Direct glycosylations with 1-hydroxy glycosyl donors using trifluoromethanesulfonic anhydride and diphenyl sulfoxide

Full text of DOI:10.1021/ja971067y

J. Am. Chem. Soc. 1997, 119, 7597-7598
7597
Scheme 1
Direct Glycosylations with 1-Hydroxy Glycosyl
Donors using Trifluoromethanesulfonic Anhydride
and Diphenyl Sulfoxide
Brian A. Garcia, Jennifer L. Poole, and David Y. Gin*
Department of Chemistry, UniVersity of Illinois at
Scheme 2
Urbana-Champaign, Urbana, Illinois 61801
ReceiVed April 4, 1997
Considerable effort has been devoted to the development of
new methods for glycosidic coupling due to the growing
importance of synthetic oligosaccharides in glycobiology.1 The
synthesis of complex oligosaccharides and glycoconjugates has
traditionally employed multistep glycosylation protocols involv-
ing (1) functionalization of the anomeric hydroxyl to form an
isolable glycosyl donor and (2) reaction of the donor with a
promoter or catalyst to induce irreversible carbohydrate transfer
to a nucleophilic acceptor.2 However, a direct substitution of
the glycosyl anomeric hydroxyl with the desired acceptor offers
a potentially more efficient strategy for glycosylation as this
obviates the need for anomeric derivatization prior to the
coupling event.3 We now report a new method for glycosidic
bond construction directly from the free hemiacetal of the
glycosyl donor. This one-step procedure is applicable to the
glycosylation of a wide range of acceptors and involves the in
situ activation of 1-hydroxy glycosyl donors with trifluoro-
methanesulfonic anhydride and diphenyl sulfoxide.
The facility of this protocol is exemplified by direct glyco-
sylation with 2,3,4,6-tetra-O-benzyl-D-glucopyranose (1),4 em-
ploying isopropyl alcohol as a model glycosyl acceptor (Scheme
1). In this representative procedure, trifluoromethanesulfonic
anhydride (1.4 equiv) was added to a solution of 1 (1 equiv)
and diphenyl sulfoxide (2.8 equiv) in a mixture of toluene and
dichloromethane (3:1) at -78 °C.5 The reaction mixture was
stirred at -40 °C for 1 h, and the acid scavenger 2-chloropy-
ridine6 (5 equiv) and the glycosyl acceptor isopropyl alcohol
(3 equiv) were then added sequentially at this temperature. The
solution was stirred at 0 °C for 15 min and then at 23 °C for 1
h before the addition of excess triethylamine7 (8 equiv).
Aqueous workup of the reaction mixture followed by silica gel
column chromatography afforded isopropyl 2,3,4,6-tetra-O-
benzyl-D-glucopyranoside (2)8 in 86% yield (27:73; R:â).9
A proposed mechanism for this transformation (Scheme 2)
involves initial activation of diphenyl sulfoxide with trifluoro-
methanesulfonic anhydride to form diphenyl sulfide bis(trifluo-
romethanesulfonate) (3).10 In situ activation of the hemiacetal
hydroxyl function in 1 by 3 would afford the oxosulfonium
trifluoromethanesulfonate 4, which can expel diphenyl sulfox-
ide11 to generate the glycosyl oxocarbenium trifluoromethane-
sulfonate 5. Reaction of 5 with isopropyl alcohol would then
afford the isopropyl glucopyranoside 2.12
To illustrate the scope of this direct dehydrative glycosylation
method, a variety of acceptors in addition to isopropyl alcohol
were coupled with 1 (Table 1). Oxygen, sulfur, carbon, and
nitrogen nucleophiles were all found to be suitable glycosyl
acceptors using this protocol. For example, phenol, ethanethiol,
and 1,3,5-trimethoxybenzene underwent efficient glycosylation
with 1 to yield the corresponding O-aryl-,13 S-alkyl-,14 and
C-aryl-glycosides15 in good yield (89%, 84%, 81%; entries
1-3). In addition, the N-glycosylation of amide functionalities,
which has been reported to occur with only the most reactive
of nonenzymatic glycosylation procedures,16 was found to
proceed smoothly with 1 and N-(trimethylsilyl)trimethylacet-
(1) (a) Synthetic Oligosaccharides. Indispensable Probes for the Life
Sciences; Kovac, P., Ed.; ACS Symposium Series 560; American Chemical
Society: Washington, DC, 1994. (b) Dwek, R. A. Chem. ReV. 1996, 96,
683.
(2) Many synthetically valuable anomeric functional groups have been
developed in this context. General Reviews: (a) PreparatiVe Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker, Inc.: New York, 1997.
Chapters 12-22. (b) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503.
(c) Sinay¨, P. Pure Appl. Chem. 1991, 63, 519. (d) Glycal donors:
Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1380. (e) Trichloroacetimidate donors: Schmidt, R. R.; Kinzy, W. AdV.
Carbohydr. Chem. Biochem. 1994, 50, 21.
(3) (a) Fischer, E. Chem. Ber. 1893, 26, 2400. (b) Koto, S.; Sato, T.;
Morishima, N.; Zen, S. Bull. Chem. Soc. Jpn. 1980, 53, 1761. (c) Susaki,
H. Chem. Pharm. Bull. 1994, 42, 1917. (d) Suda, S.; Mukaiyama, T. Chem.
Lett. 1991, 431. (e) Uchiro, H.; Mukaiyama, T. Chem. Lett. 1996, 79, and
references therein. (f) Inanaga, J.; Yokoyama, Y.; Hanamoto, T. J. Chem.
Soc., Chem. Commun. 1993, 1090.
(4) Perrine, T. D.; Glaudemans, C. P. J.; Ness, R. K.; Kyle, J.; Fletcher,
H. G., Jr. J. Org. Chem. 1967, 32, 664.
(5) Glycosylations performed in toluene did not proceed to completion
due to incomplete solubility of 1 at -78 °C to -40 °C. Reactions performed
in CH2Cl2 were generally not as efficient, leading to lower yields (60-
70%). The preparation of 2 in toluene, CH2Cl2, and propionitrile led to
similar R:â selectivity.
(8) Briner, K.; Vasella, A. HelV. Chim. Acta 1989, 72, 1371.
(9) Yields were determined by isolation of the mixture of anomeric
products after silica gel chromatography. Trehalose-linked disaccharides
arising from self-coupling of the hemiacetal donor were not detected.
Anomeric ratios were determined by 1H NMR analysis. Analytical samples
of each anomer were obtained by preparative TLC or HPLC and did not
exhibit anomeric epimerization when resubjected to the glycosylation
reaction conditions.
(10) Activation of dimethyl sulfoxide with trifluoromethanesulfonic
anhydride has been employed in Swern-type oxidations, sulfilimine
synthesis, and quinone methide generation: (a) Hendrickson, J. B.;
Schwartzman, S. M. Tetrahedron Lett. 1975, 273. (b) Coburn, M. D.;
Hayden, H. H. Synthesis 1986, 490. (c) Corey, E. J.; Gin, D. Y.; Kania, R.
S. J. Am. Chem. Soc. 1996, 118, 9202.
(11) Glycosidic bond formation via direct displacement of Ph2SO in 4
by the acceptor may also be a contributing pathway. Alkoxy dimethylsul-
fonium ions have been shown to be susceptible to nucleophilic attack
resulting in displacement of DMSO: Hollinshead, D. M.; Howell, S. C.;
Ley, S. V.; Mahon, M.; Ratcliffe, N. M.; Worthington, P. A. J. Chem. Soc.,
Perkin Trans. 1 1983, 1579.
(12) Attempts at the direct triflation of 1 in the absence of diphenyl
sulfoxide (Tf2O, 2,6-lutidine or 2-chloropyridine, -78 °C to 20 °C) followed
by addition of isopropyl alcohol did not afford 2.
(6) The use of 2,6-lutidine as the acid scavenger led to diminished yields,
presumably a result of its reactivity toward the electrophilic reactive
intermediates formed in the reaction pathway (Scheme 2). The use of
2-chloropyridine avoided this problem. See: Myers, A. G.; Tom, N. J.;
Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem Soc. 1997, 119,
6072.
(13) Briner, K.; Vasella, A. HelV. Chim. Acta 1990, 73, 1764.
(14) (a) Dasgupta, F.; Garegg, P. J. Acta Chem. Scand. 1989, 43, 471.
(b) Li, Z.; Liu, P.; Qiu, D.; Cai, M. Synth. Commun. 1990, 20, 2169.
(15) Stewart, A. O.; Williams, R. M. J. Am. Chem. Soc. 1985, 107, 4289.
(16) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem.
Soc. 1989, 111, 6881.
(7) The addition of excess triethylamine serves to neutralize 2-chloro-
pyridinium trifluoromethanesulfonate prior to aqueous workup.
S0002-7863(97)01067-6 CCC: $14.00 © 1997 American Chemical Society

7598 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Communications to the Editor
glucopyranoside (7)19 to form the corresponding (1,6)- and (1,4)-
linked disaccharides20 in 88% and 85% yield, respectively
(entries 5 and 6).
Table 1. Glycosylations with Trifluoromethanesulfonic Anhydride
and Diphenyl Sulfoxide
To determine whether C(2)-neighboring group effects would
influence the glycosylation stereochemistry, 2,3,4,6-tetra-O-
benzoyl-D-glucopyranose (8)21 was also prepared as a donor.
When 8 was coupled with benzyl alcohol (entry 7), benzyl
2,3,4,6-tetra-O-benzoyl-â-D-glucopyranoside22 was isolated in
71% yield as the sole product of glycosylation. The high
â-selectivity was also observed when carbohydrate acceptors
such as 6 and 7 were employed in the coupling with 8, yielding
exclusively the â(1,6)- and the â(1,4)-linked disaccharides,20
respectively, with similar efficiency (entries 8 and 9). This
stereoselectivity is consistent with neighboring group participa-
tion of the equatorial C(2)-acyl substituent to favor â-glycoside
formation.2 Moreover, these experiments illustrate for the first
time a single-step dehydrative glycosylation method that is
compatible with deactivated carbohydrate donors incorporating
multiple electron-withdrawing protective groups.3
All of the glycosylations reported in Table 1 were carried
out with the glycosyl donor as the limiting substrate. Although
a large excess of the acceptor can be used (3-5 equiv; entries
1-4, and 7) to decrease reaction times, couplings can also be
performed in good yield with a modest excess of the glycosyl
acceptor (1.6 equiv; entries 5, 6, 8, and 9) when synthetically
valuable coupling partners are employed. In each of these cases,
the excess nucleophile can be recovered from the reaction
mixture.
It is worth noting that the mechanism proposed in Scheme 2
involves the regeneration of diphenyl sulfoxide.23 Efforts to
synthesize and screen various sulfoxide reagents to effect
catalytic turnover of the sulfoxide species as well as to determine
the effect of various sulfoxide structures on R:â selectivity24
are currently underway and will be reported in due course.
In summary, a new dehydrative glycosylation method is
described, involving in situ activation of the anomeric hydroxyl
with trifluoromethanesulfonic anhydride and diphenyl sulfoxide.
This one-pot procedure allows for the construction of a wide
variety of glycoconjugates directly from 1-hydroxy glycosyl
donors.
Acknowledgment. Financial support from the Department of
Chemistry at the University of Illinois at Urbana-Champaign is
gratefully acknowledged.
Supporting Information Available: Experimental details and
spectral/analytical data for the glycosylation products (11 pages). See
any current masthead page for ordering and Internet access instructions.
JA971067Y
a Anomeric ratios determined by 1H NMR analysis. b 3 equiv of
glycosyl acceptor. c 5 equiv of glycosyl acceptor. d 1.6 equiv of glycosyl
acceptor.
(19) DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C. Tetrahedron Lett.
1995, 36, 669.
(20) Kim, W.-S.; Hosono, S.; Sasai, H.; Shibasaki, M. Heterocycles 1996,
42, 795.
(21) (a) Ness, R. K.; Fletcher, H. G., Jr.; Hudson, C. S. J. Am. Chem.
Soc. 1950, 72, 2200. (b) Itoh, T.; Takamura, H.; Watanabe, K.; Araki, Y.;
Ishido, Y. Carbohydr. Res. 1986, 156, 241.
amide17 to afford the corresponding glycosyl amide with com-
plete R-selectivity (89% yield, entry 4). Of critical importance
is the application of this glycosylation method to the construction
of oligosaccharides. Thus, 1 was coupled with the carbohydrate
acceptors methyl 2,3,4-tri-O-benzyl-R-D-glucopyranoside (6)18
and the sterically hindered methyl 2,3,6-tri-O-benzyl-R-D-
(22) Helferich, W. Chem. Ber. 1956, 89, 314.
(23) Diphenyl sulfoxide was recovered in 89% in the preparation of 2.
The preparation of 2 with 0.3 equiv of diphenyl sulfoxide proceeded slowly,
leading to low yields (<30%).
(24) The synthesis of 2 was also attempted with dimethyl sulfoxide. The
yield of 2 was similar to that with diphenyl sulfoxide with an anomeric
ratio of 1:1; however, the addition of isopropyl alcohol to the anomeric
center proceeded much more slowly (23 °C, 18 h) in the reaction employing
DMSO.
(17) Glover, S. A.; Beckwith, A. L. J. Aust. J. Chem. 1987, 40, 701.
(18) Hashimoto, H.; Asano, K.; Fujii, F.; Yoshimura, J. Carbohydr. Res.
1982, 104, 87.