oxidative glycosylations.6 This allows for the one-pot
conversion of glucal substrates to 2-hydroxyglucopyranosides
via stereoselective oxygen atom transfer from the sulfoxide
reagent to the C(2)-position of the glycal donor (Scheme 2,
Scheme 3
Scheme 2
1 f 3). This discovery led us to pursue the prospect of
achieving complementary stereochemical control in our
sulfonium-mediated oxidative glycosylation reaction to ad-
dress the long-standing challenge of direct mannopyranoside
synthesis from glucals, especially in light of the abundance
of mannopyranose residues in nature.
R:â) as a single C(2)-diastereomer. No glucopyranose
products were detected. Similarly, when 4 is activated with
DBTO and Tf2O, employing 2-propanol (3 equiv) as the
glycosyl acceptor (Scheme 3b), 2-propyl 3,4,6-tri-O-benzyl-
mannopyranoside (7, 72%) is isolated as the only product
of oxidative glycosylation. These results highlight several
key aspects of this novel transformation, including (1) the
establishment of DBTO and Tf2O as a new glycal activating
agent; (2) the demonstration of exquisite stereochemical
control over the newly formed C(2)-stereocenter in the
oxidative glycosylation reaction simply by appropriate selec-
tion of the sulfoxide reagent; and (3) the first realization of
a method for direct stereoselective conversion of glucals to
mannopyranosides.
A proposed mechanism for this stereoselective glycosy-
lation reaction is summarized in Scheme 4. The initial step
is believed to be the activation of DBTO with triflic
anhydride to form dibenzothiophene bis(triflate) (8) in situ.7
The electrophilic species 8 can subsequently activate the
glycal nucleophile from the more sterically accessible R-face
to generate the oxocarbenium species 9, which incorporates
a latent sulfide leaving group at C(2). In the presence of
excess DBTO, addition of a second equivalent of the
sulfoxide from the â-face would afford the anomeric oxo-
sulfonium intermediate 10. Following addition of the hy-
droxyl nucleophilic acceptor (R′OH, 3 equiv) and the acid
scavenger diisopropylethylamine, nucleophilic addition of the
first equivalent of the acceptor (R′OH) to the oxosulfonium
center of 10 would lead to heterolytic cleavage of the S-O
bond, resulting in concomitant intramolecular displacement
of dibenzothiophene from C(2). The result would entail
formation of the â-1,2-anhydropyranoside 11, as well as the
byproducts dibenzothiophene (12) and the acceptor-derived
sulfonium salt 13 (which is hydrolyzed upon aqueous workup
of the reaction to regenerate the acceptor and DBTO). The
final stages of the oxidative glycosylation can then proceed
by Lewis acid (ZnCl2) mediated epoxide ring opening by
It was envisioned that the structure of the sulfoxide reagent
in this transformation would have a significant influence on
the stereochemical course in the oxidative glycosylation
reaction. This hypothesis was verified when dibenzothiophene-
5-oxide (DBTO, 6) was employed as the sulfoxide reagent
in combination with triflic anhydride in the glucal activation/
oxidation process. The use of this reagent pair led to a
dramatic reversal in the stereochemical outcome of the
oxidative glycosylation, resulting in the stereoselective
formation of 2-hydroxymannopyranosides (Scheme 3). For
example, treatment of a mixture of tri-O-benzyl-D-glucal (4)
and DBTO (5 equiv) with Tf2O (2 equiv) at -78 °C led to
complete activation of the glycal (Scheme 3a); subsequent
introduction of water as a nucleophile/glycosyl acceptor in
the presence of diisopropylethylamine and ZnCl2 provided
3,4,6-tri-O-benzyl-D-mannopyranose (5) in 83% yield (7:1,
(3) Review: (a) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1380-1419. For C2-nitrogen substituents, see: (b)
Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57, 1244-1251. (c)
Leblanc, Y.; Fitzsimmons, B. J.; Springer, J. P.; Rokach, J. J. Am. Chem.
Soc. 1989, 111, 2995-3000. (d) Griffith, D. A.; Danishefsky, S. J. J. Am.
Chem. Soc. 1990, 112, 5811-5819. (e) Czernecki, S.; Ayadi, E. Can. J.
Chem. 1995, 73, 343-350. (f) Rubinstenn, G.; Esnault, J.; Mallet, J.-M.;
Sinay¨, P. Tetrahedron: Asymmetry 1997, 8, 1327-1336. (g) Du Bois, J.;
Tomooka, C. S.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119,
3179-3180. (h) Das, J.; Schmidt, R. R. Eur. J. Org. Chem. 1998, 1609-
1613. (i) Di Bussolo, V.; Liu, J.; Huffman, L. G. Angew. Chem. Int. Ed.
2000, 39, 204-207. (j) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Vega,
J. A. Angew. Chem. Int. Ed. 2000, 39, 2525-2529. For C2-halo-substituents,
see: (k) Lemieux, R. U.; Levine, S. Can. J. Chem. 1965, 43, 2190-2198.
(l) Tatsuta, K.; Fujimoto, K.; Kinoshita, M.; Umezawa, S. Carbohydr. Res.
1977, 54, 85-104. (m) Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978,
696-699. (n) Burkart, M. D.; Zhang, Z.; Hung, S.-C.; Wong, C.-H. J. Am.
Chem. Soc. 1997, 119, 11743-11746. For C2-sulfur/selenium substituents,
see: (o) Jaurand, G.; Beau, J.-M.; Sinay¨, P. J. Chem. Soc., Chem. Commun.
1981, 572-573. (p) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1987, 28, 2723-
2726. (q) Preuss, R.; Schmidt, R. R. Synthesis 1988, 694-697. (r) Perez,
M.; Beau, J.-M. Tetrahedron Lett. 1989, 30, 75-78. (s) Grewal, G.; Kaila,
N.; Franck, R. W. J. Org. Chem. 1992, 57, 2084-2092. (t) Roush, W. R.;
Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53, 8837-8852. For C2-
carbon substituents, see: (u) Linker, T.; Sommermann, T.; Kahlenberg, F.
J. Am. Chem. Soc. 1997, 119, 9377-9384. (v) Beyer, J.; Madsen, R. J.
Am. Chem. Soc. 1998, 120, 12137-12138.
(4) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
(5) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.; Danishefsky, S. J.
J. Am. Chem. Soc. 1997, 119, 10064-10072.
(6) Di Bussolo, V.; Kim, Y.-J.; Gin, D. Y. J. Am. Chem. Soc. 1998,
120, 13515-13516.
(7) It is unclear whether the activated sulfoxide intermediate 8 exists/
reacts as a sulfonium species or a σ-sulfurane species.
304
Org. Lett., Vol. 3, No. 2, 2001