S-benzoxazolyl (SBox) glycosides as novel, versatile glycosyl donors for stereoselective 1,2-cis glycosylation

Article abstract of DOI:10.1021/ol0273452

(Matrix presented) Novel glycosyl donors, S-benzoxazolyl (SBox) glycosides, have been synthesized, tested toward various protecting group manipulations, and applied to the highly stereoselective 1,2-cis glycosylation. These compounds fulfill the requireme

Full text of DOI:10.1021/ol0273452

ORGANIC
LETTERS
2003
Vol. 5, No. 4
455-458
S-Benzoxazolyl (SBox) Glycosides as
Novel, Versatile Glycosyl Donors for
Stereoselective 1,2-Cis Glycosylation
Alexei V. Demchenko,* Nelli N. Malysheva, and Cristina De Meo
Department of Chemistry and Biochemistry, UniVersity of Missouri-St. Louis,
8001 Natural Bridge Road, St. Louis, Missouri 63121
demchenkoa@umsl.edu
Received November 24, 2002
ABSTRACT
Novel glycosyl donors, S-benzoxazolyl (SBox) glycosides, have been synthesized, tested toward various protecting group manipulations, and
applied to the highly stereoselective 1,2-cis glycosylation. These compounds fulfill the requirements for a modern glycosyl donor such as
accessibility, high stability toward protecting group manipulations, and mild activation conditions. It was also demonstrated that SBox glycosides
withstand other glycosyl donor activation conditions and therefore allow selective glycosylations of O-pentenyl and thioglycosides.
The majority of carbohydrates found in nature exist as
polysaccharides, glycoconjugates, or glycosides in which
monosaccharide units are joined together via O-glycosidic
bonds. The necessity to form either a 1,2-cis or 1,2-trans
glycosidic bond with complete stereoselectivity is the main
reason chemical O-glycosylation is placed among the most
challenging problems of modern synthetic chemistry. To
address these challenges, many new glycosyl donors that can
be synthesized under mild reaction conditions and are
sufficiently stable to be purified, modified, and stored have
been developed.1,2 Highly efficient strategies for the oli-
gosaccharide synthesis have become available.3 Methods for
solid-phase synthesis have been reported, and these proce-
dures often shorten oligosaccharide synthesis.4 However,
these developments are often compromised when applied to
the stereoselective synthesis of 1,2-cis glycosides, which are
often present as components in a wide variety of natural
compounds.5-8
It is well established that 1,2-trans glycosides can be
prepared with the assistance of a neighboring participating
group.9 In principle, 1,2-cis glycosides (R-glycosides for
D-glucose, D-galactose, and L-fucose, or â-glycosides for
D-mannose, L-arabinose, etc.) can be synthesized with a
glycosyl donor bearing a nonparticipating group at C-2 (O-
benzyl, azido). However, the reaction often proceeds via an
SN1 mechanism and therefore with poor stereoselectivity.
Despite considerable progress, no successful general method
for 1,2-cis glycosylation has yet emerged.10 Although the
first 1,2-cis glycosylations were performed many decades
ago,10 even nowadays each particular case requires a careful
selection of techniques, especially when applied to the
synthesis of complex oligosaccharides.
As a part of the program to develop novel, versatile
methods and strategies for the oligosaccharide synthesis, we
have become interested in a class of glycosyl donors with a
(6) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
(7) Hakomori, S. Acta Anat. 1998, 161, 79-90.
(1) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(2) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40,
1576-1624.
(3) Boons, G. J. Tetrahedron 1996, 52, 1095-1121.
(4) Seeberger, P. H.; Haase, W. C. Chem. ReV. 2000, 100, 4349-4393.
(5) Varki, A. Glycobiology 1993, 3, 97-130.
(8) Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek, R. A.
Science 2001, 291, 2370-2376.
(9) Nukada, T.; Berces, A.; Zgierski, M. Z.; Whitfield, D. M. J. Am.
Chem. Soc. 1998, 120, 13291-13295.
(10) Demchenko, A. V. Curr. Org. Chem. 2003, 7, 35-79.
10.1021/ol0273452 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/22/2003

generic leaving group SCR1dNR2 (substituted thioimidoyl
derivatives). It should be noted that a number of such
moieties have been previously employed at the anomeric
center in an attempt to achieve better stereocontrol of the
glycosylation process.10 For example, benzothiazolyl,11 pyridin-
2-yl,12-14 pyrimidin-2-yl,12,15 imidazolin-2-yl,12 and 1′-phenyl-
1H-tetrazolyl16 1-thio derivatives performed exceptionally
well, in most cases providing high anomeric selectivity.
Unfortunately, the lower stability of these derivatives in
comparison to that of “stable” glycosyl donors, O-pentenyl17
or thioglycosides,18,19 toward protecting group manipulations
is the major drawback of these glycosylation approaches,
which limits their application for convergent oligosaccharide
synthesis. We decided to explore this concept taking into
consideration the following advantageous features of the
substituted thioimidates. First, these compounds can be
synthesized via a number of well-established reaction
pathways starting from anomeric halides, acetates, or 1,2-
anhydro sugars and are therefore easily accessible. Second,
we assumed that their glycosyl donor reactivity can be
adjusted by varying the electronic properties of R1 and R2
substituents. Third, the overall size of the anomeric sub-
stituent may influence the reactivity/stability of these thio
derivatives dramatically,20 which would allow the application
of various (chemo)selective glycosylation approaches.3
Here we describe the synthesis of novel 1,2-trans-S-
benzoxazolyl derivatives (SBox glycosides) and their ap-
plication for stereoselective 1,2-cis glycosylation.21 For this
purpose 3,4,6-tri-O-acetyl-2-O-benzyl-R-D-glucopyranosyl
bromide (1a)22,23 was reacted with 2-mercapto-benzoxazole
in the presence of K2CO3 in acetone at 50 °C to afford
benzoxazolyl 3,4,6-tri-O-acetyl-2-O-benzyl-1-thio-â-D-gly-
copyranoside (2a) in 92% yield (Scheme 1). Similarly, the
SBox glycoside of D-galactose 2b was prepared from 1b24,25
in 90% yield. Interestingly, the newly synthesized compounds
were shown to be able to withstand rather harsh reaction
Scheme 1. Synthesis of Novel SBox Derivatives 2a and 2b
conditions required for protective group manipulations, i.e.,
acetylation, deacetylation, benzylation, and triphenylmethy-
lation, as well as benzylidene acetal formation and cleavage.
In addition, alternative approaches for the synthesis of
nonparticipating SBox glycosides have been explored. Thus,
acetobromoglucose was reacted with 2-mercaptobenzoxazole
in the presence of K2CO3 in acetone at 50 °C, followed by
Zemplen deacetylation (MeONa/MeOH) and benzylation
(BnBr/NaH), to allow benzoxazolyl 2,3,4,6-tetra-O-benzyl-
1-thio-â-D-glycopyranoside in 52% yield over three steps.
The SBox moiety could also be introduced via Lewis acid
(BF3‚Et2O, TMSOTf)-catalyzed glycosidation of pentaacetyl
â-D-glucose. Analogous thiazolyl 2,3,4,6-tetra-O-benzyl-1-
thio-â-D-glucopyranoside has been accordingly prepared by
reaction of acetobromoglucose with 2-mercaptothiazoline in
the presence of NaH in MeCN, followed by deacetylation
and benzylation. Application of these derivatives for glyco-
sylation will be reported in due course. It should be noted
that syntheses of per-acetylated thiazolylthio26 and benzox-
azolylthio27,28 derivatives have been previously reported.
Having synthesized SBox glycosides 2a and 2b, we turned
our attention to the evaluation of their glycosyl donor pro-
perties. Considering the multifunctional character of the leav-
ing group, we anticipated that these donors could be activated
via a number of conceptually different modes (Figure 1).
(11) Mukaiyama, T.; Nakatsuka, T.; Shoda, S. I. Chem. Lett. 1979, 487-
490.
(12) Hanessian, S.; Bacquet, C.; Lehong, N. Carbohydr. Res. 1980, 80,
c17-c22.
(13) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward,
D. E.; Au-Yeung, B. W.; Balaram, P.; Browne, L. J.; Card, P. J.; Chen, C.
H. J. Am. Chem. Soc. 1981, 103, 3215-3217.
(14) Reddy, G. V.; Kulkarni, V. R.; Mereyala, H. B. Tetrahedron Lett.
1989, 30, 4283-4286.
(15) Chen, Q.; Kong, F. Carbohydr. Res. 1995, 272, 149-157.
(16) Tsuboyama, K.; Takeda, K.; Torii, K.; Ebihara, M.; Shimizu, J.;
Suzuki, A.; Sato, N.; Furuhata, K.; Ogura, H. Chem. Pharm. Bull. 1990,
38, 636-638.
(17) Fraser-Reid, B.; Anilkumar, G.; Gilbert, M. B.; Joshi, S.; Kraehmer,
R. In Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W.,
Sinay, P., Eds.; Wiley-VCH: 2000; Vol. 1, pp 135-154.
(18) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-
205.
(19) Oscarson, S. In Carbohydrates in Chemistry and Biology; Ernst,
B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: 2000; Vol. 1, pp 93-116.
(20) Boons, G. J.; Geurtsen, R.; Holmes, D. Tetrahedron Lett. 1995, 36,
6325-6328.
(21) Malysheva, N. N.; De Meo, C.; Demchenko, A. V. Presented at
the 21st International Carbohydrate Symposium, July 7-12, 2002, Cairns,
Australia.
(22) Brennan, S.; Finan, P. A. J. Chem. Soc., C 1970, 1742-1744.
(23) Excoffier, G.; Gagnaire, D. Y.; Vignon, M. R. Carbohydr. Res. 1976,
46, 215-226.
(24) Lemieux, R. U.; Kondo, T. Carbohydr. Res. 1974, 35, C4-C6.
(25) Kochetkov, N. K.; Klimov, E. M.; Malysheva, N. N.; Demchenko,
A. V. Carbohydr. Res. 1991, 212, 77-91.
Figure 1. Plausible Reaction Intermediates for the Activation of
SBox Glycosides.
Thus, heavy metal salt-based promoter systems would
complex sulfur and nitrogen, improving the leaving group
ability by producing a partial positive charge on sulfur (A).
(26) Cottier, L.; Descotes, G.; Kudelska, W. C. R. Acad. Sci. Paris, Serie
II 1992, 314, 657-660.
(27) Zinner, H.; Pfeifer, M. Ber. 1963, 96, 432-437.
(28) Zinner, H.; Peseke, K. Chem. Ber. 1965, 98, 3515-3519.
456
Org. Lett., Vol. 5, No. 4, 2003

Table 1. Glycosylation Reaction between 2a and 3a
entry
promoter system
time
yield
R/â ratiob
1
2
3
4
5
6
7
8h
NIS/TMSOTf/4 Å MS
MeOTf/3 Å MS
TMSOTf
3 h
16 h
24 h
48 h
16 h
2 h
82%
89%
d
15/1
R onlyc
Figure 2. Glycosyl Acceptors Tested for the Glycosylations with
2a and 2b.
AgCO3
e
AgCO3/AgOTf
ZrCl4/AgCO3
AgOTf/3 Å MS
TrClO4
75%
70%
92%g
88%
R only
10/1f
R only
15/1
1 h
40 h
O-acetyl substituents. These observations make SBox deriva-
tives suitable candidates for the development of various
chemoselective and orthogonal strategies for convergent
oligosaccharide synthesis.3
To reveal the scope and possible limitations of the novel
approach for the synthesis of glycosidic linkages of different
origin, a number of partially protected glycosyl acceptors
were investigated (Figure 2). Thus, commercially available
diacetone acetals of galactose 5 and glucose 7, as well as
other common building blocks 6,33 8,34 and 9,35 were
glycosylated with 2a and 2b. Results of these glycosylation
experiments are summarized in Table 2. Most commonly,
a All glycosylations were performed in CH2Cl2 under argon at room
temperature. b Anomeric ratios were obtained by comparison of the integral
intensities of the corresponding signals in 1H NMR spectra. c No 1,2-trans-
linked product could be detected; anomeric selectivity > 20/1. d Sluggish
reaction (incomplete in 24-48 h) and high or complete anomeric selectivity;
however, low isolated yield (35-60%) was observed; similar results were
obtained with BF3‚Et2O, BF3‚Me2O, and Cu(OTf)2/TMSOTf. e No reaction
within 48 h, similar results were obtained in the presence of Cu(OTf)2,
HgO/HgBr2, CSA, IDCP, or NBS. f Reaction proceeded via 1-chloro
derivative generated in situ. g AgOTf-Promoted glycosylations in the absence
of added MS or in the presence of 4 Å MS provided glycosylation products
with complete stereoselectivity but lower yields (82-84%). h Methyl 2,3,4-
tri-O-benzoyl-6-O-triphenylmethyl-R-D-glucopyranoside was used as a
glycosyl acceptor.
Alternatively, thiophilic, alkylating, or electrophilic reagents
would act via B or C.
Table 2. Glycosylation Reaction between 2a,b and 5-9 in the
Presence of AgOTf or MeOTfa,b
With these considerations in mind, and in order to evaluate
the glycosyl donor properties of SBox glycosides, 2a was
coupled with methyl 2,3,4-tri-O-benzoyl-R-D-glucopyrano-
side (3)29 in the presence of a promoter and in the presence
or absence of molecular sieves (MS) in dry CH2Cl2. These
results are summarized in Table 1. Thus, the highest
stereoselectivities and yields for the synthesis of 4 were
obtained not only with the conventional promoters used for
the activation of alkyl/aryl thioglycosides such as NIS/
TMSOTf (entry 1, Table 1) or MeOTf (entry 2)19 but also
in the presence of AgOTf (2.0 mol equiv, entry 7), which is
more typically used for the activation of glycosyl halides30
or selenoglycosides.31 In addition, the 6-O-triphenylmethy-
lated derivative of the glycosyl acceptor 3 could be glyco-
sylated in the presence of TrClO4 (entry 8).
entry
donor
acceptor
promoter
yield
R/â ratio
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
2b
5
6
6
7
8
9
5
6
AgOTf
AgOTfc
AgOTf
MeOTf
MeOTf
MeOTf
AgOTf
AgOTf
99%
85%
97%
88%
88%
78%
90%
80%
11/1
15/1
R only
8/1
R only
3/1
10/1
R only
a Typically, the glycosyl acceptor was reacted with a glycosyl donor (10
mol % excess) in the presence of MeOTf (3 equiv) or AgOTf (2.0 equiv)
and activated MS (3 Å, unless otherwise noted) in CH2Cl2 at room
temperature until completion (typically 1-2 h). All synthesized di- and
trisaccharides have adequate 1H and 13C NMR and HRMS data. b All
glycosylations were performed in the presence of each promoter; however,
only the best results are listed. c Used 4 Å MS.
Surprisingly, 2a has remained inert in the presence of other
common thioglycoside activating agents such as iodonium-
(di-γ-collidine)perchlorate (IDCP) or NBS. In this context,
high stability toward IDCP, a promoter that is often used
for the activation of “armed” thioglycosides,32 can be
correlated with the number of the remote deactivating
alcohol reactivity is inversely correlated with the 1,2-cis
stereoselectivity.10 Remarkably, somewhat better results in
terms of both stereoselectivity and yields were achieved when
highly nucleophilic primary hydroxyl-containing glycosyl
acceptors were employed. For example, glycosylation of 5
(29) Byramova, N. E.; Ovchinnikov, M. V.; Backinowsky, L. V.;
Kochetkov, N. K. Carbohydr. Res. 1983, 124, C8-C11.
(30) Hanessian, S.; Banoub, J. Carbohydr. Res. 1977, 53, C13-C16.
(31) Mehta, S.; Pinto, B. M. Tetrahedron Lett. 1991, 32, 4435-4438.
(32) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron
Lett. 1990, 31, 1331-1334.
(33) Valashek, I. E.; Shakhova, M. K.; Minaev, V. A.; Samokhvalov,
G. I. Zh. Obshch. Khim. 1974, 44, 1161-1164.
(34) Nilsson, U.; Ray, A. K.; Magnusson, G. Carbohydr. Res. 1994, 252,
117-136.
(35) Jansson, K.; Ahlfors, S.; Frejd, T.; Kihlberg, J.; Magnusson, G.;
Dahmen, J.; Noori, G.; Stenvall, K. J. Org. Chem. 1988, 53, 5629-5647.
Org. Lett., Vol. 5, No. 4, 2003
457

O-pentenyl glycoside 12.37 For example, using standard
reaction conditions in the presence of AgOTf afforded
disaccharide 13 in 76% yield as an anomeric mixture (8/1
R/â). This result could be sufficiently improved by applying
a larger excess (up to 2.0 equiv) of the glycosyl donor; in
this case, 13 was isolated in 99% yield (Scheme 2).
Furthermore, disaccharide 11 can be also reacted with 12 in
accordance with the recently introduced “semi-orthogonal”
glycosylation strategy38 to afford 14 in the high yield of 92%.
Clearly, trisaccharide 14 could be employed for subsequent
glycosylation without protecting group manipulations.
It is to be expected that the observed high stability of SBox
glycosides toward electrophilic activators would also allow
selective activation of SPh glycosides with NBS39 or armed
O-pentenyl glycosides (IDCP).40 Further exploration of these
interesting features of SBox derivatives as well as their
application for convergent oligosaccharide synthesis is on
the way.
Scheme 2. Selective Activation of SBox Derivatives in the
Presence of S-Ethyl and O-Pentenyl Glycosides
In summary, we developed a new class of glycosyl donors,
benzoxazolyl (Box) thioglycosides, which were applied to
the highly stereoselective 1,2-cis glycosylation. These com-
pounds fulfill the necessary requirements of a modern
glycosyl donor such as accessibility, high stability toward
major protecting group manipulations, and mild activation
conditions. It was also demonstrated that SBox glycosides
withstand other glycosyl donor activation conditions and
therefore allow selective glycosylations of O-pentenyl and
thioglycosides. Considering the unique glycosyl donor
properties of the SBox glycosides, we believe that they will
occupy an important niche in the arsenal of modern synthetic
methods.
with 2a in the presence of AgOTf afforded the corresponding
disaccharide in 99% yield as an 11/1 R/â-mixture (entry 1,
Table 2). Also, glycosylation of 6 afforded the disaccharide
with complete stereoselectivity in 97% yield (entry 3).
Interestingly, when the latter reaction was performed in the
presence of 4 Å MS, lower anomeric selectivity (15/1) and
yield (85%) were detected (entry 2). In this context,
galactosyl donor 2b performed similarly (entries 7 and 8).
Acknowledgment. This work was supported by the
University of Missouri-St. Louis, UM Research Board
Award, and “The Foundation BLANCEFLOR Boncompagni-
Ludovisi, ne´e Bildt”.
To extend this novel method for the rapid synthesis of
oligosaccharides with multiple 1,2-cis glycosidic residues
without requiring any protecting group manipulations, we
tested a number of conditions for selective activation of SBox
glycosides in the presence of other common glycosyl donors.
Thus, pilot glycosylation of ethyl thiogalactoside 1036 with
2a in the presence of AgOTf and 3 or 4 Å MS provided
disaccharide 11 with complete stereoselectivity in 98% yield
(Scheme 2), whereas application of other suitable promoters,
e.g., TMSOTf or ZrCl4/AgCO3, resulted in lower stereose-
lectivities and yields.
Supporting Information Available: Experimental pro-
cedures for the synthesis of 2a, 2b, 11, 13, and 14 and their
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0273452
(36) Birberg, W.; Lonn, H. Tetrahedron Lett. 1991, 32, 7453-7456.
(37) Houdier, S.; Vottero, P. J. A. Angew. Chem., Int. Ed. Engl. 1994,
33, 354-356.
(38) Demchenko, A. V.; De Meo, C. Tetrahedron Lett. 2002, 43, 8819-
8822.
(39) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.
1983, 1983, 2430-2434.
(40) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J.
Am. Chem. Soc. 1988, 110, 5583-5584.
In addition, a range of reaction conditions (MeOTf,
AgOTf, TMSOTf, etc.) allowed efficient synthesis of the
disaccharide derivative 13 by selective activation of 2a over
458
Org. Lett., Vol. 5, No. 4, 2003