donors 14 and 15 were examined which have a C-3 benzoyl
ester and allyloxycarbonate, respectively, and as expected,
the use of these compounds led to the selective formation
of R-anomeric products (26-29).
Next, attention was focused on examining the importance
of the constitution of the chiral auxiliary for controlling
anomeric selectivity (Scheme 3). Recently, oxathiane donor
of R-glucosides. The geminal OMe substituent of 30 was
critical since glycosyl donor 31 exhibited compromised
R-anomeric selectivities.
It is well-known that substituents can enhance ring
stability, and this observation is, for example, embodied in
the “gem-dialkyl” or Thorpe-Ingold effect.24-26 Substitu-
tions can also promote the rate of ring formation by
increasing the probability of correct alignment for ring
formation.27 Saccharides also respond to these effects, and
alkylation of the aldofuranose ring shifts the equilibrium
between aldofuranoses and the corresponding acyclic alde-
hydes in the direction of the cyclic forms.28 Thus, it is likely
that the additional substituent of the auxiliary of 30 selec-
tively increased the stability of the sulfonium ion thereby
promoting glycosylations by an SN2-like mechanism. The
latter is supported by our observation that a glycosyl donor
which has no substituent at the auxiliary (2-O-phenylsulfanyl-
ethyl substituent) forms an intermediate ꢀ-sulfonium ion but
upon glycosylation gives mixtures of anomers.8
Scheme 3. Effects of Substitution Pattern of the C-2 Auxiliary
Previously, it has been reported that anomeric sulfonium
ion intermediates may not necessarily be the species that
undergo glycosylation and parameters such as the potency
of the nucleophile may determine whether a reaction
proceeds through SN2 displacement of a sulfonium ion or
by substitution of an oxacarbenium ion.29 Here, we demon-
strate that protecting groups and the chemical nature of the
sulfonium ion can have a profound influence on the stere-
ochemical outcome of glycosylations, and it has been found
that by disfavoring oxacarbenium ion formation by electronic
or stereoelectronic effects, exclusive R-anomeric selectivity
can be accomplished. These observations can be used as a
guide to select glycosyl donors that are expected to give
exclusive 1,2-cis stereoselectivity and be employed for
further improvement of chiral auxiliary mediated glycosy-
lation methodology.
a The R/ꢀ ratios were determined by the integration of key signals in
the 1H NMR spectra of the disaccharide products after purification by LH-
20 size exclusion chromatography. b Isolated yields of the R/ꢀ mixture of
disaccharide products.
30 was introduced, which can be activated by triflation of
the sulfoxide followed by electrophilic aromatic substitution
with 1,3,5-trimethoxy benzene to form an intermediate
sulfonium ion, which can then react with alcohols to give
glycoside products.22
In addition, we investigated similar glycosylations with
donor 31, which was obtained by reduction of the acetal of
30 using triethylsilane in the presence of BF3·Et2O.23 Thus,
oxathiane 30 was activated by addition of trifluoromethane-
sulfonic anhydride (Tf2O) in the presence of 1,3,5-tri-
methoxybenzene in 1,2-dichloroethane (DCE) at -35 °C.
After completion of the electrophilic aromatic substitution
and formation of the intermediate sulfonium ion, alcohols 3
or 4 were added, and after a reaction time of 16 h at 50 °C
the disaccharides 32 and 33, respectively, were formed as
only the R-anomers albeit in moderate yields. On the other
hand, similar glycosylations with 31 led to the formation of
disaccharides 34 and 35 as mixtures of anomers. Although
30 is protected with benzyl ethers at C-3, C-4, and C-6,
glycosylation with this compound took place with inversion
of the anomeric configuration leading to selective formation
Acknowledgment. This research was supported by the
National Institute of General Medicine (NIGMS) of the
National Institutes of Health (Grant No 2R01GM065248).
1
Supporting Information Available: H and 13C NMR
spectra and experimental procedures for the preparation of
compounds 2, 7, 8, 11-29, and 31-35. This material is
OL1027267
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