Electrochemical generation of glycosyl triflate pools

Article abstract of DOI:10.1021/ja072440x

Glycosyl triflates, which serve as important intermediates in glycosylation reactions, were generated and accumulated by the low-temperature electrochemical oxidation of thioglycosides such as thioglucosides, thiogalactosides, and thiomannosides in the pr

Full text of DOI:10.1021/ja072440x

Published on Web 08/14/2007
Electrochemical Generation of Glycosyl Triflate Pools
Toshiki Nokami,† Akito Shibuya,† Hiroaki Tsuyama,† Seiji Suga,† Albert A. Bowers,‡
David Crich,‡ and Jun-ichi Yoshida*,†
Contribution from the Departments of Synthetic Chemistry, Biological Chemistry,
Graduate School of Engineering, Kyoto UniVersity, Katsura, Kyoto 615-8510, Japan,
and Department of Chemistry, UniVersity of Illinois at Chicago,
Chicago, Illinois 60607-7061
Received April 7, 2007; E-mail: yoshida@sbchem.kyoto-u.ac.jp
Abstract: Glycosyl triflates, which serve as important intermediates in glycosylation reactions, were
generated and accumulated by the low-temperature electrochemical oxidation of thioglycosides such as
thioglucosides, thiogalactosides, and thiomannosides in the presence of tetrabutylammonium triflate (Bu4-
NOTf) as a supporting electrolyte. Thus-obtained solutions of glycosyl triflates (glycosyl triflate pools) were
characterized by low-temperature NMR measurements. The thermal stability of glycosyl triflates and their
reactions with glycosyl acceptors were also examined.
Introduction
eration of glycosyl triflates or related intermediates before the
addition of glycosyl acceptors.5 These glycosyl triflates usually
Among the many glycosyl cation equivalents, glycosyl
triflates have been recognized as important intermediates in
modern chemical glycosylation methodologies.1 Kronzer and
Schuerch developed the silver triflate-assisted methanolysis of
glycosyl chloride and proposed the existence of glycosyl triflate
intermediates.2 Although related intermediates such as glycosyl
toluenesulfonates were isolated and characterized in their
subsequent studies,3 glycosyl triflates have been successfully
characterized only recently using low-temperature NMR
mesurements.1a,4 Since then, several methods for iterative
glycosylation have been developed on the basis of the pregen-
have been generated from thioglycosides, which are the glycosyl
donors of choice, because of their stability under atmospheric
conditions and a variety of reaction conditions. However, this
very stability on occasion leads to difficulties in the activation
process. Indeed, strong thiophilic reagents are required for the
generation of glycosyl triflates from thioglycosides resulting in
the formation of activator-based byproducts, which can influence
the stability and reactivity of glycosyl triflates. Therefore, a new
straightforward method for the generation of glycosyl triflates
is highly desired.
The electrochemical reactions serve as powerful methods for
activation of organic compounds without using highly reactive
chemical reagents.6 We have developed the “cation pool”
method that involves the irreversible electrochemical oxidative
generation and accumulation of highly reactive carbocations in
the absence of nucleophiles.7 Successful generation and ac-
cumulation of alkoxy carbenium ions from R-silyl ethers
encouraged us to generate and accumulate the glycosyl cations
as “glycosyl cation pools” (Scheme 1). Unfortunately, the Bu4-
NBF4/CH2Cl2 system that is the standard supporting electrolyte/
solvent system of the “cation pool” method gave fluoroglyco-
sides from thioglycosides.8,9 By using tetrabutylammonium
perchlorate (Bu4NClO4) as a supporting electrolyte, however,
we could accumulate glycosyl cation equivalents that gave
† Kyoto University.
‡ University of Illinois at Chicago.
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Litjens, R. E. J. N.; van den Bos, L. J.; Overkleeft, H. S.; van der Marel,
G. A. Chem. Soc. ReV. 2005, 34, 769. (c) Toshima, K.; Tatsuta, K. Chem.
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J. AM. CHEM. SOC. 2007, 129, 10922-10928
10.1021/ja072440x CCC: $37.00 © 2007 American Chemical Society

Electrochemical Generation of Glycosyl Triflate Pools
A R T I C L E S
Scheme 1
Scheme 2
Figure 1. Oxidation potentials of thioglucosides.
glycosylation products after the addition of nucleophiles (Scheme
2).8 Although the formation of glycosyl perchlorates was most
likely, it proved difficult to determine the electrochemically
generated species by NMR. We envisioned that the glycosyl
triflates, which serve as important intermediates in glycosylation
reactions, could be generated and accumulated by the electro-
chemical method using tetrabutylammonium triflate (Bu4NOTf)
as a supporting electrolyte. This idea has now been reduced to
practice, and we report herein the successful generation and
accumulation of glycosyl triflates and their characterization by
Figure 2. Electrochemical oxidation of thioglucosides followed by the
reactions with methanol. a The reaction was carried out with 3.0 equiv of
Bu4NOTf.
the low-temperature NMR analysis. The thermal stability of
glycosyl triflates and their reactions with glycosyl acceptors are
also described.
(7) (a) Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.;
Fujiwara, K. J. Am. Chem. Soc. 1999, 121, 9546. (b) Suga, S.; Suzuki, S.;
Yamamoto, A.; Yoshida, J. J. Am. Chem. Soc. 2000, 122, 10244. (c) Suga,
S.; Okajima, M.; Yoshida, J. Tetrahedron Lett. 2001, 42, 2173. (d) Suga,
S.; Okajima, M.; Fujiwara, K.; Yoshida, J. J. Am. Chem. Soc. 2001, 123,
7941. (e) Suga, S.; Suzuki, S.; Yoshida, J. J. Am. Chem. Soc. 2002, 124,
30. (f) Yoshida, J.; Suga, S. Chem.-Eur. J. 2002, 8, 2650. (g) Suga, S.;
Watanabe, M.; Yoshida, J. J. Am. Chem. Soc. 2002, 124, 14824. (h) Suga,
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Soc. 2005, 127, 6930. (o) Maruyama, T.; Suga, S.; Yoshida, J. J. Am. Chem.
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Results and Discussion
Oxidation Potentials of Thioglycosides. We initiated our
study by determining the oxidation potentials of thioglycosides
by rotating disk electrode voltammetry using Bu4NOTf as a
supporting electrolyte in CH2Cl2 (Figure 1). All these thiogly-
cosides 1-3 have sufficiently low oxidation potentials for
preparative electrochemical oxidation in the Bu4NOTf/CH2Cl2
system. It should be noted that the 4,6-O-benzylidene protecting
group, which has been indispensable for the â-selective man-
nosylation, was oxidized and cleaved during the electrochemical
oxidation. However, the use of the 4,6-O-p-chlorobenzylidene
protecting group was effective for the selective oxidation of
thiomannosides.
Coupling of Electrochemically Generated Glycosyl Tri-
flates with Methanol. With data for oxidation potentials in
hand, we examined the constant current electrochemical oxida-
tion of thioglycosides 1-3 in the absence of an acceptor in
CH2Cl2 at -78 °C, with Bu4NOTf (6.0 equiv) intended to serve
as both the supporting electrolyte and the source of a triflate
anion. The use of a smaller amount of Bu4NOTf resulted in
higher cell voltage (>50 V). An H-type divided cell equipped
with a carbon felt anode, a platinum plate cathode, and a glass
filter separator was used, and the electrolysis was conducted
under the conditions of constant current (4.0 mA, 1.5-2.0 F/mol
of electricity). In the next step, the thus-generated intermediate
was allowed to react with methanol (Figure 2). Under these
conditions, thioglycoside 1 afforded the corresponding methyl
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A R T I C L E S
Nokami et al.
glucoside 4 in 84% yield (R/â ) 6/94). Di(p-tolyl)disulfide was
obtained as a byproduct (55%), which is inactive to thioglyco-
sides.
Chemical generation of the glycosyl triflate from 1 was also
examined. Treatment of 1 with trifluoromethanesulfonic acid
in the presence of diphenylsulfoxide (DPSO) and tri-t-butylpy-
rimidine (TTBP) in CH2Cl2 at -78 °C for 15 min followed by
the reaction of thus-generated species with methanol at the same
temperature for 1 h gave 4 in 87% yield (R/â ) 36/64).10 It is
important to note that R/â selectivity of the chemical method
is lower than that of the electrochemical method, although the
yield is comparable. Another advantage of the electrochemical
method is no use of TTBP, which is rather difficult to remove
by simple operation, whereas the supporting electrolyte (Bu4-
NOTf) can be easily removed by filtration through a short silica
gel column. Separation of di(p-tolyl)disulfide formed by the
electrochemical method is also easy. Therefore, higher R/â
selectivity and purification ease are benefits of the present
electrochemical protocol from a synthetic point of view.
Thiogalactoside 2 also gave the corresponding â-methyl
galactoside 5 with moderate selectively. On the other hand, the
reaction of thiomannoside 3a afforded a ca. 1:1 mixture of the
R- and â-methyl mannoside 6a. It is interesting to note that
both yield and â-selectivity of the mannosylation reaction were
improved by the introduction of p-chloro-4,6-O-benzylidene
protecting group. Moreover, the use of a smaller amount of Bu4-
NOTf (3.0 equiv) led to better â-selectivity in the case of the
mannosides. These selectivities fit the pattern previously
established for glycosylation reactions conducted with chemi-
cally generated glycosyl triflates.4 If the R-glycosyl triflate is
viewed as a reservoir for a transient â-selective contact ion pair
and an associated R-selective solvent-separated ion pair, the
decrease in â-selectivity seen with the benzylidene-protected
mannosyl donor with increased concentration of Bu4NOTf must
be due to the corresponding increase in solvent polarity which
supports a greater concentration of the solvent separated ion
pair.4k Alternatively, the possibility that increased triflate
concentration promotes in situ anomerization and the interme-
diacy of a low concentration of a more reactive R-selective
â-glycosyl triflate and associated contact ion pair cannot be
excluded.11 The generally increased â-selectivity seen with the
benzylidene-protected mannosyl triflate derived from 3b over
that seen with the corresponding perbenzyl system 3a is due to
the locking of the C5-C6 bond in its most electron-withdrawing
trans-gauche conformation, which limits the concentration of
the solvent-separated ion pair.12
solution was characterized by low-temperature NMR spectros-
copy. For example, the anodic solution obtained by the low-
temperature electrochemical oxidation of thioglucoside 1 in
1
CD2Cl2 at -78 °C exhibited a single set of signals in its H
NMR spectrum (Figure 3). Together with the absence of the
signals from the starting thioglucoside 1, this indicates complete
conversion and the formation of a single new species. A signal
3
at δ 6.10 (doublet, J H1H2 ) 2.9 Hz) was assigned to the
anomeric proton. No signal around 9.5 ppm due to the proton
adjacent to the cationic carbon was observed.7b Therefore, the
observed species is covalent rather than ionic. The coupling
constant points to the glucosyl triflate 7 being the R-anomer.13
A single set of signals was also observed by 13C NMR
spectroscopy, with the resonance at δ 106.9 assigned to the
anomeric carbon, as confirmed by the presence of a cross-peak
1
1
with the H signal at δ 6.10 in the H-13C HMQC spectrum.
On the basis of these observations, it is reasonable to consider
that an R-glucosyl triflate 7 was generated and accumulated
under the conditions of the low-temperature electrochemical
oxidation.
The thermal stability of glucosyl triflate 7 was investigated
by the method we reported previously (Figure 4).7b A solution
of glucosyl triflate 7, which was produced by the electrochemical
oxidation of thioglycoside 1 at -78 °C, was allowed to warm
to the second temperature. After equilibration for 30 min, the
resulting solution was recooled to -78 °C and then allowed to
react with methanol for 30 min. Figure 4 shows that yields of
methyl glucoside 4 changed around 10% at temperatures
between -78 and -50 °C. Thus, we assume that glucosyl triflate
7 is stable at temperatures lower than -50 °C.
Electrochemical Generation of a Glucosyl Triflate Pool.
To confirm the generation of glycosyl triflates, the anodic
(10) (a) Code´e, J. D. C.; Litjens, R. E. J. N.; den Heeten, R.; Overkleeft, H. S.;
van Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1519. (b) van
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van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft, H. S.; van Boom, J. H.;
van der Marel, G. A. Org. Lett. 2003, 5, 1947. (d) Code´e, J. D. C.; van
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van Boom, J. H.; Overkleeft, H. S.; van der Marel, G. A. Org. Lett. 2004,
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den Berg, R. J. B. H. N.; Overkleeft, H. S.; van der Marel, G. A. Eur. J.
Org. Chem. 2005, 918.
Electrochemical Generation of a Galactosyl Triflate Pool.
Successful characterization of glucosyl triflate 7 encouraged us
to confirm the generation of other glycosyl triflates by low-
temperature NMR spectroscopy. The anodic solution obtained
by the low-temperature electrochemical oxidation of thiogalac-
toside 2 in CD2Cl2 at -78 °C exhibited a single set of signals
in its 1H NMR spectrum (Figure 5). Together with the absence
of the signals from the starting thiogalactoside 2, this indicates
complete conversion and the formation of a single new species.
A signal at δ 6.14 (doublet, 3J H1H2 ) 3.4 Hz) was assigned to
(11) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am. Chem.
Soc. 1975, 97, 4056.
(12) (a) Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am. Chem. Soc. 2004, 126,
9205. (b) Litjens, R. E. J. N.; van den Bos, L. J.; Code´e, J. D. C.; Overkleeft,
H. S.; van der Marel, G. A. Carbohydr. Res. 2007, 342, 419.
(13) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217.
9
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Electrochemical Generation of Glycosyl Triflate Pools
Figure 3. 1H NMR spectrum of glucosyl triflates 7.
Figure 4. Thermal stability of glucosyl triflates 7.
A R T I C L E S
Figure 6. Thermal stability of galactosyl triflates 8.
Figure 7. 1H NMR spectrum of mannosyl triflate 9.
equilibration for 30 min, the resulting solution was recooled to
-78 °C and then allowed to react with methanol for 30 min. It
is evident that galactosyl triflate 8 is stable at temperatures lower
than -60 °C. This result indicates that the thermal stability of
galactosyl triflate 8 is almost the same as that of glucosyl triflate
7.
Figure 5. 1H NMR spectrum of galactosyl triflates 8.
the anomeric proton. The chemical shift indicated that the
observed species is covalent rather than ionic. The coupling
constant points to the galactosyl triflate 8 being the R-anomer.
A single set of signals was also observed by 13C NMR
spectroscopy, with the resonance at δ 108.2 assigned to the
anomeric carbon, as confirmed by the presence of a cross-peak
with the H signal at δ 6.14 in the H-13C HMQC spectrum.
On the basis of these observations, it is reasonable to consider
that an R-galactosyl triflate 8 was also generated and ac-
cumulated under the conditions of the low-temperature elec-
trochemical oxidation.
The thermal stability of galactosyl triflate 8 was also
investigated by the same method used to study glucosyl triflate
7 (Figure 6). A solution of galactosyl triflate 8, which was
produced by the electrochemical oxidation of thiogalactoside 2
at -78 °C, was allowed to warm to a second temperature. After
Electrochemical Generation of a Mannosyl Triflate Pool.
Mannosyl triflate 9, generated from the corresponding thio-
mannoside 3b, was also characterized by NMR spectroscopy
(Figure 7). A signal at δ 6.04 (singlet) was assigned to the
anomeric proton. Again, the chemical shift indicated that the
observed species is covalent rather than ionic. A single set of
signals was also observed by 13C NMR spectroscopy, with the
resonance at δ 105.3 assigned to the anomeric carbon, as
1
1
1
confirmed by the presence of a cross-peak with the H signal
at δ 6.04 in the 1H-13C HMQC spectrum. Additionally, the 1H
NMR spectrum of triflate 9 generated by the electrochemical
method matched that obtained from thioglycoside 3b by the
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A R T I C L E S
Nokami et al.
Figure 8. Thermal stability of mannosyl triflates 9.
more conventional activation with DPSO and trifluoromethane-
sulfonic anhydride (Supporting Information).10 In the glucose
and galactose series, we assume that the â-selective glycosyl-
ations with methanol stem from the R-configuration of the
intermediate glycosyl triflates. The reason for the lower
â-selectivity observed in the reaction of mannosyl triflate 9,
which also has the R-configuration, remains to be clarified.
The thermal stability of mannosyl triflate 9 was also
investigated (Figure 8). A solution of mannosyl triflate 9, which
was produced by the electrochemical oxidation of thiomannoside
3b at -78 °C, was allowed to warm to a second temperature.
After equilibration for 30 min, the resulting solution was
recooled to -78 °C and then allowed to react with methanol
for 30 min. Although it is difficult to explain why yields were
the same at -40 to -78 °C, mannosyl triflate 9 gave the methyl
mannoside in moderate yield even at -40 °C.14 This result
indicates the higher thermal stability of mannosyl triflate 9. The
diminished donation of electrons into the σ* orbital of the
C-OTf bond by a carbon-oxygen bond relative to a carbon-
hydrogen bond seems to be responsible for the enhanced stability
of the mannosyl triflate.
Figure 9. Preparation of disaccharides. a Reactions were carried out with
1.5 equiv of Bu4NOTf.
as acceptors. For example, the electrochemical oxidation of
thioglycosides 1 and 2 followed by reaction with a thioglycoside
acceptor afforded disaccharides 14 and 15, respectively, which
can be used as donors in further glycosylation reactions. The
ability to work with thioglycoside-bearing acceptors in this
manner is significant. First, it indicates that, unlike the chemical
systems where an additional thiophile such as a trialkyl
phosphite must be added in such instances,13a the byproduct of
the electrochemical activation process (i.e., diaryldisulfide) is
not itself an oxidant for thioglycosides. Second, it opens up the
possibility of sequential glycosylation sequences without the
need for intermediate functional group manipulations.1b
Conclusions
In conclusion, we have developed a new and simple method
for access to glycosyl triflate intermediates using electrochemical
oxidation. Solutions of triflates generated by this method are
free from byproducts derived due to activator, which are
inevitably present when chemical methods are employed. This
feature should be advantageous not only from the viewpoint of
mechanistic studies but also in the synthesis of polysaccharides.
Further mechanistic studies and applications to iterative gly-
cosylation are in progress.
Reactions of Glycosyl Triflates with Carbohydrate Ac-
ceptors. To examine reactivity of electrochemically generated
glycosyl triflate pools, couplings to carbohydrate acceptors were
performed (Figure 9). Reactions of triflates 7, 8, and 9 with
methyl 2,3,4-tri-O-benzyl-R-D-glucoside gave the disaccharides
11, 12, and 13a, respectively, in moderate yields and moderate-
to-high â-selectivity. It is interesting to note that the reaction
of 9 with methyl 2,3-O-isopropylidene-R-L-rhamnopyranoside
as a glycosyl acceptor gave only the â-isomer of the disaccharide
13b. The bulkiness of the acceptor may be responsible for the
excellent stereoselectivity. In this method, it is advantageous
that thioglycosides having a free hydroxyl group can be used
Experimental Section
General Procedures. 1H and 13C NMR spectra were recorded on a
Varian MercuryPlus-400 spectrometer (1H 400 MHz, 13C 100 MHz).
Low-temperature 1H, 13C NMR, and 1H-13C HMQC spectra were
recorded on a JEOL ECA-600P spectrometer (1H 600 MHz, 13C 150
MHz). EI and CI mass spectra were recorded on a JEOL JMS-SX102A
spectrometer, and FAB mass spectra were recorded on a JEOL JMS-
HX110A spectrometer. Unless otherwise noted, all materials were
obtained from commercial suppliers and used without further purifica-
tion. Dichloromethane was washed with water, distilled from P2O5,
redistilled from dried K2CO3 to remove a trace amount of acid, and
stored over molecular sieves 4 A. Rotating-disk electrode voltammetry
was carried out using a BAS 600BS analyzer and BAS RDE-2 rotating
disk electrode. Measurements were carried out in 0.1 M Bu4NOTf/
(14) Although we elongated the reaction time of mannosyl triflate 9 with
methanol, yields were not improved.
9
10926 J. AM. CHEM. SOC. VOL. 129, NO. 35, 2007

Electrochemical Generation of Glycosyl Triflate Pools
A R T I C L E S
CH2Cl2 using a glassy carbon disk working electrode, a platinum wire
counter electrode, and an SCE reference electrode with sweep rate of
10 mV/s at 3000 rpm.
Selected data of major product. Methyl 2,3,4,6-Tetra-O-benzyl-
â-D-glucopyranosyl-(1 f 6)-2,3,4-tri-O-benzyl-r-D-glucopyranoside
(11â).15 1H NMR (400 MHz) δ 7.34-7.14 (m, 35 H), 4.96 (d, J )
11.2 Hz, 1 H), 4.95 (d, J ) 10.4 Hz, 1 H), 4.89 (d, J ) 10.8 Hz, 1 H),
4.79 (d, J ) 9.6 Hz, 1 H), 4.77 (d, J ) 11.2 Hz, 2 H), 4.73 (d, J )
11.2 Hz, 1 H), 4.70 (d, J ) 10.8 Hz, 1 H), 4.64 (d, J ) 12.0 Hz, 1 H),
4.59 (d, J ) 3.6 Hz, 1 H), 4.55 (d, J ) 11.6 Hz, 2 H), 4.52 (d, J )
10.0 Hz, 1 H), 4.50 (d, J ) 10.0 Hz, 1 H), 4.33 (d, J ) 7.6 Hz, 1 H),
4.17 (dd, J ) 10.8, 2.0 Hz, 1 H), 3.98 (t, J ) 8.8 Hz, 1 H), 3.84-3.80
(m, 1 H), 3.71 (dd, J ) 10.8, 2.0 Hz, 1 H), 3.66 (d, J ) 10.8 Hz, 1 H),
3.65 (d, J ) 10.8 Hz, 1 H), 3.61 (d, J ) 8.8 Hz, 1 H), 3.57 (d, J ) 9.2
Hz, 1 H), 3.53-3.49 (m, 3 H), 3.46 (d, J ) 8.8 Hz, 1 H), 3.42 (ddd,
J ) 9.6, 4.4, 2.0 Hz, 1 H), 3.32 (s, 3 H). 13C NMR (100 MHz) δ
138.7, 138.4, 138.2, 138.2, 138.1, 138.0, 137.9, 128.3, 128.2, 128.2,
128.2, 128.0, 127.9, 127.8, 127.8, 127.8, 127.7, 127.7, 127.6, 127.6,
127.5, 127.5, 127.4, 127.4, 127.4, 103.7, 98.0, 84.8, 82.1, 82.0, 79.8,
78.0, 77.9, 75.7, 75.7, 75.0, 75.0, 74.9, 73.4, 73.3, 69.9, 69.0, 68.6,
55.2.
Low-Temperature NMR Analysis of Electrochemically Gener-
ated Glycosyl Triflates. The anodic oxidation was carried out in an
H-type divided cell (4G glass filter) equipped with a carbon felt anode
(Nippon Carbon JF-20-P7, ca. 160 mg, dried at 250 °C/1 mmHg for
2.5 h before use) and a platinum plate cathode (10 mm × 10 mm). In
the anodic chamber were placed 1 (64.6 mg, 0.10 mmol) and 0.1 M
Bu4NOTf in CD2Cl2 (5.0 mL). In the cathodic chamber were placed
trifluoromethanesulfonic acid (22 µL, 0.25 mmol) and 0.1 M Bu4NOTf
in CD2Cl2 (5.0 mL). The constant current electrolysis (4.0 mA) was
carried out at -78 °C with magnetic stirring. After 1.25 F/mol of
electricity was consumed, an aliquot of the anodic solution was
transferred to a 5 mm φ NMR tube with a septum cap under Ar
atmosphere at -78 °C. The NMR measurement was carried out at -80
°C. Chemical shifts were reported using signals of CH2Cl2 at 5.32 ppm
(1H NMR) and CD2Cl2 at 53.8 ppm (13C NMR) as standards.
Triflyl 2,3,4,6-Tetra-O-benzyl-r-D-glucopyranoside (7). Selected
data for 7 (6.5-3.5 ppm for 1H NMR and 110-60 ppm for 13C NMR).
1H NMR (CD2Cl2, 600 MHz) δ 6.10 (d, J ) 2.8 Hz, 1 H, anomeric
H), 4.90 (d, J ) 10.3 Hz, 1 H), 4.80 (d, J ) 9.6 Hz, 1 H), 4.79 (d, J
) 9.7 Hz, 1 H), 4.72 (d, J ) 11.6 Hz, 1 H), 4.69 (d, J ) 12.4 Hz, 1
H), 4.49 (d, J ) 11.0 Hz, 1 H), 4.42 (d, J ) 10.3 Hz, 1 H), 4.36 (d, J
) 11.0 Hz, 1 H), 3.90-3.86 (m, 2 H), 3.81 (d, J ) 9.6 Hz, 1 H), 3.77
(dm, J ) 8.9 Hz, 1 H), 3.71 (dd, J ) 9.6, 2.8 Hz, 1 H), 3.62 (d, J )
9.6 Hz, 1 H). 13C NMR (CD2Cl2, 150 MHz) δ 106.9 (C1), 79.7, 76.4,
75.5, 75.0, 74.4, 73.8, 73.0, 72.5, 66.1.
Methyl 2,3-Di-O-benzyl-4,6-O-p-chlorobenzyliden-r-D-mannopy-
ranosyl-(1 f 6)-2,3,4-tri-O-benzyl-r-D-glucopyranoside (13ar). Gly-
cosylation of 3b (176 mg, 0.30 mmol) with methyl 2,3,4-tri-O-benzyl-
R-D-glucopyranoside (284 mg, 0.61 mmol) afforded 13aR (138 mg,
0.15 mmol) and 13aâ (12 mg, 0.013 mmol) in 54% yield (13aR/13bâ
) 8/92). TLC (hexane/ethyl acetate 5:2): Rf 0.30 (13aR), 0.25 (13aâ).
1H NMR (CDCl3, 400 MHz) δ 7.39-7.18 (m, 29 H), 5.57 (s, 1 H),
4.99 (d, J ) 10.8 Hz, 1 H), 4.88-4.85 (m, 2 H), 4.82-4.77 (m, 3 H),
4.74-4.61 (m, 4 H), 4.55 (d, J ) 3.6 Hz, 1 H), 4.49 (d, J ) 10.8 Hz,
1 H), 4.21 (t, J ) 9.6 Hz, 1 H), 4.14 (dd, J ) 9.6, 3.6 Hz, 1 H), 3.97
(t, J ) 9.2 Hz, 1 H), 3.88 (dd, J ) 9.6, 2.8 Hz, 1 H), 3.84-3.75 (m,
4 H), 3.69-3.66 (m, 1 H), 3.60 (d, J ) 11.2 Hz, 1 H), 3.45 (dd, J )
9.6, 3.6 Hz, 1 H), 3.38-3.32 (m, 1 H), 3.29 (s, 3 H). 13C NMR (CDCl3,
150 MHz) δ 138.5, 138.2, 138.0, 137.9, 136.1, 134.5, 128.4, 128.3,
128.21, 128.18, 127.88, 127.85, 127.81, 127.78, 127.66, 127.56, 127.4,
100.7, 99.6, 97.8, 82.0, 80.0, 79.1, 77.6, 76.3, 75.8, 75.7, 75.0, 73.5,
73.3, 72.9, 69.8, 68.8, 66.2, 64.3, 55.1. HRMS (FAB) m/z calcd for
C55H57ClO11 [M - H]+, 927.3511; found, 927.3527.
Methyl 2,3-Di-O-benzyl-4,6-O-p-chlorobenzyliden-â-D-mannopy-
ranosyl-(1 f 6)-2,3,4-tri-O-benzyl-r-D-glucopyranoside (13aâ). 1H
NMR (CDCl3, 400 MHz) δ 7.43-7.13 (m, 29 H), 5.53 (s, 1 H), 5.15
(d, J ) 10.8 Hz, 1 H), 4.90 (d, J ) 12.0 Hz, 1 H), 4.84-4.75 (m, 5
H), 4.66 (d, J ) 11.6 Hz, 2 H), 4.57 (d, J ) 11.6 Hz, 2 H), 4.49 (d, J
) 11.6 Hz, 1 H), 4.23 (dd, J ) 10.4, 4.8 Hz, 1 H), 4.15 (t, J ) 9.6 Hz,
1 H), 4.07-4.05 (m, 1 H), 4.01 (t, J ) 9.6 Hz, 1 H), 3.88 (t, J ) 10.0
Hz, 1 H), 3.84-3.68 (m, 2 H), 3.51-3.41 (m, 4 H), 3.32 (s, 3 H), 3.19
(td, J ) 9.6, 4.8 Hz, 1 H). 13C NMR (CDCl3, 100 MHz) δ 138.6, 138.2,
138.1, 137.9, 136.0, 134.6, 128.6, 128.4, 128.33, 128.26, 128.22, 128.1,
128.02, 127.97, 127.92, 127.83, 127.79, 127.54, 127.48, 127.45, 127.39,
101.9, 100.6, 97.8, 82.2, 79.8, 78.6, 77.8, 75.7, 75.6, 74.7, 74.6, 73.3,
72.4, 69.6, 68.5, 68.3, 67.5, 55.1. HRMS (FAB) m/z calcd for C55H57-
ClO11 [M - H]+, 927.3511; found, 927.3527.
Methyl 2,3-Di-O-benzyl-4,6-O-p-chlorobenzylidene-â-D-mannopy-
ranosyl-(1 f 4)-2,3-O-isopropylidene-r-L-rhamnopyranoside (13b).
Glycosylation of 3b (217 mg, 0.37 mmol) with methyl 2,3-O-
isopropylidene-R-L-rhaminoside (165 mg, 0.76 mmol) afforded 13b
(173 mg, 0.25 mmol) as a sole product in 68% yield TLC (hexane/
ethyl acetate 5:1): Rf 0.30. 1H NMR (CDCl3, 400 MHz) δ 7.46-7.41
(m, 4 H), 7.36-7.26 (m, 10 H), 5.58 (s, 1 H), 5.00 (s, 1 H), 4.92 (d,
J ) 12.0 Hz, 1 H), 4.87 (s, 1 H), 4.81 (d J ) 12.4 Hz, 1 H), 4.63 (d,
J ) 12.8 Hz, 1 H), 4.59 (d, J ) 12.4 Hz, 1 H), 4.26 (dd, J ) 10.4, 4.8
Hz, 1 H), 4.19 (t, J ) 9.6 Hz, 1 H), 4.14-4.09 (m, 2 H), 3.98-3.92
(m, 2 H), 3.71-3.61 (m, 3 H), 3.41 (s, 3 H), 3.37-3.27 (m, 1 H), 1.51
(s, 3 H), 1.34 (s, 6 H). 13C NMR (CDCl3, 100 MHz) δ 138.4, 138.1,
136.0, 134.5, 128.2, 128.0, 127.4, 127.4, 127.4, 127.3, 109.2, 100.6,
Triflyl 2,3,4,6-Tetra-O-benzyl-r-D-galactopyranoside (8). The
anodic oxidation of 2 (64.6 mg, 0.10 mmol) afforded 8. Selected data
for 8. (6.5-3.4 ppm for 1H NMR and 110-60 ppm for 13C NMR). 1H
NMR (CD2Cl2, 600 MHz) δ 6.14 (d, J ) 3.4 Hz, 1 H, anomeric H),
4.86 (d, J ) 10.3 Hz, 1 H), 4.78-4.72 (m, 4 H), 4.47 (d, J ) 11.7 Hz,
1 H), 4.44 (d, J ) 10.3 Hz, 1 H), 4.38 (d, J ) 11.7 Hz, 1 H), 4.15-
4.11 (m, 3 H), 3.90 (dd, J ) 10.3, 2.0 Hz, 1 H), 3.49 (d, J ) 6.8 Hz,
2 H). 13C NMR (CD2Cl2, 150 MHz) δ 108.2 (C1), 77.1, 74.8, 73.4,
72.94, 72.89, 72.7, 72.1, 71.8, 66.6.
Triflyl 2,3-Di-O-benzyl-4,6-O-p-chlorobenzylidene-r-D-mannopy-
ranoside (9). The anodic oxidation of 3b (125 mg, 0.21 mmol) afforded
1
9. Selected data for 9 (6.5-3.4 ppm for H NMR and 110-60 ppm
for 13C NMR). 1H NMR (CD2Cl2, 600 MHz) δ 6.04 (s, 1 H, anomeric
H), 5.59 (s, 1 H), 4.74 (d, J ) 11.7 Hz, 1 H), 4.73 (d, J ) 11.0 Hz, 1
H), 4.64 (d, J ) 11.0 Hz, 1 H), 4.60 (d, J ) 11.7 Hz, 1 H), 4.25-4.21
(m, 2 H), 4.00-3.96 (m, 2 H), 3.92 (td, J ) 10.3, 4.8 Hz, 1 H), 3.82
(sm, 4 H). 13C NMR (CD2Cl2, 150 MHz) δ 105.3 (C1), 100.2, 76.2,
74.14, 74.11, 73.9, 72.6, 66.9, 66.7.
Reaction of Electrochemically Generated Glycosyl Triflates.
Typical Procedure. The anodic oxidation was carried out in an H-
type divided cell (4G glass filter) equipped with a carbon felt
anode (Nippon Carbon JF-20-P7, ca. 160 mg, dried at 250 °C/1 mmHg
for 2.5 h before use) and a platinum plate cathode (10 mm × 20 mm).
In the anodic chamber was placed a solution of tolyl thioglucoside 1
(64.2 mg, 0.10 mmol) in 0.1 M Bu4NOTf/CH2Cl2 (5 mL). In the
cathodic chamber was placed a solution of TfOH (22 µL, 0.25 mmol)
in 0.1 M Bu4NOTf/CH2Cl2 (5 mL). The constant current electrolysis
(4 mA) was carried out at -78 °C with magnetic stirring until 1.5
F/mol of electricity was consumed. Methyl 2,3,4-tri-O-benzyl-R-D-
glucopyranoside (93 mg, 0.2 mmol, 0.2 M CH2Cl2 solution) was added
to the solution in the anodic chamber. After additional stirring (-78
°C, 1 h), Et3N (70 µL, 0.5 mmol) was added and the mixture was
warmed to room temperature. After filtering through a short column
(2 × 3 cm) of silica gel to remove Bu4NOTf and evaporation of the
solvent under reduced pressure, the crude product was purified with
preparative gel permeation chromatography (eluent: CHCl3) to afford
a mixture of methyl glucosides 11R and 11â in 68% yield (66.3 mg,
0.067 mmol, 11R/11â ) 12/88).
(15) Jona, H.; Mandai, H.; Chavasiri, W.; Takeuchi, K.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 2002, 75, 291.
9
J. AM. CHEM. SOC. VOL. 129, NO. 35, 2007 10927

A R T I C L E S
Nokami et al.
100.1, 97.8, 78.6, 78.4, 78.0, 77.8, 76.4, 76.1, 74.9, 72.1, 68.6, 67.6,
64.2, 54.9, 27.9, 26.5, 17.8. HRMS (FAB) m/z calcd for C37H43ClO10
[M - H]+, 681.2467; found, 681.2470.
and the NIH (GM62160) for the support of his work in Chicago.
We thank Dr. Takeshi Yamada of Kyoto University for fruitful
discussions.
Acknowledgment. J.Y. and T.N. dedicate this article to the
late Professor Yoshihiko Ito in honor of his outstanding
contribution to synthetic chemistry. This work was financially
supported in part by a Grant-in-Aid for Scientific Research from
the Japan Society for the Promotion of Science. A.A.B. thanks
JSPS and NSF for financial support for a study visit to Japan,
Supporting Information Available: Experimental procedures
and spectroscopic data of compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA072440X
9
10928 J. AM. CHEM. SOC. VOL. 129, NO. 35, 2007