Direct oxidative glycosylations with glycal donors [2]

Full text of DOI:10.1021/ja982112k

J. Am. Chem. Soc. 1998, 120, 13515-13516
13515
Scheme 1
Direct Oxidative Glycosylations with Glycal Donors
Valeria Di Bussolo, Yong-Jae Kim, and David Y. Gin*
Department of Chemistry
UniVersity of Illinois at Urbana-Champaign
Urbana, Illinois 61801
ReceiVed June 18, 1998
In this procedure, triflic anhydride (1.5 equiv) is added to a
solution of glucal 1 (1 equiv), diphenyl sulfoxide (3 equiv), and
2,6-di-tert-butyl-4-methylpyridine (DTBMP, 3-4 equiv)7 in
dichloromethane at -78 °C. Following an initial activation period
of 1 h at -40 °C, anhydrous methyl alcohol (1 equiv) and
triethylamine (3 equiv) are introduced. The reaction is allowed
to proceed at 23 °C for 1 h, at which time the glycosyl acceptor
(Nu-H, 2-3 equiv) and a Lewis acid (ZnCl2, 1-2 equiv) are
added to afford the C(2)-hydroxy-â-D-glucopyranoside product
2.
The above-mentioned protocol outlines novel methodology for
enol ether oxidation within the context of glycosidic bond
formation.8 In these reactions, an excess of the sulfoxide reagent
(2:1 ratio, Ph2SO/Tf2O) is required for the coupling to proceed
efficiently;9 moreover, diphenyl sulfide is formed in significant
amounts (70-80% yield) as a reaction byproduct. On the basis
of these preliminary observations, it is likely that the oxidative
coupling initially proceeds through oxygen transfer from diphenyl
sulfoxide to the glycal donor to generate a transient 1,2-
anhydropyranoside intermediate in situ.10 This hypothesis is also
in accord with the requirement of a Lewis acid to effect glycosidic
bond formation in the final stage of the reaction.3a
To illustrate the scope of this glycosylation method, a number
of glycosyl acceptors were employed in couplings with 3,4,6-
tri-O-benzyl-D-glucal (3, Table 1). In these experiments, primary11
and secondary alcohols (entries 1-3) as well as amino-glycosyl
acceptors (e.g., benzylamine, entry 4) are glycosylated in good
yields. In addition, one-pot glycosylation of hindered hydroxyl
nucleophiles such as tert-butyl alcohol and methyl 2,3,6-tri-O-
benzyl-R-D-glucopyranoside (5)12 can be accomplished (entries
5 and 6) to afford the corresponding C(2)-hydroxy-glucopyrano-
side adducts. It is worth noting that the glycosylation of the
sterically shielded carbohydrate hydroxyl in 5 (entry 6) could not
be accomplished with ZnCl2 as the Lewis acid in the final stage
of the coupling. Instead, a stronger Lewis acid, Sc(OTf)3 (0.3
equiv),13 was required, leading to the selective formation of the
The development of new methods for glycosidic bond forma-
tion is a major focus in carbohydrate synthesis due to the many
roles of complex oligosaccharides and glycoconjugates in biol-
ogy.1 Many methods have been developed for the anomeric
activation of carbohydrates for coupling reactions;2 however, the
use of glycal substrates in oligosaccharide synthesis is particularly
attractive in that glycosidic bond formation as well as C(2)-
functionalization of the carbohydrate donor is achieved in the
process.3 Traditionally, procedures for glycosylation with con-
comitant C(2)-hydroxylation of glycal donors have involved (1)
epoxidation of the glycal, followed by (2) acid-mediated oxirane
ring-opening of the 1,2-anhydrosugar in the presence of a
nucleophilic glycosyl acceptor. This strategy has been elegantly
refined over the years by Danishefsky and co-workers, employing
dimethyl dioxirane as the glycal oxidant.3a,4 We now report a
method for oxidative glycosylation with glycal donors, employing
the reagent combination of triflic anhydride (Tf2O) and diphenyl
sulfoxide.5,6 The method involves a new process for glycal
activation and allows for the diastereoselective construction of
C(2)-hydroxy-glucopyranosides from protected glucal substrates
in a one-pot procedure.
This oxidative glycosidic coupling is illustrated in Scheme 1,
employing a tri-O-protected-D-glucal 1 as a typical glycosyl donor.
(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) (a) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212. (b)
Fugedi, P.; Garegg, P. J.; Lohn, H.; Norberg, T. Glycoconjugate J. 1987, 4,
97. (c) Sinay¨, P. Pure Appl. Chem. 1991, 63, 519. (d) Toshima, K.; Tatsuta,
K. Chem. ReV. 1993, 93, 1503. (e) Boons, G.-J. Tetrahedron 1996, 52, 1095.
(f) PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker:
New York, 1997, Chapters 12-22.
(3) Review (2-hydroxy-, 2-halo-, and 2-aza-glycosides): (a) Danishefsky,
S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380. 2-Aza-
glycosides: (b) Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57,
1244. (c) Leblanc, Y.; Fitzsimmons, B. J.; Springer, J. P.; Rokach, J. J. Am.
Chem. Soc. 1989, 111, 2995. (d) Czernecki, S.; Ayadi, E. Can. J. Chem. 1995,
73, 343. (e) Rubinstenn, G.; Esnault, J.; Mallet, J.-M.; Sinay¨, P. Tetrahe-
dron: Asymmetry 1997, 8, 1327. (f) Du Bois, J.; Tomooka, C. S.; Hong, J.;
Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179. 2-Halo-glycosides: (g)
Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2190. (h) Tatsuta,
K.; Fujimoto, K.; Kinoshita, M.; Umezawa, S. Carbohydr. Res. 1977, 54, 85.
(i) Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978, 696. (j) Burkart, M.
D.; Zhang, Z.; Hung, S.-C.; Wong, C.-H. J. Am. Chem. Soc. 1997, 119, 11743.
2-Thio- and 2-seleno-glycosides: (k) Jaurand, G.; Beau, J.-M.; Sinay¨, P. J.
Chem. Soc., Chem. Commun. 1981, 572. (l) Ito, Y.; Ogawa, T. Tetrahedron
Lett. 1987, 28, 2723. (m) Preuss, R.; Schmidt, R. R. Synthesis 1988, 694. (n)
Perez, M.; Beau, J.-M. Tetrahedron Lett. 1989, 30, 75. (o) Grewal, G.; Kaila,
N.; Franck, R. W. J. Org. Chem. 1992, 57, 2084. (p) Roush, W. R.; Sebesta,
D. P.; James, R. A. Tetrahedron 1997, 53, 8837. 2-C-glycosides: (q) Linker,
T.; Sommermann, T.; Kahlenberg, F. J. Am. Chem. Soc. 1997, 119, 9377.
(4) The reagent combination of m-chloroperoxybenzoic acid and potassium
fluoride has also been shown to be effective in glycal epoxidation: Bellucci,
G.; Catelani, G.; Chiappe, C.; D’Andrea, F. Tetrahedron Lett. 1994, 35, 8433.
(5) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997, 119,
7597.
(8) Investigations into the use of this oxidation protocol on acyclic enol
ethers are currently underway.
(9) Glycosylations performed with a 1:1 ratio of Ph2SO/Tf2O (1 equiv each)
led to incomplete consumption of the glucal starting material, giving low yields
(<20%) of C(2)-hydroxy-glycopyranoside products.
(10) A likely reaction pathway for the oxidative coupling involves enol
ether activation with the triflated sulfoxide, followed by oxygen transfer to
the pyranose ring from the excess sulfoxide reagent.
(6) Dimethylsulfide bis(triflate) has been employed for the functionalization
of alkenes to form mixtures of vinylic and allylic sulfides: (a) Nenajdenko,
V. G.; Vertelezkij, P. V.; Gridnev, I. D.; Shevchenko, N. E.; Balenkova, E.
S. Tetrahedron 1997, 53, 8173. For other uses of dimethylsulfide bis(triflate),
see: (b) Hendrickson, J. B.; Schwartzman, S. M. Tetrahedron Lett. 1975,
273. (c) Coburn, M. D.; Hayden, H. H. Synthesis 1986, 490. (d) Corey, E. J.;
Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202. For the use of
triflic anhydride in the activation of glycosyl sulfoxide donors, see: (e) Kahne,
D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111,
6881. (f) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239.
(7) The acid scavenger is introduced to neutralize trace amounts of triflic
acid that can lead to decomposition of the glucal starting material.
(11) For the synthesis of 4, see: Jiang, L.; Chan, T.-H. Tetrahedron Lett.
1998, 39, 355.
(12) DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C. Tetrahedron Lett.
1995, 36, 669.
(13) (a) Crotti, P.; Di Bussolo, V.; Favero, L.; Pineschi, M.; Pasero, M. J.
Org. Chem. 1996, 61, 9548. (b) Crotti, P.; Di Bussolo, V.; Favero, L.;
Minutolo, F.; Pineschi, M. Tetrahedron: Asymmetry 1996, 7, 1347.
10.1021/ja982112k CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/30/1998

13516 J. Am. Chem. Soc., Vol. 120, No. 51, 1998
Table 1. Direct Oxidative Glycosylations
Communications to the Editor
Scheme 2
To probe the mechanism of this transformation, an 18O-labeling
study was conducted to determine whether C(2)-hydroxylation
of the glycal donor occurs via oxygen transfer from the sulfoxide
reagent.10 This indeed was verified (Scheme 2) when the 18O-
labeled analogue of diphenyl sulfoxide was synthesized (Ph2S18O,
94% 18O incorp.)18 and employed in a coupling reaction with
glucal 3 and a non-hydroxy-glycosyl acceptor (e.g., benzylamine).
In this case, near quantitative transfer of 18O from the sulfoxide
reagent to the product glycopyranoside (92% 18O incorp.)19 was
observed. Additional investigations focused on the detection of
the proposed 1,2-anhydropyranoside intermediate which presum-
ably is formed during the course of the reaction. This hypothesis
was also confirmed (Scheme 2) as the 1,2-anhydropyranoside 8
1
was observed as the principle carbohydrate intermediate by H
NMR analysis upon activation of tri-O-benzyl-D-glucal (3) using
the above-mentioned protocol.20 Efforts are currently underway
to further investigate the mechanistic details of the process, as
well as to elucidate the origin of the oxidation/glycosylation
stereoselectivity.
In summary, a new method employing the reagent combination
of triflic anhydride and diphenyl sulfoxide for glycosylation with
glucal donors is described. Key features of the coupling reaction
include (1) a novel method for glycal oxidation/activation via
oxygen transfer from the sulfoxide reagent to the C(2)-position
of the product glycoside and (2) the one-pot diastereoselective
synthesis of C(2)-hydroxy-glucopyranosides from glucal sub-
strates.
Acknowledgment. This research was supported by the Department
of Chemistry at the University of Illinois at Urbana-Champaign, the
Petroleum Research Fund, and the Arnold and Mabel Beckman Founda-
tion (BYI). We thank Ms. Ji-Young Kim for preliminary investigations
into the glycosylation of benzylamine.
Supporting Information Available: Experimental details and spectral/
analytical data for the glycosylation products (13 pages, print/PDF). See
any current masthead page for ordering information and Web access
instructions.
JA982112K
a 2 to 3 equiv of glycosyl acceptor. b Lewis acid was not required
for coupling to proceed. c The Lewis acid Sc(OTf)3 (30 mol %) was
required for the coupling to proceed.
(15) Anomeric selectivity in the opening of 1,2-anhydropyranosides has
been found to be dependent on the nature of the Lewis acid (see: Evans, D.
A.; Trotter, B. W.; Coˆte´, B. Tetrahedron Lett. 1998, 39, 1709). For example,
when Sc(OTf)3 (0.3 equiv) was employed instead of ZnCl2 in our oxidative
glycosylation of isopropyl alcohol with tri-O-benzyl-D-glucal, a 3.5:1 R:â
anomeric ratio (1H NMR) of the isopropyl glycoside was obtained. In addition,
treatment of isopropyl-3,4,6-tri-O-benzyl-â-D-glucopyranoside with Sc(OTf)3
(0.3 equiv) in the presence of Ph2SO, Ph2S, and DTBMP (1 equiv each) did
not lead to anomeric epimerization after 24 h at 23 °C.
corresponding R-linked disaccharide.14,15 The latter entries in the
table demonstrate that this glycosylation protocol is not exclu-
sively compatible with glucal 3. For example, 3-O-benzyl-4,6-
di-O-isopropylidene-D-glucal (6)16 was coupled with phenol to
yield phenyl 3-O-benzyl-4,6-di-O-isopropylidene-â-D-glucopy-
ranoside (entry 7) with complete stereoselectivity. Furthermore,
both benzyl alcohol and dihydrocholesterol were glycosylated with
tri-O-p-methoxybenzyl-D-glucal (7)17 to afford the corresponding
2-hydroxy-â-D-glucopyranosides (entries 8 and 9).
(16) Kjølberg, O.; Neumann, K. Acta Chem. Scand. 1993, 47, 843.
(17) Prepared from the treatment of D-glucal with sodium hydride and
p-methoxybenzyl chloride.
(18) Prepared by the oxidation of Ph2S with N-chlorosuccinimide, followed
by the addition of 98% 18OH2.
(19) Determined by FAB+ mass spectrometry.
(20) Following the initial activation of 3 as described in our oxidative
coupling procedure (Ph2SO, Tf2O, DTBMP, CH3OH, Et3N), 1H NMR data
(see Supporting Information) of the reaction mixture were acquired and then
compared to that of a sample of the 1,2-anhydropyranoside 8 that was prepared
independently (see ref 4).
(14) Epoxidation of 3 by established methods (see ref 4) followed by
treatment with 5 and 0.3 equiv of Sc(OTf)3 led to the generation of the R-linked
1,4-disaccharide as the principle disaccharide product, albeit in diminished
yields.