Dehydrative glycosylation with activated diphenyl sulfonium reagents. Scope, mode of C(1)-hemiacetal activation, and detection of reactive glycosyl intermediates

Article abstract of DOI:10.1021/ja993595a

The development of a method for direct dehydrative glycosylations with 1-hydroxyglycosyl donors employing the reagent combination of triflic anhydride and diphenyl sulfoxide is described. The one-pot coupling method is a facile process which is applicable

Full text of DOI:10.1021/ja993595a

J. Am. Chem. Soc. 2000, 122, 4269-4279
4269
Dehydrative Glycosylation with Activated Diphenyl Sulfonium
Reagents. Scope, Mode of C(1)-Hemiacetal Activation, and Detection
of Reactive Glycosyl Intermediates
Brian A. Garcia and David Y. Gin*
Contribution from the Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
ReceiVed October 6, 1999
Abstract: The development of a method for direct dehydrative glycosylations with 1-hydroxyglycosyl donors
employing the reagent combination of triflic anhydride and diphenyl sulfoxide is described. The one-pot coupling
method is a facile process which is applicable to a variety of carbohydrate coupling partners. Oxygen-18-
labeling studies are consistent with the first step in carbohydrate activation being the formation of an anomeric
oxosulfonium intermediate. This reactive glycosyl species (35) is observable in low-temperature NMR
experiments when 2,3,4,6-tetra-O-methyl-D-mannopyranose is activated as the glycosyl donor. When the
dehydrative glycosylation reaction is performed in the presence of the triflic acid scavenger 2-chloropyridine,
NMR analysis reveals that the glycosyl oxosulfonium intermediate 35 is converted to the corresponding anomeric
2-chloropyridinium species 36.
Introduction
Scheme 1
The many important roles that complex carbohydrates play
in biology have made synthesis of this class of molecules a
major focus in synthetic organic chemistry.1 The key reaction
for rational carbohydrate synthesis is the formation of the
glycosidic bond as this is the primary means for the controlled
assembly of complex oligosaccharides and glycoconjugates from
monosaccharide precursors. Most carbohydrate coupling strate-
gies have concentrated on the refinement of the approach
outlined in Scheme 1a.2 Traditionally, the anomeric substituent
of a carbohydrate (1) is derivatized to become a latent leaving
group (LG), and the intermediate glycosyl donor 2 is usually
isolated. In a second step the leaving group is then activated in
the presence of a nucleophilic glycosyl acceptor (Nu-H) to form
the glycosidic bond (2 f 3). During the past century, the bulk
of the methodology development in this area has concentrated
on the invention of new latent leaving groups for the preparation
of isolable glycosyl donors 2 that can undergo efficient
activation and coupling in the second step of the process.
A far less developed strategy for glycosidic bond formation
is a dehydrative coupling strategy shown in Scheme 1b, in which
a 1-hydroxy carbohydrate (1) can be employed directly as the
glycosyl donor. This approach would offer a complementary if
not more efficient strategy for glycosylation in that it combines
all of the processes of anomeric derivatization, activation, and
bond formation into a one-pot procedure for the conversion of
1 to 3. However, despite the potential advantages of such an
approach, this strategy has not been extensively used in complex
molecule synthesis due to a number of inherent difficulties. For
example, lack of control over the reversibility of the transforma-
tion is most evident in the original Fischer glycosylation protocol
in which the glycosyl acceptor must also function as the reaction
solvent to force the equilibrium toward the glycoside product.3
Moreover, when dehydrative glycosylations are performed in
the absence of a vast excess of glycosyl acceptor, there is the
propensity for the hemiacetal donor to self-couple under dehy-
drating conditions. Over the past several years, a handful of
direct dehydrative glycosylation methods have been developed
to address these difficulties via the in situ generation of a variety
of reactive glycosyl donors.4 Herein we report details on our
efforts in the establishment and understanding of a novel process
for direct dehydrative glycosylation that involves a new method
for hemiacetal activation using diphenyl sulfonium reagents.
(1) Synthetic Oligosaccharides. Indispensable Probes for the Life Sci-
ences; Kovac, P., Ed.; ACS Symposium Series 560; American Chemical
Society: Washington, DC, 1994. (b) Dwek, R. A. Chem. ReV. 1996, 96,
683-720.
Results and Discussion
(2) (a) PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997; Chapters 12-22. (b) Boons, G.-J. Tetrahedron
1996, 52, 1095-1121. (c) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1380-1419. (d) Schmidt, R. R.; Kinzy, W. AdV.
Carbohydr. Chem. Biochem. 1994, 50, 21-123. (e) Toshima, K.; Tatsuta,
K. Chem. ReV. 1993, 93, 1503-1531. (f) Sinay¨, P. Pure Appl. Chem. 1991,
63, 519-528.
Development of the Dehydrative Coupling Method. Our
development of a dehydrative glycosylation reaction arose from
(3) (a) Fischer, E. Chem. Ber. 1893, 26, 2400-2412. (b) Bochkov, A.
F.; Zaikov, G. E. Chemistry of the O-Glycosidic Bond; Pergamon: Oxford,
1979.
10.1021/ja993595a CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/21/2000

4270 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
Garcia and Gin
considering the possibility that a reactive anomeric oxosulfonium
species (4), generated directly from a C(1)-hydroxy donor, could
oxidation via intramolecular proton transfer.6 Triflic anhydride
was chosen as the sulfoxide activator due to the ability of this
reagent to rapidly activate the sulfoxide functionality at low
temperatures, as evidenced by the earlier work of Hendrickson,7
Kahne,8 and others.9 An additional advantage of triflic anhydride
is that the anionic byproduct of activation, triflate, should truly
be a spectator anion and thus should not obstruct glycosidic
bond formation with the desired glycosyl acceptor. However,
the use of triflic anhydride generates 2 equiv of triflic acid during
the course of the coupling process; hence, the inexpensive triflic
acid scavenger, 2-chloropyridine,10 is added after hemiacetal
activation to avoid possible acid-mediated decomposition of the
newly formed glycoside product.11 It is also worth noting that
an excess (∼2.0-2.8 equiv) of diphenyl sulfoxide is typically
employed to ensure rapid and complete hemiacetal activation
at low temperature to minimize self-condensation of the donor.
Scope. We have applied this new glycosylation procedure to
a host of substrates to afford the glycoside products 7-24
(Figure 1). A variety of selectively protected hemiacetal donors
are compatible with the dehydrative coupling process, such as
gluco-, manno-, and xylopyranose substrates. In addition,
furanose donors can be efficiently activated with 5 to form the
corresponding furanosides (19 and 21). A wide variety of
glycosyl acceptors have been shown to be suitable nucleophiles
in the coupling, including primary, secondary, and tertiary
alcohols, as well as phenols, thiols, electron-rich C-aryl nu-
cleophiles, N-silyl amides, N-silyl pyrimidines, azide, and
carboxylic acids.12 From these examples, it is worth noting that
(1) extremely hindered nucleophiles such as tert-butyl alcohol
and methyl 2,3,6-tri-O-benzyl-R-D-glucopyranoside can be gly-
cosylated (12, 17, and 18) in good yields, (2) the free N-H of
a carbamate functionality tolerates the sulfoxide-triflic anhy-
dride reagent, allowing one access to protected 2-aza-2-deoxy
glycosides 10, and (3) a variety of nitrogen nucleophiles can
be employed, including azide, pyrimidines, and amides, to allow
direct access to glycosylamine precursors as well as to analogues
of nucleosides and glycopeptide linkages.
function as an efficient glycosylating agent. This hypothesis was
indeed confirmed when the reagent combination of triflic
anhydride and diphenyl sulfoxide was employed for hemiacetal
activation.5
Scheme 2
This procedure, outlined in Scheme 2, begins with the addition
of triflic anhydride to a solution of the hemiacetal donor 1 and
diphenyl sulfoxide at -78 °C. Under these reaction conditions
it is presumed that the sulfoxide reagent is converted to diphenyl
sulfide bis(triflate) (5) in situ. This highly reactive species is
believed to activate the hemiacetal donor 1 by C(1)-hydroxyl
addition to the sulfonium center of 5, leading to formation of
the glycosyl oxosulfonium intermediate 6. The nucleophilic
acceptor subsequently adds to the anomeric center with regen-
eration of diphenyl sulfoxide to yield the desired product
glycoside 3 in an overall one-pot procedure.
In all of the glycosylation reactions, 1.5-3 equiv of the
acceptor coupling partner is usually employed, so a large excess
of the nucleophilic coupling partner is not necessary.13 For
donors possessing a C(2)-participating group such as an ester
functionality, the C(1)-C(2)-trans-configured glycosides are
generated exclusively. For glycosyl donors that do not incor-
porate such a C(2)-functionality, the anomeric ratio of the
glycoside products varies with the nature of the glycosyl
acceptor. However, on the basis of low-temperature NMR
In the development of this method, diphenyl sulfoxide was
selected as the sulfoxide reagent because it lacks potentially
reactive protons adjacent to the sulfur center, thereby precluding
(4) Glycosyl halides: (a) Koto, S.; Morishima, N.; Zen, S. Bull. Chem.
Soc. Jpn. 1982, 55, 1543-1547. (b) Koto, S.; Morishima, N.; Kusuhara,
C.; Sekido, S.; Yoshida, T.; Zen, S. Bull. Chem. Soc. Jpn. 1982, 55, 2995-
2999. Glycosyl sulfonates: (c) Leroux, J.; Perlin, A. S. Carbohydr. Res.
1978, 67, 163-178. (d) Lacombe, J. M.; Pavia, A. A. J. Org. Chem. 1983,
48, 2557-2563. (e) Koto, S.; Miura, T.; Hirooka, M.; Tomaru, A.; Iida,
M.; Kanemitsu, M.; Takenaka, K.; Masuzawa, S.; Miyaji, S.; Kuroyanagi,
N.; Yagishita, M.; Zen, S.; Yago, K.; Tomonaga, F. Bull. Chem. Soc. Jpn.
1996, 69, 3247-3259. (f) Szeja, W. Synthesis 1988, 223-224. Oxophos-
phonium intermediates: (g) Grochowski, E.; Jurczak, J. Carbohydr. Res.
1976, 50, C15-C16. (h) Szarek, W. A.; Jarrell, H. C.; Jones, J. K. N.
Carbohydr. Res. 1977, 57, C13-C16. (i) Smith, A. B. III; Rivero, R. A.;
Hale, K. J.; Vaccaro, H. A. J. Am. Chem. Soc. 1991, 113, 2092-2112. (j)
Nicolaou, K. C.; Groneberg, R. D. J. Am. Chem. Soc. 1990, 112, 4085-
4086. (k) Chida, N.; Ohtsuka, M.; Nakazawa, K.; Ogawa, S. J. Org. Chem.
1991, 56, 2976-2983. (l) Roush, W. R.; Lin, X.-F. J. Am. Chem. Soc. 1995,
117, 2236-2250. Oxo titanium intermediates: (m) Suda, S.; Mukaiyama,
T. Chem. Lett. 1991, 431-434. Glycosyl isoureas: (n) Tsutsumi, H.; Ishido,
Y. Carbohydr. Res. 1981, 88, 61-75. Lewis acid catalysis: (o) Inanaga,
J.; Yokoyama, Y.; Hanamoto, T. J. Chem. Soc., Chem. Commun. 1993,
1090-1091. (p) Mukaiyama, T.; Matsubara, K.; Hora, M. Synthesis 1994,
1368-1373. (q) Uchiro, H.; Mukaiyama, T. Chem. Lett. 1996, 79-80. (r)
Shimomura, N.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1994, 67, 2532-
2541.
(6) Tidwell, T. T. Synthesis 1990, 857-870.
(7) Hendrickson, J. B.; Schwartzman, S. M. Tetrahedron Lett. 1975, 273-
276.
(8) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc.
1989, 111, 6881-6882.
(9) (a) Coburn, M. D.; Hayden, H. H.; Coon, C. L.; Mitchell, A. R.
Synthesis 1986, 490-492. (b) Nenajdenko, V. G.; Vertelezkij, P. V.;
Gridnev, I. D.; Shevchenko, N. E.; Balenkova, E. S. Tetrahedron 1997,
53, 8173-8180. (c) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem.
Soc. 1996, 118, 9202-9203.
(10) Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D.
J. J. Am. Chem Soc. 1997, 119, 6072-6094.
(11) 2,6-Di-tert-butyl-4-methylpyridine can also be used as a triflic acid
scavenger in the coupling reaction.
(12) Glycosylations were performed in a 3:1 (v/v) mixture of toluene/
CH2Cl2. Many of the reactions in pure toluene did not proceed to completion
due to incomplete solubility of the donor at -78 to -40 °C. Reactions
performed in pure CH2Cl2 proceeded well, but led to slightly diminished
yields in some cases compared with the 3:1 v/v toluene/CH2Cl2 solvent
mixture. Glycosylations performed in both the toluene/CH2Cl2 solvent
mixture and in pure CH2Cl2 led to similar R:â selectivity.
(13) For nonvolatile acceptors, the excess nucleophile can be reisolated
with good recovery.
(5) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997, 119,
7597-7598.

Glycosylation with Diphenyl Sulfonium Reagents
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4271
Scheme 3
Scheme 4
and are not reflective of a thermodynamic product distribution
arising from postcoupling anomeric epimerization (vide infra).
Mode of C(1)-Hemiacetal Activation. In the glycosylation
reaction, it is proposed (Scheme 3) that activation of diphenyl
sulfoxide to form diphenyl sulfide bis(triflate) (5) is immediately
followed by hemiacetal addition into the sulfonium center of 5.
This would lead to the formation of the glycosyl oxosulfonium
intermediate 26, which can then proceed to glycosylate the
nucleophilic acceptor. However, an alternate reaction pathway
(Scheme 4) could involve addition of the hemiacetal hydroxyl
into the sulfonyl center of 5. This would result in the initial
expulsion of diphenyl sulfoxide and the immediate formation
of the glycosyl triflate 27, which could then effect glycosylation.
In both of these reaction manifolds, a dehydrative glycosylation
is carried out and diphenyl sulfoxide is regenerated during the
course of the transformation.
To distinguish between the two carbohydrate activation
pathways, an 18O-labeling study was carried out employing a
C(1)-18O-labeled hemiacetal donor (25). If Scheme 3 is the
operative reaction pathway, a net transfer of 18O from the
hemiacetal to the sulfoxide reagent would be observed. If, on
the other hand, Scheme 4 is operative, 18O would be transferred
to the triflic acid (or triflate) byproduct, leaving the diphenyl
sulfoxide reagent unlabeled. The preparation of 1-18OH-2,3,4,6-
tetra-O-benzyl-D-glucopyranose was accomplished (Scheme 5)
via the glycosylation of 18OH2 (98% incorporation) with 2,3,4,6-
tetra-O-benzyl-D-glucopyranose (28), affording the C(1)-O-
labeled carbohydrate 29 (87 ( 5% 18O-incorporation).14 Sub-
mission of this donor to our procedure for dehydrative gly-
cosylation of 2-propanol led to the recovery of diphenyl sul-
Figure 1. Products of dehydrative glycosylation. Yield (R:â). Key:
a, acceptor ) dihydrocholesterol; b, acceptor ) N,N′-bis(TMS)thymine;
c, acceptor
NaN3.
) N-TMS-2,2,2-trimethylacetamide; d, acceptor )
monitoring of the dehydrative glycosylation of 2-propanol to
form the isopropyl mannopyranoside 8, it appears that the
anomeric ratios of the glycoside products are kinetically derived
(14) Content of 18O determined by FAB+ mass spectrometry.

4272 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
Garcia and Gin
Scheme 5
Scheme 6
foxide with 47 ( 5% 18O-incorporation. Since 2 equiv of di-
phenyl sulfoxide reagent was used in the dehydrative coupling
procedure, this result indicates near-quantitative 18O-transfer
from the hemiacetal hydroxyl of 29 to the sulfoxide reagent.
Thus, the operative reaction pathway is considered to be Scheme
3, in which the initial step of carbohydrate activation involves
hemiacetal addition to the sulfonium center of 5 to generate
the oxosulfonium species 30.
Detection of Reactive Glycosyl Intermediates. Although
the 18O-labeling experiment suggests that the anomeric oxo-
sulfonium intermediate 6 is the first activated carbohydrate
species formed (Scheme 6), it is possible that other reactive
intermediates are generated in the subsequent stages of the
reaction. For example, dissociation of diphenyl sulfoxide from
6 could lead to formation of the glycosyl triflate 31; moreover,
in the presence of a triflic acid scavenger such as 2-chloropy-
ridine, it is possible that the base could add to the anomeric
center to generate the glycosyl pyridinium intermediate 32. Each
of these reactive intermediates could effect glycosylation to yield
the observed glycoside products.
To determine which intermediates are formed during the
glycosylation process, low-temperature NMR spectroscopy was
employed to track the course of the reaction. Thus, the first
step in our study was to independently synthesize each of the
putative intermediates 6, 31, and 32 so that they could be
unambiguously identified should they be formed during our
dehydrative coupling reaction.
Figure 2. Independent synthesis and 1H NMR characterization of
putative glycosyl intermediates: (a) glycosyl triflate 34; (b) glycosyl
oxosulfonium 35; (c) glycosyl pyridinium 36.
The glycosyl triflate 31 was the first in our series of putative
reactive intermediates to be independently synthesized and
characterized. For our NMR experiments, the 2,3,4,6-tetra-O-
methyl-D-mannopyranosyl sugar (Figure 2) was selected for
study for two key reasons. First, we have shown that this
hemiacetal is an effective donor in our glycosylation reaction
(e.g., 8, Figure 1). Second, the glycosyl triflate of 2,3,4,6-tetra-
O-methyl-D-mannopyranose (34) has recently been synthesized
and characterized by NMR in an elegant study by Crich and
Sun15 to probe the mechanism of the Kahne glycosyl sulfoxide
glycosylation method.16 Thus, this substrate provided a conve-
(15) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.

Glycosylation with Diphenyl Sulfonium Reagents
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4273
nient starting point for our independent syntheses of the putative
reactive intermediates outlined in Scheme 6.
In the Crich study, the method reported for the independent
generation of trifluoromethanesulfonyl-2,3,4,6-tetra-O-R-D-
mannopyranoside (34) involved the treatment of the correspond-
ing mannosyl bromide with AgOTf at -78 °C. However, we
desired a method to generate 34 that would allow for this species
to be further converted to the other putative glycosyl intermedi-
ates in the absence of insoluble silver salts. Consequently, we
employed an alternate method in which the more stable glycosyl
fluoride 33 was treated with a slight excess of TMSOTf as a
fluoride scavenger to afford the mannosyl triflate 34 (Figure
2a).17 Using this reagent, the glycosyl fluoride 33 was smoothly
converted to the corresponding mannosyl triflate 34 within 2 h
at -60 °C in CD2Cl2 (85% conversion) with concomitant
formation of TMS-F as a soluble and benign byproduct. The
successful preparation of 34 is illustrated in the 1H NMR
spectrum in Figure 2a wherein the anomeric proton resonance
resides at δ 6.15,18 a chemical shift which is consistent with
that of the Crich study.
With this new method for the low-temperature generation of
the glycosyl triflate, the independent synthesis of the glycosyl
oxosulfonium species 35 was then addressed. It was reasoned
that diphenyl sulfoxide should be an effective nucleophile for
displacement of the anomeric triflate functionality in 34, thereby
leading to the facile generation and characterization of the
putative glycosyl oxosulfonium species 35. Thus, to a solution
of freshly prepared mannosyl triflate 34 (prepared from 33) in
CD2Cl2 was added 2 equiv of the sulfoxide reagent (Figure 2b).
In these experiments, bis(pentadeuteriophenyl) sulfoxide19 was
employed to minimize the number of NMR proton resonances
that could potentially complicate interpretation. This sulfoxide
was added to the solution of 34 to afford complete consumption
of the glycosyl triflate within 20 min at -60 °C, leading to the
formation of a new intermediate which is considered to be the
oxosulfonium species 35. On the basis of low-temperature
COSY and HMQC NMR data,20 the broad anomeric proton
resonance at δ 6.3221 is consistent with its assignment as the
anomeric proton of 35. In addition, the R-oxosulfonium anomer
is shown to be stereoselectively formed as evidenced by
NOE enhancement of the C(2)-OCH3 proton resonance (3.6%)
upon irradiation of the anomeric proton resonance (i.e., 35,
Figure 3).
Figure 3. NOE evidence for anomeric configurations of putative
glycosyl intermediates.
both anomers of the glycosyl pyridinium species 36 within 20
min at -60 °C. Two resonances at δ 6.63 and 6.49 were
assigned by HMQC NMR data22 to be the C(1)-protons of the
anomeric mixture of 36 in a ratio of 24:76 (R:â), respectively.
Interestingly, the â-pyridinium diastereomer is found to be the
principal anomer in solution on the basis of NOE data.23
Irradiation of the anomeric proton in the major anomer of the
glycosyl pyridinium intermediate 37 (Figure 3) resulted in NOE
enhancement of the C(3)- and C(5)-proton resonances.24
The successful independent preparation and NMR charac-
terization of each of the intermediates 34-36 provides the basis
for possible detection of these reactive species during the course
of the coupling reaction (Figure 4). Therefore, the dehydrative
glycosylation reaction was performed with 2,3,4,6-tetra-O-
methyl-D-mannose (38) in CD2Cl2 (Figure 4a). When a mixture
of 38 and (C6D5)2SO at -60 °C was treated with triflic
anhydride, complete consumption of the hemiacetal 38 had
occurred within 20 min, resulting in the formation of a glycosyl
intermediate (Figure 4b). 1H NMR spectral data of this
intermediate coincided with the glycosyl oxosulfonium species
35 that we independently synthesized and characterized earlier
(cf. Figure 2b). The subsequent stage in the coupling protocol
involved the introduction of the triflic acid scavenger 2-chlo-
ropyridine (3 equiv). The reaction was allowed to warm to -40
°C, and it was observed (Figure 4c,d) that complete conversion
of the oxosulfonium species 35 to both anomers of the glycosyl
pyridinium species 36r and 36â (19:81) proceeded within 2
h.25 The final step in the coupling transformation involved the
introduction of a nucleophilic acceptor, 2-propanol. Upon
introduction of the acceptor (Figure 4e,f), the corresponding
isopropyl glycoside 8 was formed within 2.5 h at 15 °C in a
54:46 (R:â) mixture (anomeric proton resonances at δ 4.91 and
4.41, respectively). This anomeric ratio, which is believed to
be kinetically derived,26 is similar to that obtained earlier (i.e.,
8, Figure 1).
Finally, a similar experiment was conducted for the formation
of the glycosyl pyridinium intermediate 36 (Figure 2c). Upon
treatment of the mannosyl triflate 34 with 3 equiv of 2-chlo-
ropyridine, the glycosyl triflate was completely converted to
The above experiments thus allow for a clearer definition of
the dehydrative coupling process. First, it appears that the initial
(16) For additional studies on the detection of reactive glycosyl
intermediates in the Kahne sulfoxide glycosylation method, see: Gilder-
sleeve, J.; Pascal, R. A., Jr.; Kahne, D. J. Am. Chem. Soc. 1998, 120, 5961-
5969.
(17) For the use of substoichiometric quantities of TMSOTf in glycosidic
couplings with glycosyl fluorides, see: Hashimoto, S.; Hayashi, M.; Noyori,
R. Tetrahedron Lett. 1984, 25, 1379-1382.
(18) The doublet resonance at δ 5.68 (J ) 51 Hz) corresponds to the
anomeric proton of traces of unreacted mannosyl fluoride 33.
(19) Prepared from the treatment of C6D6 with aluminum trichloride and
thionyl chloride, following a known procedure for the preparation of
diphenyl sulfoxide. See: Shriner, R. L.; Struck, H. C.; Jorison, W. J. J.
Am. Chem. Soc. 1930. 52, 2060-2069.
(20) The low-temperature COSY experiment was performed on the
2,3,4,6-tetrakis-O-(trideuteriomethyl) analogue of 35. Thus, it was possible
to confidently identify the pyranoside ring protons in the absence of
overlapping OCH3 resonances. HMQC NMR data showed that the proton
resonance at δ 6.38 correlated with the C(1) carbon-13 resonance (δ 107.2)
in 35.
(22) HMQC NMR data showed that the proton resonances at δ 6.63
and 6.49 correlated with the C(1) carbon-13 resonances (δ 87.35 and 89.58,
respectively) in the anomeric mixture of 37.
(23) Formation of the â-anomer of 36 as the major diastereomer may
result from the minimization of nonbonding interactions with the sterically
demanding pyridinium moiety, or possibly arise as a result of a reverse
anomeric effect. For recent discussions on the reverse anomeric effect,
see: (a) Jones, P. G.; Kirby, A. J.; Komarov, I. V.; Wothers, P. D. Chem.
Commun. 1998, 1695-1696. (b) Vaino, A. R.; Chan, S. S. C.; Szarek, W.
A.; Thatcher, G. R. J. J. Org. Chem. 1996, 61, 4514-4515. (c) Perrin, C.
L. Tetrahedron 1995, 51, 11901-11935.
(24) The mannosyl pyridinium intermediate 37, in which all of the CH3
protective groups were replaced with CD3, was used for the stereochemical
assignment of the pyridinium intermediates because it permitted us to clearly
assign all of the pyranoside ring protons in the absence of overlapping OCH3
resonances. Thus, it was possible to confidently identify the enhancement
of the C(3) and C(5) protons in the NOE experiment.
(25) From the NMR study, the conversion of 35 f 36 is not instantaneous
at -40 °C. Therefore, in the reactions to form glycosides 7-24, it is likely
that the extent of conversion to the glycosyl pyridinium intermediate prior
to the introduction of the acceptor varies with the nature of the coupling
partners.
(21) The trace resonances at δ 7.45 arise from residual toluene that was
employed for azeotropic removal of water from the sulfoxide reagent prior
to the reaction.

4274 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
Garcia and Gin
glycosyl pyridinium species 36 can accumulate in solution
during the course of the reaction. However, one must be aware
of the caveat that simple detection of 36 as the principal species
in solution does not necessarily establish it to be the reactiVe
species undergoing coupling to form the product glycoside.
Indeed, the lack of correlation between the anomeric ratios of
the glycosyl pyridinium intermediate 36 (19:81, R:â) and the
isopropyl glycoside product 8 (54:46, R:â) suggests that the
glycosylation of 2-propanol is unlikely to proceed exclusively
through direct invertive displacement of the anomeric pyridinium
moieties in 36râ. Thus, the actual glycosidic-bond-forming
event may proceed, at least in part, via other reactive intermedi-
ates that were not detected by NMR. Candidates include the
glycosyl oxosulfonium 35 and/or the oxocarbenium 39,27 which
may exist in exceedingly small quantities even after the
introduction of 2-chloropyridine.
Finally, it is clear from the NMR experiments that diphenyl
sulfoxide can be expelled from the anomeric center of 35 by
2-chloropyridine prior to addition of the glycosyl acceptor. This
observation presents the possibility for catalytic turnover of
diphenyl sulfoxide in the hemiacetal activation phase of the
reaction. However, this potential catalytic cycle would only be
feasible if expulsion of the anomeric sulfoxide moiety is
sufficiently rapid so that the rate of hemiacetal activation is fast
relative to that of self-condensation of the C(1)-hydroxy donor.
When activation of the hemiacetal 38 was carried out with 0.2
equiv of (C6D5)2SO in the presence of triflic anhydride (3 equiv)
and 2-chloropyridine (1.4 equiv) in CD2Cl2, self-condensation
was indeed found to be a competitive process. Under these
conditions, 56% of the hemiacetal donor 38 is converted to the
undesired 1,1′-R,R′-linked disaccharide 40 in the unproductive
self-condensation pathway as determined by 1H NMR. Thus, it
(26) It is clear that the 54:46 (R:â) ratio obtained is not the thermody-
namic anomeric distribution, which is >95:5 (R:â). This thermodynamic
ratio was established when the glycosyl triflate 34 in CD2Cl2 was treated
with 2-propanol in the absence of any acid scavenger. This led to the
immediate formation of 8 in a ∼1:1 ratio at -60 °C, followed by anomeric
epimerization within 30 min at 0 °C to form the R-anomer exclusively. In
Figure 4, the glycoside 8 emerges in a constant ratio (54:46; R:â) during
the course of anomeric bond formation at 15 °C, and this ratio remains
unchanged even when the reaction is monitored for an additional hour after
the reaction is complete. At higher temperature (i.e., 23 °C), a small amount
(∼6%) of anomerization (â f R) is observed over the course of 1.5 h.
Thus, postcoupling anomeric epimerization is unlikely to be a significant
contributor to the observed anomeric ratios.
(27) A dehydrative glycosylation reaction of 2-propanol with 38,
employing the nonnucleophilic acid scavenger 2,4,6-tri-tert-butylpyridine,
led to the formation of the glycoside product 8 in a 46:54 (R:â) anomeric
ratio. A similar result was obtained when a mixture of 2,4,6-tri-tert-
butylpyridine and 2-propanol was introduced directly to a solution of the
glycosyl triflate 34 (independently derived from the glycosyl fluoride 33),
affording 8 in an anomeric ratio of 53:47 (R:â). The striking similarity in
the product ratios in all of these reactions (cf. Figure 4) again alludes to
the possibility that the glycosidic-bond-forming event in these transforma-
tions may proceed at least in part through a common reactive intermediate
such as 39. Future studies will involve the assessment of the kinetic
competency of the reactive glycosyl intermediates.
1
Figure 4. Dehydrative glycosylation monitored by H NMR in CD2-
Cl2: (a) hemiacetal 38 and (C6D5)2SO at -60 °C; (b) -60 °C, 20 min
after addition of Tf2O; (c) -40 °C, 20 min after addition of 2-Cl-pyr;
(d) -40 °C, 2 h after addition of 2-Cl-pyr; (e) 15 °C, 30 min after
addition of 2-propanol; (f) 15 °C, 2.5 h after addition of 2-propanol.
carbohydrate intermediate detected in the activation process is
the glycosyl oxosulfonium species 35, which is consistent with
the findings of the 18O-labeling study. Second, it is clear that
when 2-chloropyridine is used as the triflic acid scavenger, the

Glycosylation with Diphenyl Sulfonium Reagents
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4275
downfield from tetramethylsilane and are referenced to residual protium
in the NMR solvent (CHCl3, δ 7.26; CHDCl2, δ 5.32; C6HD5, δ 7.16).
Data are presented as follows: chemical shift, multiplicity (s ) singlet,
d ) doublet, t ) triplet, br s ) broad singlet, m ) multiplet and/or
multiple resonances), integration, and coupling constants in hertz (Hz).
Optical rotations were acquired on a JASCO DIP-360 digital polarim-
eter. Melting points were recorded with a Fisher melting apparatus and
are uncorrected. HPLC was performed on a Rainin Dynamax system
(model SD-200) with a Dynamax 100 Å SiO column (21.5 mm × 25
cm) and a Dynamax model UV-1 detector (254 nm).
General Procedure for Dehydrative Glycosylation. Isopropyl
2,3,4,6-tetra-O-benzyl-D-glucopyranoside (7). Trifluoromethanesul-
fonic anhydride (45 µL, 0.27 mmol, 1.4 equiv) was added to a solution
of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (103 mg, 0.191 mmol, 1
equiv) and diphenyl sulfoxide (108 mg, 0.535 mmol, 2.8 equiv) in a
mixture of toluene and dichloromethane (8 mL, 3:1 v/v) at -78 °C.
The reaction mixture was stirred at this temperature for 5 min and then
at -40 °C for 1 h. 2-Chloropyridine (90 µL, 0.96 mmol, 5.0 equiv)
and isopropyl alcohol (44 µL, 0.57 mmol, 3.0 equiv) were added
sequentially at -40 °C. The solution was stirred at this temperature
for 1 h, then at 0 °C for 30 min, and finally at 23 °C for 1 h before the
addition of excess triethylamine (212 µL, 1.53 mmol, 10 equiv). The
reaction was diluted with dichloromethane (100 mL) and was washed
sequentially with saturated aqueous sodium bicarbonate solution (2 ×
100 mL) and saturated aqueous sodium chloride solution (100 mL).
The organic layer was dried (sodium sulfate) and concentrated, and
the residue was purified by silica gel flash column chromatography
(gradient elution: 9% f 10% f 30% ethyl acetate in hexane) to afford
7 (95 mg, 86%; 27:73, R:â) as a white solid.28 Anal. Calcd for
C37H42O6: C, 76.26; H, 7.26. Found (anomeric mixture): C, 76.57; H,
7.57. Analytical samples of each anomer were obtained by preparative
appears that for the present protocol the use of at least a
stoichiometric quantity of diphenyl sulfoxide is needed to ensure
rapid and complete activation of the donor at low temperature,
allowing for efficient coupling with the desired acceptor.
Conclusion
A method for direct dehydrative glycosylations with 1-hy-
droxyglycosyl donors employing the reagent combination of
triflic anhydride and diphenyl sulfoxide has been developed.
The one-pot coupling method is a facile process and appears to
be applicable to a wide variety of carbohydrate coupling
partners. Oxygen-18-labeling studies indicate that the first step
of carbohydrate activation in the coupling process involves the
addition of the hemiacetal hydroxyl to the sulfonium center of
diphenyl sulfide bis(triflate), leading to the formation of an
anomeric oxosulfonium intermediate. The glycosyl oxosulfo-
nium intermediate 35 was detected by low-temperature NMR
analysis of the dehydrative glycosylation process. When the
reaction is performed in the presence of the triflic acid scavenger
2-chloropyridine, the corresponding anomeric 2-chloropyri-
dinium species 36 accumulates during the course of the reaction.
However, on the basis of the anomeric ratio of the glycoside
products, the mode of anomeric bond formation is not likely to
proceed exclusively through direct invertive displacement of
the anomeric pyridinium group in 36, even though 36 may be
the principal species in solution. It is more likely that the actual
C(1)-bond-forming event proceeds, at least in part, through an
oxocarbenium (39) which may exist in the reaction mixture in
exceedingly small quantities. In addition, glycosylation experi-
ments with substoichiometric quantities of diphenyl sulfoxide
highlight the importance of the sulfoxide reagent in the
activation stage of the reaction. In the case of the mannosyl
donor 38, sufficient quantities of the sulfoxide reagent are
required for rapid activation of the hemiacetal, thereby minimiz-
ing unwanted reaction manifolds such as self-condensation of
the hemiacetal donor. These findings should allow for the further
development of new sulfoxide/triflic anhydride reagents for
glycosylation as well as for hydroxyl activation in general.
TLC (20% ethyl acetate in hexane). R-Anomer: viscous oil; Rf ) 0.43
1
(33% ethyl acetate in hexane); [R]20 ) +28° (c ) 0.4, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.4-7.1 (m, 20 H), 5.00 (d, 1 H, J ) 10.8
Hz), 4.88 (d, 1 H, J ) 3.8 Hz, H 1), 4.83 (d, 1 H, J ) 10.6 Hz), 4.82
(d, 1 H, J ) 10.8 Hz), 4.78 (d, 1 H, J ) 12.0 Hz), 4.65 (d, 1 H, J )
12.0 Hz), 4.62 (d, 1 H, J ) 12.3 Hz), 4.47 (d, 2 H, J ) 12.1 Hz), 4.00
(t, 1 H, J ) 9.3 Hz), 3.90 (m, 1 H), 3.85 (ddd, 1 H, J ) 10.2, 3.4, 2.0
Hz), 3.74 (dd, 1 H, J ) 10.5, 3.6 Hz), 3.64 (m, 2 H), 3.56 (dd, 1 H, J
) 9.6, 3.8 Hz), 1.13 (d, 3 H, J ) 6.3 Hz), 1.18 (d, 3 H, J ) 6.0 Hz);
13C NMR (126 MHz, CDCl3) δ 139.0, 138.3, 138.3, 138.0, 128.5, 128.4,
128.4, 128.2, 128.0, 128.0, 127.9, 127.9, 127.8, 127.7, 127.6, 94.8,
82.2, 79.9, 77.9, 75.7, 75.2, 73.5, 73.2, 70.0, 69.0, 68.5, 23.2, 21.2;
FTIR (neat film) 3064, 3030, 2922, 1454, 1364, 1157, 1072, 1040,
1029, 1015 cm-1; HRMS (FAB) m/z calcd for C37H41O6 (M - H)
581.2903, found 581.2903. â-Anomer: white solid; mp 105 °C (lit. mp
Experimental Section
General Procedures. All reactions were performed in flame-dried
modified Schlenk (Kjeldahl shape) flasks fitted with a glass stopper or
rubber septum under a positive pressure of argon, unless otherwise
noted. Air- and moisture-sensitive liquids and solutions were transferred
via syringe or stainless steel cannula. Organic solutions were concen-
trated by rotary evaporation below 30 °C at ca. 25 Torr. Flash column
chromatography was performed employing 230-400 mesh silica gel.
Thin-layer chromatography (analytical and preparative) was performed
using glass plates precoated to a depth of 0.25 mm with 230-400 mesh
silica gel impregnated with a fluorescent indicator (254 nm).
Dichloromethane, 2-chloropyridine, triethylamine, toluene, and
2-propanol were distilled from calcium hydride at 760 Torr. Diphenyl
sulfoxide was purchased from Aldrich and was dried by azeotropic
removal of water with toluene prior to use. Trifluoromethanesulfonic
anhydride was triply distilled from phosphorus pentoxide. CD2Cl2 was
stored over CaH2 (>24 h) and vacuum transferred immediately prior
to use in the low-temperature NMR experiments.
Infrared (FTIR) spectra were obtained using a Perkin-Elmer Spec-
trum BX spectrophotometer referenced to a polystyrene standard. Data
are presented as the frequency of absorption (cm-1). Proton and carbon-
13 nuclear magnetic resonance (1H NMR or 13C NMR) spectra were
recorded on a Varian Unity 400, a Varian Unity 500, a Varian Unity
Inova 500WB, or a Varian Unity Inova 750NB NMR spectrometer.
Low-temperature detection of the reactive glycosyl intermediates
(Figures 2 and 4) was performed on the Varian Unity Inova 500WB
spectrometer. Chemical shifts are expressed in parts per million (δ scale)
107-108 °C); Rf ) 0.33 (33% ethyl acetate in hexane); [R]20D ) +10°
1
(c ) 0.9, CHCl3) (lit. [R]25 ) +11°, c ) 1, CDCl3); H NMR (500
D
MHz, CDCl3) δ 7.4-7.1 (m, 20 H), 5.00 (d, 1 H, J ) 11.0 Hz), 4.95
(d, 1 H, J ) 10.9 Hz), 4.84 (d, 1 H, J ) 11.1 Hz), 4.81 (d, 1 H, J )
10.8 Hz), 4.73 (d, 1 H, J ) 10.9 Hz), 4.63 (d, 1 H, J ) 12.3 Hz), 4.59
(d, 1 H, J ) 11. Hz), 4.57 (d, 1 H, J ) 10.8 Hz), 4.50 (d, 1 H, J ) 7.8
Hz, H 1), 4.05 (m, 1 H), 3.76 (dd, 1 H, J ) 10.8, 1.8 Hz), 3.70 (m, 1
H), 3.58 (t, 1 H, J ) 9.64 Hz), 3.48 (m, 1 H), 3.46 (dd, 1 H, J ) 9.1,
7.9 Hz), 1.34 (d, 3 H, J ) 6.2 Hz), 1.27 (d, 3 H, J ) 6.2 Hz); 13C
NMR (126 MHz, CDCl3) δ 138.7, 138.6, 138.4, 138.2, 128.4, 128.3,
128.0, 127.9, 127.8, 127.8, 127.7, 127.6, 127.6, 102.2, 84.9, 82.4, 78.0,
75.7, 75.0, 74.9, 74.9, 73.5, 72.4, 69.2, 23.8, 22.3; FTIR (neat film)
3031, 2904, 1454, 1121, 1104, 1069, 1039 cm-1; HRMS (FAB) m/z
calcd for C37H41O6 (M - H) 581.2903, found 581.2903.
Isopropyl 2,3,4,6-Tetra-O-methyl-D-mannopyrannoside (8). Vis-
cous oil. Anal. Calcd for C13H26O6: C, 56.10; H, 9.42. Found (anomeric
mixture): C, 55.47; H, 9.57. Analytical samples of each anomer were
obtained by preparative TLC (12.5% ethyl acetate in dichloromethane).
R-Anomer: viscous oil; Rf ) 0.25 (33% ethyl acetate in hexane); [R]23
D
1
) +68° (c ) 0.5, CHCl3); H NMR (500 MHz, CD2Cl2) δ 4.91 (s, 1
H, H 1), 3.88 (hept, 1 H, J ) 6.02), 3.58-3.28 (m, 20 H), 1.17 (d, 3
H, J ) 6.23), 1.13 (d, 3 H, J ) 6.06); 13C NMR (126 MHz, CD2Cl2)
(28) (a) Briner, K.; Vasella, A. HelV. Chim. Acta 1989, 72, 1371-1382.
(b) Jansson, K.; Noori, G.; Magnusson, G. J. Org. Chem. 1990, 55, 3181-
3185.

4276 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
Garcia and Gin
δ 95.46, 81.75, 78.05, 76.77, 72.04, 71.60, 69.26, 60.59, 59.18, 59.12,
57.57, 23.37, 21.40; FTIR (neat film) 2974, 2930, 2825, 1456, 1380,
1193, 1113, 1060, 1063 cm-1; HRMS (FAB) m/z calcd for C13H26O6-
Na (M + Na+) 301.1627, found 301.1629. â-Anomer: viscous oil; Rf
) 0.18 (33% ethyl acetate in hexane); [R]23D ) -106° (c ) 0.3, CHCl3);
1H NMR (500 MHz, CD2Cl2) δ 4.41 (s, 1 H, H 1), 3.93 (hept, 1 H, J
) 6.42), 3.61-3.60 (m, 15H), 3.22 (t, 1 H, J ) 9.36), 3.17 (ddd, J )
2.04, 5.05, 9.56), 3.13 (dd, 1 H, J ) 3.10, 9.27), 1.21 (d, 3H, J )
6.35), 1.13 (d, 3 H, J ) 6.12); 13C NMR (126 MHz, CD2Cl2) δ 99.86,
84.69, 78.07, 76.74, 75.86, 72.38, 71.23, 61.59, 60.88, 59.47, 57.43,
53.78, 53.57, 23.84, 21.87; FTIR (neat film) 2974, 2930, 2833, 1468,
1371, 1194, 1111, 1070, 970 cm-1; HRMS (FAB) m/z calcd for
C13H26O6Na (M + Na+) 301.1627, found 301.1627.
4.57 (d, 1 H, J ) 10.8 Hz), 4.56 (d, 1 H, J ) 12.1 Hz), 4.47 (d, 1 H,
J ) 9.9 Hz, H 1), 3.75 (dd, 1 H, J ) 10.7, 1.8 Hz), 3.68 (m, 2 H), 3.61
(t, 1 H, J ) 9.5 Hz), 3.47 (m, 1 H), 3.45 (t, 1 H, J ) 9.3 Hz), 2.77 (m,
2 H), 1.33 (t, 3 H, J ) 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 138.5,
138.2, 138.1, 138.0, 128.5, 128.4, 128.4, 128.0, 127.9, 127.8, 127.8,
127.7, 127.6, 86.7, 85.1, 81.8, 79.1, 78.0, 75.8, 75.5, 75.1, 73.4, 69.1,
25.0, 15.2; FTIR (neat film) 3030, 2922, 1453, 1126, 1088, 735 cm-1
;
HRMS (FAB) m/z calcd for C36H39O5S (M - H) 583.2518, found
583.2517. Anal. Calcd for C36H40O5S: C, 73.94; H, 6.89. Found: C,
73.59; H, 7.02.
tert-Butyl 2,3,4,6-Tetra-O-benzyl-D-glucopyranoside (12). Viscous
oil. Anal. Calcd for C38H44O6: C, 76.48; H, 7.43. Found (anomeric
mixture): C, 76.58; H, 7.36. Analytical samples of each anomer were
separated by HPLC (10% ethyl acetate in hexane). R-Anomer: viscous
oil; Rf ) 0.53 (20% ethyl acetate in hexane); [R]23D ) +25° (c ) 0.3,
1-Deoxy-1-(C-2′,4′,6′-trimethoxyphenyl)-2,3,4,6-tetra-O-benzyl-
D-glucopyranoside (9).29 Viscous oil; Rf ) 0.40 (10% ethyl acetate in
benzene); [R]20 ) +8° (c ) 1.0, CHCl3) (lit. [R]25 ) +5.4°, c )
1
CHCl3); H NMR (500 MHz, C6D6) δ 7.35-7.06 (m, 25 H), 5.16 (d,
D
D
1
0.4, CHCl3); H NMR (500 MHz, CDCl3) δ 7.4-6.9 (m, 20 H), 6.19
(d, 1 H, J ) 2.1 Hz), 6.12 (d, 1 H, J ) 6.1 Hz), 4.98 (d, 1 H, J ) 10.7
Hz), 4.95 (d, 1 H, J ) 10.1 Hz), 4.94 (d, 1 H, J ) 10.8 Hz), 4.92 (d,
1 H, J ) 10.1 Hz), 4.81 (d, 1 H, J ) 12.2 Hz), 4.75 (d, 1 H, J ) 10.8
Hz), 4.55 (d, 1 H, J ) 12.2 Hz), 4.54 (d, 1 H, J ) 10.4 Hz), 4.40 (dd,
1 H, J ) 9.8, 8.8 Hz), 4.13 (d, 1 H, J ) 10.5 Hz, H 1), 3.93 (dd, 1 H,
J ) 11.7, 3.8 Hz), 3.88 (t, 1 H, J ) 9.4 Hz), 3.84 (s, 3 H), 3.80 (s, 3
H), 3.79 (m, 2 H), 3.72 (s, 3 H), 3.59 (m, 1 H); 13C NMR (126 MHz,
CDCl3) δ 161.2, 160.8, 159.7, 158.9, 138.8, 138.5, 138.3, 128.3, 128.3,
128.1, 128.1, 128.0, 128.0, 127.9, 127.5, 127.5, 127.3, 127.2, 127.1,
91.6, 90.7, 87.4, 79.9, 79.5, 78.3, 75.8, 75.0, 74.4, 73.0, 72.5, 69.0;
1 H, J ) 3.75, H 1), 5.00 (dd, 2 H, J ) 11.57), 4.49 (d, 1 H, J )
11.53), 4.47 (d, 1 H, J ) 11.68), 4.38 (d, 1 H, J ) 12.20), 4.31 (t, 1
H, J ) 9.31), 4.27 (ddd, 1 H, J ) 1.69, 4.31, 10.02), 3.83 (dd, 1 H, J
) 9.03, 9,99), 3.80 (dd, 1 H, J ) 4.35, 10.62), 3.68 (dd, 1 H, J )
1.62, 10.39), 3.56 (dd, 1 H, J ) 3.63, 9.68), 1.23 (s, 9 H); 13C NMR
(126, MHz, C6D6) δ 140.36, 139.87, 139.593, 139.589, 128.91, 128.90,
128.82, 128.79, 128.38, 128.36, 128.16, 128.08, 127.98, 127.93, 127.76,
91.97, 82.96, 81.44, 79.26, 75.83, 75.48, 75.36, 73.85,73.35, 71.31,
70.20, 29.09; FTIR 2976, 2929, 2866, 1454, 1366, 1157, 1089, 1073,
1042, 735, 697 cm-1; HRMS (FAB) m/z calcd for C38H44O6Na (M +
Na+) 619.3036, found 619.3030. â-Anomer: viscous oil; Rf ) 0.53
FTIR (neat film) 3029, 2936, 1608, 1592, 1205, 1154, 1067, 697 cm-1
;
1
(20% ethyl acetate in hexane); [R]23 ) +44° (c ) 1.1, CHCl3); H
D
HRMS (FAB) m/z calcd for C43H47O8 (M + H) 691.3271, found
691.3268. Anal. Calcd for C43H46O8: C, 74.76; H, 6.71. Found: C,
75.15; H, 6.84.
NMR (500 MHz, C6D6) δ 7.41-7.06 (m, 25 H), 5.09 (d, 1 H, J )
11.54), 5.03 (d, 1 H, J ) 11.22), 4.88 (d, 1 H, J ) 11.22), 4.84 (d, 1
H, J ) 11.18), 4.75 (d, 1 H, J ) 11.44), 4.56 (m, 2 H, H 1), 4.48 (d,
1 H, J ) 3.46, 9.32), 1,27 (s, 9 H); 13C NMR (126 MHz, C6D6) δ
140.01, 139.96, 139.76, 139.53, 128.89, 128.85, 128.84, 128.82, 128.45,
128.44, 128.33, 128.24, 128.13, 127.97 127.94, 127.89, 98.84, 85.79,
83.20, 78.90, 75.95, 75.88, 75.44, 75.23, 75.10, 73.78, 70.12,29.36;
FTIR (neat film) 3031, 2975, 2904, 2867, 1454, 1364, 1070, 735, 697;
HRMS (FAB) m/z calcd for C38H44O6Na (M + Na+) 619.3034, found
619.3030.
Isopropyl 3,4,6-Tri-O-benzyl-2-N-benzyloxycarbonyl-2-deoxy-â-
D-glucopyranoside (10). Rf ) 0.79 (15% ethyl acetate in dichlo-
1
romethane); H NMR (400 MHz, CDCl3) δ 7.4-7.2 (m, 20 H), 5.08
(m, 2 H), 4.95 (br s, 1 H, H 1), 4.79 (d, 1 H, J ) 11.0 Hz), 4.76 (d, 1
H, J ) 11.2 Hz), 4.65 (d, 1 H, J ) 11.3 Hz), 4.61 (d, 1 H, J ) 12.0
Hz), 4.58 (d, 1 H, J ) 11.3 Hz), 4.55 (d, 1 H, J ) 12.3 Hz), 4.04 (br
s, 1 H), 3.91 (septet, 1 H), 3.74 (dd, 1 H, J ) 10.9, 2.2 Hz), 3.68 (dd,
1 H, J ) 10.8, 4.7), 3.57 (m, 1 H), 3.52 (m, 1 H), 3.19 (br s, 1 H), 1.22
(d, 3 H, J ) 6.1 Hz), 1.06 (d, 3 H, J ) 6.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 145.5, 138.1, 138.1, 136.5, 131.0, 129.3, 128.4, 128.3, 128.3,
128.3, 127.9, 127.8, 127.7, 127.5, 124.7, 95.3, 78.8, 74.9, 74.7, 74.6,
73.3, 71.9, 68.9, 66.4, 58.3, 23.4, 21.8; FTIR (neat film) 3317, 3030,
1695, 1579, 1091 cm-1; HRMS (FAB) m/z calcd for C38H42NO7 (M -
H) 624.2961, found 624.2961.
Methyl-O-(2,3,4,6-tetra-O-benzoyl-?-D-mannopyranosyl)-(1 f
4)-2,3,6-tri-O-benzyl-R-D-glucopyranoside (13). Viscous oil; Rf ) 0.56
1
(11% ethyl acetate in benzene); [R]23 ) -28° (c ) 2.5, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 8.35 (m, 2 H), 8.09 (m, 2 H), 8.02 (m, 4
H), 7.41 (m, 4 H), 7.25-6.84 (m, 2 H), 6.74 (m, 2 H), 6.65 (t, 1 H, J
) 10.2 Hz), 6.40 (dd, 1 H, J ) 3.2, 10.0 Hz), 6.24 (dd, 1 H, J ) 1.7,
3.3 Hz), 5.93 (d, 1 H, J ) 1.7 Hz, H 1), 5.09 (d, 1 H, J ) 11.2 Hz),
4.93 (d, 1 H, J ) 11.2 Hz), 4.84 (dd, 1 H, J ) 2.6, 12.2 Hz), 4.68 (m,
1 H), 4.62 (d, 1 H, J ) 3.4 Hz, H 1′), 4.61 (d, 1 H, J ) 12.0 Hz), 4.56
(d, 1 H, J ) 12.0 Hz), 4.44 (dd, 1 H, J ) 3.4, 12.2 Hz), 4.37 (d, 1 H,
J ) 11.9 Hz), 4.34 (d, 1 H, J ) 11.9 Hz), 4.28 (t, 1 H, J ) 9.3 Hz),
4.17 (t, 1 H, J ) 9.3 Hz), 3.95 (m, 2 H), 3.78 (m, 1 H), 3.47 (dd, 1 H,
J ) 3.4, 9.5 Hz), 3.20 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 166.28,
166.23, 166.05, 165.52, 139.5, 139.36, 139.22, 138.22, 133.62, 133.48,
133.38, 133.18, 131.71, 131.21, 130.60, 130.57, 130.43, 130.37, 130.36,
130.17, 130.10, 129.67, 129.66, 129.05, 129.00, 128.98, 128.95, 128.90,
128.76, 128.67, 128.36, 128.25, 128.16, 127.68, 126.03, 100.05, 98.46,
81.82, 81.75, 77.10, 75.69, 74.12, 73.10, 71.49, 71.15, 70.66, 70.65,
70.02, 67.76, 63.12, 55.39, 21.74; FTIR (neat film) 3033, 2904, 1729,
1452, 1265, 1106, 1048, 1027, 710 cm-1; HRMS (FAB) m/z calcd for
C62H57O15 (M - H) 1041.3697, found 1041.3694. Anal. Calcd for
C62H58O15: C, 71.39; H, 5.60. Found: C, 71.32; H, 5.67.
1-Deoxy-1-(S-ethyl)-2,3,4,6-tetra-O-benzyl-D-glucopyranoside (11).30
R-Anomer: white solid; mp 88-89 °C (lit. mp 91 °C); Rf ) 0.42 (5%
ethyl ether in benzene); [R]20 ) +108° (c ) 1.7, CHCl3) (lit. [R]22
D
D
) +108°, c ) 2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.4-7.2 (m,
20 H), 5.44 (d, 1 H, J ) 4.9 Hz, H 1), 4.97 (d, 1 H, J ) 11.0 Hz), 4.85
(d, 1 H, J ) 10.7 Hz), 4.79 (d, 1 H, J ) 10.7 Hz), 4.75 (d, 1 H, J )
11.7 Hz), 4.69 (d, 1 H, J ) 11.7 Hz), 4.63 (d, 1 H, J ) 12.0 Hz), 4.49
(d, 1 H, J ) 10.7 Hz), 4.48 (d, 1 H, J ) 12.0 Hz), 4.22 (m, 1 H), 3.87
(m, 2 H), 3.79 (dd, 1 H, J ) 10.6, 3.7 Hz), 3.66 (m, 2 H), 2.58 (m, 2
H), 1.30 (t, 1 H, J ) 7.4 Hz); 13C NMR (126 MHz, CDCl3) δ 138.8,
138.4, 138.0, 138.0, 128.5, 128.4, 128.4, 128.4, 128.2, 128.1, 127.9,
127.9, 127.9, 127.7, 127.7, 127.6, 83.1, 82.6, 79.6, 77.5, 75.7, 75.0,
73.5, 72.4, 70.5, 68.6, 23.8, 14.8; FTIR (neat film) 3030, 2955, 1596,
1453, 1363, 1074, 735 cm-1; HRMS (FAB) m/z calcd for C36H39O5S
(M - H) 583.2518, found 583.2517. Anal. Calcd for C36H40O5S: C,
73.94; H, 6.89. Found: C, 73.89; H, 6.78. â-Anomer: white solid, mp
Dihydrocholesteryl-2,3,4,6-tetra-O-benzoyl-r-D-mannopyrano-
88 °C (lit. mp 94 °C); Rf ) 0.51 (5% ethyl ether in benzene); [R]20
)
side (14). Viscous oil; Rf ) 0.50 (20% ethyl acetate in hexanes); [R]23
D
D
+9° (c ) 0.8, CHCl3) (lit. [R]24D ) +4.7°, c ) 2.0, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.4-7.1 (m, 20 H), 4.94 (d, 1H, J ) 10.9 Hz),
4.93 (d, 1 H, J ) 10.1 Hz), 4.85 (d, 1 H, J ) 11.1 Hz), 4.82 (d, 1 H,
J ) 10.8 Hz), 4.74 (d, 1 H, J ) 10.1 Hz), 4.61 (d, 1 H, J ) 12.2 Hz),
) -22° (c ) 2.7, CHCl3) 1H NMR (500 MHz, C6D6) δ 8.30-8.18
(m, 4 H), 8.00-7.94 (m, 4 H), 7.15-6.65 (m, 12 H), 6.56 (t, 1 H, J )
10.1 Hz), 6.40 (dd, 1 H, J ) 9.9, 3.3 Hz), 6.07 (dd, 1 H, J ) 3.2, 1.8
Hz), 5.21 (d, 1 H, J ) 1.8 Hz, H 1), 4.84 (dd, 1 H, J ) 12.2, 9.8 Hz),
4.70 (m, 1 H), 4.47 (dd, 1 H, J ) 12.2, 4.8 Hz), 3.49 (m, 1 H), 1.99
(m, 1 H), 1.84 (m, 1 H), 1.70-0.46 (m, 44 H); 13C NMR (126 MHz,
C6D6) δ 166.25, 166.23, 166.10, 165.99, 150.29, 138.47, 133.72, 133.63,
133.39, 133.27, 131.20, 130.56, 130.54, 130.48, 130.45, 130.36, 130.10,
130.06, 129.20, 128.99, 128.96, 128.77, 128.68, 128.49, 128.45, 128.30,
(29) Stewart, A. O.; Williams, R. M. J. Am. Chem. Soc. 1985, 107, 4289-
4296.
(30) (a) Dasgupta, F.; Garegg, P. J. Acta Chem. Scand. 1989, 43, 471.
(b) Li, Z.; Liu, P.; Li, Z.; Qui, D.; Cai, M. Synth. Commun. 1990, 14, 2169.
(c) Weygand, F.; Ziemann, H. Liebigs Ann. Chem. 1962, 657, 179-193.

Glycosylation with Diphenyl Sulfonium Reagents
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4277
124.65, 122.29, 96.84, 78.56, 72.18, 71.26, 70.06, 68.27, 63.58, 57.16,
57.09, 54.93, 45.42, 43.28, 40.81, 40.27, 37.33, 37.01, 36.58, 36.47,
36.07, 36.04, 32.78, 29.32, 29.03, 28.75, 28.14, 24.94, 24.69, 23.39,
23.14, 21.92, 19.38, 12.79, 12.72; FTIR (neat film) 2934, 2866, 1730,
1452, 1267, 1108, 1070, 710 cm-1; HRMS (FAB) m/z calcd for
C61H75O10 (MH+) 967.5360, found 967.5373. Anal. Calcd for
C61H74O10: C, 75.75; H, 7.71. Found: C, 75.56; H, 7.67.
Methyl-O-(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl)-(1 f 4)-
2,3,6-tri-O-benzyl-r-D-glucopyranoside (17). R-Anomer: viscous oil;
Rf ) 0.67 (3% ethyl acetate in dichloromethane); [R]20D ) +40° (c )
1
1.1, CHCl3) (lit. [R]23 ) +47.5°, c ) 0.71, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.32-7.06 (m, 35 H), 5.70 (d, 1 H, J ) 3.6 Hz, H 1),
5.04 (d, 1 H, J ) 11.5 Hz), 4.88 (d, 1 H, J ) 10.84 Hz), 4.80 (d, 1 H,
J ) 11.7 Hz), 4.78 (d, J ) 10.6 Hz), 4.77 (d, 1 H, J ) 10.9 Hz), 4.70
(d, 1 H, J ) 12.17 Hz), 4.60 (d, 1 H, J ) 3.57 Hz, H 1′), 4.59 (d, 1 H,
J ) 11.9 Hz), 4.57 (d, 1 H, J ) 12.2 Hz), 4.54 (d, 1 H, J ) 11.9 Hz),
4.52 (d, 1 H, J ) 12.2 Hz), 4.49 (s, 2H), 4.41 (d, 1 H, J ) 10.86 Hz),
4.27 (d, 1 H, J ) 12.1 Hz), 4.09 (t, 1 H, J ) 8.8 Hz), 4.07 (t, 1 H, J
) 9.0 Hz), 3.90 (dd, 1 H, J ) 9.8, 8.6 Hz), 3.84 (m, 2H), 3.67 (m,
3H), 3.59 (dd, 1 H, J ) 9.2, 3.7 Hz), 3.49 (dd, 1 H, J ) 9.7, 3.6 Hz),
3.48 (dd, 1 H, J ) 10.7, 2.9 Hz), 3.38 (dd, 1 H, J ) 10.66, 1.56 Hz),
3.37 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 138.9, 138.8, 138.5, 138.2,
138.0, 138.0, 128.5, 128.4, 128.3, 128.3, 128.3, 128.1, 128.0, 127.9,
127.9, 127.7, 127.7, 127.6, 127.5, 127.4, 127.3, 127.1, 126.8, 110.0,
97.8, 96.7, 82.1, 82.1, 80.2, 79.5, 77.8, 76.8, 75.0, 74.4, 73.5, 73.4,
73.3, 73.2, 72.3, 71.0, 69.5, 69.0, 68.2, 55.2; FTIR (neat film) 3028,
2926, 1453, 1156, 1095, 1028, 734 cm-1; HRMS (FAB) m/z calcd for
C62H65O11 (M - H) 985.4527, found 985.4531. â-Anomer: white solid;
mp 88-89 °C (lit. mp 87-88 °C); Rf ) 0.56 (3% ethyl acetate in
Methyl-O-(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl)-(1 f 6)-
2,3,4-tri-O-benzyl-D-glucopyranoside (15).31 R-Anomer: white solid,
mp 107-108 °C (lit. mp 101 °C); Rf ) 0.65 (33% ethyl acetate in
hexane); [R]20 ) +49° (c ) 0.6, CHCl3) (lit. [R]23 ) +57.1°, c )
D
D
1.97, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.4-7.1 (m, 35 H), 4.98
(d, 1 H, J ) 3.7 Hz, H 1), 4.96 (d, 1 H, J ) 11.0 Hz), 4.94 (d, 1 H,
J ) 10.9 Hz), 4.91 (d, 1 H, J ) 11.0 Hz), 4.82 (d, 1 H, J ) 11.0 Hz),
4.81 (d, 1 H, J ) 10.9 Hz), 4.77 (d, 1 H, J ) 10.9 Hz), 4.71 (d, 1 H,
J ) 11.9 Hz), 4.66 (s, 2 H), 4.64 (d, 1 H, J ) 11.3 Hz), 4.57 (d, 1 H,
J ) 12.1 Hz), 4.57 (d, 1 H, J ) 12.0 Hz), 4.55 (d, 1 H, J ) 3.5 Hz,
H 1′), 4.45 (d, 1 H, J ) 11.0 Hz), 4.42 (d, 1 H, J ) 12.1 Hz), 3.98 (t,
1 H, J ) 9.3 Hz), 3.95 (t, 1 H, J ) 9.3 Hz), 3.79 (m, 3 H), 3.71 (dd,
1 H, J ) 11.3, 2.7 Hz), 3.65 (m, 3 H), 3.55 (dd, 1 H, J ) 10.7, 2.2
Hz), 3.54 (dd, 1 H, J ) 9.7, 3.5 Hz), 3.44 (dd, 1 H, J ) 9.6, 3.6 Hz),
3.35 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 138.8, 138.5, 138.4,
138.2, 138.1, 128.4, 128.4, 128.3, 128.3, 128.0, 128.0, 127.9, 127.9,
127.8, 127.7, 127.6, 127.6, 127.6, 127.5, 127.5, 98.0, 97.3, 82.2, 81.7,
80.1, 80.0, 77.8, 77.6, 75.7, 75.5, 75.0, 74.9, 73.4, 72.3, 70.4, 70.2,
68.5, 66.0, 55.1; FTIR (neat film) 3030, 2924, 1453, 1159, 1136, 1028,
736 cm-1; HRMS (FAB) m/z calcd for C62H65O11 (M - H) 985.4527,
found 985.4531. Anal. Calcd for C62H66O11: C, 75.43; H, 6.74.
Found: C, 75.30; H, 6.78. â-Anomer: white solid; mp 128-130 °C
dichloromethane); [R]20 ) +20° (c ) 1.0, CHCl3) (lit. [R]23
)
D
D
+24.2°, c ) 2.23, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.49-7.20
(m, 35 H), 5.14 (d, 1 H, J ) 11.1 Hz), 4.91 (d, 1 H, J ) 10.8 Hz), 4.85
(d, 1 H, J ) 11.02 Hz), 4.85 (d, 1 H, J ) 11.1 Hz), 4.84 (s, 1 H), 4.83
(d, 1 H, J ) 11.05 Hz), 4.80 (d, 1 H, J ) 10.6 Hz), 4.80 (d, 1 H, J )
11.4 Hz), 4.65 (d, 1 H, J ) 12.2 Hz), 4.62 (d, 1 H, J ) 12.0 Hz), 4.62
(d, 1 H, J ) 3.7 Hz, H 1′), 4.60 (d, 1 H, J ) 11.0 Hz), 4.48 (d, 1 H,
J ) 12.0 Hz), 4.44 (d, 1 H, J ) 11.8 Hz), 4.43 (d, 1 H, J ) 7.9 Hz,
H 1), 4.42 (d, 1 H, J ) 12.0 Hz), 4.01 (dd, 1 H, J ) 10.0, 9.0 Hz),
3.90 (t, 1 H, J ) 9.2 Hz), 3.89 (dd, 1 H, J ) 11.0, 3.3 Hz), 3.88 (dd,
1 H, J ) 11.0, 3.2 Hz), 3.76 (dd, 1 H, J ) 11.0, 1.9 Hz), 3.65 (dd, 1
H, J ) 9.8, 8.8 Hz), 3.64 (dd, 1 H, J ) 9.8, 2.8 Hz), 3.59 (dd, 1 H, J
) 11.2, 4.8 Hz), 3.53 (dd, 1 H, J ) 10.9, 2.0 Hz), 3.51 (t, 1 H, J ) 8.9
Hz), 3.51 (m, 1 H), 3.41 (dd, 1 H, J ) 9.0, 7.9 Hz), 3.41 (s, 3H), 3.34
(ddd, 1 H, J ) 9.8, 4.6, 1.8 Hz); 13C NMR (126 MHz, CDCl3) δ 139.8,
138.8, 138.8, 138.6, 138.6, 138.1, 128.7, 128.6, 128.6, 128.5, 128.4,
128.3, 128.2, 128.2, 128.0, 128.0, 127.9, 127.8, 127.8, 127.7, 127.5,
127.3, 102.7, 98.6, 85.1, 83.0, 80.6, 79.0, 78.3, 76.9, 76.8, 75.8, 75.6,
75.4, 75.1, 75.0, 73.8, 73.6, 73.5, 70.2, 70.1, 69.2, 68.1, 55.5; FTIR
(neat film) 3028, 2926, 1453, 1156, 1095, 1028, 734 cm-1; HRMS
(FAB) m/z calcd for C62H65O11 (M - H) 985.4527, found 985.4531.
(lit. mp 133-135 °C); Rf ) 0.61 (33% ethyl acetate in hexane); [R]20
D
) +18.5° (c ) 1.3, CHCl3) (lit. [R]23 ) +18.6°, c ) 0.49, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 7.4-7.1 (m, 35 H), 4.97 (d, 1 H, J )
11.0 Hz), 4.96 (d, 1 H, J ) 10.7 Hz), 4.90 (d, 1 H, J ) 10.8 Hz), 4.79
(m, 4 H), 4.74 (d, 1 H, J ) 11.2 Hz), 4.71 (d, 1 H, J ) 11.1 Hz), 4.65
(d, 1 H, J ) 12.1 Hz), 4.60 (d, 1 H, J ) 3.4 Hz, H 1′), 4.58 (d, 1 H,
J ) 10.9 Hz), 4.52 (m, 3 H), 4.34 (d, 1 H, J ) 7.8 Hz, H 1), 4.18 (dd,
1 H, J ) 10.6, 2.0 Hz), 3.98 (t, 1 H, J ) 9.3 Hz), 3.82 (m, 1 H), 3.72
(dd, 1 H, J ) 11.1, 1.7 Hz), 3.67 (dd, 1 H, J ) 10.8, 4.9 Hz), 3.62 (t,
1 H, J ) 9.0 Hz), 3.56 (t, 1 H, J ) 9.4 Hz), 3.51 (m, 3 H), 3.42 (m,
1 H), 3.32 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 138.8, 138.4, 138.4,
138.1, 137.9, 128.4, 128.3, 128.2, 128.0, 127.8, 127.8, 127.7, 127.7,
127.6, 127.5, 97.9, 97.2, 82.1, 81.6, 80.1, 79.9, 77.7, 77.5, 75.7, 75.5,
75.0, 74.9, 73.4, 72.3, 70.3, 70.2, 68.4, 66.0, 55.1; FTIR (neat film)
3029, 2945, 1497, 1388, 1068, 739 cm-1; HRMS (FAB) m/z calcd for
C62H65O11 (M - H) 985.4527, found 985.4531. Anal. Calcd for
C62H66O11: C, 75.43; H, 6.74. Found: C, 75.59; H, 6.79.
Methyl-O-(2,3,4,6-tetra-O-benzoyl-â-D-glucopyranosyl)-(1 f 4)-
2,3,6-tri-O-benzyl-r-D-glucopyranoside (18). Viscous oil; Rf ) 0.54
(15% ethyl acetate in benzene); [R]20 ) +1° (c ) 1.5, CHCl3) (lit.
D
1
[R]25 ) +1°, c ) 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 8.0-
Methyl-O-(2,3,4,6-Tetra-O-benzoyl-â-D-glucopyranosyl)-(1 f 6)-
2,3,4-tri-O-benzyl-r-D-glucopyranoside (16). Viscous oil; Rf ) 0.40
D
7.2 (m, 35 H), 5.62 (t, 1 H, J ) 9.5 Hz), 5.55 (t, 1 H, J ) 9.6 Hz),
5.46 (dd, 1 H, J ) 9.6, 8.0 Hz), 5.07 (d, 1 H, J ) 11.2 Hz), 4.81 (d,
1 H, J ) 11.1 Hz), 4.78 (d, 1 H, J ) 8.1 Hz, H 1), 4.76 (d, 1 H, J )
12.9 Hz), 4.75 (d, 1 H, J ) 12.4 Hz), 4.60 (d, 1 H, J ) 12.2 Hz), 4.56
(d, 1 H, J ) 3.5 Hz, H 1′), 4.40 (dd, 1 H, J 12.1, 3.6 Hz), 4.34 (d, 1
H, J ) 12.2 Hz), 4.26 (dd, 1 H, J ) 12.1, 5.0 Hz), 3.96 (t, 1 H, J )
9.4 Hz), 3.88 (t, 1 H, J ) 9.1 Hz), 3.73 (m, 2 H), 3.50 (m, 1 H), 3.46
(dd, 1 H, J ) 9.5, 3.7 Hz), 3.42 (dd, 1 H, J ) 10.7, ∼1 Hz), 3.28 (s,
3 H); 13C NMR (126 MHz, CDCl3) δ 166.1, 165.8, 165.1, 164.9, 145.6,
139.3, 138.4, 137.9, 133.4, 133.4, 133.2, 133.0, 131.1, 129.8, 129.7,
129.7, 129.4, 129.1, 128.9, 128.9, 128.5, 128.4, 128.4, 128.3, 128.1,
127.8, 127.4, 127.2, 124.8, 100.4, 98.5, 80.0, 78.8, 77.3, 75.4, 73.6,
73.6, 73.2, 72.3, 71.8; FTIR (neat film) 3032, 2939, 1736, 1731, 1601,
1451, 1265, 1093, 710 cm-1; HRMS (FAB) m/z calcd for C62H57O15
(M - H) 1041.3697, found 1041.3693. Anal. Calcd for C62H58O15: C,
71.39; H, 5.60. Found: C, 71.08; H, 5.73.
(33% ethyl acetate in hexane); [R]20 ) +18° (c ) 1.4, CHCl3) (lit.
D
1
[R]21 ) +19.6°, c ) 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.99 (m, 1 H), 7.88 (m, 1 H), 7.82 (m, 1 H), 7.6-7.0 (m, 35 H), 5.89
(t, 1 H, J ) 9.6 Hz), 5.68 (t, 1 H, J ) 9.69 Hz), 5.60 (dd, 1 H, J ) 9.6,
7.8 Hz), 4.90 (d, 1 H, J ) 10.89 Hz), 4.83 (d, 1 H, J ) 7.8 Hz, H 1),
4.74 (d, 1 H, J ) 12.1 Hz), 4.69 (d, 1 H, J ) 11.1 Hz), 4.61 (dd, 1 H,
J ) 12.1, 3.6 Hz), 4.60 (d, 1 H, J ) 12.1 Hz), 4.51 (m, 3 H, incorporates
H 1′), 4.29 (d, 1 H, J ) 11.1 Hz), 4.15 (d, 1 H, J ) 10.3 Hz), 4.15 (m,
1 H), 3.89 (t, 1 H, J ) 9.3 Hz), 3.74 (m, 2 H), 3.43 (dd, 1 H, J ) 9.6,
3.6 Hz), 3.83 (t, 1 H, J ) 9.3 Hz), 3.21 (s, 3 H); 13C NMR (126 MHz,
CDCl3) δ 166.2, 166.9, 165.2, 165.0, 138.8, 138.2, 138.1, 133.5, 133.3,
133.2, 133.1, 129.9, 129.8, 129.7, 129.6, 129.4, 129.2, 128.8, 128.7,
128.5, 128.4, 128.3, 128.3, 128.3, 128.3, 128.2, 127.9, 127.9, 127.6,
127.5, 127.5, 127.0, 124.8, 101.3, 98.0, 81.9, 79.8, 77.4, 75.6, 74.7,
73.4, 72.9, 72.2, 71.8, 69.8, 69.5, 68.3, 63.3, 55.0; FTIR (neat film)
3032, 2930, 1735, 1731, 1602, 1452, 1267, 1093, 710 cm-1; HRMS
(FAB) m/z calcd for C62H57O15 (M - H) 1041.3697, found 1041.3693.
Anal. Calcd for C62H58O15: C, 71.39; H, 5.60. Found: C, 71.08; H,
5.40.
2′,3′,5′-Tri-O-benzoylthymidine (19). Viscous oil; Rf ) 0.13 (33%
ethyl acetate in hexanes); [R]23D ) -102° (c ) 1.7, CHCl3); 1H NMR
(500 MHz, C6D6) δ 8.12 (m, 2 H), 7.88 (m, 2 H), 7.84 (m, 2 H), 7.66
(m, 1 H), 7.56-7.48 (m, 4 H), 7.40-7.26 (m, 5 H), 6.47 (d, 1 H, J )
9.6 Hz, H 1), 6.31 (t, 1 H, J ) 2.6 Hz), 5.55 (m, 1 H), 5.49 (dt, 1 H,
J ) 9.8, 2.7 Hz), 4.33 (dd, 1 H, J ) 11.0, 5.7 Hz), 4.24 (t, 1 H, J )
11.0 Hz),1.95 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 165.41, 165.11,
164.85, 134.49, 133.84, 133.78, 133.66, 129.98, 129.87, 129.25, 128.86,
(31) (a) Kim, W.-S.; Hosono, S.; Sasai, H.; Shibasaki, M. Heterocycles
1996, 42, 795-809. (b) Fukase, K.; Hasuoka, A.; Kinoshita, I.; Aoki, Y.;
Kusumoto, S. Tetrahedron 1995, 51, 4923. (c) Koide, K.; Ohno, M.;
Kobayashi, S. Tetrahedron Lett. 1991, 48, 7065-7068.

4278 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
Garcia and Gin
128.74, 128.59, 128.52, 128.18, 112.17, 78.55, 69.19, 68.20, 66.74,
64.28, 15.58; FTIR (neat film) 3250 (br), 3030, 1731, 1698, 1694, 1265,
1108, 1094, 709 cm-1; HRMS (FAB) m/z calcd for C31H27N2O9 (MH+)
571.1717, found 571.1719. Anal. Calcd for C31H26N2O9: C, 65.26; H,
4.59; N, 4.91. Found: C, 64.90; H, 4.91; N, 4.45.
acetate in hexane); [R]20D ) +86° (c ) 0.6, CHCl3) (lit. [R]20D ) +83°,
c ) 3.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.42-7.00 (m, 25 H),
5.51 (d, 1 H, J ) 3.5 Hz, H 1), 5.09 (d, 1 H, J ) 10.9 Hz), 4.93 (d, 1
H, J ) 10.9 Hz), 4.87 (d, 1 H, J ) 11.8 Hz), 4.82 (d, 1 H, J ) 12.1
Hz), 4.71 (d, 1 H, J ) 12.1 Hz), 4.62 (d, 1 H, J ) 11.9 Hz), 4.52 (d,
1 H, J ) 10.7 Hz), 4.42 (d, 1 H, J ) 12.0 Hz), 4.24 (t, 1 H, J ) 9.2
Hz), 3.91 (m, 1 H), 3.82 (dd, 1 H, J ) 10.0, 8.8 Hz), 3.76 (m, 2 H),
3.59 (dd, 1 H, J ) 10.8, 2.1 Hz); 13C NMR (126 MHz, CDCl3) δ 156.6,
138.7, 138.1, 137.9, 137.7, 129.3, 128.4, 128.3, 128.3, 128.2, 127.9,
127.8, 127.8, 127.8, 127.6, 127.5, 122.2, 116.7, 95.3, 81.9, 79.6, 75.7,
75.0, 73.3, 73.2, 70.7, 68.1; FTIR (neat film) 3088, 2922, 1597, 1495,
1225, 1099, 1046, 1028, 697 cm-1; HRMS (FAB) m/z calcd for
C41H41O6 (M + H) 629.2903, found 629.2906. â-Anomer: white solid;
mp 85-86 °C (lit. mp 84.5-86 °C); Rf ) 0.75 (33% ethyl acetate in
hexane); [R]20 ) -11° (c ) 0.5, CHCl3) (lit. [R]25 ) -11.8°, c )
1.2, CHCl3); H NMR (500 MHz, CDCl3) δ 7.37-7.05 (m, 25 H),
5.05 (d, 1 H, J ) 11.0 Hz), 5.01 (m (X of ABX), 1 H, JH1,H2 ) 7.57
Hz, H 1) 4.96 (d, 1 H, J ) 11.0 Hz), 4.84 (m, 3 H), 4.60 (d, 1 H, J )
12.0 Hz), 4.57 (d, 1 H, J ) 10.2 Hz), 4.53 (d, 1 H, J ) 12.1 Hz), 3.80
(dd, 1 H, J ) 10.8, 1.9 Hz), 3.77 (m, 2 H), 3.71 (m, 1 H), 3.69-3.60
(m, 3 H); 13C NMR (126 MHz, CDCl3) δ 138.4, 138.1, 138.0, 137.8,
129.4, 128.3, 128.3, 128.2, 128.1, 127.8, 127.7, 127.7, 127.6, 127.6,
127.5, 127.4, 122.5, 116.7, 101.5, 84.5, 81.9, 77.5, 75.7, 75.0, 74.9,
74.9, 73.4, 68.7; FTIR (neat film) 3030, 2968, 1495, 1453, 1229, 1070,
1028, 696 cm-1; HRMS (FAB) m/z calcd for C41H41O6 (M + H)
629.2903, found 629.2906.
1-Deoxy-1-(N-trimethylacetyl)-2,3,4,6-tetra-O-benzyl-D-glucopy-
ranoside (20). Viscous oil; Rf ) 0.52 (33% ethyl acetate in hexane);
[R]20D ) +54° (c ) 1.1°, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.2-
7.2 (m, 20 H), 6.30 (d, 1 H, J ) 6.6 Hz), 5.81 (dd, 1 H, J ) 6.6, 5.6
Hz, H 1), 4.93 (d, 1 H, J ) 10.9 Hz), 4.80 (d, 1 H, J ) 11.0 Hz), 4.79
(d, 1 H, J ) 10.3 Hz), 4.64 (d, 1 H, J ) 12.1 Hz), 4.55 (m, 2 H), 4.52
(d, 1 H, J ) 10.6 Hz), 4.48 (d, 1 H, J ) 12.1 Hz), 3.85 (dd, 1 H, J )
9.2, 5.4 Hz), 3.80 (dd, 1 H, J ) 10.8, 3.1 Hz), 3.76 (dd, 1 H, J ) 9.6,
9.0 Hz), 3.68 (dd, 1 H, J ) 10.7, 2.2 Hz), 3.60 (t, 1 H, J ) 9.0 Hz),
3.59 (m, 1 H), 1.23 (s, 9 H); NOE 12.11% enhancement of H-2 upon
irradiation of H-1; 13C NMR (126 MHz, CDCl3) δ 179.3, 138.3, 137.8,
137.8, 137.1, 128.4, 128.4, 128.3, 128.2, 128.0, 127.9, 127.9, 127.8,
127.7, 127.7, 127.6, 127.6, 81.9, 77.5, 76.7, 75.4, 75.1, 74.6, 73.5, 72.0,
71.0, 68.1, 27.4; FTIR (neat film) 2871, 1672, 1497, 1454, 1084, 1073,
1028, 736, 697 cm-1; HRMS (FAB) m/z calcd for C39H46NO6 (M +
H) 624.3325, found 624.3325. Anal. Calcd for C39H45NO6: C, 75.09;
H, 7.27; N, 2.25. Found: C, 74.86; H, 7.25; N, 2.34.
D
1
D
Azido-2,3,5-tri-O-benzyl-L-arabinoside (21). Viscous oil. Anal.
Calcd for C26H27N3O4: C, 70.09; H, 6.11; N, 9.43. Found (anomeric
mixture): C, 70.31; H, 6.05; N, 9.17. Analytical samples of each anomer
were separated by HPLC. R-Anomer: viscous oil; Rf ) 0.58 (20%
1
ethyl acetate in hexane); [R]23 ) -102° (c ) 0.7, CHCl3); H NMR
Myristoyl-3,4,6-tri-O-acetyl-2-deoxy-2-N-phthalamido-â-D-glu-
D
(500 MHz, C6D6) δ 7.27-7.46 (m, 27H), 5.24 (d, 1 H, J ) 1.48, H 1),
4.50 (q, 1 H, J ) 10.37), 4.40 (d, 1 H, J ) 12.24), 4.37 (d, 1 H J )
11.99), 4.29 (d, 1 H, J ) 12.21), 4.26 (d, 1 H, J ) 12.11), 4.17 (d, 1
H, J ) 11.80), 4.15 (dd, 1 H, J ) 2.64, 8.00), 4.09 (d, 1 H, J ) 11.78),
3.95 (dd, 1 H, J ) 1.61, 2.52), 3.50 (d, 2 H, J ) 5.61); 13C NMR (126
MHz, C6D6) δ 139.07, 138.67, 138.13, 128.99, 128.93, 128.91, 128.68,
128.45, 128.39, 128.36, 128.25, 128.20, 128.09, 94.94, 88.52, 84.20,
84.06, 73.75, 72.52, 72.39, 70.12; FTIR (neat film) 3031, 2865, 2106,
1454, 1240, 1097, 736, 697 cm-1; HRMS (FAB) m/z calcd for
C26H27N3O4Na (M + Na+) 468.1899, found 468.1890. â-Anomer:
viscous oil; Rf ) 0.48 (20% ethyl acetate in hexane); [R]23D ) +111°
(c ) 0.7, CHCl3); 1H NMR (500 MHz, C6D6) δ 7.25-7.03 (m, 16 H),
4.89 (d, 1 H, J ) 4.8, H 1), 4.44 (d, 1 H, J ) 11.86), 4.40 (d, 1 H, J
) 12.13), 4.34 (d, 1 H, J ) 11.75), 4.29 (s, 2 H), 4.21-4.16 (m, 3 H),
3.84 (t, 1 H, J ) 4.80), 3.59-3.51 (m, 2 H); 13C NMR (126 MHz,
C6D6) δ 139.08, 138.89, 138.34, 129.03, 128.91, 128.90, 128.46, 128.37,
128.29, 128.19, 128.09, 90.79, 84.75, 82.74, 81.89, 73.80, 73.00, 72.53,
71.28; FTIR (neat film) 3064, 3031, 2866, 2118, 1496, 1454, 1365,
1250, 1068, 1028, 736, 697 cm-1; HRMS (FAB) m/z calcd for
C26H27N3O4Na (M + Na+) 468.1899, found 468.1895.
Methyl-O-(2,3,4-tri-O-pivaloyl-â-D-xylopyranosyl)-(1 f 6)-2,3,4-
tri-O-benzyl-D-glucopyranoside (22). Rf ) 0.14 (11% ethyl acetate
in hexane); [R]23D ) -8.7 (c ) 1.8, CHCl3); 1H NMR (400 MHz, C6D6)
δ 7.28-7.20 (m, 6 H), 7.16-7.00 (m, 9 H), 5.34 (t, 1 H, J ) 9.0 Hz),
5.21 (dd, 1 H, J ) 7.1, 9.1 Hz), 4.98 (m, 1 H), 4.95 (d, 1 H, J ) 11.4
Hz), 4.91 (d, 1 H, J ) 11.5 Hz), 4.71 (d, 1 H, J ) 11.5 Hz), 4.59 (d,
1 H, J ) 3.3 Hz, H 1′), 4.57 (d, 1 H, J ) 11.4 Hz), 4.47 (d, 1 H, J )
12.1 Hz), 4.40 (d, 1 H, J ) 12.1 Hz), 4.23 (d, 1 H, J ) 7.2 Hz, H 1),
4.18 (t, 1 H, J ) 9.2 Hz), 3.94 (m, 2 H), 3.77 (dd, 1 H, J ) 5.6, 10.6
Hz), 3.48 (m, 2 H), 3.20 (s, 3 H), 2.82 (dd, 1 H, J ) 9.5, 11.5 Hz),
1.18 (s, 9 H), 1.10 (s, 9 H), 1.05 (s, 9 H); 13C NMR (100 MHz, C6D6)
δ 177.29, 176.99, 176.55, 140.04, 139.58, 139.48, 128.89, 128.80,
128.37, 128.36, 128.32, 128.28, 128.13, 128.05, 128.88, 102.06, 98.49,
82.56, 81.26, 78.80, 75.88, 75.15, 73.12, 72.49, 71.69, 70.97, 69.73,
69.10, 62.76, 55.47, 39.18, 39.15, 39.08, 27.72, 27.66, 27.53; FTIR
(neat film) 2971, 1742, 1480, 1455, 1279, 1143, 1074, 698 cm-1. Anal.
Calcd for C48H64O13: C, 67.90; H, 7.60. Found: C, 67.93; H, 7.62.
Phenyl 2,3,4,6-Tetra-O-benzyl-D-glucopyranoside (23).32 Viscous
oil. Anal. Calcd for C40H40O6: C, 77.90; H, 6.54. Found (anomeric
mixture): C, 77.79; H, 6.63. Analytical samples of each anomer were
separated by HPLC. R-Anomer: viscous oil; Rf ) 0.75 (33% ethyl
copyranoside (24). Viscous oil; Rf ) 0.65 (50% ethyl acetate in
1
hexanes); [R]23 ) +40° (c ) 3, CHCl3); H NMR (500 MHz, C6D6)
D
δ 7.46 (dd, 1 H, J ) 4.8, 3.3 Hz,), 7.12 (d, 1 H, J ) 8.9 Hz, H 1), 6.82
(dd, 1 H, J ) 5.5, 3.0 Hz), 6.27 (dd, 1 H, J ) 10.7, 9.3 Hz), 5.44 (dd,
1 H, J ) 10.1, 9.4 Hz), 4.88 (dd, 1 H, J ) 10.4, 8.7 Hz), 4.28 (dd, 1
H, J ) 12.7, 3.9 Hz), 3.97 (dd, 1 H, J ) 12.4, 1.9 Hz), 3.402 (ddd, 1
H, J ) 10.3, 2.3, 1.5 Hz), 1.90 (dt, 2 H, J ) 7.4, 2.2 Hz), 1.71 (s, 3
H), 1.62 (s, 3 H), 1.48 (s, 3 H), 1.36-0.80 (m, 25 H); 13C NMR (126
MHz, C6D6) δ 17107, 170.4, 170.3, 169.6, 128.7, 128.5, 128.4, 128.3,
90.6, 73.4, 71.5, 68.8, 61.5, 54.9, 34.3, 32.7, 30.5, 30.5, 30.4, 30.3,
30.2, 30.0, 29.8, 29.4, 25.1, 23.5, 20.6, 20.5, 20.2, 20.2, 14.7; FTIR
(neat film) 2926, 2854, 1756, 1723, 1386, 1227, 1082, 1045, 722 cm-1
;
HRMS (FAB) m/z calcd for C34H47NO11Na (MNa+) 668.3046, found
668.3047. Anal. Calcd for C34H47NO11: C, 63.24; H, 7.34; N, 2.17.
Found: C, 63.36; H, 7.49; N, 2.22.
General Procedure for the Detection of Reactive Glycosyl
Intermediates. Trifluoromethanesulfonyl 2,3,4,6-Tetra-O-methyl-D-
mannopyrannoside (34). To a solution of 2,3,4,6-tetra-O-methyl-R-D-
mannopyranosyl fluoride (33) (15 mg, 0.063 mmol, 1.0 equiv) in
CD2Cl2 (0.8 mL) in a 5 mm NMR tube at -78 °C was added TMSOTf
(19 µL, 0.095 mmol, 1.5 equiv). The reaction was briefly agitated
(∼2-3 s; Fisher Vortex Genie 2) and was placed in the NMR probe at
-60 °C. The conversion of 33 to 34 was monitored at this temperature
over the course of 2 h (85% conversion; Figure 2a).
Bis(pentadeuteriophenyl)sulfonium 2,3,4,6-Tetra-O-methyl-r-D-
mannopyranoside (35). To a freshly prepared solution of glycosyl
triflate 34 (vide supra) at -78 °C was added a solution of bis-
(pentadeuteriophenyl) sulfoxide (40 mg, 0.19 mmol, 3.0 equiv) in CD2-
Cl2 (0.2 mL). After the solution was briefly agitated, the reaction was
placed in the NMR probe at -60 °C. The conversion of 34 to 35 was
complete within 20 min at this temperature (Figure 2b).
1-Deoxy-2,3,4,6-tetra-O-methyl-D-mannopyranosyl 2-Chloropy-
ridinium Triflate (36). To a freshly prepared solution of glycosyl
triflate 34 (vide supra) at -78 °C was added 2-chloropyridine (24 µL,
0.25 mmol, 4.0 equiv). After the solution was briefly agitated, the
reaction was placed in the NMR probe at -60 °C. The conversion of
34 to 36 was complete within 20 min at this temperature (Figure 2c).
Dehydrative Glycosylation with 2,3,4,6-Tetra-O-methyl-D-man-
nopyranose (38) To Form the Isopropyl 2,3,4,6-Tetra-O-methyl-D-
Mannopyranoside (8). To a solution of 2,3,4,6-tetra-O-methyl-D-
mannopyranose (38) (8.0 mg, 0.034 mmol, 1.0 equiv) and bis(pentadeu-
teriophenyl) sulfoxide (14 mg, 0.068 mmol, 2.0 equiv) in CD2Cl2 (1
mL) at -78 °C in a 5 mm NMR tube was added triflic anhydride (8
µL, 0.05 mmol, 1.4 equiv). After the solution was briefly agitated, the
(32) (a) Briner, K.; Vasella, A. HelV. Chim. Acta 1990, 73, 1764-1778.
(b) Koto, S.; Morishima, N.; Araki, M.; Tsuchiya, T.; Zen, S. Bull. Chem.
Soc. Jpn. 1981, 54, 1895-1896.

Glycosylation with Diphenyl Sulfonium Reagents
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4279
reaction was placed in the NMR probe at -60 °C. The conversion of
38 to 35 was complete within 20 min at this temperature (Figure 4b).
The reaction was removed from the NMR probe, cooled to -78 °C,
and 2-chloropyridine was added (10 µL, 0.102 mmol, 3.0 equiv). After
the solution was briefly agitated, the reaction was placed in the NMR
probe at -60 °C and then warmed to -40 °C. Conversion of 35 to the
the Alfred P. Sloan Foundation. We also thank Ms. Jennifer
Poole and Ms. Jannine Haberman for their assistance in the
preparation of glycosides 10, 16, and 18. NMR spectra were
obtained in the Varian Oxford Instrument Center for Excellence
in NMR Laboratory, funded in part by the W.M. Keck
Foundation, the National Institutes of Health (Grant PHS 1 S10
RR10444), and the National Science Foundation (Grant NSF
CHE 96-10502). The assistance of Drs. Vera Mainz, Feng Lin,
and Paul Molitor of the VOICE NMR Spectroscopy Lab at the
University of Illinois is recognized.
1
glycosyl pyridinium intermediate 36 was monitored via H NMR at
-40 °C and was found to be complete within 30 min at this temperature
(Figure 4d). The reaction was removed from the NMR probe and cooled
to -78 °C, and 2-propanol (8 µL, 0.1 mmol, 3.0 equiv) was added.
After the solution was briefly agitated, the reaction was placed in the
NMR probe at -40 °C and then warmed to 15 °C. Conversion to the
isopropyl glycoside (8) was monitored via 1H NMR at 15 °C and was
found to be complete within 2.5 h at this temperature (Figure 4f).
Supporting Information Available: 1H NMR data of 34-
37, COSY NMR data of 35 and 37, HMQC NMR data of 35
and 37, and NOE NMR data of 35 and 37 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by the
National Institutes of Health (Grant GM-58833), the Arnold and
Mabel Beckman Foundation (BYI), Glaxo Wellcome Inc., and
JA993595A