436 J. Am. Chem. Soc., Vol. 120, No. 2, 1998
Table 2. Formation of Hindered Glucosidesa
Communications to the Editor
15 and 2,6-dimethylphenol (17) under the influence of PhSOTf
gave 49% of the R- and 37% of the â-glycoside (Table 2, entry
2). This result differs somewhat from the analogous coupling
achieved by the sulfoxide method when an 80% yield of a pure
â-glucoside was reported. This difference must reflect minor
variations in temperature and concentration and so changing
influences of triflates, ion pairs, and neighboring group participa-
tion on the actual glycosylation subsequent to the initial formation
of glucosyl triflates. Finally, we note that the tertiary alcohol 12
could be coupled to either an armed or disarmed thioglucoside
in excellent yield and complete â-selectivity (Table 2, entries 3
and 6). These results correspond to those described by Kahne
for tertiary alcohols by the sulfoxide method11 and presumably
reflect the increased influence of 1,3-diaxial interactions in the
formation of R-glycosides with tertiary alcohols.
It is appropriate to note that methylsulfenyl triflate (MeSOTf)
has previously been described as a reagent for the activation of
thioglycosides;12,13 however, it has not been widely adopted.
Indeed, MeSOTf has been found to be less satisfactory than
PhSOTf for the activation of glycosyl xanthates.7 Likewise,
benzeneselenenyl triflate (PhSeOTf) has been recorded as a
reagent for the activation of thioglycosides.14 In our hands
exposure of thioglycoside 5 to PhSeOTf in CD2Cl2 at -78 °C
did not result in the formation of triflate 3 as determined by NMR
spectroscopy. Rather an unidentified species was formed which
returned the thioglycoside on exposure to MeOH at -78 °C:
PhSeOTf is therefore less efficient than PhSOTf for the activation
of thioglycosides at low temperature.
In conclusion, PhSOTf is a convenient reagent for the in situ
fomation of glycosyl triflates from thioglycosides.15 Highly
hindered alcohols may be glycosylated in this manner without
the need for prior activation of the thioglycoside as a sulfoxide.
With the correct choice of protecting groups â-mannopyranosides
may be formed in excellent yield and selectivity by this reaction.
a Unless otherwise noted all reactions were conducted in dichloro-
methane. b Reaction conducted in 1:1 dichloromethane/diethyl ether.
c Reaction conducted in diethyl ether.
previously noted for reactions with the analogous sulfoxides, this
fall off in yield and selectivity probably reflects the fine balance
between associative and dissociative displacement mechanisms
of the intermediate R-mannosyl triflates.2,5
Of course, this new glycosylation protocol is not limited to
the preparation of â-mannopyranosides. Table 2 sets out several
examples of glucoside formation using a disarmed (15) and an
armed (18) thioglucoside as donor.10 The acceptors are chosen
for ease of comparison of the new method with the sulfoxide
protocol.3,11 Of the six examples presented in Table 2, four require
comment; otherwise the results are directly analogous to those
reported previously for the sulfoxide method. With the highly
hindered sterol 16, thioglycoside 15 gave 61% of a pure
â-glucoside when the reaction was run in CH2Cl2/Et2O (Table 2,
entry 1). In either pure Et2O or pure CH2Cl2 the yield in this
last example was considerably lower owing to the low solubility
of one or other of the two reaction partners in one of the two
solvents. This observation prompts us to stress the importance
of choosing a solvent that dissolves both reaction partners and
the intermediate triflate at the low temperatures used. This is
particularly important in the case of â-mannoside formation when
an inappropriate choice of solvent can prevent coupling until the
acceptor dissolves on warming, when reduced yields and selec-
tivities are observed. Coupling of the perpivaloyl thioglycoside
Acknowledgment. We thank the NSF (Grant CHE 9625256) for
support of this work.
Supporting Information Available: Lists of spectral data for those
disaccharides not previously reported in ref 2 (8 pages). See any current
masthead page for ordering and Internet access instructions.
JA9734814
(12) Birberg, W.; Lonn, H. Tetrahedron Lett. 1991, 32, 7453-7456.
(13) Dasgupta, F.; Garegg, P. J. Carbohydr. Res. 1990, 202, 225-238.
(14) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1988, 29, 1061-1064.
(15) General Experimental Protocol. To a stirred solution of AgOTf (83
mg, 0.324 mmol) under a nitrogen atmosphere in the chosen solvent (1.5 mL)
at -78 °C is added a solution of PhSCl (39 mg, 0.27 mmol) in the same
solvent (1.5 mL). After the resulting solution is stirred for 5 min at -78 °C,
a solution of the thioglycoside (0.11 mmol) and DTBMP (67 mg, 0.33 mmol)
in the same solvent is added dropwise. After the resulting solution is stirred
for a further 5 min at that temperature the glycosyl acceptor (0.22 mmol) is
added dropwise in the same solvent (1.5 mL). The reaction mixture is then
allowed to warm to -20 °C over 40 min before being quenched with saturated
aqueous NaHCO3, and filtered through Celite. The filtrate is washed with
brine, dried (Na2SO4), and concentrated under vacuum, and the disaccharides
are isolated by chromatography on silica gel. The excess acceptor may also
be recovered by chromatography.
(10) In the terminology of Fraser-Reid and co-workers, armed and disarmed
glycosyl donors are more or less activated, respectively, toward glycosylation
by virtue of the properties of their protecting groups: Mootoo, D. R.;
Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110,
5583-5584.
(11) Yan, L.; Kahne, D. Synlett 1995, 523-524.