Mechanism of Sulfoxide-Catalyzed Hemiacetal Activation
toluene in vacuo and subsequently handled and stored under
a nitrogen atmosphere. Trimethylsilyl trifluoromethane-
sulfonate was distilled at reduced pressure prior to use.
Infrared (IR) spectra were obtrained using a Perkin-Elmer
Spectrum BX spectrophotometer referenced to a polystyrene
standard. Data are presented as the frequency of absorption
(cm-1) and intensity of absorption (s ) strong, m ) medium,
w ) weak). Proton and carbon-13 nuclear magnetic resonance
(1H NMR or 13C NMR) spectra were recorded on a Varian 500
or a Varian Inova 500 NMR spectrometer; chemical shifts are
expressed in parts per million (δ scale) downfield from tet-
ramethylsilane and are referenced to the residual protium in
However, the data present in Scheme 14 are by them-
selves insufficient to distinguish between the distinct
glycosylation pathways. Future detailed studies on the
glycosylation event of this reaction will examine the
hybridization of the anomeric carbon in the rate deter-
mining transition state for the formation of both R- and
â-mannoside (15) products through the measurement of
kinetic isotope effects.33c,34
Conclusion
the NMR solvent (CHCl3: δ 7.26 for 1H NMR, δ 77.00 for 13
C
The concept of sulfoxide-covalent catalysis has been
established in the context of a versatile hemiacetal
hydroxyl activation/substitution reaction for the forma-
tion of anomeric linkages. Mechanistic studies focused
on the hemiacetal activation process show that this
transformation proceeds through the intermediacy of a
glycosyl sulfonate species (10), which serves as a resting
state prior to the addition of an external nucleophile and
subsequent glycosidic bond formation. Successful deter-
mination of the proportion of 18O-incorporation in 10 as
a function of its formation, via the technique of dynamic
monitoring of 13C-16/18O isotopic chemical shift perturba-
tions, provides strong evidence that hemiacetal activation
proceeds through initial nucleophilic addition of the
hemiacetal hydroxyl to the S(IV)-center of putative
sulfonium sulfonate 6. Further confirmation was ob-
tained through the independent synthesis, structure
verification, and 1H NMR detection of glycosyl oxosulfo-
nium 11 during the sulfoxide-catalyzed conversion of
hemiacetal 3 to glycosyl sulfonate 10. Future studies will
focus on the mechanism of anomeric bond formation
following the addition of an external nucleophile to
glycosyl sulfonate 10. The results of these studies should
allow for the expansion of the scope of sulfoxide-covalent
catalysis to more general hydroxyl functionalization
reactions.
NMR).
Benzenesulfonyl 2,3,4,6-Tetra-O-methyl-r-D-mannopy-
ranose (10). To a solution of 2,3,4,6-tetra-O-methyl-R-D-
mannopyranosyl fluoride (12)19 (15.7 mg, 0.066 mmol, 1.0
equiv) in CD2Cl2 (660 µL) at 0 °C was added trimethylsilyl
benzenesulfonate20 (41 µL, 0.20 mmol, 3.0 equiv). After stirring
for 5 h at -2 °C, the reaction was warmed to 22 °C and
transferred via cannula to a dry 5 mm NMR tube at 22 °C
fitted with a rubber septum whereupon it was placed in the
NMR probe at 20 °C. The mannosyl sulfonate 10 (85%
conversion) was then characterized by 1H and 13C NMR
(Scheme 9).
Bis(n-butyl)sulfonium 2,3,4,6-Tetra-O-methyl-r-D-man-
nopyranoside (11). To a solution of 2,3,4,6-tetra-O-methyl-
R-D-mannopyranosyl fluoride (12)19 (15.2 mg, 0.058 mmol, 1.0
equiv) in CD2Cl2 (585 µL) at -78 °C was added trimethylsilyl
trifluoromethanesulfonate (63 µL, 0.35 mmol, 6.0 equiv). After
2 min, the solution was warmed to -45 °C for 23 min, and
then cooled again to -78 °C at which point n-butyl sulfoxide
(80 µL, 0.41 mmol, 7.0 equiv) was added via syringe. The
reaction was warmed to 21 °C and transferred via cannula to
a dry 5 mm NMR tube at 21 °C fitted with a rubber septum
whereupon it was placed in the NMR probe at 20 °C. The
mannosyl oxosulfonium 11 (66% conversion) was then char-
1
acterized by H NMR (Scheme 12).
Bis(n-butyl)sulfonium 2,3,4,6-Tetra-O-methyl-r-D-[1-
13C, 16/18O]-mannopyranoside (11[13C1-18O]). To a solution of
2,3,4,6-tetra-O-methyl-R-D-[1-13C]-mannopyranosyl fluoride
(12[13C1])
19 (16.3 mg, 0.068 mmol, 1.0 equiv) in CD2Cl2 (680 µL)
at -78 °C was added trimethylsilyl trifluoromethanesulfonate
(75 µL, 0.41 mmol, 6.0 equiv). After 3 min, the solution was
warmed to -45 °C for 30 min, and then cooled again to -78
°C at which point n-butyl sulfoxide (49% 18O-incorp) (94 µL,
0.48 mmol, 7.0 equiv) was added via syringe. The reaction was
warmed to 21 °C, and transferred via cannula to a dry 5 mm
NMR tube at 22 °C fitted with a rubber septum whereupon it
was placed in the NMR probe at 20 °C. The mannosyl
oxosulfonium 11[13C1-18O] (53% conversion) was then character-
ized by 13C NMR (Scheme 12).
Experimental Section
General Procedures. All reactions were performed in
flame-dried modified Schlenk (Kjeldahl shape) flasks fitted
with a glass stopper under a positive pressure of argon unless
otherwise noted. NMR tubes were dried over calcium sulfate
at high vacuum. Dichloromethane, acetonitrile, and toluene
were purified by passage through two packed columns of
neutral alumina under an argon atmosphere. d2-Dichlo-
romethane was dried by vacuum transfer from calcium hy-
dride. 2-Propanol was distilled from calcium hydride at 760
Torr onto magnesium from which it was freshly distilled at
760 Torr as needed. Benzenesulfonic anhydride was recrystal-
lized35 from 10:1 diethyl ether:benzene, dried by azeotropic
removal of water with acetonitrile followed by dichloromethane
in vacuo, and subsequently handled and stored under a
nitrogen atmosphere. n-Butyl sulfoxide was dried over 4 Å
molecular sieves at 50 °C, stored under argon, and melted
under argon prior to use. 18O-Labeled n-butyl sulfoxide was
dried by azeotropic removal of water with toluene in vacuo,
and then melted under argon prior to use. 2,4,6-Tri-tert-
butylpyridine was dried by azeotropic removal of water with
Activation of 2,3,4,6-Tetra-O-methyl-r-D-mannopyra-
nose (3) To Form Benzenesulfonyl 2,3,4,6-tetra-O-meth-
yl-r-D-mannopyranose (10). 2,3,4,6-Tetra-O-methyl-R-D-
mannopyranoside (3) (7.5 mg, 0.032 mmol, 1.0 equiv) in a 5
mm NMR tube was dried by azeotropic removal of water with
CH3CN (250 µL, ×2) and then CH2Cl2 (250 µL) in vacuo. To
the dried mannose hemiacetal was added 2,4,6-tri-tert-bu-
tylpyridine (19.6 mg, 0.079 mmol, 2.5 equiv) and benzene-
sulfonic anhydride (11.5 mg, 0.038 mmol, 1.2 equiv) whereupon
the NMR tube was fitted with a rubber septum. The resulting
solid mixture was dissolved in CD2Cl2 (615 µL) and inserted
into the NMR probe equilibrated at 20 °C. After acquisition
1
of an H NMR spectrum, the reaction was removed from the
(34) For kinetic isotope effects associated with glycosidic bond
formation/hydrolysis, see: Schramm, V. L. In Enzyme Mechanism from
Isotope Effects; Cook, P. F., Ed.; CRC Press: Ann Arbor, MI, 1991; pp
367-388. (b) Bennet, A. J.; Sinnot, M. L. J. Am. Chem. Soc. 1986, 108,
7287-7294. (c) Lee, J. K.; Bain, A. D.; Berti, P. J. J. Am. Chem. Soc.
2004, 126, 3769-3776.
NMR probe and a solution of n-butyl sulfoxide (1.5 µL, 0.0077
mmol, 0.24 equiv) in CD2Cl2 (20 µL) was added via syringe.
The reaction was briefly agitated (∼5 s using a vortex
apparatus, holding the NMR tube at a 45° angle) and then
1
replaced in the NMR probe. H NMR spectra were acquired
(35) Field, L. J. Am. Chem. Soc. 1952, 74, 394-398.
at a rate of once every 10 s. Consumption of 3 was complete
J. Org. Chem, Vol. 70, No. 15, 2005 5825