Efficient procedure for reductive opening of sugar 4,6-O-benzylidene acetals in a microfluidic system

Article abstract of DOI:10.1055/s-2006-958410

An efficient procedure for the reductive opening of 4,6-O-benzylidene acetals was established under microfluidic conditions. 4,6-O-Benzylidene acetals of the glucose, glucosamine, and galactose derivatives were selectively converted into the corresponding

Full text of DOI:10.1055/s-2006-958410

164
LETTER
Efficient Procedure for Reductive Opening of Sugar 4,6-O-Benzylidene
Acetals in a Microfluidic System
R
eductive Opening
a
of
S
ugar
4
t
, 6-
O
-B
s
e
nzyliden
u
e
A
cetals by
n
a
Microfluid
o
ic System ri Tanaka, Koichi Fukase*
Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama 1-1, Toyonaka, Osaka 560-0043, Japan
Fax +81(6)68505419; E-mail: koichi@chem.sci.osaka-u.ac.jp
Received 30 September 2006
and is therefore recognized as innovative technology in
Abstract: An efficient procedure for the reductive opening of 4,6-
recent organic synthesis.9,10 Furthermore, once the reac-
tion conditions are optimized for small-scale operation,
O-benzylidene acetals was established under microfluidic condi-
tions. 4,6-O-Benzylidene acetals of the glucose, glucosamine, and
the same conditions are directly applicable to large-scale
galactose derivatives were selectively converted into the corre-
sponding 4- or 6-O-benzyl derivatives in nearly quantitative yields. synthesis, since the reaction is conducted under the flow
process.
Key words: microfluidic system, reductive opening, 4,6-O-ben-
zylidene acetal, oligosaccharides
First, optimal conditions for reductive opening of 4,6-O-
benzylidene acetals by a microfluidic system were exam-
ined using the glucose 4,6-O-benzylidene acetal 1
(Table 1). Benzylidene acetal 1 (0.1 M) and Et3SiH (1.0
M) dissolved in dichloromethane were mixed with vari-
ous concentrations of BF3·OEt2 in dichloromethane (0.1
M–1.0 M) at 0 °C using a micromixer (Techno Applica-
tions Co., Ltd., Tokyo, Japan)11 at the flow rate of 0.5 mL/
min (Table 1). After the reaction mixture was allowed to
flow at room temperature for an additional 45 seconds
through a reactor tube (F = 1.0 mm, l = 0.9 m), the
mixture was quenched by saturated sodium hydrogen-
carbonate solution at 0 °C.
Reductive opening of the sugar 4,6-O-benzylidene acetals
by the combination of acid/hydride reagents is one of the
most useful transformations in the field of carbohydrate
chemistry,1 since the benzyl-protected derivatives at ei-
ther the C4- or C6-hydroxyl can be selectively prepared
by the choice of the reagents and/or the solvents systems.
For example, the treatment of 4,6-O-benzylidene protect-
ed glucose derivative 1 with triethylsilane (Et3SiH)–boron
trifluoride–diethyl ether complex (BF3·OEt2)2 in dichlo-
romethane provides the 6-O-benzyl derivative 5, while the
3
treatment with BH3·Me2NH–BF3·OEt2 gives the 4-O-
When 0.1 M solution of BF3·OEt2 in dichloromethane was
used, only a hydrolyzed compound was obtained in about
50% yield accompanied with recovery of the starting
material 1. However, we were pleased to find that the
yield of 6-O-benzyl derivative 512 dramatically increased
when the concentration of BF3·OEt2 was increased up to
1.0 M; the desired 5 was obtained in 93% yield together
with 5% of the 4-O-benzyl derivative,13 and no hydro-
lyzed by-product was detected (Table 1, entry 1). Interest-
ingly, the reaction with a more concentrated BF3·OEt2
solution (BF3·OEt2–CH2Cl2 = 1:1) similarly provided 5 in
an excellent yield. The reaction was very rapid and 5 was
obtained within a minute after mixing with the acid in the
micromixer device. These results are in marked contrast
to those of the batch reaction, which requires a diluted
concentration of the Lewis acid and longer reaction time
in order to keep the hydrolysis to a minimum. Although
this phenomenon cannot be explained completely, the
efficient micromixing between substrate, hydride and
high concentration of the acid might accelerate the reac-
tion, while the rapid heat transfer prevents the undesired
hydrolysis.
benzyl derivative 6 in good selectivity (see Table 1, batch
reaction of entries 1 and 2). A variety of the acid/reducing
reagents has been reported and successfully used as a key
protecting group manipulation during the synthesis of
complex oligosaccharides.4–8
The typical procedure for the reductive opening of the
acetals involves the very slow addition of the acid to a
mixture of the substrate and excess hydride reagent at
0 °C, followed by continuous stirring at room temperature
for another few hours to ensure completion of the reac-
tion. Since the reaction is exothermic, it is important to
control the addition speed of the acid addition, i.e., by us-
ing a syringe pump, in order to prevent concomitant acid-
catalyzed hydrolysis of the benzylidene groups. However,
the yields are not always reproducible, especially when
the reaction is performed on a large scale, giving rise to
hydrolyzed byproducts, the 4,6-diols. The precise tem-
perature control and the mixing efficiency between the
substrate, acid, and hydride source are critical for this
transformation.
In order to facilitate the synthetic procedure, in this paper,
we used a continuous-flow microreactor, which is report-
ed to realize the efficient mixing and fast heat transfer,
Gratifyingly, by applying the established conditions as
mentioned above, the glucose, glucosamine, and galac-
tose 4,6-O-benzylidene acetals 1–4 were selectively
transformed into the corresponding 4- or 6-O-benzyl de-
rivatives 6–10 in nearly quantitative yields (entries 2–6).
Thus, the treatment of 1 with BH3·Me2NH selectively
SYNLETT 2007, No. 1, pp 0164–0166
0
4.
0
1.
2
0
0
7
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-958410; Art ID: U11706ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reductive Opening of Sugar 4,6-O-Benzylidene Acetals in a Microfluidic System
165
provided 4-O-benzyl derivative 6 in a quantitative yield O-benzyl derivatives 714 and 815 in excellent yields, re-
(entry 2).3,12 The benzylidene group of glucosamine spectively (entries 3 and 4). The BH3·Me3N in acetonitrile
derivative 2 was also selectively cleaved under the system was also applicable to the microflow reduction of
microfluidic condition by utilizing either Et3SiH or muramic acid derivative 3, which contains a lactic acid es-
BH3·Me2NH as a hydride source to provide the 6- and 4- ter at the C3-hydroxyl, affording 6-O-benzyl derivative 9
Table 1 Reductive Opening of 4,6-O-Benzylidene Acetals in a Microfluidic System
Ph
(0.1 M)
O
4
O
6
Hydride
+
(0.5–1.0 M)
R1
0.5 mL/min
OH OBn
R2
in CH2Cl2 or MeCN
OBn OH
4
temp: 0 °C
Micromixer
6
R1
R1
or
R2
R2
Φ = 1.0 mm
l = 0.9 m
BF3·OEt2
in CH2Cl2 or MeCN
(1.0 M)
(4-OBn)
(6-OBn)
0.5 mL/min
sat. NaHCO3 aq
Entry
Substrate
Reducing
agent
Solvent
Product
Yield
Yield
(%, microfluidic)a (%, batch)a,b
BnO
O
BnO
1
2
3
Et3SiH
(1.0 M)
CH2Cl2
CH2Cl2
CH2Cl2
93c
(6-OBn)
58
90
83
Ph
Ph
Ph
O
O
O
HO
BnO
HO
OMe
OMe
HO
OMe
OMe
1
1
5
BH3·Me2NH
(0.5 M)
100
(4-OBn)
HO
O
O
O
O
BnO
BnO
BnO
HO
HO
6
Et3SiH
(1.0 M)
91
(6-OBn)
BnO
HO
O
O
O
O
BnO
BnO
TrocHN
TrocHN
OAllyl
OAllyl
OAllyl
OAllyl
2
7
4
5
BH3·Me2NH
(0.5 M)
CH2Cl2
MeCN
100
(4-OBn)
86
HO
BnO
Ph
O
O
O
O
BnO
BnO
TrocHN
TrocHN
OAllyl
2
8
BH3·Me3N
(0.5 M)
100
(6-OBn)
NAd
BnO
Ph
O
O
O
O
HO
O
O
AllocHN
AllocHN
Me
CO2Et
OAllyl
Me
CO2Et
3
9
6
Et3SiH
(1.0 M)
CH2Cl2
91
(6-OBn)
62
Ph
OBn
HO
O
O
O
OPNP
BzO
O
OPNP
BzO
OBz
OBz
4e
10
a Isolated yields.
b Reaction was performed at 100–500-mg scale.
c 4-O-Benzyl derivative was obtained in 5% yield.
d Yields for the corresponding N-Troc derivative: 60–70%.
e PNP = p-nitrophenyl.
Synlett 2007, No. 1, 164–166 © Thieme Stuttgart · New York

166
K. Tanaka, K. Fukase
LETTER
as a single isomer (entry 5).16 Finally, the selective reduc-
tion of galactose derivative 4 gave the 6-O-benzyl deriva-
tive 10 in 91% yield (entry 6).17 It is worth mentioning
that the established microfluidic reaction reproducibly
provided the O-benzylated compounds 5–10 in greater
than 90% yields in all cases, out of the three experiments
performed in each entry of Table 1. Furthermore, no spe-
cial dehydration procedures, such as pre-drying of the re-
action apparatus and the solvents by molecular sieves, are
necessary, making the present microflow reaction a prac-
tical procedure in large-scale syntheses.18
(10) For recent applications, see: (a) Pennemann, H.; Hessel, V.;
Loewe, H. Chem. Eng. Sci. 2004, 59, 4789. (b) Jahnisch,
K.; Hessel, V.; Loewe, H.; Baerns, M. Angew. Chem. Int. Ed.
2004, 43, 406. (c) Nagaki, A.; Togai, M.; Suga, S.; Aoki, N.;
Mae, K.; Yoshida, J.-I. J. Am. Chem. Soc. 2005, 127, 11666.
(d) Ratner, D. M.; Murphy, E. R.; Jhunjhunwala, M.;
Snyder, D. A.; Jensen, K. F.; Seeberger, P. H. Chem.
Commun. 2005, 578.
(11) A new micromixing device, ‘Comet X-01’ (Techno
Applications Co., Ltd., 34-16-204, Hon, Denenchofu, Oota,
Tokyo 1450072, Japan), was used. It exhibited much
superior mixing efficiency to the simple T-shape mixer and
similar efficiency to the IMM micromixer for acid-catalyzed
reaction, such as dehydration (data not reported). This new
device is well suited for a large-scale synthesis and for
establishing a micro chemical plant. The detailed structure
and mixing system will be reported elsewhere.
In summary, we have realized an efficient microfluidic
procedure for the reductive opening of the sugar 4,6-O-
benzylidene acetals. It is of note that the continuous
microflow reaction established in Table 1 can be readily
applied to large-scale reactions. The present microflow
process is now being utilized in our laboratory for the
synthesis of complex oligosaccharides.
(12) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.;
Carmona, A. T.; Gomez-Guillen, M. Tetrahedron:
Asymmetry 2004, 15, 429.
(13) The products ratio of 4- and 6-O-benzyl derivatives was
same as those obtained by batch reaction.
(14) Tanaka, S.; Takashina, M.; Tokimoto, H.; Fujimoto, Y.;
Tanaka, K.; Fukase, K. Synlett 2005, 2325.
Acknowledgment
(15) Sakai, Y.; Oikawa, M.; Yoshizaki, H.; Ogawa, T.; Suda, Y.;
Fukase, K.; Kusumoto, S. Tetrahedron Lett. 2000, 41, 6843.
(16) Inamura, S.; Fukase, K.; Kusumoto, S. Tetrahedron Lett.
2001, 42, 7613.
(17) El-Shenawy, H.; Schuerch, C. Carbohydr. Res. 1984, 131,
227.
We acknowledge Dr. Yukio Matsubara, the general manager of
Techno Applications Co., Ltd., Tokyo, Japan, for generously provi-
ding us with a new micromixer device, ‘Comet X-01’. The present
work was financially supported in part by Grant-in-Aid for Scienti-
fic Research No. 17310128 and No. 18850014 from the Japan
Society for the Promotion of Science and also by The Mitsubishi
Foundation, Research Grants in the Natural Sciences.
(18) Microfluidic Reaction; Typical Procedure: A solution of
BF3·OEt2 (3 mL, 23.7 mmol, 1.0 M) in CH2Cl2 (23.7 mL)
was injected in advance to the micromixer by using a syringe
pump at a flow-rate of 0.5 mL/min. Subsequently, a solution
of benzylidene acetal 1 (1 g, 2.69 mmol, 0.1 M) and Et3SiH
(4.3 mL, 26.9 mmol, 1.0 M) dissolved in CH2Cl2 (26.9 mL)
was also injected to the micromixer by another syringe pump
at the flow rate of 0.5 mL/min and mixed at 0 °C. After the
reaction mixture was allowed to flow at r.t. for an additional
45 s through a Teflon reactor tube (F = 1.0 mm, l = 0.9 m),
the mixture was quenched by pouring it to a sat. NaHCO3
solution at 0 °C. It took about 7 min to consume 1 g of the
substrate 1 under above conditions. The mixture was
extracted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo to give the crude
product. The residue was purified by preparative TLC on
silica gel (50% EtOAc in hexane) to afford 5 (935 mg, 93%).
The conditions established herein can be readily applied to
the scale-up synthesis simply by preparing the stock
solutions of substrate and reagents and pumping them
continuously into the micromixer.
References and Notes
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(3) Oikawa, M.; Liu, W.-C.; Nakai, Y.; Koshida, S.; Fukase, K.;
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(4) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res.
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(5) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans.
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(6) Guindon, Y.; Girard, Y.; Berthiaume, S.; Gorys, V.;
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(9) For representative reviews, see: (a) Microreaction
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