Oligosaccharide synthesis based on a one-pot electrochemical glycosylation-fmoc deprotection sequence

Article abstract of DOI:10.1246/cl.2008.942

We have found that tetrabutylammonium inflate (Bi₄NOTf) serves as an effective electrolyte for electrochemical glycosylation using thioglycosides. Based on this method, a one-pot electrochemical glycosylation-Fmoc group deprotection sequence has been developed. This sequence has been successfully applied to the synthesis of a pentasaccharide. Copyright

Full text of DOI:10.1246/cl.2008.942

942
Chemistry Letters Vol.37, No.9 (2008)
Oligosaccharide Synthesis Based on a One-pot Electrochemical
Glycosylation–Fmoc Deprotection Sequence
Toshiki Nokami, Hiroaki Tsuyama, Akito Shibuya, Takayuki Nakatsutsumi, and Jun-ichi Yoshidaꢀ
Department of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto 615-8510
(Received June 13, 2008; CL-080596; E-mail: yoshida@sbchem.kyoto-u.ac.jp)
Table 1. Effect of solvent/electrolyte systems for electrochem-
ical glycosylation
We have found that tetrabutylammonium triflate (Bu4NOTf)
serves as an effective electrolyte for electrochemical glycosyla-
tion using thioglycosides. Based on this method, a one-pot elec-
trochemical glycosylation–Fmoc group deprotection sequence
has been developed. This sequence has been successfully applied
to the synthesis of a pentasaccharide.
BzO
O
Anodic
oxidation
BzO
BzO
BzO
HO
BnO
O
O
O
BzO
BzO
O
+
SEt
BnO
BzO
BnO
BnO
BzO
BnO
OMe
BnO
1a
2a
3a
OMe
Entry
Solvent
Electrolyte
Selectivity
Yields/%
1
2
3
4
5
6
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
Bu4NClO4
Bu4NClO4
Bu4NBF4
Bu4NBF4
Bu4NOTf
Bu4NOTf
ꢀ only
ꢀ only
ꢀ only
ꢀ only
ꢀ only
ꢀ only
trace
30
65
44
70
79
The chemical synthesis of oligosaccharides plays a crucial
role in recent carbohydrate studies.1 Among many glycosyl
donors for chemical glycosylations, thioglycosides serve as
powerful building blocks from a practical point of view, because
thioglycosides are stable under atmospheric conditions and are
compatible with a variety of reaction conditions. Indeed, many
chemical glycosylation strategies are based upon the use of
thioglycosides as both donors and acceptors.2 However, such
strategies suffer from the use of strong oxidizing reagents for ac-
tivation of thioglycosides, which might affect other functional
groups during the reaction.3
Electrochemical oxidation is a powerful method for oxidiz-
ing organic compounds under mild conditions.4 Electrochemical
glycosylations using various glycosyl donors have been reported
by several groups.5 A single-electron-transfer (SET) reagent
was also effective for glycosylations.6 Thus, it was evident that
electron-transfer reactions are useful for activation of glycosyl
donors.
the formation of these products, because ClO4ꢁ is known to gen-
erate a very strong acid under electrolytic conditions.12 Use of
Bu4NBF4 gave the desired disaccharide 3a in moderate yields
(Entries 3 and 4). The yields were further improved using
Bu4NOTf as an electrolyte (Entries 5 and 6). CH2Cl2 was found
to be superior to CH3CN as solvent. Therefore, hereafter we use
a Bu4NOTf/CH2Cl2 system for glycosylation reactions.
The electrochemical glycosylation with several donors 1a,
4, and 5 and acceptors 2a and 2b were examined and the results
are summarized in Figure 1. In some cases, the reaction suffered
from low yields of the products, but yields were improved using
an excess amount of a donor (1.2–1.5 equiv).
Recently, we reported that electrochemical oxidation of
thioglycosides followed by the reaction with glycosyl acceptors
led to effective glycosylation.7 Tanaka and co-workers also
reported the electrochemical activation of thioglycosides in the
absence of a nucleophile.8 Nokami and co-workers revealed
that thioglycosides having benzoyl groups are readily activated
electrochemically in the presence of catalytic amount of
NaOTf.9 Very recently, we revealed that glycosyl triflates are
accumulated in the electrochemical oxidation of thioglycosides
using Bu4NOTf by low-temperature NMR studies.10 Although
various methods based on electrochemical glycosylations have
been reported, the development of new methods that are practi-
cally useful for synthesis of a variety of oligosaccharides is still
needed. In this paper, we report a method based on one-pot
electrochemical glycosylation–Fmoc deprotection sequence
and its application to the synthesis of a pentasaccharide.
We initiated our study by investigating several solvent/
electrolyte systems for the reaction of glycosyl donor 1a
(0.1 mmol) and glycosyl acceptor 2a (0.1 mmol) under constant
current conditions at room temperature (Table 1).11 The glycosy-
lation using Bu4NClO4 as a supporting electrolyte in CH3CN
(Entry 1) and CH2Cl2 (Entry 2) gave 1,6-anhydroglucoside
and methyl tetrabenzoylglucoside as major products. The
electrochemically generated acid seems to be responsible for
For sequential oligosaccharide synthesis, it is necessary to
introduce at least one temporary protecting group to hydroxy
groups of glycosyl donors. Several protecting groups such as,
tert-butyldimethylsilyl (TBS), p-methoxybenzyl (PMB), and 9-
fluorenylmethoxycarbonyl (Fmoc)13 were examined to protect
one of the hydroxy groups. Among these protecting groups, only
OBz
BzO
BnO
HO
OBz
O
BzO
BzO
BnO
BzO
O
O
O
SEt
SEt
BnO
BzO
BzO
BzO
BnO
BzO
BzO
OMe
SEt
1a
4
5
2b
OBz
BzO
BzO
O
BzO
BzO
BzO
O
O
BnO
BzO
O
BzO
O
BzO
BzO
O
O
BnO
O
BzO
O
BnO
BnO
BnO
BnO
BzO
BnO
OMe
BnO
BnO
OMe
3a 91%
3b 75%
6a 87%
OMe
OBz
O
BzO
BzO
OBz
O
BzO
BzO
OBz
BzO
BzO
BzO
OBn
BzO
BnO
O
O
O
O
O
O
O
BnO
BnO
BnO
BnO
BzO
BnO
BnO
OMe
OMe
BnO
6b 94%
7a 71%
7b 81%
OMe
Figure 1. Disaccharide obtained by the electrochemical glyco-
sylation.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.9 (2008)
943
Fmoc group was revealed to survive under the electrochemical
oxidation conditions. The electrochemical glycosylations
using glycosyl donors 1b and 1c were performed under normal
conditions and thus-obtained mixtures were treated with Et3N
in the same pot (eqs 1 and 2). Quantitative removal of the
Fmoc group afforded disaccharides 3c (90%) and 3d (93%),
which could be used for the next glycosylation as accepters.
References and Notes
1
2
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O
BzO
BzO
HO
BnO
FmocO
BzO
BzO
Anodic
O
1)
3
4
O
O
oxidation
ð1Þ
BzO
O
BnO
BnO
SEt
BnO
+
BnO
BzO
2) Et3N
BnO
OMe
OMe
1b
2a
3c 90%
BnO
BnO
BnO
FmocO
BnO
Anodic
O
HO
1)
O
O
oxidation
O
HO
O
BzO
SEt
BzO
BnO
ð2Þ
BnO
+
BzO
BnO
OMe
BzO
1c
BnO
2) Et3N
OMe
2b
3d 93%
In order to demonstrate the utility of the present method
involving electrochemical glycosylations followed by the
one-pot Fmoc group deprotection sequence, pentasaccharide
10 was synthesized (Figure 2). The use of 1.2 equiv of thioglyco-
side donor 1b for each glycosylation steps gave the correspond-
ing pentasaccharide 10 as a single product in 63% yield over 6
steps (See Supporting Information for the details).14
5
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O
O
oxidation
donor: 1b
1)
BzO
O
O
BzO
BzO
BzO
O
BzO
O
BnO
BzO
O
2) Et3N
BnO
BnO
BnO
BnO
OMe
HO
BzO
BnO
3c
8 90%
OMe
O
O
BzO
BzO
O
Anodic
BzO
BzO
O
oxidation
1)
BzO
donor: 1b
O
BzO
BzO
O
BnO
BzO
2) Et3N
O
BnO
9 83%
BnO
HO
BzO
OMe
O
O
BzO
BzO
O
BzO
BzO
O
6
a) A. Marra, J.-M. Mallet, C. Amatore, P. Sinay, Synlett 1990,
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Anodic
BzO
O
BzO
BzO
oxidation
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O
¨
donor: 1b
BzO
O
BzO
BzO
BzO
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O
2) Et3N
O
10 84%
BnO
BnO
7
8
9
BnO
OMe
Figure 2. Sequential oligosaccharide synthesis using the
electrochemical glycosylations.
In summary, we have developed a highly efficient electro-
chemical glycosylation reaction using Bu4NOTf as an electro-
lyte. The combination of the electrochemical glycosylation with
the subsequent one-pot Fmoc group deprotection serves as a
highly practical method for the synthesis of oligosaccharides.
The scope and limitations of the present method and its applica-
tion to the synthesis of biologically active oligosaccharides are
under investigation in our laboratory.
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11 It takes 40 min for the constant current electrolysis of 0.1 mmol
of thioglycoside with 4 mA of current.
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The authors gratefully acknowledge financial supports from
a Grant-in-Aid for Scientific Research (Grant Nos. 18750085,
17205012, and 20245008) from the JSPS and a Grant-in-Aid
for the Global COE program from the MEXT, Japan. The au-
thors thank Dr. Shino Manabe of RIKEN for fruitful discussions.
T. N. thanks Meiji Seika Kaisha, Ltd. for financial support.
14 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/.
Published on the web (Advance View) August 2, 2008; doi:10.1246/cl.2008.942