Electrochemical Glycosylation as an Enabling Tool for the Stereoselective Synthesis of Cyclic Oligosaccharides

Article abstract of DOI:10.1002/open.201900185

Electrochemical glycosylation of a linear oligosaccharide with a protecting-group-free primary hydroxyl group afforded cyclic oligo-saccharides, up to hexasaccharides, in high yields. Precursors of the cyclic oligosaccharides were prepared by automated electro-chemical assembly-a method for the automated electrochemical solution-phase synthesis of oligosaccharides. We demonstrated that electrochemical glycosylation is useful not only for intermolecular glycosylation but also for intramolecular glycosylation to synthesize cyclic oligosaccharides.

Full text of DOI:10.1002/open.201900185

DOI: 10.1002/open.201900185
Communications
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Electrochemical Glycosylation as an Enabling Tool for the
Stereoselective Synthesis of Cyclic Oligosaccharides
Sujit Manmode,[a] Shichidai Tanabe,[a] Takashi Yamamoto,[a] Norihiko Sasaki,[a]
Toshiki Nokami,*[a, b] and Toshiyuki Itoh*[a, b]
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improvements in the synthetic methodology were considered
desirable.
Electrochemical glycosylation of a linear oligosaccharide with a
protecting-group-free primary hydroxyl group afforded cyclic
oligo-saccharides, up to hexasaccharides, in high yields.
Precursors of the cyclic oligosaccharides were prepared by
automated electro-chemical assembly-a method for the auto-
mated electrochemical solution-phase synthesis of oligosac-
charides. We demonstrated that electrochemical glycosylation
is useful not only for intermolecular glycosylation but also for
intramolecular glycosylation to synthesize cyclic oligosacchar-
ides.
During our study of electrochemical glycosylation,[13] we
developed automated electrochemical assembly a method for
the automated electrochemical solution-phase synthesis of
oligosaccharides. The method has already been successfully
applied to the synthesis of linear oligoglucosamines,[14a] TMG-
Chitotriomycin,[14b,c,f] GPI anchor trisaccharides[14d] and 1,3-1,6-β-
linked oligoglucosides.[14e] Thus, we envisioned that precursors
of cyclic oligosaccharides, especially oligoglucosamines, could
also be readily prepared using this method, and that subse-
quent electrochemical glycosylation might be an alternative
method for the chemical and enzymatic synthesis of cyclic
oligosaccharides. Here, we demonstrate that electrochemical
glycosylation is useful not only for intermolecular glycosylation
but also for intramolecular glycosylation to synthesize cyclic
oligosaccharides.
Cyclic oligosaccharides such as cyclodextrins, which involve 1,4-
α-glycosidic linkages of D-glucopyranose, have attracted the
interest of researchers for more than a century because of their
unique structures and properties.[1,2] Both chemical[3] and
enzymatic[4] approaches have been developed to prepare
natural and unnatural cyclodextrins. Chemical modification of
the exocyclic hydroxyl groups of cyclodextrins alters the funda-
mental properties of cyclic oligosaccharides.[5] Cyclic oligosac-
charides composed of monosaccharides other than glucose
have also been investigated.[6–11] Recently, Nifantiev and co-
workers[12] reported the synthesis of cyclic oligo-1,6-β-D-glucos-
amines using thioglycosides as precursors and N-iodosuccini-
mide (NIS) and triflic acid (TfOH) as a promoter system in their
pioneering works. However, the scope of this system was found
to be limited. It was unable to afford the stereochemically pure
β-isomer of oligosaccharide as a single product, even in the
presence of a N-phthalimide group at the C-2 position, which
secures β stereoselectivity in glycosylation. To address the issue
of stereoselectivity and yield of cyclic oligosaccharides, further
We commenced our study by developing the terminal
building block with a temporary protecting group at the C-6
hydroxyl group (6-OH). We created a series of thioglycosides
1a–e equipped with a C-2 N-phthalimide group, to ensure a
stereochemical outcome in the glycosylation, and various
substituents at the remaining hydroxyl groups. With these
thioglycosides in hand, these compounds were evaluated as
building blocks by synthesizing disaccharide (Table 1). The
electro-chemical glycosylation of terminal building blocks 1a–e
and building block 3, was performed under the same conditions
Table 1. Optimization of monosaccharide terminal building block.
[a] Dr. S. Manmode, Mr. S. Tanabe, Mr. T. Yamamoto, N. Sasaki,
Prof. T. Nokami, Prof. T. Itoh
Department of Chemistry and Biotechnology, Graduate School of Engineer-
ing, Tottori University
4-101 Koyamachominami, Tottori city 680-8552 Tottori Japan
E-mai:
E-mail: tnokami@tottori-u.ac.jp
Building
block
R1
R2
Product
Yield
(%)
Selectivity
titoh@tottori-u.ac.jp
[b] Prof. T. Nokami, Prof. T. Itoh
92a
59b
NDc
45
β only
β only
–
β only
β only
Center for Research on Green Sustainable Chemistry, Faculty of Engineering,
Tottori University
4-101 Koyamachominami, Tottori city 680-8552 Tottori, Japan
1a
1b
1c
1d
1e
Ac
Ac
Bn
Bn
Bn
Ac
4a
Fmoc
MOM
ClAc
ClAc
4b (R1 =H)
4c
4d
4e
© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This
is an open access article under the terms of the Creative Commons Attri-
bution Non-Commercial NoDerivs License, which permits use and distribu-
tion in any medium, provided the original work is properly cited, the use is
non-commercial and no modifications or adaptations are made.
57
°
[a] Reference 13a. [b] Glycosylation at À 40 C and yield after Fmoc
deprotec-tion (R1 =H). [c] Not detected.
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Communications
as
reported
previously
for
the
synthesis
of
Table 2. Optimization of disaccharide terminal building block.
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oligoglucosamines.[14a] To our delight, glycosylation of 1b
afforded the desired product 4b in 59% yield with perfect β-
selectivity (entry 2); however, the yield was much lower than
that achieved with 1a (entry 1). Building block 1c with
methoxymethyl (MOM) protection at 6-OH and benzyl (Bn)
protection at the C-4 hydroxyl group (4-OH) equipped donor
did not afford even a trace amount of the desired disaccharide
4c. Building block 1d bearing chloroacetyl (ClAc) and Bn
groups at 6-OH and 4-OH, respectively, gave a decreased
glycosylation yield of 45% (entry 4). Finally, building block 1e
bearing ClAc and Bn groups at 6-OH and 4-OH, respectively,
afforded disaccharide 4e in 57% yield (entry 5). These results
may be attributed to tolerance of the protecting groups under
the electrochemical conditions and stability of the glycosyl
triflate formed during the reactions.[15]
Building
block
R
Product
Yield (%)
Selectivity
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4f
Fmoc
MOM
ClAc
Lev
5b
5c
5d
5 g
47
7
β only
β only
–
4c
4d
4 g
NDa
12
β only
[a] Not detected.
The best building block 1b with 9-fluorenylmethoxycarbon-
yl (Fmoc) at 6-OH was then used in the automated electro-
chemical assembly with building block 3 for chain elongation
for the synthesis of tetrasaccharides (Scheme 1). Subsequent
°
NIS and TfOH at À 15 C. The reaction afforded both α- and β-
isomers of cyclic oligoglucosamine 6α and 6β in 12% and 30%
yields, respectively. This result is in agreement with the finding
reported by Nifantiev and coworkers.[12a] Therefore the choice of
protecting groups at 4-OH and 3-OH is not crucial for obtaining
cyclic oligoglucosamine stereoselectively.
To improve the efficiency of intramolecular glycosylation of
tetrasaccharide 5b, we optimized the reaction conditions of
electrochemical glycosylation (Table 3). Tetrabutylammonium
tetrafluoroborate (Bu4NBF4), a typical electrolyte for electro-
chemical reactions, afforded the corresponding β-isomer of
cyclic oligosaccharide 6β stereoselectively, but the yield was
moderate and the corresponding glycosyl fluoride of the tetra-
saccharide was observed by ESI-MS (m/z calc. for C92H85FN4O28K
[M+K]+, 1751.4966; found, 1751.4931). Tetrabutyl bis(trifluor-
omethanesulfonylimide) (Bu4NNTf2) led to an improved yield of
6; however, selectivity was not perfect. Finally, we determined
tetrabutylammonium triflate (Bu4NOTf) to be the best choice of
electrolyte; it afforded 6β in high yield and with high stereo-
selectivity. To investigate the influence of reaction temperature,
we also performed the reaction at elevated temperature at
Scheme 1. Automated electrochemical assembly and subsequent one-pot
Fmoc deprotection for synthesis of the precursor of the cyclic tetrasacchar-
ide.
one-pot deprotection of Fmoc group afforded the desired
tetrasaccharide 5b in 19% overall yield, which was much lower
than that of the tetrasaccharide assembled from the terminal
building block 1a.[14a] Therefore, improvement in the choice of
terminal building block is highly desirable in efforts to address
the precursors of cyclic oligosac-charides.
°
À 15 C. Although the yield was decreased, complete β-
selectivity was observed. Therefore, the lower reaction temper-
ature was not crucial to obtain cyclic oligosaccharide 6β
stereoselectively. We propose the same reaction mechanism as
the glycosyl triflate pool, which is an electrochemical con-
To reduce the negative influence of the protecting group at
6-OH, we then examined the synthesis of tetrasaccharide from
disaccharide terminal building blocks (Table 2). The di-saccha-
ride building block 4f with the Fmoc group afforded tetrasac-
charide 5b without the Fmoc group in 47% yield. Although
fewer elongation cycles were required for the synthesis of
tetrasaccharide 5b from 4f than from the monosaccharide
building block 1b, the average yield was >10% higher than
from 1b. We also considered other disaccharide building blocks
4 equipped with temporary protecting groups, such as MOM,
ClAc and levulinoyl (Lev). However, the yields of the corre-
sponding tetrasaccharides 5 were lower than those obtained
from using the terminal building block 4f with the Fmoc group.
We then carried out the intramolecular cyclization of
tetrasaccharide 5b under conventional chemical glycosylation
conditions (Scheme 2).[16] Tetrasaccharide 5b was treated with
Scheme 2. Intramolecular glycosylation under the conventional chemical
glycosylation conditions.
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Table 3. Effect of electrolyte on intramolecular electrochemical glycosyla-
tion.
Table 4. Effect of concentration and chain length on intramolecular
electrochemical glycosylation.
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Electrolyte
Yield (%)
Selectivity
Bu4NBF4
Bu4NNTf2
Bu4NOTf
Bu4NOTf
17
66
65
52a
6β only
6α/6β 15:85
6β only
6β only
°
[a] The reaction was performed at À 15 C.
Oligosaccharide
Conc. [M]
Yield (%)
Product
Selectivity
5b (n=2)
5b (n=2)
7 (n=3)
0.008
0.032
0.008
0.008
81
78
93
78
6β
6β
9
β only
β only
β only
β only
version of a thioglycoside into the glycosyl triflate at low
temperature.[17] The reaction is initiated by single electron
transfer from the linear oligosaccharide and thus-generated
glycosyl cation is immediately trapped by triflate anion to afford
the corresponding glycosyl triflate intermediate. The intra-
molecular glycosylation may occur from the glycosyl triflate
gradually. Therefore, lower temperature is important to obtain
the desired cyclic oligosaccharides in better yields.
Next the intramolecular cyclization of longer oligosacchar-
ides under anodic oxidation conditions was investigated
(Table 4). The following model reaction was carried out. An
electrochemical cell charged with 0.008 M linear tetrasaccharide
8 (n=4)
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improvement of the procedures is necessary, global deprotec-
tion of the cyclic tetrasaccharide was also achieved in 24% (6
steps from 5e, See the Supporting Information for the details).
In summary, we have developed a protocol for the stereo-
selective synthesis of cyclic oligoglucosamines, up to the
hexasaccharides based on the automated electrochemical
assembly of oligosaccharide precursors. The choice of electro-
lyte is crucial to obtain the desired cyclic oligosaccharides in
reasonable yield and with complete stereoselectivity. A simpli-
fied protocol to obtain cyclic oligosaccharides, which is based
on higher reactivity of the primary hydroxyl group of
oligosaccharides, was demonstrated. Thus, we believe that this
°
5b was electrochemically activated at À 60 C by means of 1.6
F/mol electricity. The reaction temperature was gradually
°
increased to 0 C over a period of 2.5 h. The reaction was finally
quenched with Et3N (See the Supporting Information for the
detailed procedure). Purification of the reaction products by
simple extraction with EtOAc avoiding tedious chromato-
graphic methods, resulted cyclic tetrasaccharide 6β as a single
compound in 81% yield.[18] Increasing the concentration of
substrate and then using a fourfold higher concentration than
that used in the standard reaction conditions did not lead to a
significant change in the glycosylation yield. This indicated high
efficiency of the intramolecular glycosylation (Table 4). Similarly,
cyclic pentasaccharide 9 and hexasaccharide 10 were also
efficiently synthesized; yields were 93% and 78%, respectively.
The excellent results obtained for electrochemical cycliza-
tion encouraged us for detailed investigation of reactivity based
selective cyclization in the presence of both primary and
secondary sugar alcohols (Figure 1). We first prepared tetrasac-
charide 5e from 1a.[14] Subsequent treatment with hydrochloric
acid afforded the partially protected tetrasaccharide 5f in
quantitative yield.[19] This method was then used for the
partially protected tetrasaccharide 5f. After acetylation the
cyclic tetra-saccharide 11 with complete stereoselectivity was
obtained in 84% yield (3 steps from 5e). Although further
Figure 1. Selective intramolecular electrochemical glycosylation of the 6-OH
primary alcohol.
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Communications
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celc.201900215
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Experimental Section
The electrochemical synthesis of cyclotetrakis-(1!6)-(3-O-acetyl-4-
O-benzyl-2-deoxy-2-phthalimido-β-D-glucop-yranosyl) (6β) was car-
ried out in an H-type divided cell (4G glass filter) equipped with a
carbon felt anode (Nippon Carbon JF-20-P7) and a platinum plate
cathode (10 mm×20 mm). In the anodic chamber were placed 4-
Fluorophenyl-3-O-acetyl-4-O-benzyl-2-deoxy-2-phthalimido-β-D-
glucopyranosyl-(1!6)-3-O-acetyl-4-O-benzyl-2-deoxy-2-phthalimi-
do-β-D-glucopyranosyl-(1!6)-3-O-acetyl-4-O-benzyl-2-deoxy-2-
phthalimido-β-D-glucopyranosyl-(1!6)-3-O-acetyl-4-O-benzyl-2-de-
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oxy-2-phthalimido-1-thio-β-D-glucopyranoside
5b
(0.072 g,
0.039 mmol), Bu4NOTf (0.195 g, 0.50 mmol) and CH2Cl2 (5.0 mL). In
the cathodic chamber were placed trifluoromethanesulfonic acid
(3.5 μL), Bu4NOTf (0.195 g, 0.50 mmol) and CH2Cl2 (5.0 mL). The
constant current electrolysis (8.0 mA (current density: 2.0 mA/cm2),
°
43 V (electrode distance: 4.5 cm)) was carried out at À 80 C with
magnetic stirring until 1.6 F/mol of electricity was consumed. After
°
the electrolysis, the temperature was raised to 0 C and Et3N
(0.5 mL) was added and the mixture was evaporated under reduced
pressure and extracted five times with ethyl acetate. The extract is
then evaporated under reduced pressure and kept under strong
vacuum for extreme dryness to furnish desired cyclic oligosacchar-
ide 6β in 81% isolated yield (54 mg, 0.031 mmol). 1H NMR
(pyridine-d5, 600 MHz) δ 1.61 (s, 3 H), 3.94 (pseudo-d, J=7.8 Hz, 1
H), 4.08 (t, J=7.8 Hz, 1 H), 4.31 (d, J=10.8 Hz, 1 H), 4.38 (pseudo-d,
J=10.8 Hz, 1 H), 4.47 (pseudo-d, J=10.8 Hz, 1 H), 4.60 (pseudo-d, J=
9.6 Hz, 1 H), 4.76 (td, J=11.4, 5.4 Hz, 1 H), 6.04 (d, J=7.8 Hz, 1 H),
6.13 (td, J=12.0, 3.0 Hz, 1 H), 7.00 (bd, J=2.4 Hz, 2 H), 7.14 (bd, J=
1.8 Hz, 2 H), 7.35 (s, 1 H), 7.42 (s, 1 H), 7.58 (s, 1 H), 7.64 (s, 1 H), 7.77
(s, 1 H); 13C NMR (pyridine-d5, 150 MHz) δ 170.9, 169.1, 168.4, 138.6,
136.1, 128.9, 128.3, 124.2, 99.1, 77.5, 75.5, 75.3, 74.2, 69.6, 56.0, 20.6;
HRMS (ESI) m/z calcd for C92H84N4O28K [M+K]+, 1731.4904; found,
1731.4893.
Acknowledgements
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Yoshida, J. Am. Chem. Soc. 2007, 129, 10922–10928.
[18] Solubility of cyclic oligoglucosamines in conventional organic solvents
was so low that we could purify the com-pound by washing the crude
product with EtOAc. The β-isomer of tetrasaccharide 6β has the lowest
solubility among them.
[19] HCl/Et2O mediated hydrolysis of acetate resulted mixture of mono, di-
and tri-acetate protected tetrasaccharide detected by ESI-MS. The rate
of hydrolysis of the acetyl group of the primary hydroxyl group is faster
than that of secondary hydroxyl group, thus we considered that the
primary alcohol was fully hydrolyzed. Contrary, Zemplén’s condition
gave complete deacetalized product; however, insolubility of the
compound in CH2Cl2 renders its use for cyclization.
The study has been financially supported by the Grant-in-Aid for
Scientific Research on Innovative Areas: “Middle Molecular
Strategy” (No. 2707) from the JSPS (No. JP15H05844) and the
Presidential Fund of Tottori University. The authors acknowledge
fruitful suggestion of Professor Mahito Atobe of Yokohama Na-
tional University. The authors also thank KOGANEI corporation for
the development of the latest version of the automated elec-
trochemical synthesizer.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: cyclic
glycosylation
stereoselectivity
oligosaccharides
glucosamine automated synthesis
·
electrochemical
·
·
·
Manuscript received: May 27, 2019
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© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA