Glycosyl sulfonium ions as storable intermediates for glycosylations

Article abstract of DOI:10.1021/ol200242u

Glycosyl sulfonium ions, which serve as persistent glycosyl cation equivalents, were prepared by the addition of diorganosulfides to an electrochemically generated glycosyl triflate. Low-temperature and variable-temperature NMR studies were performed to r

Full text of DOI:10.1021/ol200242u

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1544–1547
Glycosyl Sulfonium Ions as Storable
Intermediates for Glycosylations
Toshiki Nokami,† Yuki Nozaki,† Yoshihiro Saigusa,† Akito Shibuya,† Shino Manabe,*,‡
Yukishige Ito,‡,§ and Jun-ichi Yoshida*,†
Department of Synthetic Chemistry, Biological Chemistry, Graduate School of
Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan, RIKEN Advanced
Science Institute, Hirosawa, Wako, Saitama 351-0198, Japan, and ERATO JST,
Hirosawa, Wako, Saitama 351-0198, Japan
smanabe@riken.jp; yoshida@sbchem.kyoto-u.ac.jp
Received January 25, 2011
ABSTRACT
Glycosyl sulfonium ions, which serve as persistent glycosyl cation equivalents, were prepared by the addition of diorganosulfides to an
electrochemically generated glycosyl triflate. Low-temperature and variable-temperature NMR studies were performed to reveal the structure,
stability, and reactivity of glycosyl sulfonium ions. The glycosyl sulfonium ions could be used as storable intermediates for reactions with various
glycosyl acceptors including thioglycosides to give the corresponding disaccharides.
Recent progress in the development of methodologies
for oligosaccharide synthesis enables us to access complex
oligosaccharides and glycoconjugates readily.1 Glycosyl
triflates,2,3 which have been used for stereoselective glyco-
sylation and iterative glycosylation for many years, are one
of the most reactive glycosylation intermediates among the
spectroscopically observable intermediates.4 Although
various methods including the electrochemical method5
have been developed to generate glycosyl triflates from
stable glycosyl donors, glycosyl triflates are so reactive that
it is necessary to use them immediately after their prepara-
tion or generate them in the presence of glycosyl acceptors.
If it were possible to store such highly reactive glycosylation
intermediates for prolonged periods of time, this might
open many new possibilities in chemical glycosylation.
Therefore, it is highly desired to develop novel glycosylation
intermediates that have enough stability for storage and
sufficientreactivitytocouplewith glycosyl acceptors under
mild reaction conditions without any activation steps.
Various glycosyl cation equivalents such as glycosyl
sulfonates2,3,6 and glycosyl onium ions already existed.3,7
Schuerch performed pioneering work on glycosyl sulfo-
nium ions in the development of R-selective glycosylation.8
Boons and co-workers prepared β-glycosyl sulfonium ions
in inter- and intramolecular manners and elegantly applied
† Kyoto University.
‡ RIKEN Advanced Science Institute.
§ ERATO JST.
(1) Reviews: (a) Boons, G. J. Tetrahedron 1996, 52, 1095. (b) See-
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A. V. Synlett 2003, 1225. (d) Codee, J. D. C.; Litjens, R. E. J. N.; van den
Bos, L. J.; Overkleeft, H. S.; van der Marel, G. A. Chem. Soc. Rev. 2005,
34, 769. (e) Galoni, D. P.; Gin, D. Y. Nature 2007, 446, 1000. (f)
Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046. (g) Wang, Y.;
Ye, X.-S. Org. Biomol. Chem. 2007, 5, 2189. (h) Werz, D. B.; Ranzinger,
R.; Herget, S.; Adibekian, A.; von der Lieth, C.-W.; Seeberger, P. H.
ACS Chem. Biol. 2007, 2, 685. (i) Seeberger, P. H. Chem. Soc. Rev. 2008,
37, 19. (j) Boltje, T. J.; Buskas, T.; Boons, G. J. Nat. Chem. 2009, 1, 611.
(k) Nambu, H.; Nakamura, S.; Suzuki, N.; Hashimoto, S. Trends
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r
10.1021/ol200242u
Published on Web 02/16/2011
2011 American Chemical Society

a β-form (Scheme 1).12 The corresponding glycosyl sulfo-
nium ions 3 were prepared by the reaction of diorgano-
sulfide (R1SR2) and the highly reactive glycosyl triflate 2
that was electrochemically generated from thioglycoside 1
at -78 °C.
Scheme 1. Preparation of Glycosyl Sulfonium Ions 3 via Elec-
trochemically Generated Glycosyl Triflate 2
1H NMR spectra of glycosyl triflate 2 and that of
glycosyl sulfonium ion 3a are shown in Figure 1. Although
it was not possible to determine the structure of the minor
product due to their instability,13 R-triflate was obtained
exclusively (Figure 1a). The addition of dimethyl sulfide
(Me2S) toa solution of glycosyl triflate2 gavea single set of
peaks of the β-isomer (Figure 1b). On the other hand,
glycosyl sulfonium ion 3b, which was obtained by the reac-
tion with unsymmetrical methyl phenyl sulfide (MeSPh),
exhibited two sets of peaks. These two species are attrib-
uted to the two diastereomers of glycosyl sulfonium ion 3b,
because the sulfur atom is a stereogenic center (Figure 1c).
them to R-selective glycosylations.9 These findings prompted
us and other groups to investigate the stability and reac-
tivity of glycosyl sulfonium ions.10,11 We developed a novel
method for preparing glycosyl sulfonium ions using the
reaction of electrochemically generated glycosyl triflates
with diorganosulfides. On the basis of these results, it is
reasonable to assume that stability and reactivity of gly-
cosyl sulfonium ions can be tunedby changing substituents
on the sulfur atom. In this study, we demonstrate that
glycosyl sulfonium ions bearing appropriate substituents
on the sulfur atom can serve as storable intermediates for
glycosylation.
Thioglycoside 1, which has a N-phthalimide (N-Phth)
group, was chosen as a glycosyl donor because this group
could be expected to suppress formation of the orthoester
and control the stereochemistry of generating glycosides in
(4) Observation of highly reactive glycosylation intermediates other
than glycosyl triflates: (a) Gildersleeve, J.; Pascal, R. A.; Kahne, D. J.
Am. Chem. Soc. 1998, 120, 5961. (b) Garcia, B. A.; Gin, D. Y. J. Am.
Chem. Soc. 2000, 122, 4269.
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D.; Suga, S.; Yoshida, J. J. Am. Chem. Soc. 2007, 128, 10922. (b)
Nokami, T.; Tsuyama, H.; Shibuya, A.; Nakatsutsumi, T.; Yoshida, J.
Chem. Lett. 2008, 37, 942. (c) Nokami, T.; Shibuya, A.; Yoshida, J.
Trends Glycosci. Glycotechnol. 2008, 20, 175.
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R.; Schuerch, C. Carbohydr. Res. 1976, 50, 203. (c) Marousek, V.; Lucas,
T. J.; Wheat, P. E.; Schuerch, C. Carbohydr. Res. 1978, 60, 85. (d) Eby,
R.; Schuerch, C. Carbohydr. Res. 1979, 77, 61. (e) Eby, R. Carbohydr.
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(9) (a) Kim, J.-H.; Yang, H.; Boons, G. J. Angew. Chem., Int. Ed.
2005, 44, 947. (b) Kim, J.-H.; Yang, H.; Park, J.; Boons, G. J. J. Am.
Chem. Soc. 2005, 127, 12090. (c) Park, J.; Kawatkar, S.; Kim, J.-H.;
Boons, G. J. Org. Lett. 2007, 9, 1959. (d) Boltje, T. J.; Kim, J.-H.; Park,
J.; Boons, G. J. Nat. Chem. 2010, 2, 552. (e) Boltje, T. J.; Kim, J.-H.;
Park, J.; Boons, G. J. Org. Lett. 2011, 13, 284.
Figure 1. 1H NMR spectra at -80 °C: (a) glycosyl triflate 2, (b)
glycosyl sulfonium ion 3a, and (c) glycosyl sulfonium ion 3b.
Electrospray ionization (ESI) and cold-spray (CS) TOF
MS analyses were also performed to confirm the genera-
tion of the glycosyl sulfonium ions. Although the parent
peak was observed in addition to several fragments in the
case of glycosyl sulfonium ion 3a, only fragment peaks
were observed for 3b in both ESI and CS-TOF MS spectra.
These results indicate that glycosyl sulfonium ion 3b is less
stable than 3a. (For 13C NMR, H-H-COSY, HMQC, and
ESI/CS-TOF MS spectra, see the Supporting Information).
The thermal stability of glycosyl sulfonium ions 3 was
particularly important in helping us to optimize the reac-
tion conditions in an efficient manner. We performed
(10) Nokami, T.; Shibuya, A.; Manabe, S.; Ito, Y.; Yoshida, J.
Chem.;Eur. J. 2009, 15, 2252.
(11) (a) Fascione, M. A.; Adhead, S. J.; Stalford, S. A.; Kilner, C. A.;
Leach, A. G.; Turnbull, W. B. Chem. Commun. 2009, 5841. (b) Stalford,
S. A.; Kilner, C. A.; Leach, A. G.; Turnbull, W. B. Org. Biomol. Chem.
2009, 7, 4842. (c) Geng, Y.; Ye, X.-S. Synlett 2010, 2506. (d) Fascione,
M. A.; Turnbull, W. B. Beilstein J. Org. Chem. 2010, 6, doi: 10.3762/
bjoc.6.19. Published Online: Feb 22, 2010.
(12) Examples of the synthesis of oligosaccharides containing 2-ami-
no-2-deoxy glucose: (a) Nicolaou, K. C.; Bockovich, N. J.; Carcanague,
D. R.; Hummel, C. W.; Even, L. F. J. Am. Chem. Soc. 1992, 114, 8701.
(b) Ikeshita, S.; Sakamoto, A.; Nakahara, Y.; Nakahara, Y.; Ogawa, T.
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Org. Chem. 2007, 72, 6107. (g) Yang, Y.; Li, Y.; Yu, B. J. Am. Chem. Soc.
2009, 131, 12076.
(13) R-Glycosyl triflate 2 is also unstable and gradually decomposes
in a freezer at -80 °C.
Org. Lett., Vol. 13, No. 6, 2011
1545

Next, the reactions of glycosyl sulfonium ions 3a and 3b
with the glycosyl acceptor 4 were compared with those of
glycosyl triflate 2 (Table 1). The most reactive glycosyl
triflate 2 afforded the corresponding disaccharide 5 in 56%
yield at -78 °C (entry 1). As we expected, the yield of 5 was
improved from 56% to 90% by raising the reaction tem-
perature from -78 to -60 °C (entry 2). Taking the thermal
stability of the glycosyl sulfonium ion 3a into considera-
tion, glycosylation of 3a with 4 was performed at 23 °C
(entries 3 and 4). The yield of disaccharide 5 was
moderate even at ambient temperature (23 °C) with 30
Table 2. Glycosylation of Glycosyl Triflate and Glycosyl Sul-
fonium Ions with Carbohydrate Acceptors
Figure 2. The decomposition profile of two diastereomers of
glycosyl sulfonium ion 3b (3ba/3bb) between -80 and -10 °C.
variable-temperature (VT) NMR measurements from -80
to -10 °C to obtain the decomposition profile of the two
diastereomers of glycosyl sulfonium ion 3b (3ba/3bb)
(Figure 2). The probe temperature was raised in 20 min
intervals and an NMR spectrum was recorded every 10 °C.
Although more than 60% of glycosyl sulfonium ion 3a,
which waspreparedfrom Me2S, remained unchanged after
remaining at 0 °C for 17 h, glycosyl sulfonium ion 3b,
prepared from MeSPh, immediately decomposed at 0 °C.
Signals derived from one of the two diastereomers 3ba,
which is the major isomer at -80 °C (Figure 1c), gradually
decreased above -60 °C. There was a clear difference of
stability in the two diastereomers, with the minor diaster-
eomer 3bb starting to decompose above -30 °C, then
completely disappearing at around -10 °C. The major
decomposition product was found to be the corresponding
β,β-trehalose14 of glucosamine.15 Although the change in
the ratio of two diastereomers suggests an isomerization
between two diastereomers of glycosyl sulfonium ion 3b,
the decomposition profile revealed that 3b was stable
below -40 °C.
Table 1. Glycosylation of Glycosyl Triflate and Glycosyl Sul-
fonium Ions with a Glycosyl Acceptor
entry
donor (X)
second temp/reaction time
yield, a
%
1
2
3
4
5
6
2 (OTf)
- /-
56
90
52
69
62
93
2 (OTf)
-60 °C/0.5 h
23 °C/0.5 h
23 °C/3.0 h
-30 °C/0.5 h
-10 °C/0.5 h
3a (Me2S)
3a (Me2S)
3b (MeSPh)
3b (MeSPh)
a Excess amount of glycosyl donor (1.5 equiv) was used. b Glycosyl
sulfonium ion was stored at -80 °C for 24 h before use. c Excess amount
of glycosyl acceptor (2.0 equiv) was used.
a NMR yield based on 1,1,2,2-tetrachloroethane as an internal
standard.
1546
Org. Lett., Vol. 13, No. 6, 2011

min reaction time (entry 3). Due to the stability of
glycosyl sulfonium ion 3a, the yield was improved from
52% to 69% with extended reaction time (entry 4) at 23
°C. The decomposition profile (Figure 2) suggested that
glycosylation with glycosyl sulfonium ion 3b should be
carried out below 0 °C. Indeed, 3b reacted with 4 to give 5
in 62% yield at -30 °C but the yield improved to 93%
at -10 °C (entries 5 and 6). It is important to note that
glycosyl sulfonium ion 3b afforded disaccharide 5 in
comparable yield with that of glycosyl triflate 2.
Although the optimum reaction temperature was differ-
ent, glycosyl sulfonium ion 3b also serves as a reactive
glycosylation intermediate.
Glycosylation of other glycosyl acceptors 6-10 were
also examined under the optimized conditions (Table 2).
The secondary hydroxyl group of glycosyl acceptor 6 is
effective to give the corresponding disaccharide 11 in 91%
yield (entry 1). It is important to note that the yield of
disaccharide 11 was 90% when glycosyl sulfonium ion 3b
was stored for 24 h before use.16 This result clearly shows
the storability of the glycosyl sulfonium ion 3b. The
disaccharide 12, which has 2-azido and 4,6-benzylidene
protecting groups, was obtained in 74% yield (entry 2).
The diol glycosyl acceptor 8 affords both (1f3) and (1f4)
β-linked disaccharides13a and 13b in 37% and 32% yields,
respectively (entry 3).17 Another benefit of this method is
that thioglycosides could be used as glycosyl acceptors
(entries 4 and 5). Although there was a possibility that
glycosyl sulfonium ion 3b works as an activator of thiogly-
cosides, thioglycosides 9 and 10 afforded the correspond-
ing disaccharides 14 (73%) and 15 (52%), respectively,
without affecting anomeric S-tolyl groups. The yield of 15
was moderate, however, presumably because of low reac-
tivity of glycosyl acceptor 10 due to the steric hindrance of
the N-Phth group.2g,18 The resulting thioglycosides 14 and
15 could be directly used as glycosyl donors for the
subsequent glycosylations. The disaccharide 14 is a part
of lipid A19 and disaccharide 15 is also a part of the core
unit of N-linked oligosaccharide20 and Nod factor.12a,b
In summary, we have found that glycosyl sulfonium ions
prepared by the reaction of electrochemically generated
glycosyl triflates and diorganosulfides have both reason-
able stability and reactivity for glycosylation reactions.
The reactivity of glycosyl sulfonium ions can be tuned by
placing appropriate substituents on the sulfur atom.
Furthermore, it has been clearly shown that the glycosyl
sulfonium ions serve as glycosyl donors in the presence of a
thioglycoside acceptor. This methodology can be achieved
by accumulation of glycosyl sulfonium ions in a pure form
by the assistance of electrochemistry. Scope and limita-
tions, mechanistic studies,21 and further applications in-
cluding space integration22 of glycosylation using flow
microreactors by taking advantage of the stability and
reactivity of glycosyl sulfonium ions are currently in pro-
gress in our laboratory.
Acknowledgment. This work was supported by the
Grant-in-Aid for Scientific Research on Inovative Areas
(No. 2105) from the MEXT. T.N. is thankful for financial
support from a Meiji Seika Kaisha. Ltd. Award in Syn-
thetic Organic Chemistry. The authors thank Mr. Haruo
Fujita, Mr. Tadashi Yamaoka, and Dr. Keiko Kuwata of
Kyoto University for assistance with the low-temperature
NMR measurements and MS analyses.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Kusumoto, S. Trends Glycosci. Glycotechnol. 2010, 22, 107.
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Iserloh, U.; Lloyd, K. O.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001,
40, 1728. (b) Matsuo, I.; Wada, M.; Manabe, S.; Yamaguchi, Y.; Otake,
K.; Kato, K.; Ito, Y. J. Am. Chem. Soc. 2003, 125, 3402.
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162, 227.
(21) Glycosyl sulfonium ions and related species have been paid
much attention from mechanistic viewpoints: (a) Beaver, M. G.; Billings,
S. B.; Woerpel, K. A. Eur. J. Org. Chem. 2008, 771. (b) Hou, D.; Taha,
H. A.; Lowary, T. L. J. Am. Chem. Soc. 2009, 131, 12937.
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14, 7450 and references cited therein. (b) Suga, S.; Yamada, D.; Yoshida,
J. Chem. Lett. 2010, 39, 404. (c) Nagaki, A.; Kim, H.; Usutani, H.;
Matsuo, C.; Yoshida, J. Org. Biomol. Chem. 2010, 8, 1212. (d) Nagaki,
A.; Kim, H.; Moriwaki, Y.; Matsuo, C.; Yoshida, J. Chem.;Eur. J.
2010, 16, 11167. (e) Nagaki, A.; Kenmoku, A.; Moriwaki, Y.; Hayashi,
A.; Yoshida, J. Angew. Chem., Int. Ed. 2010, 49, 7543. (f) Nagaki, A.;
Takizawa., E.; Yoshida, J. Chem.;Eur. J. 2010, 16, 14149.
(15) Although we observed β,β-trehalose as a major product in the
reaction mixture after the disappearance of glycosyl sulfonium ion 3b,
β,β-trehalose might be obtained by the reaction with adventitious water
during variable-temperature NMR measurement.
(16) We transferred glycosyl sulfonium ion 3b from the electrolysis
cell to the Schlenk tube and stored it in a freezer at -80 °C for 24 h before
use.
(17) Paulsen, H.; Steiger, K.-M. Carbohydr. Res. 1987, 169, 105.
(18) Crich, D.; Vinod, A. U. Org. Lett. 2003, 8, 1297 and references
cited therein.
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