A Glycosylation Protocol Based on Activation of Glycosyl 2-Pyridyl Sulfones with Samarium Triflate

Article abstract of DOI:10.1021/ol005579k

(Equation Presented) Reaction of glycosyl 2-pyridyl sulfones (e.g., 2) with alcohols and samarium(III) triflate affords glycosides in moderate to excellent yields. Benzylated sulfones can be activated in preference to their benzoylated counterparts, and t

Full text of DOI:10.1021/ol005579k

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1505-1508
A Glycosylation Protocol Based on
Activation of Glycosyl 2-Pyridyl
Sulfones with Samarium Triflate
Grace X. Chang and Todd L. Lowary*
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210
lowary.2@osu.edu
Received January 24, 2000
ABSTRACT
Reaction of glycosyl 2-pyridyl sulfones (e.g., 2) with alcohols and samarium(III) triflate affords glycosides in moderate to excellent yields.
Benzylated sulfones can be activated in preference to their benzoylated counterparts, and the methodology has been used to prepare di- and
trisaccharides containing both furanose and pyranose residues. Thioglycosides do not react under these conditions, and the sulfones are
inert to the N-iodosuccinimide/silver triflate promoter system commonly used to activate thioglycosides. This selectivity allowed the efficient
preparation of oligosaccharides via orthogonal glycosylation protocols.
Oligosaccharides are key players in a number of biological
recognition processes,1 and their preparation has attracted
the attention of synthetic chemists for many years.2 Although
a number of glycosylation procedures are available, there is
still a need for the development of glycosyl donors that can
be activated selectively in the presence of other potential
donors. Such compounds allow the efficient synthesis of
oligosaccharides via orthogonal glycosylation protocols.3
These methodologies are attractive alternatives to more
classical approaches, which often involve a number of tedious
(and yield lowering) protection and deprotection steps on
precious oligosaccharide intermediates.
widespread application as donor species in the synthesis of
oligosaccharides, the corresponding sulfones have not been
widely investigated. To the best of our knowledge, the only
previous reports of glycoside bond formation using sulfone
donors were published by Ley and co-workers about 10 years
ago.6 This work, an extension of their studies on the
formation of tetrahydropyran and tetrahydrofuran acetals,
showed that two different glycosyl phenyl sulfones could
be activated with magnesium bromide etherate and coupled
to simple alcohols. In one case, a carbohydrate alcohol was
used to form a disaccharide.6b Best yields were obtained upon
either heating or ultrasonication. A related study is detailed
in a report by Sanders and Kiessling.7 In this work it was
shown that heating glucose 1,2 cyclic sulfites with simple
alcohols and lanthanide triflates afforded glucosides. We have
now found that benzylated glycosyl 2-pyridyl sulfones (e.g.,
2) react with a range of simple and carbohydrate alcohols
upon activation with samarium(III) triflate (Sm(OTf)3) to
yield R:â mixtures of glycosides in moderate to excellent
yield.
In this paper we report that hydrolytically stable glycosyl
2-pyridyl sulfones can be used as glycosylation agents.
Although thioglycosides4 and glycosyl sulfoxides5 have found
(1) (a) Varki, A. Essent. Glycobiol. 1999, 57. (b) Imperiali, B. Acc. Chem.
Res. 1997, 30, 452. (c) Dwek, R. A. Chem. ReV. 1996, 96, 683.
(2) Reviews: (a) Boons, G.-J. Tetrahedron 1996, 52, 1095. (b) Kanie,
O.; Ogawa, T.; Ito, Y. Yuki Gosei Kagaku Kyokaishi 1998, 5, 952. (c)
Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503. (d) Schmidt, R. R.;
Kinzy, W.; P. J. AdV. Carbohydr. Chem. Biochem. 1994, 50, 21. (e)
Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1380.
(3) (a) Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073.
(b) Paulsen, H.; Angew. Chem., Int. Ed. Engl. 1995, 34, 1432. (c) Zhu, T.;
Boons, G.-J. Tetrahedron Lett. 1998, 39, 2187.
(4) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179.
(5) (a) Norberg, T. Front. Nat. Prod. Res. 1996, 1, 82. (b) Kahne, D.;
Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111, 6881.
(6) (a) Brown, D. S.; Ley, S. V.; Vile, S. Tetrahedron Lett. 1988, 29,
4873. (b) Brown, D. S.; Ley, S. V.; Vile, S.; Thompson, M. Tetrahedron
1991, 47, 1329. (c) Charreau, P.; Ley, S. V.; Vettiger, T. M.; Vile, S. Synlett
1991, 415.
(7) Sanders, W. J.; Kiessling, L. L. Tetrahedron Lett. 1994, 35, 7335.
10.1021/ol005579k CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/05/2000

mixtures. The preparation of the benzoylated pyridyl sul-
fones, p-cresyl sulfones, and pyridyl sulfoxides (see below)
is outlined in the Supporting Information and proceeded
without incident.
Scheme 1. Synthesis of Sulfonesa
With a route available for the efficient preparation of the
required donors, we first explored the possibility that the
pyridyl sulfones could be activated in preference to other
potential glycosylation agents. Accordingly, we reacted a
panel of glycosyl sulfones, sulfoxides, and thioglycosides
with methanol in the presence of a stoichiometric amount
a Legend: (a) PySSPy, n-Bu3P, CH2Cl2, rt; (b) m-CPBA,
NaHCO3, CH2Cl2, rt, 75% (two steps).
9
of Sm(OTf)3 as detailed in Table 1.
The sulfone starting materials are readily prepared as
illustrated in Scheme 1.8 Reaction of the commercially
available benzylated arabinofuranose derivative 1 with dipyr-
idyl disulfide and tri-n-butylphosphine provided an anomeric
mixture of pyridyl thioglycosides in excellent yield. Subse-
quent oxidation with m-CPBA afforded the target sulfones.
Two other sulfones, possessing the mannopyranosyl, 3,8 and
galactopyranosyl, 4, stereochemistry (Figure 1), were syn-
thesized in an analogous fashion. For 2 and 3, the R-sulfone
could be separated from its â-isomer, but for 4 this was not
possible. It was found, however, that both isomers could be
used in the glycosylation reactions with equal efficiency and
consequently the sulfones were isolated and used as anomeric
Table 1. Reaction of Various Protected Arabinofuranoside
Derivatives with Sm(OTf)3 and Methanola
entry
R
R′
yield (%)b
R:â ratioc
1
2
3
4
5
6
7
8
SO2Py
SPy
Bn
Bn
Bn
Bn
Bz
Bz
Bz
Bz
Bn
Bn
92
5:1
NRd
49
SO2Cre
SCr
4:1
NR
trf
NR
NR
NR
81
SO2Py
SPy
SO2Cr
SCr
SOPy
SO2Py
9
10g
5:1
7:1
93
a Conditions: donor (1.0 equiv), methanol (20 equiv), Sm(OTf)3 (1.0
equiv). The reactions were carried out on a 0.2 mmol scale in 10 mL of
refluxing CH2Cl2 under argon for 18 h. b Isolated yield after chromatog-
raphy. c Ratio determined by integration of OCH3 and H-1 resonances in
1
the H NMR spectrum. The R- and â-glycosides of 7 were inseparable by
chromatography. d No reaction observed by TLC. This was confirmed by
1H NMR spectroscopy of the products isolated after chromatography of
the reaction mixture. e Cr ) p-CH3C6H4. f As detected by TLC. Following
chromatography of the reaction mixture, 90% of the unreacted sulfone was
recovered. g Yb(OTf)3 used in place of Sm(OTf)3.
Among the substrates tested, the benzylated glycosyl
pyridyl sulfones were the best, providing methyl glycoside
7 in 92% yield (entry 1). The pyridyl nitrogen appears to be
important for the reaction to proceed efficiently; when the
benzylated p-cresyl sulfone was used, the yield dropped to
49% (entry 3). Both benzylated thioglycosides (entries 2 and
4) do not react as determined by TLC. This was confirmed
by 1H NMR spectroscopy of the products that were recovered
after chromatography of the reaction mixture. In contrast to
the benzylated sulfones, which provided moderate to excel-
lent yields of 7, the benzoylated sulfones were much poorer
reaction substrates. Only the benzoylated pyridyl sulfone
(entry 5) provided any product, in trace amounts. The
benzylated sulfoxides (entry 9) were also activated under
these conditions, giving an 81% yield of the product. We
have found that ytterbium(III) triflate could be used as the
(8) Urban, D.; Skrydstrup, T.; Beau, J. M. J. Org. Chem. 1998, 63, 2507.
(9) Activation could also be achieved by using 0.5 equiv of Sm(OTf)3;
however, reactions times were significantly longer.
Figure 1.
1506
Org. Lett., Vol. 2, No. 11, 2000

promoter with equal efficiency (entry 10). In all cases,
mixtures of glycosides were formed, with the R-isomer
predominating.
Scheme 3a
We have also determined that these pyridyl sulfones are
not activated by the N-iodosuccinimide/silver triflate10
promoter system used to activate thioglycosides. Attempted
reaction of 2 with methanol as outlined in Scheme 2 yielded
only the unreacted sulfones.
Scheme 2a
a Legend: (a) CH3OH, N-iodosuccinimide, silver triflate, CH2Cl2,
0 °C to rt, 18 h.
Although we have not carried out any mechanistic
investigations, the activation of these sulfones is most likely
via “remote activation” 11 by complexation of the metal ion
with the pyridyl nitrogen and one of the sulfone oxygens.
Subsequent cleavage of the C1-S bond in this activated
complex would lead to an oxonium ion, which is, in turn,
trapped by the alcohol. The reactivity trends and product
ratios detailed in Table 1 are easily rationalized. The lower
reactivity of the benzoylated substrates relative to their
benzylated counterparts is presumably due to their disarmed
nature.12 The lack of stereocontrol in these glycosylations is
expected given that the donors possess nonparticipating
benzyl protecting groups on O-2.
a Legend: (a) 3, Sm(OTf)3, toluene, 70 °C, 75%, R:â 3:1; (b)
n-octanol, NIS, AgOTf, -78 to 0 °C, 66%, R:â 1.4:1.0; (c) 2,
Sm(OTf)3, toluene, 70 °C, 71%, R:â 3:1; (d) 5, NIS, AgOTf, 0 °C,
75%, R:â 1.3:1.
We next investigated the glycosylation of other simple
alcohols by 2 (Table 2, entries 2-4). Under the same
conditions as those used for the synthesis of 7 (20 equiv of
the alcohol, refluxing dichloromethane, 1 equiv of Sm-
(OTf)3), good to excellent yields of glycosides were obtained
with 1-octanol, cyclohexanol, and tert-butyl alcohol. Again,
mixtures of glycosides were formed, but the R-isomer was
favored.
Encouraged by the results with these simple alcohols, we
then tested the ability of 2 to glycosylate carbohydrate
alcohols 513 and 614 (Table 2, entries 5 and 6). The
disaccharide products (11 and 14) were obtained in good
yield. As in the other glycosylations, the R-glycosides
predominated. The glycosylation of alcohols 5 and 6 by the
mannosyl and galactosyl sulfones 3 and 4 was also explored
as detailed in Table 2 (entries 7-10). With the carbohydrate
Table 2. Synthesis of Glycosides by Reaction of Glycosyl
2-Pyridyl Sulfones with Various Alcohols in the Presence of
Samarium Triflatea
entry sulfone
alcohol
product/yield (%)b R:â ratioc
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
3
3
4
4
CH3OH
octanol
cyclohexanol
t-BuOH
5
6
5
6
5
6
7/92
8/94
9/76
10/81
11/75
14/71
12/53
15/89
13/56
16/40
5:1
2:1
4:1
3:2
2.7:1
2:1
2:1
10:1
4:1
10
4.5:1
a Conditions. (1) For sulfone 2 with simple alcohols: donor (1.0 equiv),
alcohol (20 equiv), Sm(OTf)3 (1.0 equiv). The reactions were carried out
on a 0.2 mmol scale in 10 mL of refluxing CH2Cl2, under argon for 18 h.
(2) For sulfones 2, 3, and 4 with carbohydrate alcohols: donor (1.3 equiv),
alcohol (1.0 equiv), Sm(OTf)3 (1.0 equiv). The reactions were carried out
on a 0.14 mmol scale in 10 mL of toluene at 70 °C, under argon for 18 h.
b Isolated yield after chromatography. c When the two glycosides were
separable (entries 6, 7, 9 and 10), the ratio was determined by recovered
product yields. In all other cases, the ratio was determined by integration
(10) (a) Lowary, T. L.; Eichler, E.; Bundle, D. R. J. Org. Chem. 1995,
60, 7316. (b) Veeneman, G. H.; van Leewen, S. H.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 1331.
(11) (a) Hanessian, S. Glycoside Synthesis Based on the Remote
Activation Concept: An Overview. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Dekker: New York, 1997; pp 381-388 and references
therein. (b) Mereyala, H. B.; Reddy, G. V. Tetrahedron 1991, 47, 6435.
(12) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. F. J.
Am. Chem. Soc. 1988, 110, 5583.
1
of OCH3 or H-1 resonances in the H NMR spectrum.
(13) A° berg, P.-M.; Ernst, B. Acta Chem. Scand. 1994, 48, 228.
(14) Johnston, B. D.; Pinto, B. M. Carbohydr. Res. 1998, 310, 17.
Org. Lett., Vol. 2, No. 11, 2000
1507

alcohols, better yields were obtained if the reactions were
carried out in toluene at 70 °C. Despite the relatively high
temperatures required, the only detectable side product was
the hydrolyzed sulfone. In general (Table 2), the furanose
derivatives gave better yields; however, the stereoselectivity
for the R-linked disaccharide was higher in the pyranose
series.
On the basis of the results presented in Table 1, we were
confident that we could rapidly assemble oligosaccharides
by the selective coupling of glycosyl 2-pyridyl sulfones to
thioglycoside acceptors. This was demonstrated by the
synthesis of disaccharide 19 and trisaccharide 21 (Scheme
3). Deprotection of these oligosaccharides would provide
fragments of the lipoarabinomannan (LAM) found in the cell
wall complex of Mycobacterium tuberculosis.
Both oligosaccharides were synthesized without difficulty
as outlined in Scheme 3. Reaction of thioglycoside 1715 with
sulfone 3 provided a 75% yield disaccharide 18 in a 3:1 R:â
ratio. The R-glycoside was separated by chromatography and
then coupled to n-octanol using a promoter system of
N-iodosuccinimide and silver triflate. Following column
chromatography, disaccharide 19 was obtained pure in 66%
yield. The synthesis of trisaccharide 21 proceeded along
similar lines. Coupling of thioglycoside 17 with sulfone 2
provided a 3:1 R:â mixture of disaccharides in 71% yield.
The desired R-glycoside 20 could be isolated pure after
chromatography. Reaction of this thioglycoside with 5 and
N-iodosuccinimide/silver triflate provided a 75% yield of
trisaccharide 21 as a 1.3:1 R:â mixture, which could not be
separated.
In summary, we report here a novel glycosylation proce-
dure in which glycosyl 2-pyridyl sulfones are coupled to
alcohols using samarium triflate as the promoter. Moderate
to excellent yields of simple glycosides and oligosaccharides
are obtained. The sulfones can be activated selectively in
the presence of thioglycosides. This enabled the rapid
synthesis of oligosaccharides 19 and 21 in two-three steps
from monosaccharide building blocks 2, 3, and 17. We have
also demonstrated that the sulfones are not activated by a
standard method for activating thioglycosides (N-iodosuc-
cinimide/silver triflate). In its present form the method is
limited by the high temperatures required for the reaction to
proceed and by the fact that disarmed (acylated) sulfones
do not serve as glycosylation partners. The latter limitation
is the most serious in that it prohibits controlling the
stereochemistry of glycosylation via neighboring group
participation of O-2 protecting groups on the donor. We are
currently investigating methods by which both of these
limitations can be overcome.
Acknowledgment. This work was supported by The Ohio
State University and by the National Institutes of Health
(AI44045-01). We thank Christopher S. Callam, Assen B.
Kantchev, and Vinodkhumar Subramaniam for technical
assistance.
Supporting Information Available: General procedure,
scheme detailing the preparation of the sulfones and thiogly-
cosides not described in the text, experimental data, and 1H
and 13C NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Ottosson, H. Carbohydr. Res. 1990, 197, 101.
OL005579K
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