol derivatives,
the traditional procedure provided a 48% overall yield in
four steps.23 By comparison, our procedure provides a more
Table 2. Regioselective De-O-benzylation of Perbenzylated
Disaccharides and Trisaccharides
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as Organic Raw Materials; Lichtenthaler, F. W., Ed.; VCH: Weinheim,
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Chem. 2000, 19, 693–715. (b) Jarosz, S.; Mach, M. Pol. J. Chem. 1999,
73, 981–988. (c) Mach, M.; Jarosz, S. J. Carbohydr. Chem. 2001, 20, 411–
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Ramos, A. M. J. Org. Chem. 2004, 69, 7772–7775.
a Isolated yield. b Additional reagents were added after a period of
reaction time.
Indeed, when the perbenzylated p-methylphenyl lactoside
11a, which has two primary and five secondary benzyloxy
protecting groups, was treated with 3 equiv of Co2(CO)8 and
10 equiv of Et3SiH in benzene under 1 atm CO at 50 °C, it
generated the 6-O-TES product 11b in a yield of 80% (Table
2, entry 1). The selective debenzylation and silylation of the
6-OBn of S-glucoside over O-galactoside indicated that
(21) For review, see: Jarosz, S.; Mach, M. Eur. J. Org. Chem. 2002,
769–780.
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.
538
Org. Lett., Vol. 12, No. 3, 2010

convenient preparation of sucrose derivatives with free
primary hydroxyl groups in high selectivity and yield.
Usually, the differentiation between 6-OH and 6′-OH was
achieved by selective protection of 6,6′-diol compound with
TBDPSCl in a yield of 60%.20f Using our procedure, 6′-
OAc derivative 13a was easily prepared from 12b, which
was further modified to afford the orthogonally protected
6-O-TES derivative 13b in 78% yield (Table 2, entry 3).
After the successful selective de-O-benzylation of disac-
charides, we investigated the selective deprotection of more
challenging natural saccharides such as melezitose and
raffinose, which have more primary hydroxyl groups. The
reported selective chemical modifications of primary hy-
droxyl groups in melezitose and raffinose, by using Mit-
sunobu reaction,24 selective protection with trityl chloride
or sulfuryl chloride16,25 or acetalization,26 produce complex
mixtures and the isolated yields are low.
electrophilic, so it acts to transform benzyl ethers to silyl
ethers, and the resultant BnCo(CO)4, via insertion of CO,
oxidative addition with triethylsilane and reductive elimina-
tion, generates PhCH2CHO, which reacts with triethylsilane
to produce cis-PhCHdCH(OTES) separated by SiO2 chro-
matography and identified by NMR (Scheme 2). The process
is similar to Murai’s mechanism.28a
Scheme 2. Proposed Mechanism
Using our procedure, the perbenzylated raffinose 14a19 was
converted to 6,6′′-di-O-TES derivative 14b in 80% yield
(Table 2, entry 4). We were unable to control the reaction
to achieve monosilylation in good yield because of the
competing de-O-benzylation at 6′′ position. To our surprise,
for perbenzylated melezitose 15a,19 which has four primary
and seven secondary benzyloxy protecting groups, the
reaction was very clean and gave the 6′-O-TES product 15b
in a yield of 85% after SiO2 chromatographic separation
(Table 2, entry 5). The reaction can be readily performed
on a 0.5 g scale in our hands with yield and selectivity not
being affected.
In conclusion, a highly selective, efficient, and mild de-
O-benzylation method has been developed. The method can
be applied to the selective de-O-benzylation of various per-
O-benzylated monosaccharides and more complex natural
oligosaccharides. The method is complementary to past
selective protection strategies and provides a short-cut for
the rapid preparation of saccharides with free primary
hydroxyl groups, which can be used for further modification
or construction of more complex natural products.29
The active intermediate involved in the transformation of
benzyl ethers to silyl ethers may be Et3SiCo(CO)4, which is
easily prepared by mixing Co2(CO)8 with Et3SiH in situ.
Et3SiCo(CO)4 was first developed by Chalk,27 and it has
found wide applications in organometallic chemistry.28 The
silicon atom in Et3SiCo(CO)4 is strongly Lewis acidic and
Acknowledgment. This work was financially supported
by the National Natural Science Foundation of China (No.
20732001, 90713004, 30672525).
Supporting Information Available: All experimental
procedures and data for compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL902717Y
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