A new, powerful glycosylate method: Activation of thioglycosides with dimethyl disulfide-triflic anhydride

Article abstract of DOI:10.1021/ol702139u

(Formula Presented) Dimethyl disulfide reacts with triflic anhydride to provide a highly reactive electrophile. Various thioglycosides, differing in their thio aglycons, carbohydrate units, and protecting group pattern, were activated with Me₂S

Full text of DOI:10.1021/ol702139u

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4647-4650
A New, Powerful Glycosylation Method:
Activation of Thioglycosides with
Dimethyl Disulfide−Triflic Anhydride
Ja´nos Tatai and Pe´ter Fu1gedi*
Department of Carbohydrate Chemistry, Chemical Research Center,
Hungarian Academy of Sciences, Pusztaszeri u´t 59-67, H-1025 Budapest, Hungary
pfugedi@chemres.hu
Received August 31, 2007
ABSTRACT
Dimethyl disulfide reacts with triflic anhydride to provide a highly reactive electrophile. Various thioglycosides, differing in their thio aglycons,
carbohydrate units, and protecting group pattern, were activated with Me2S2 Tf2O in the presence of different glycosyl acceptors. The reactions
−
proceeded at low temperatures within a short time, affording oligosaccharides in high yields both on primary and secondary hydroxyls.
Armed and disarmed glycosyl donors were activated equally efficiently.
The development of efficient glycosylation methods is crucial
for the synthesis of oligosaccharides, glycoconjugates, and
other carbohydrate-containing complex natural products, as
well as for the improvement of solid-phase synthesis of
oligosaccharides.1 Major advances have been achieved by
introducing a variety of different types of glycosyl donors
and promoter systems for their activation.1a Among the
various classes of glycosyl donors, thioglycosides proved to
be particularly advantageous,2 and today they are the most
frequently used type of compounds in oligosaccharide
syntheses.3 Thioglycosides are mostly crystalline and have
long shelf lives, and as they are stable under most protecting
group transformations, highly functionalized derivatives are
made relatively easily.2,4 Importantly, as a result of the
stability of the thioglycoside function, this class of com-
pounds can serve not only as glycosyl donors but also as
glycosyl acceptors. This feature, combined with the tunable
reactivity of thioglycosides, could be taken advantage of in
the development of various synthetic strategies for higher
oligosaccharides.5
The very stability of thioglycosides, however, has pre-
sented problems for a long time in attempts to use them as
glycosyl donors. Early methods to activate thioglycosides
with heavy metal salts, by analogy with the Koenigs-Knorr
reaction, proved to be of limited usefulness.6 A different
concept, activating thioglycosides by organosulfur com-
pounds, has been developed by one of us, which resulted in
the introduction of dimethyl(methylthio)sulfonium triflate
(DMTST) as a promoter.7 DMTST is a powerful alkylsul-
fenylating agent7 that proved to be efficient in a wide range
of glycosylation reactions. Following the introduction of
DMTST, other reagents, based on the same principle,
including methylsulfenyl triflate,8 phenylsulfenyl triflate,9 and
the related seleno analog,10 have been developed. Sulfena-
(1) (a) Fu¨gedi, P. In The Organic Chemistry of Sugars; Levy, D. E.,
Fu¨gedi, P., Eds.; CRC Press: Boca Raton, FL, 2005; pp 89-179. (b)
Demchenko, A. V. Curr. Org. Chem. 2003, 7, 35-79. (c) Davis, B. G. J.
Chem. Soc., Perkin Trans. 1 2000, 2137-2160. (d) Fraser-Reid, B.; Madsen,
R.; Campbell, A. S.; Roberts, C. S.; Merritt, J. R. In Bioorganic
Chemistry: Carbohydrates; Hecht, S. M., Ed.; Oxford University Press:
Oxford, 1999; pp 89-133. (e) Gin, D. J. Carbohydr. Chem. 2002, 21, 645-
665. (f) Crich, D. J. Carbohydr. Chem. 2002, 21, 667-690. (g) Sears, P.;
Wong, C.-H. Science 2001, 291, 2344-2350. (h) Nicolaou, K. C.; Mitchell,
H. J. Angew. Chem., Int. Ed. 2001, 40, 1576-1624. (i) Seeberger, P. H.;
Haase, W.-C. Chem. ReV. 2000, 100, 4349-4393.
(2) (a) Fu¨gedi, P.; Garegg, P. J.; Lo¨nn, H.; Norberg, T. Glycoconjugate
J. 1987, 4, 97-108. (b) Garegg, P. J. AdV. Carbohydr. Chem. Biochem.
1997, 52, 179-205.
(3) Fu¨gedi, P. 11th European Carbohydrate Symposium, Lisbon, Portugal
2001; Abstract OC31.
(4) Oscarson, S. In Glycoscience: Chemistry and Chemical Biology;
Tatsuta, K. T., Fraser-Reid, B. O., Thiem, J., Eds.; Springer-Verlag: Berlin,
Heidelberg, 2001; pp 643-671.
(5) (a) Fu¨gedi, P. In The Organic Chemistry of Sugars; Levy, D. E.,
Fu¨gedi, P., Eds.; CRC Press: Boca Raton, FL, 2005; pp 181-221. (b)
Demchenko, A. V. Lett. Org. Chem. 2005, 2, 580-589. (c) Boons, G.-J.
Tetrahedron 1996, 52, 1095-1121.
(6) (a) Ferrier, R. J.; Hay, R. W.; Vethaviyasar, N. Carbohydr. Res. 1973,
27, 55-61. (b) Mukaiyama, T.; Nakatsuka, T.; Shoda, S. Chem. Lett. 1979,
487-490. (c) Hanessian, S.; Bacquet, C.; Lehong, N. Carbohydr. Res. 1980,
80, C17-C22. (d) Woodward, R. B. et al. J. Am. Chem. Soc. 1981, 103,
3215-3217. (e) Garegg, P. J.; Henrichson, C.; Norberg, T. Carbohydr. Res.
1983, 116, 162-165.
10.1021/ol702139u CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/02/2007

mide-type activators in combination with Lewis acids such
as the PhSNPhth-TMSOTf,11 EtSNPhth-TrB(C6F5)4,12 and
N-(phenylthio)-ꢀ-caprolactam-Tf2O13 systems have also
been proposed. More recently the list of organosulfur
compounds activating thioglycosides was further expanded
by using various sulfinates in admixture with triflic anhy-
dride.14 These sulfinates include S-(4-methoxyphenyl)ben-
zenethiosulfinate,15 benzenesulfinyl-piperidine (BSP),16 di-
phenyl sulfoxide,17 and benzenesulfinyl-morpholine.18
An attractive feature of some of these promoter systems
containing sulfinyl derivatives lies in their power, glycosyl-
ation successfully being performed at low temperatures.
Nevertheless, as most of these sulfinyl derivatives are not
commercially available,19 improvement of their synthetic
accessibility, as well as their stability and solubility, is
desired.20
Scheme 1. Glycosylation of a Primary Hydroxyl Using
Me2S2-Tf2O
and 2.0 equiv of Me2S2-Tf2O, the yields of 5 were 55%,
72%, 79%, and 79%, respectively. These results indicate that
a stoichiometric amount of the promoter is needed, and in
subsequent work a 1.5-fold excess of the reagent was used.
We were interested in developing a powerful promoter
system for the activation of thioglycosides that could be used
at low temperatures and at the same time use commercially
available inexpensive chemicals. We hypothesized that, by
analogy with the preparation of DMTST, dimethyl disulfide
might react not only with methyl triflate but also with triflic
anhydride. The primary product of this reaction could be
expected to be more reactive than DMTST as one of the
methyl groups of DMTST would be replaced by the strongly
electron-withdrawing trifluoromethanesulfonyl group. Al-
though in the literature we found no data on the reaction of
disulfides with sulfonic acid anhydrides, an NMR-tube
experiment clearly showed that dimethyl disulfide reacts with
triflic anhydride in a fast reaction.
Scheme 2. Effect of the Amount of Promoter on Yield
The thioglycoside activating capability of the dimethyl
disulfide-triflic anhydride (Me2S2-Tf2O) reagent was tested
by the reaction of the benzoylated thioglycoside (1) with the
D-glucose acceptor (2) having a primary hydroxyl group free
(Scheme 1). The reaction was complete in 10 min at 0 °C
and afforded the disaccharide (3) in 93% yield.
The amount of the reagent required for promoting glyco-
sylations was studied on the coupling of 1 with the
D-glucosamine derivative 4 (Scheme 2). Using 0.5, 1.0, 1.5,
Some of the essential reaction conditions having been
established, the scope of this new glycosylation reaction was
investigated by using a variety of different glycosyl donors
and acceptors (Table 1).
Me2S2-Tf2O-promoted glycosylations of thioglycosides
on secondary hydroxyls proceeded easily. Reactions of 1 with
the D-glucose derivatives 6, 8, and 10 (entries 1-3) having
a free hydroxyl group at the C-4, C-3, and C-2 positions,
respectively, were performed at -40 °C and afforded the
disaccharides 7, 9, and 11 within a few minutes. As can be
seen from Table 1, the promoter activates glycosyl donors
not only from neutral monosaccharides of different configu-
rations (D-gluco, D-galacto, L-ido, D-manno) but the amino-
sugar (12) and the uronic acid (14) thioglycosides as well.
Several of the acceptors had the 4-OH group free, to which
generally low reactivity is attributed. The yields obtained
with these acceptors (entries 1, 5, 7-11) indicate that the
low reactivity of the 4-OH group was readily overcome by
the power of the activation method. The thioglycoside donors
had the most frequently used aglycons (Me, Et, Ph); they
all reacted equally well, irrespective of their aglycon. The
reagent and the reaction conditions are compatible with most
of the commonly used protecting groups. In the case of
reactants containing the acid-sensitive acetal and tert-butyl
groups (entries 2, 3, 5, 9, 10), the reaction mixture was
buffered by 2,6-di-tert-butyl-4-methylpyridine. The disarmed
thioglycosides in Table 1 invariably afforded trans-glycosides
as a result of neighboring group participation.
(7) (a) Fu¨gedi, P.; Garegg, P. J. Carbohydr. Res. 1986, 149, C9-C12.
(b) Andersson, F.; Fu¨gedi, P.; Garegg, P. J.; Nashed, M. Tetrahedron Lett.
1986, 27, 3919-3922. (c) Fu¨gedi, P. In E-EROS, Electronic Encyclopedia
of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley-Interscience,
2002; http://www.mrw.interscience.wiley.com/eros/eros_articles_fs.html.
(8) Dasgupta, F.; Garegg, P. J. Carbohydr. Res. 1988, 177, C13-C17.
(9) (a) Martichonok, V.; Whitesides, G. M. J. Org. Chem. 1996, 61,
1702-1706. (b) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(10) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1988, 29, 1061-1064.
(11) Shimizu, H.; Ito, Y.; Ogawa, T. Synlett 1994, 535-536.
(12) Jona, H.; Takeuchi, K.; Saitoh, T.; Mukaiyama, T. Chem. Lett. 2000,
1178-1179.
(13) Duro´n, S. G.; Polat, T.; Wong, C.-H. Org. Lett. 2004, 6, 839-841.
(14) For a review on the use of sulfoxides and sulfinates as donors and
promoters, see: Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115-251.
We thank one of the reviewers for drawing our attention to this publication.
(15) Crich, D.; Smith, M. Org. Lett. 2000, 2, 4067-4069.
(16) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(17) 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, 1519-1522.
(18) Wang, C.; Wang, H.; Huang, X.; Zhang, L.-H.; Ye, X.-S. Synlett
2006, 2846-2850.
(19) Diphenyl sulfoxide is commercial. We thank one of the reviewers
informing us that BSP also became commercially avialable recently.
(20) Crich, D.; Banerjee, A.; Li, W.; Yao, Q. J. Carbohydr. Chem. 2005,
24, 415-424.
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Org. Lett., Vol. 9, No. 22, 2007

Table 1. Glycosylations Using Me2S2-Tf2O
As expected, the promoter activates armed thioglycosides
even more easily. Reaction of the benzylated thioglycoside
27 with 6 in dichloromethane afforded the disaccharides 28
and 29 in excellent combined yield but in low stereoselec-
tivity (Scheme 3). The R/â ratio could be shifted significantly
toward the R isomer by using ether or toward the â isomer
by using acetonitrile as cosolvents. Similar solvent effects
have been observed before in other glycosylation
methods1a,b,7b,21 and can be explained by the participation of
the solvent.
In summary, using commercially available, inexpensive
dimethyl disulfide we have developed a highly powerful
Org. Lett., Vol. 9, No. 22, 2007
4649

Since our results were presented at different symposia,22
successful applications of our glycosylation method have
already been implemented.23
Scheme 3. Solvent Effects on the Stereoselectivity of
Glycosylations
Acknowledgment. This work was supported by projects
1/A/005/2004 NKFP MediChem2 (Hungary) and Center of
Excellence on Biomolecular Chemistry QLK2-CT-2002-
90436 (EU). The skillful technical assistance of Ms. Katalin
T. Palcsu (Department of Carbohydrate Chemistry, Chemical
Research Center, Hungarian Academy of Sciences) is grate-
fully acknowledged.
Supporting Information Available: Experimental pro-
cedures and full characterization for all new disaccharides.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL702139U
promoter for the activation of thioglycosides. The Me2S2-
Tf2O reagent activates thioglycosides at low temperatures,
and glycosylations are complete within a short time.
(22) (a) Fu¨gedi, P.; Tatai, J. 13th European Carbohydrate Symposium,
Bratislava, Slovakia 2005; Abstract OP51. (b) Fu¨gedi, P. 23rd International
Carbohydrate Symposium, Whistler, Canada 2006; Abstract TUE-C4A-
PM.2.
(21) (a) Pougny, J.-R.; Sinay¨, P. Tetrahedron Lett. 1976, 4073-4076.
(b) Schmidt, R. R.; Ru¨cker, E. Tetrahedron Lett. 1980, 21, 1421-1424.
(c) Lo¨nn, H. J. Carbohydr. Chem. 1987, 6, 301-306.
(23) (a) Attolino, E.; Cumpstey, I.; Fairbanks, A. J. Carbohydr. Res. 2006,
341, 1609-1618. (b) Attolino, E.; Fairbanks, A. J. Tetrahedron Lett. 2007,
48, 3061-3064.
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