A general strategy for stereoselective glycosylations

Article abstract of DOI:10.1021/ja052548h

The principal challenge that the synthesis of oligosaccharides of biological importance presents is the development of a general approach for the stereoselective introduction of a glycosidic linkage. It is shown here that a (1S)-phenyl-2-(phenylsulfanyl)e

Full text of DOI:10.1021/ja052548h

Published on Web 08/05/2005
A General Strategy for Stereoselective Glycosylations
Jin-Hwan Kim, Hai Yang, Jin Park, and Geert-Jan Boons*
Contribution from the Complex Carbohydrate Research Center, UniVersity of Georgia,
315 RiVerbend Road, Athens, Georgia 30602
Received April 19, 2005; E-mail: gjboons@ccrc.uga.edu
Abstract: The principal challenge that the synthesis of oligosaccharides of biological importance presents
is the development of a general approach for the stereoselective introduction of a glycosidic linkage. It is
shown here that a (1S)-phenyl-2-(phenylsulfanyl)ethyl moiety at C-2 of a glycosyl donor can perform
neighboring group participation to give a quasi-stable anomeric sulfonium ion. Due to steric and electronic
factors, the sulfonium ion is formed as a trans-decalin ring system. Displacement of the sulfonium ion by
a hydroxyl leads to the stereoselective formation of R-glycosides. NMR experiments were employed to
show convincingly the presence of the â-linked sulfonium ion intermediate. The (1S)-phenyl-2-(phenylsul-
fanyl)ethyl moiety could be introduced by reaction of a sugar alcohol with acetic acid (1S)-phenyl-2-
(phenylsulfanyl)ethyl ester in the presence of BF3-OEt2. Furthermore, it could be removed by conversion
into acetate by treatment with BF3-OEt2 in acetic anhydride. The introduction as well as the cleavage
reaction proceeds through the formation of an intermediate episulfonium ion. The use of the new
methodology in combination with traditional neighboring group participation by esters to introduce
â-glycosides makes it possible, for the first time, to synthesize a wide variety of oligosaccharides by routine
procedures. The latter was demonstrated by the synthesis of the Galili trisaccharide, which has been
identified as an epitope that can trigger acute rejections in xeno-transplantations, by the one-pot two-step
glycosylation sequence.
Introduction
compounded by the fact that, in biological samples, complex
carbohydrates are often found in low concentrations and in
Glycoconjugates are the most functionally and structurally
diverse molecules in nature, and it is now well established that
protein- and lipid-bound saccharides play essential roles in many
molecular processes impacting eukaryotic biology and disease.1-3
Examples of such processes include fertilization, embryogenesis,
neuronal development, hormone activities, the proliferation of
cells, and their organization into specific tissues. Remarkable
changes in the cell-surface carbohydrates occur with tumor
progression, which appears to be intimately associated with the
dreaded state of metastasis. Furthermore, carbohydrates are
capable of inducing a protective antibody response, which is a
major contributor to the survival of the organism during
infection.
microheterogeneous forms, which greatly complicates their
isolation and characterization.
The chemical synthesis of complex carbohydrates involves
the coupling of a fully protected glycosyl donor bearing a
leaving group at its anomeric center, with a suitably protected
glycosyl acceptor that contains often only one free hydroxyl
group.7 In many cases, these reactions lead to a mixture of two
stereoisomers that differ in the configuration of the anomeric
center. The most reliable method for stereoselective glyco-
sylations is based on the neighboring group participation by a
2-O-acyl functionality (Scheme 1a).4 In these reactions, a
promoter activates an anomeric leaving group resulting in its
departure and the formation of an oxocarbenium ion. Subse-
quent, neighboring group participation of the 2-O-acyl protecting
group will give a more stable acetoxonium ion. An alcohol can
attack the anomeric center of the acetoxonium ion from only
one face providing a 1,2-trans-glycoside. Thus, in the case of
glucosyl-type donors, â-linked products will be formed while
mannosides will give R-glycosides. The introduction of 1,2-
cis-glycosidic linkages, such as R-glucosides and R-galactosides,
requires glycosyl donors with a nonassisting functionality at C-2.
Invariably, the use of these glycosyl donors leads to the
formation of mixtures of anomers.5 Separation of these anomers
requires time-consuming purification protocols resulting in loss
of material. It also limits the use of one-pot multistep glyco-
The development of routine procedures for the chemical
synthesis of oligonucleotide fragments (DNA and RNA) and
peptides has altered the face of modern biology. Although
significant improvements have been made,4-6 there is still no
general method for the preparation of complex carbohydrates
of biological importance. In general, the chemical synthesis of
a target compound is a research project that may require many
months and perhaps years to be completed. These problems are
(1) Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek, R. A. Science
2001, 291, 2370-2376.
(2) Varki, A. Glycobiology 1993, 3, 97-130.
(3) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
(4) Boons, G.-J. Contemp. Org. Synth. 1996, 3, 173-200.
(5) Demchenko, A. V. Synlett 2003, 1225-1240.
(6) Koeller, K. M.; Wong, C. H. Chem. ReV. 2000, 100, 4465-4493.
(7) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357--2364.
9
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J. AM. CHEM. SOC. 2005, 127, 12090-12097
10.1021/ja052548h CCC: $30.25 © 2005 American Chemical Society

General Strategy for Stereoselective Glycosylations
A R T I C L E S
Scheme 1. Conventional and New Approaches for Stereoselective
Scheme 2. Preparation of Glycosyl Donors 4 and 8
Glycosylation
sylations6,8 and automated polymer-supported synthesis9-11 to
oligosaccharides that only contain 1,2-trans-glycosides. Thus,
the stereoselective formation of 1,2-cis-glycosides is the prin-
cipal challenge of complex oligosaccharide synthesis.
had been formed. Compounds 2 and 6 could be converted into
glycosyl donors 4 and 8 by either removal of the anomeric acetyl
ester or allyl ether followed by conversion of the hemiacetals
into anomeric trichloroacetimidate using standard reaction
conditions (Scheme 2).16
With glycosyl donors 4 and 8 at hand, attention was focused
on the glycosylation of a range of different glycosyl acceptors
(Scheme 3). Thus, coupling of 4 or 8 with glycosyl acceptor 9
using a catalytic amount of TMSOTf in dichloromethane at -78
°C followed by gradual warming to 10 °C gave, after a reaction
time of 3 h, disaccharides 10 and 11 as only the R-glycosides
in good yields (protocol A). To demonstrate the generality of
the approach, glycosyl acceptors 12, 15, and 18 were also
coupled with 4 and 8 and as can be seen in Scheme 3; in each
case, only the expected R-anomer was isolated.
TLC analysis of the reaction mixture indicated that the
glycosyl donor had been consumed within 10 min after adding
TMSOTf. The glycoside products were, however, formed over
a period of 3 h indicating the presence of a quasi-stable
intermediate anomeric sulfonium ion. Furthermore, it was
observed that some degradation had occurred probably due to
the acidic nature of the reaction conditions. To address the latter
problem, the glycosylations were performed by an alternative
protocol (Scheme 3, protocol B) whereby the glycosyl donor
was first activated with TMSOTf followed by the addition of
the acceptor in the presence of the base 2,6-di-tert-butyl-4-
methylpyridine. As expected, under these conditions no deg-
radation was observed and, in each case, the disaccharides were
isolated in improved and near quantitative yield.
The fact that the glycosylations lead to the formation of
exclusively R-anomers provides strong support that the reactions
proceed through an equatorially substituted anomeric sulfonium
ion. To confirm the presence of this intermediate, glycosyl donor
8 in CD2Cl2 at -50 °C was treated with 1 equiv of TMSOTf,
and after the temperature was raised to -20 °C, 1H, 1H-TOCSY,
HSQC, and HMBC NMR spectra were recorded. The collected
We describe here a novel strategy for the stereoselective
introduction of 1,2-cis-glycosides, which in combination with
conventional methods using neighboring group participation by
C-2 esters5 will allow the routine preparation of a wide variety
of complex oligosaccharides. The new glycosylation approach
is based on neighboring group participation of a (1S)-phenyl-
2-(phenylsulfanyl)ethyl moiety at C-2 of a glycosyl donor
(Scheme 1b). Upon formation of an oxocarbenium ion, the
nucleophilic phenylsulfanyl moiety of the C-2 functionality will
participate, leading to the formation of an intermediate sulfonium
ion as either trans- or cis-decalin. The formation of the trans-
decalin is expected due to the absence of unfavorable gauche
interactions. In addition, the cis-decalin system will place the
phenyl substituent in an axial position inducing further unfavor-
able steric interactions.12 Displacement of the equatorial ano-
meric sulfonium ion by a sugar alcohol will then lead to the
formation of a 1,2-cis-glycoside.
Results and Discussion
The (1S)-phenyl-2-(phenylsulfanyl)ethyl moiety could easily
be installed by reaction with a sugar alcohol, such as 113 and
5,14 with acetic acid (1S)-phenyl-2-(phenylsulfanyl)ethyl ester
in the presence of BF3-OEt2.15 This reaction proceeds by a
BF3-OEt2-promoted departure of the acetate with concomitant
formation of an episulfonium ion. Subsequently, nucleophilic
attack at the benzylic position of the episulfonium ion by a sugar
hydroxyl leads to the required substituted benzyl ether with
overall retention of configuration. Detailed NMR analysis of
products 2 and 6 revealed that no other regio- or stereoisomers
(8) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem. Soc.,
Perkin Trans. 1 1998, 51-65.
(9) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
(10) Seeberger, P. H.; Haase, W. C. Chem. ReV. 2000, 100, 4349.
(11) Kahne, D. Curr. Opin. Chem. Biol. 1997, 1, 130-135.
(12) Kim, J. H.; Yang, H.; Boons, G. J. Angew. Chem., Int. Ed. 2005, 44, 947-
949.
(13) Yu, H.; Ensley, H. E. Tetrahedron Lett. 2003, 44, 9363-9366.
(14) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6661-
6666.
(15) Fox, D. J.; House, D.; Warren, S. Angew. Chem.-Int. Edit. 2002, 41, 2462-
(16) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994, 50,
21-123.
2482.
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A R T I C L E S
Kim et al.
Scheme 3. Stereoselective Glycosylations with Glycosyl Donors 4
and 8
Scheme 4 a
a
Key: (i) TMSOTf, CD2Cl2, -50 to 0 °C; (ii) MeOH, -20 to 0 °C.
1
1
(a) H NMR spectrum of glycosyl donor 8. (b) H TOCSY 1D spectrum
on irradiation of H4 of sulfonium ion 21. (c) HMBC spectrum of sulfonium
ion 21.
Scheme 5. Glycosylations with Glycosyl Donors 23, 25, 27, and 8
data showed the formation of a single new compound, which
was unambiguously identified as the sulfonium ion 21 (Scheme
4). Upon activation, the anomeric proton of 8 (δ 6.58, d, J1,2
)
2.5 Hz) shifted upfield (δ 5.30, d, J1,2 ) 9.5 Hz) and its large
vicinal coupling constant established an equatorial orientation
of the anomeric substituent. The coupling constants of the other
saccharide protons showed that no conformational distortion of
the saccharide ring had occurred. The HMBC spectrum, which
allows the determination of three-bond proton-carbon cou-
plings, showed a correlation between C-1 and H8eq, proving
that the trans-decalin system of 21 had been formed. Treatment
of 21 with methanol resulted in the clean formation of the
R-methyl glycoside 22, demonstrating that the glycosylation
proceeds by inversion of configuration of the anomeric center.
Next, a number of experiments were performed to establish
which features of the (1S)-phenyl-2-(phenylsulfanyl)ethyl moiety
are important for controlling the R-anomeric selectivity. In this
respect, a reaction of an intermediate oxocarbenium ion with
an externally delivered sulfide may also lead to the formation
of an equatorially substituted sulfonium ion, which may be
displaced by a sugar alcohol to give an R-glycoside. Further-
more, the chiral center of the (1S)-phenyl-2-(phenylsulfanyl)-
ethyl moiety may not be essential for achieving absolute
R-anomeric selectivity. It may well be possible that trans- vs
cis-decalin formation in combination with stereoelectronic
effects is sufficient to induce the formation of a â-substituted
sulfonium ion reacting to an R-glycoside. To investigate these
issues, trichloroacetimidates 23, 25, and 27 were coupled with
15 using TMSOTf as a promoter and the results were compared
with a similar coupling with glycosyl donor 8 (Scheme 5). A
standard glycosylation of trichloroacetimidate 23, which has a
C-2 benzyl ether, gave the disaccharide 24 as a 3/1 mixture of
R/â anomers. When the glycosylation was performed in the
presence of ethyl phenyl sulfide (5 equiv), only a marginal
increase in R-anomeric selectivity (R/â ) 6/1) was observed.
With the establishment that intramolecular delivery of the
phenylsulfanyl moiety is important for obtaining absolute
R-anomeric selectivity, glycosylations were performed with
glycosyl donors 25 and 27, which have modified C-2 function-
alities. In the case of 25, the C-2 functionality lacks the (1S)-
9
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General Strategy for Stereoselective Glycosylations
A R T I C L E S
Scheme 6. Preparation of Glycosyl Donor 29, One-Pot Two-Step
Synthesis of Trisaccharide 32, and Deprotection
phenyl moiety whereas, in the glycosyl donor 27, it has an
opposite (1R)-stereochemistry. In the latter case, the formation
of a â-substituted sulfonium ion will place the (1R)-phenyl
substituent in an axial orientation inducing unfavorable steric
interactions. In the alternative R-substituted sulfonium ion (cis-
decalin), the (1R)-phenyl group will adopt an equatorial orienta-
tion; however, this intermediate will experience unfavorable
gauche interactions. Displacement of the R-sulfonium ion would
lead to the formation of â-glycoside. Thus, a standard glyco-
sylation with glycosyl donor 25 gave the disaccharide 26 as a
8/1 mixture of R/â anomers. A similar glycosylation with 27
resulted in the formation of 28 as an anomeric mixture (R/â )
1/1). These results indicate that a combination of an equatorially
oriented (1S)-phenyl substituent and trans-decalin formation are
important features for controlling the R-anomeric selectivity.
The new glycosylation protocol described here in combination
with traditional neighboring group participation by esters should
allow the installment of R- as well as â-glycosides. To
demonstrate the combined use of these methodologies trisac-
charide 34,17-24 which has been identified as an epitope that
can trigger acute rejections in xeno-transplantations,25,26 was
prepared. It was anticipated that this compound could be
assembled from the monomeric building blocks 29, 30, and 31
using a one-pot two-step glycosylation sequence. Galactosyl
donor 29, which possesses a (1S)-phenyl-2-(phenylsulfanyl)-
ethyl functionality at C-2, will direct the formation of an
R-galactoside, whereas the C-2 benzoyl of 30 will induce the
formation of a â-galactoside. The novel galactosyl donor 29
could be prepared in a good overall yield starting from 1,3,4,6-
tetra-O-acetyl-R-D-galactose27 using a sequence of reactions
similar to that used for the synthesis of compound 4 (Scheme
6). Glycosyl donor 29 was treated with TMSOTf to form an
intermediate anomeric sulfonium ion, which was reacted with
glycosyl acceptor 30 for 4 h at 0 °C. Next, methyl glycoside
31 and NIS were added to the reaction mixture, and within 2 h,
trisaccharide 32 was formed. This compound was isolated in a
yield of 52% as a single anomer with expected anomeric
configuration. Interestingly, the NIS/TMSOTf promoter system
does not affect the (1S)-phenyl-2-(phenylsulfanyl)ethyl group.
Furthermore, preactivation of 29 was required to achieve a high
yield.
cleophilic substitution of sulfur of the resulting intermediate
should lead to the formation of an episulfonium ion and acetyl
ester. Nucleophilic attack of acetic acid at the benzylic position
of the episulfonium ion should regenerate acetic acid (1S)-
phenyl-2-(phenylsulfanyl)ethyl ester. Indeed, treatment of 32
with BF3-OEt2 in acetic anhydride gave, after a reaction time
of 30 min, a quantitative yield of C-2′′ acetate 33 and full
recovery of acetic acid (1S)-phenyl-2-(phenylsulfanyl)ethyl ester.
The latter compound could be reused for the installment of an
(1S)-phenyl-2-(phenylsulfanyl)ethyl moiety. Compound 33 could
be further deprotected under standard conditions to give the
target compound 34.
Finally, we explored reaction conditions for the removal of
the (1S)-phenyl-2-(phenylsulfanyl)ethyl group. It was anticipated
that this functionality could be converted into an acetyl ester
by treatment with BF3-OEt2 in acetic anhydride. In this
reaction, an acetoxonium ion, generated from a reaction of BF3-
OEt2 with acetic anhydride, will react with oxygen of the (1S)-
phenyl-2-(phenylsulfanyl)ethyl moiety. An intramolecular nu-
Conclusion
It has been shown that a (1S)-phenyl-2-(phenylsulfanyl)ethyl
moiety at C-2 of a glycosyl donor can direct the formation of
R-gluco and R-galactosides. These glycosyl donors react through
a new reaction mechanism whereby the phenylsulfanyl moiety
of the C-2 functionality performs neighboring group participa-
tion to give a quasi-stable anomeric sulfonium ion. Due to steric
and electronic effects, the sulfonium ion is only formed as a
trans-decalin. Displacement of the sulfonium ion by a sugar
hydroxyl leads exclusively to the formation of an R-glycoside.
The formation of an intermediate cyclic â-linked sulfonium ion
was convincingly demonstrated by NMR experiments. This (1S)-
phenyl-2-(phenylsulfanyl)ethyl moiety can be introduced and
removed under mild reaction conditions by exploiting the high
reactivity of an episulfonium ion. It is to be expected that the
new methodology can be expanded to include the synthesis of
1,2-cis-amino sugars. A combined use of a new approach to
introduce R-glycosides and traditional neighboring group par-
(17) Yudina, O. N.; Sherman, A. A.; Nifantiev, N. E. Carbohydr. Res. 2001,
332, 363-371.
(18) Sujino, K.; Malet, C.; Hindsgaul, O.; Palcic, M. M. Carbohydr. Res. 1997,
305, 483-489.
(19) Sarkar, A. K.; Matta, K. L. Carbohydr. Res. 1992, 233, 245-250.
(20) Koike, K.; Sugimoto, M.; Sato, S.; Ito, Y.; Nakahara, Y.; Ogawa, T.
Carbohydr. Res. 1987, 163, 189-208.
(21) Zhu, T.; Boons, G. J. J. Chem. Soc., Perkin Trans. 1 1998, 857-861.
(22) Vic, G.; Tran, C. H.; Scigelova, M.; Crout, D. H. G. Chem. Commun. 1997,
169-170.
(23) Schaubach, R.; Hemberger, J.; Kinzy, W. Liebigs Ann. Chem. 1991, 607-
614.
(24) Gege, C.; Kinzy, W.; Schmidt, R. R. Carbohydr. Res. 2000, 328, 459-
466.
(25) Cooper, D. K. C. Clin. Transplant. 1992, 6, 178-183.
(26) Galili, U.; Macher, B. A.; Buehler, J.; Shohet, S. B. J. Exp. Med. 1985,
162, 573-582.
(27) Chittenden, G. J. F. Carbohydr. Res. 1988, 183, 140-143.
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A R T I C L E S
Kim et al.
5.30-5.13 (m, 3H, H-3, OCH2CHCH2), 4.96 (t, 1H, J ) 6.9 Hz, H-7),
4.43 (d, 1H, J ) 8.4 Hz, H-1), 4.49-4.26 (m, 3H, H-6a, OCHHCHCH2,
CHHPh), 4.17-4.10 (m, 2H, H-6b, OCHHCHCH2), 3.53-3.35 (m, 3H,
H-4, H-5, H-8a), 3.23 (dd, 1H, J ) 8.4, 9.6 Hz, H-2), 3.08 (dd, 1H, J
) 6.9, 13.5 Hz, H-8b), 2.01 (s, 3H, COCH3), 1.76 (s, 3H, COCH3);
13C NMR (75 MHz, CDCl3) δ 170.58, 169.75, 140.32, 137.26, 136.89,
133.71, 128.78, 128.49, 128.347, 128.29, 128.01, 127.89, 127.69,
125.69, 118.15, 102.66, 81.41, 77.19, 76.24, 75.09, 74.42, 72.49, 70.73,
62.80, 40.38, 21.09, 20.81; HR MALDI-TOF MS (m/z) calcd for
C34H38O8S [M + Na]+ 629.2185, found 629.2203.
ticipation by C-2 esters to give â-glycosides provides a general
strategy for the synthesis of a wide variety of oligosaccharides.
Experimental Section
Acetyl 3,4,6-Tri-O-acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)-
ethyl}-r-D-glucopyranose (2). Boron trifluoride diethyl etherate (381
µL, 3.0 mmol) was added to a solution of acetyl 3,4,6-tri-O-acetyl-R-
D-glucopyranose (1) (697 mg, 2.0 mmol), acetic acid (1S)-phenyl-2-
(phenylsulfanyl)ethyl ester (39) (817 mg, 3.0 mmol), and activated
molecular sieves (4Å) in dichloromethane (10 mL) at 0 °C. After 30
min, the reaction mixture was quenched with saturated aqueous
NaHCO3 (10 mL). The organic phase was dried (MgSO4) and filtered,
and the filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography (25% ethyl acetate in hexane) to
afford 2 (796 mg, 71%): colorless syrup; Rf ) 0.37 (ethyl acetate/
hexane, 1/2); [R]20D ) +124.6° (c ) 0.6, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.34-7.17 (m, 10H, aromatic), 6.46 (d, 1H, J ) 3.6 Hz,
H-1), 5.39 (t, 1H, J ) 9.6 Hz, H-3), 4.46 (t, 1H, J ) 9.6 Hz, H-4),
4.46 (dd, 1H, J ) 4.8, 8.1 Hz, H-7), 4.27-4.23 (m, 1H, H-6a), 4.08-
3.98 (m, 2H, H-6b, H-5), 3.58 (dd, 1H, J ) 3.6, 9.6 Hz, H-2), 3.22
(dd, 1H, J ) 8.1, 13.8 Hz, H-8a), 3.04 (dd, 1H, J ) 4.8, 13.8 Hz,
H-8b), 2.18 (s, 3H, COCH3), 2.04 (s, 3H, COCH3), 1.98 (s, 3H,
COCH3), 1.82 (s, 3H, COCH3); HR MALDI-TOF MS (m/z) calcd for
C28H32O10S [M + Na]+ 583.1614, found 583.1622.
3,6-Di-O-acetyl-4-O-benzyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)-
ethyl}-r-D-glucopyranosyl Trichloroacetimidate (8). Tetrakis(tri-
phenylphosphine)palladium (2.56 g, 2.22 mmol) was added to a solution
of 6 (1.35 g, 2.22 mmol) in acetic acid (15 mL) at room temperature.
The reaction mixture was stirred overnight and then diluted with
dichloromethane (20 mL) and quenched with saturated aqueous
NaHCO3. The organic phase was dried (MgSO4) and filtered, and the
filtrate was concentrated in vacuo. The residue was purified by silica
gel column chromatography (25% ethyl acetate in hexane) to afford
3,6-di-O-acetyl-4-O-benzyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)ethyl}-
D-glucopyranose (7) (1.13 g, 90%): Rf ) 0.19 (ethyl acetate/hexane,
1/2). Trichloroacetonitrile (1.99 mL, 19.9 mmol) and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) (119 µL, 0.8 mmol) were added to a solution
of 7 (1.13 g, 1.99 mmol) in dichloromethane (10 mL) at 0 °C. The
reaction mixture was stirred at the same temperature for 1 h and then
concentrated in vacuo. The residue was purified by silica gel column
chromatography (20% ethyl acetate in hexane) to afford 8 (1.32 g,
3,4,6-Tri-O-acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)ethyl}-r-
D-glucopyranosyl Trichloroacetimidate (4). Hydrazinium acetate (144
mg, 1.56 mmol) was added to a solution of 2 (796 mg, 1.42 mmol) in
DMF (10 mL) at room temperature. The reaction mixture was stirred
overnight and then quenched with saturated aqueous NaHCO3 (20 mL).
The reaction mixture was extracted with ethyl acetate (20 mL × 2).
The combined organic phase was washed with saturated aqueous NH4-
Cl (20 mL), dried (MgSO4), and filtered, and the filtrate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography (25% ethyl acetate in hexane) to afford 3,4,6-tri-O-
acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)ethyl}-D-glucopyranose (3)
(612 mg, 83%). Trichloroacetonitrile (1.18 mL, 11.8 mmol) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (71 µL, 0.47 mmol) were added
to a solution of 3 (612 mg, 1.18 mmol, 1 equiv) in dichloromethane (5
mL) at 0 °C. The reaction mixture was stirred at the same temperature
for 1 h and then concentrated in vacuo. The residue was purified by
silica gel column chromatography (20% ethyl acetate in hexane) to
93%): Rf ) 0.45 (dichloromethane/acetone, 100/1); [R]20 ) -0.03°
D
1
(c ) 6.0, CHCl3); H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H, NH),
7.37-7.16 (m, 15H, aromatic), 6.62 (d, 1H, J ) 3.6 Hz, H-1), 5.57 (t,
1H, J ) 9.6 Hz, H-3), 4.52-4.42 (m, 1H, H-7), 4.50 (d, 1H, J ) 10.5
Hz, CHHPh), 4.44 (d, 1H, J ) 10.5 Hz, CHHPh), 4.29-4.17 (m, 2H,
H-6a, H-6b), 4.13-4.08 (m, 1H, H-5), 3.55 (dd, 1H, J ) 3.6, 9.6 Hz,
H-2), 3.49 (t, 1H, J ) 9.6 Hz, H-4), 3.25 (dd, 1H, J ) 6.9, 13.5 Hz,
H-8a), 3.05 (dd, 1H, J ) 6.6, 13.5 Hz, H-8b), 2.00 (s, 3H, COCH3),
1.81 (s, 3H, COCH3); 13C NMR (75 MHz, CDCl3) δ 170.44, 169.49,
161.08, 139.80, 137.07, 136,21, 129.35, 128.97, 128.54, 128.53, 128.13,
127.22, 126.11, 93.07, 80.86, 75.51, 75.47, 74.54, 72.70, 70.96, 62.33,
41.27, 20.95, 20.77; 13C NMR (75 MHz, CDCl3) δ 170.44, 169.49,
161.08, 139.80, 137.07, 136,21, 129.35, 128.97, 128.54, 128.53, 128.13,
127.22, 126.11, 93.07, 80.86, 75.51, 75.47, 74.54, 72.70, 70.96, 62.33,
41.27, 20.95, 20.77; HR MALDI-TOF MS (m/z) calcd for C33H34Cl3-
NO8S [M + Na]+ 732.0968, found 732.0957.
afford 4 (743 mg, 95%): Rf ) 0.29 (ethyl acetate/hexane, 1/3); [R]20
) +50.0° (c ) 0.2, CHCl3); H NMR (300 MHz, CDCl3) δ 8.87 (s,
D
1
General Procedure for the Glycosylation Reaction Employing
Glycosyl Donors 4 and 8. Protocol A. A mixture of donor 4 or 8
(0.04 mmol), glycosyl acceptor (0.06 mmol), and activated molecular
sieves (4 Å) in DCM (5 mL) was stirred for 10 min under an atmosphere
of argon at room temperature. After the mixture was cooled to -78
°C, trimethylsilyl trifluoromethanesulfonate (2.2 µL, 0.012 mmol) was
added. The reaction mixture was allowed to warm slowly to 10 °C.
After the donor was consumed, the reaction mixture was quenched with
aqueous saturated NaHCO3 (5 mL) and separated. The organic phase
was dried (MgSO4) and filtered, and the filtrate was concentrated in
vacuo. The residue was purified by silica gel column chromatography
(20% ethyl acetate in hexane)
1H, NH), 7.36-7.16 (m,10H, aromatic), 6.66 (d, 1H, J ) 3.6 Hz, H-1),
5.44 (t, 1H, J ) 9.6 Hz, H-3), 4.93 (t, 1H, J ) 9.6 Hz, H-4), 4.53 (t,
1H, J ) 6.3 Hz, H-7), 4.26-4.16 (m, 2H, H-5, H-6a), 4.06-4.03 (m,
1H, H-6b), 3.67 (dd, 1H, J ) 3.6, 9.6 Hz, H-2), 3.21 (dd, 1H, J ) 7.5,
13.8 Hz, H-8a), 3.06 (dd, 1H, J ) 6.3, 13.8 Hz, H-8b), 2.02 (s, 3H,
COCH3), 1.98 (s, 3H, COCH3), 1.76 (s, 3H, COCH3); 13C NMR (75
MHz, CDCl3) δ 170.53, 169.90, 169.68, 160.86, 139.68, 136.17, 129.34,
129.02, 128.56, 126.99, 126.19, 93.02, 81.34, 75.31, 71.22, 69.77, 67.99,
61.51, 41.50, 20.65, 20.59 (2); HR MALDI-TOF MS (m/z) calcd for
C28H30Cl3NO9S [M + Na]+ 684.0604, found 684.0602.
Allyl 3,6-Di-O-acetyl-4-O-benzyl-2-O-{(1S)-phenyl-2-(phenylsul-
fanyl)ethyl}-â-D-glucopyranoside (6). Boron trifluoride diethyl ether-
ate (572 µL, 4.5 mmol) was added to a solution of allyl 3,6-di-O-acetyl-
4-O-benzyl-â-D-glucopyranoside (5) (1.18 g, 3.0 mmol), acetic acid
(1S)-phenyl-2-(phenylsulfanyl)ethyl ester (39) (1.23 g, 4.5 mmol), and
activated molecular sieves (4 Å) in dichloromethane (10 mL) at 0 °C.
After 10 min, the reaction mixture was quenched with saturated aqueous
NaHCO3 (10 mL). The organic phase was dried (MgSO4) and filtered,
and the filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography (25% ethyl acetate in hexane) to
Protocol B. A mixture of donor 4 or 8 (0.04 mmol) and activated
molecular sieves (4 Å) in DCM (5 mL) was stirred for 10 min under
an atmosphere of argon at room temperature. After the mixture was
cooled to -78 °C, trimethylsilyl trifluoromethanesulfonate (7.2 µL, 0.04
mmol) was added, and the reaction mixture was allowed to warm to 0
°C over a period of 40 min. After cooling of the reaction mixture to
-78 °C, glycosyl acceptor (0.06 mmol) and 2,6-di-tert-butyl-4-
methylpyridine (16 mg, 0.08 mmol) were added. The reaction mixture
was allowed to warm slowly to room temperature and kept overnight
at room temperature. After quenching with aqueous saturated NaHCO3
(5 mL), the organic phase was dried (MgSO4) and filtered, and the
afford 6 (1.35 g, 74%): colorless syrup; Rf ) 0.30 (ethyl acetate/hexane,
1
1/3); [R]20 ) +8.8° (c ) 1.7, CHCl3); H NMR (300 MHz, CDCl3)
D
δ 7.36-7.10 (m,15H, aromatic), 5.96-5.83 (m, 1H, OCH2CHCH2),
9
12094 J. AM. CHEM. SOC. VOL. 127, NO. 34, 2005

General Strategy for Stereoselective Glycosylations
A R T I C L E S
filtrate was concentrated in vacuo. The residue was purified by silica
gel column chromatography (20% ethyl acetate in hexane)
CHHPh), 4.43 (d, 1H, J ) 11.0 Hz, CHHPh), 4.39-4.32 (m, 2H, H-5,
H-7′), 4.23-4.21 (m, 1H, H-6a′), 4.14-4.09 (m, 2H, H-5′, H-6b′),
3.99-3.95 (m, 1H, H-6a), 3.78-3.76 (m, 1H, H-6b), 3.54 (s, 3H,
OCH3), 3.39-3.34 (m, 2H, H-2′, H-4′), 3.25 (dd, 1H, 2.06, J ) 8.0,
14.0 Hz, H-8a′), 2.92 (dd, 1H, J ) 5.0, 14.0 Hz, H-8b′), 1.92 (s, 3H,
COCH3), 1.74 (s, 3H, COCH3); 13C NMR (75 MHz, CDCl3) δ 170.59,
169.65, 165.76, 165.56, 165.41, 140.59, 137.59, 136.44, 133.48, 133.45,
133.08, 129.99, 129.87, 129.73, 129.40, 129.18, 128.93, 128.69, 128.58,
128.51, 128.47, 128.43, 128.32, 128.26, 127.88, 127.84, 126.81, 125.85,
98.47, 96.22, 81.40, 77.23, 76.06, 73.78, 72.82, 70.67, 70.07, 69.72,
68.32, 67.47, 62.87, 55.59, 41.14, 21.04, 20.74; HR MALDI-TOF MS
(m/z) calcd for C59H58O16S [M+Na]+ 1077.3342, found 1077.3392.
Methyl 3,4,6-tri-O-acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)-
ethyl}-r-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-r-D-glucopyra-
noside (16): 1H NMR (500 MHz, CDCl3) δ 7.33-7.05 (m, 25H,
aromatic), 5.36 (t, 1H, J ) 9.5 Hz, H-3′), 5.19 (d, 1H, J ) 3.5 Hz,
H-1′), 4.97-4.90 (m, 2H, CHHPh), 4.84-4.79 (m, 2H, CHHPh, H-4′),
4.73-4.69 (m, 2H, CHHPh), 4.61-4.56 (m, 2H, CHHPh, H-1), 4.49
(dd, 1H, J ) 5.0, 8.0 Hz, H-7′), 4.18-4.12 (m, 2H, H-4, H-6a′), 4.06
(d, 1H, J ) 11.0 Hz, H-6b′), 4.01-3.95 (m, 3H, H-3, H-6a, H-6b),
3.60 (dd, 1H, J ) 3.5, 9.5 Hz, H-2), 3.54-3.51 (m, 2H, H-5′, H-5),
3.51 (dd, 1H, J ) 3.5, 9.5 Hz, H-2′), 3.42 (s, 3H, OCH3), 3.25 (dd,
1H, J ) 8.0, 14.0 Hz, H-8a′), 3.07 (dd, 1H, J ) 5.0, 14.0 Hz, H-8b′),
1.99 (s, 3H, COCH3), 1.94 (s, 3H, COCH3), 1.65 (s, 3H, COCH3); HR
MALDI-TOF MS (m/z) calcd for C54H60O14S [M + Na]+ 987.3601,
found 987.3659.
Methyl 3,4,6-tri-O-acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)-
ethyl}-r-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzoyl-r-D-glucopy-
ranoside (10): [R]20D ) +56.8° (c ) 0.5, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.99-7.86 (m, 6H, aromatic), 7.53-7.08 (m, 19H, aromatic),
6.19 (t, 1H, J ) 9.5 Hz, H-3), 5.45 (t, 1H, J ) 10.0 Hz, H-3′), 5.41 (t,
1H, J ) 10.0 Hz, H-4), 5.26 (dd, 1H, J ) 4.0, 9.5 Hz, H-2), 5.23 (d,
1H, J ) 4.0 Hz, H-1), 5.07 (d, 1H, J ) 3.0 Hz, H-1′), 4.82 (t, 1H, J
) 9.5 Hz, H-4′), 4.43-4.37 (m, 2H, H-5, H-7′), 4.24-4.16 (m, 2H,
H-5′, H-6a′), 4.04-4.02 (m, 1H, H-6a), 3.93-3.89 (m, 1H, H-6b′),
3.79-3.77 (m, 1H, H-6b), 3.54 (s, 3H, OCH3), 3.48 (dd, 1H, J ) 3.0,
10.0 Hz, H-2′), 3.24 (dd, 1H, J ) 9.0, 14.0 Hz, H-8a′), 3.06 (dd, 1H,
J ) 3.5, 14.0 Hz, H-8b′), 2.06(s, 3H, COCH3), 1.95 (s, 3H, COCH3),
1.64 (s, 3H, COCH3); 13C NMR (75 MHz, CDCl3) δ 170.69, 170.02,
169.82, 165.87, 165.77, 165.56, 140.57, 136.40, 133.54, 133.366,
133.16, 133.09, 130.01, 129.96, 129.92, 129.67, 129.25, 129.09, 128.89,
128.80, 128.63, 128.58, 128.50, 128.43, 128.28, 126.54, 125.94, 96.68,
96.30, 82.20, 77.19, 72.26, 71.29, 70.47, 70.11, 68.71(2), 67.35, 67.10,
62.01, 55.61, 41.67, 20.76, 20.63, 20.56; HR MALDI-TOF MS (m/z)
calcd for C54H54O17S [M + Na]+ 1029.2979, found 1029.2910.
Methyl 3,6-di-O-acetyl-4-O-benzyl-2-O-{(1S)-phenyl-2-(phenyl-
sulfanyl)ethyl}-r-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzoyl-r-D-
1
glucopyranoside (11): [R]20 ) -14.6° (c ) 0.3, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.99-7.85 (m, 6H, aromatic), 7.52-7.09 (m,
24H, aromatic), 6.17 (t, 1H, J ) 10.0 Hz, H-3), 5.54 (t, 1H, J ) 9.0
Hz, H-3′), 5.42 (t, 1H, J ) 10.0 Hz, H-4), 5.26(dd, 1H, J ) 4.0, 10.0
Hz, H-2), 5.19 (d, 1H, J ) 4.0 Hz, H-1), 5.01 (d, 1H, J ) 3.0 Hz,
H-1′), 4.48 (d, 1H, J ) 11.0 Hz, CHHPh), 4.43 (d, 1H, J ) 11.0 Hz,
CHHPh), 4.38-4.36 (m, 2H, H-5, H-7′), 4.27-4.10 (m, 3H, H-5′,
H-6a′,H-6b′), 3.89 (t, 1H, J ) 10.0 Hz, H-6a), 3.75 (d, 1H, J ) 10.0
Hz, H-6b), 3.51 (s, 3H, OCH3), 3.38-3.34 (m, 2H, H-2′, H-4′), 3.26
(dd, 1H, J ) 8.5, 14.0 Hz, H-8a′), 3.03 (dd, 1H, J ) 5.0, 14.0 Hz,
H-8b′), 2.04 (s, 3H, COCH3), 1.70 (s, 3H, COCH3); 13C NMR (75 MHz,
CDCl3) δ 170.66, 169.71, 165.81, 165.76, 165.57, 140.69, 137.53,
136.46, 133.46, 133.29, 133.04, 129.96, 129.93, 129.67, 129.28, 129.22,
129.14, 128.82, 128.59, 128.54, 128.46, 128.43, 128.39, 128.25, 128.08,
127.85, 127.06, 126.74, 125.85, 96.62, 96.19, 81.74, 77.22, 76.14, 73.81,
72.74, 72.23, 70.53, 69.93, 68.67, 68.34, 67.12, 62.87, 55.69, 41.43,
21.98, 20.88; HR MALDI-TOF MS (m/z) calcd for C59H58O16S [M +
Na]+ 1077.3342, found 1077.3396.
Methyl 3,6-di-O-acetyl-4-O-benzyl-2-O-{(1S)-phenyl-2-(phenyl-
sulfanyl)ethyl}-r-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-r-D-
glucopyranoside (17): [R]20D ) -221.7° (c ) 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.34-7.07 (m, 30H, aromatic), 5.51 (t, 1H, J )
9.5 Hz, H-3′), 5.14 (d, 1H, J ) 3.0 Hz, H-1′), 4.96 (d, 1H, J ) 12.0
Hz, CHHPh), 4.94 (d, 1H, J ) 11.0 Hz, CHHPh), 4.82 (d, 1H, J )
11.0 Hz, CHHPh), 4.69 (d, 1H, J ) 12.0 Hz, CHHPh), 4.67 (d, 1H, J
) 12.0 Hz, CHHPh), 4.59 (d, 1H, J ) 3.0 Hz, H-1), 4.58 (d, 1H, J )
12.0 Hz, CHHPh), 4.47 (d, 1H, J ) 11.0 Hz, CHHPh), 4.48-4.41 (m,
1H, H-7′), 4.40 (d, 1H, J ) 11.0 Hz, CHHPh), 4.20 (dd, 1H, J ) 2.0,
12.0 Hz, H-6a′), 4.13 (dd, 1H, J ) 4.0, 12.0 Hz, H-6b′), 3,99 (t, 1H,
J ) 9.5 Hz, H-3), 3.92-3.91 (m, 1H, H-5′), 3.85-3.83 (m, 1H, H-5),
3.80 (m, 2H, H-6a, H-6b), 3.64 (t, 1H, J ) 9.5 Hz, H-4), 3.58 (dd, 1H,
J ) 3.0, 9.5 Hz, H-2), 3.40 (s, 3H, OCH3), 3.38-3.34(m, 2H, H-2′,
H-4′), 3.31(dd, 1H, J ) 7.0, 13.5 Hz, H-8a′), 3.05(dd, 1H, J ) 5.0,
13.5 Hz, H-8b′), 1.99 (s, 3H, COCH3), 1.72 (s, 3H, COCH3); 13C NMR
(75 MHz, CDCl3) δ 170.61, 169.66, 140.41, 138.88, 138.40, 138.22,
137.50, 136.53, 128.94, 128.75, 128.49, 128.45, 128.40, 128.34, 128.27,
128.06, 127.92, 127.76, 127.62, 127.49, 126.87, 125.85, 97.88, 96.60,
82.27, 80.93, 80.24, 78.02, 77.23, 76.12, 75.69, 75.03, 74.03, 73.27,
73.05, 70.18, 68.32, 66.37, 62.80, 55.26, 41.49, 20.91, 20.84; HR
MALDI-TOF MS (m/z) calcd for C59H64O13S [M + Na]+ 1035.3965,
found 1035.3988.
Methyl 3,4,6-tri-O-acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)-
ethyl}-r-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzoyl-r-D-manopy-
1
ranoside (13): [R]20 ) -11.0 ° (c ) 0.4, CHCl3); H NMR (500
D
MHz, CDCl3) δ 8.13-7.81 (m, 6H, aromatic), 7.64-7.08 (m, 19H,
aromatic), 5.91 (dd, 1H, J ) 3.5, 10.0 Hz, H-3), 5.81 (t, 1H, J ) 10.0
Hz, H-4), 5.69 (m, 1H, H-2), 5.45 (t, 1H, J ) 9.5 Hz, H-3′), 5.06 (d,
1H, J ) 3.50 Hz, H-1′), 4.93 (s, 1H, H-1), 4.82 (t, 1H, J ) 9.5 Hz,
H-4′), 4.41-4.37 (m, 2H, H-5, H-7′), 4.22-4.19 (m, 1H, H-5′), 4.13-
4.10 (m, 1H, H-6a′), 4.01-3.98 (m, 21H, H-6a, H-6b′), 3.81-3.79 (m,
1H, H-6b), 3.57 (s, 3H, OCH3), 3.47 (dd, 1H, J ) 3.0, 10.0 Hz, H-2′),
3.23 (dd, 1H, J ) 8.5, 14.0 Hz, H-8a′), 2.94 (dd, 1H, J ) 4.5, 14.0 Hz,
H-8b′), 1.96 (s, 3H, COCH3), 1.92 (s, 3H, COCH3), 1.69 (s, 3H,
COCH3); 13C NMR (75 MHz, CDCl3) δ 170.61, 169.94, 169.81, 165.78,
165.55, 165.40, 129.97, 129.83, 129.72, 129.37, 129.13, 128.96, 128.91,
128.70, 128.61, 128.51, 128.36, 98.51, 96.37, 81.83, 77.22, 71.32, 70.68,
70.01, 69.76, 68.66, 67.58, 67.43, 67.23, 61.98, 55.52, 41.34, 20.64
(3); HR MALDI-TOF MS (m/z) calcd for C54H54O17S [M + Na]+
1029.2979, found 1029.2934.
Methyl 3,4,6-tri-O-acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)-
ethyl}-r-D-glucopyranosyl-(1f4)-2,3,6-tri-O-benzyl-r-D-glucopyra-
1
noside (19): [R]20 ) +66.5° (c ) 0.4, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 7.38-6.97 (m, 25H, aromatic), 5.71 (d, 1H, J ) 3.5 Hz,
H-1′), 5.35 (t, 1H, J ) 10.0 Hz, H-3′), 5.07 (d, 1H, J ) 11.0 Hz,
CHHPh), 4.96 (d, 1H, J ) 11.0 Hz, CHHPh), 4.78 (t, 1H, J ) 10.0
Hz, H-4′), 4.71 (d, 1H, J ) 9.5 Hz, CHHPh), 4.63-4.54 (m, 3H, H-1,
CHHPh), 4.35 (t, 1H, J ) 7.0 Hz, H-7′), 4.17 (t, 1H, J ) 9.5 Hz, H-3),
4.10-3.93 (m, 4H, H-4, H-5, H-6a, H-5′), 3.85-3.82 (m, 1H, H-6b),
3.76-3.74 (m, 1H, H-6b′), 3.67-3.65 (m, 1H, H-6′), 3.60 (dd, 1H, J
) 3.5, 9.5 Hz, H-2), 3.38 (s, 3H, OCH3), 3.34 (dd, 1H, J ) 3.5, 10.0
Hz, H-2′), 3.25 (dd, 1H, J ) 7.0, 13.0 Hz, H-8a′), 2.89 (dd, 1H, J )
7.0, 13.0 Hz, H-8b′), 1.97 (s, 3H, COCH3), 1.94 (s, 3H, COCH3), 1.73
(s, 3H, COCH3); 13C NMR (125 MHz, CDCl3) δ 170.55, 170.04,
169.64, 140.08 139.31, 138.06, 137.97, 136.60, 128.87, 128.53, 128.54,
128.36, 128.28, 128.15, 127.92, 127.61, 127.36, 127.09, 126.87, 126.83,
125.68, 97.91, 94.97, 81.35, 81.28, 80.13, 77.22, 76.13, 74.23, 73.42,
Methyl 3,6-di-O-acetyl-4-O-benzyl-2-O-{(1S)-phenyl-2-(phenyl-
sulfanyl)ethyl}-r-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzoyl-r-D-
manopyranoside (14): [R]20D ) -181.4° (c ) 1.5, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 8.12-7.81 (m, 6H, aromatic), 7.63-7.08 (m,
24H, aromatic), 5.90 (dd, 1H, J ) 3.0, 10.0 Hz, H-3), 5.80 (t, 1H, J )
10.0 Hz, H-4), 5.67 (s, 1H, H-1), 5.57 (t, 1H, J ) 10.0 Hz, H-3′), 5.04
(d, 1H, J ) 3 Hz, H-1′), 4.90 (s, 1H, H-2), 4.96 (d, 1H, J ) 11.0 Hz,
9
J. AM. CHEM. SOC. VOL. 127, NO. 34, 2005 12095

A R T I C L E S
Kim et al.
73.29, 71.21, 69.66, 68.83, 68.69, 67.50, 61.92, 55.36, 40.83, 20.73,
20.65, 20.20; HR MALDI-TOF MS (m/z) calcd for C54H60O14S [M +
Na]+ 987.3601, found 987.3666.
and H8ax signals of 21 were assigned from 1H TOCSY 1D data
irradiated on H4 and H7. The anomeric carbon signal (C1, δ 88.0) of
21 was assigned from HSQC data. The HMBC spectrum of 21 showed
the three-bond coupling between C1 (δ 88.0) and H8eq (δ 4.32), which
confirmed the presence of the C1-H8eq bond. So, the trans-decalin
structure of the sulfonium ion 21 was proved directly from the low-
temperature NMR experiments.
Methyl 3,6-di-O-acetyl-4-O-benzyl-2-O-{(1S)-phenyl-2-(phenyl-
sulfanyl)ethyl}-r-D-glucopyranosyl-(1f4)-2,3,6-tri-O-benzyl-r-D-
1
glucopyranoside (20): [R]20 ) -103.65° (c ) 2, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.39-6.98 (m, 30H, aromatic), 5.63 (d, 1H, J )
3.0 Hz, H-1′), 5.45 (t, 1H, J ) 10.0 Hz, H-3′), 5.06 (d, 1H, J ) 12.0
Hz, CHHPh), 4.97 (d, 1H, J ) 12.0 Hz, CHHPh), 4.72 (d, 1H, J )
12.0 Hz, CHHPh), 4.61 (d, 1H, J ) 12.0 Hz, CHHPh), 4.61(d, 1H, J
) 3.0 Hz, H-1), 4.53 (d, 1H, J ) 12.0 Hz, CHHPh), 4.50 (d, 1H, J )
12.0 Hz, CHHPh), 4.47 (d, 1H, J ) 12.0 Hz, CHHPh), 4.38 (d, 1H, J
) 12.0 Hz, CHHPh), 4.33 (t, 1H, J ) 6.0 Hz, H-7′), 4.14 (t, 1H, J )
9.0 Hz, H-3), 4.08-3.89 (m, 5H, H-6a′, H-6b′, H-5′, H-5, H-6b), 3.71-
3.69 (m, 1H, H-6a), 3.63-3.61 (m, 1H, H-4), 3.58 (dd, 1H, J ) 3.0,
9.0 Hz, H-2), 3.37 (s, 3H, OCH3), 3.34-3.29 (m, 2H, H-4′, H-8b′),
3.22 (dd, 1H, J ) 3.0, 10.0 Hz, H-2′), 2.87 (dd, 1H, J ) 6.0, 14.0 Hz,
H-8a′), 1.96 (s, 3H, COCH3), 1.81 (s, 3H, COCH3); 13C NMR (125
MHz, CDCl3) δ 170.51, 169.67, 140.08 139.45, 138.12, 138.02, 137.60,
136.70, 128.81, 128.47, 128.43, 128.33, 128.25, 128.21, 128.16, 127.92,
127.41, 127.141, 127.06, 126.95, 125.56, 97.91, 94.95, 81.55, 80.90,
80.01, 77.22, 76.80, 76.11 (2), 74.36, 74.23, 73.27 (2), 72.87, 69.66,
68.74, 62.82, 55.28, 40.53, 21.04, 20.86; HR MALDI-TOF MS (m/z)
calcd for C59H64O13S [M + Na]+ 1035.3965, found 1035.3979.
Procedure for Low-Temperature NMR Experiments. The 1H
NMR spectrum of 8 (14 mg, 0.02 mmol) in CD2Cl2 (0.5 mL) was
recorded: 1H NMR (500 MHz, CD2Cl2) δ 8.67 (s, 1H, NH), 7.39-
7.18 (m, 15H, aromatic), 6.58 (d, 1H, J ) 3.0 Hz, H-1), 5.48 (t, 1H,
J ) 10.0 Hz, H-3), 4.53 (t, 1H, J ) 6.5 Hz, H-7), 4.49 (d, 1H, J )
10.5 Hz, CHHPh), 4.46 (d, 1H, J ) 10.5 Hz, CHHPh), 4.30-4.08 (m,
1H, H-6a), 4.16-4.12 (m, 1H, H-6b), 4.09-4.05 (m, 1H, H-5), 3.55
(dd, 1H, J ) 3.0, 10.0 Hz, H-2), 3.51 (t, 1H, J ) 10.0 Hz, H-4), 3.29
(dd, 1H, J ) 7.0, 14.0 Hz, H-8a), 3.08 (dd, 1H, J ) 7.0, 14.0 Hz,
H-8b), 1.98 (s, 3H, COCH3), 1.85 (s, 3H, COCH3).
3,6-Di-O-acetyl-2,4-di-O-benzyl-r-D-glucopyranosyl trichloroace-
timidate (23): 1H NMR (500 MHz, CDCl3) δ 8.60 (s, 1H, NH), 7.35-
7.24 (m, 10H, aromatic), 6.47 (d, 1H, J ) 3.5 Hz, H-1), 5.62 (t, 1H,
J ) 9.5 Hz, H-3), 4.68 (d, 1H, J ) 12.0 Hz, CHHPh), 4.59 (d, 1H, J
) 11.0 Hz, CHHPh), 4.55 (d, 1H, J ) 12.0 Hz, CHHPh), 4.53 (d, 1H,
J ) 11.0 Hz, CHHPh), 4.31 (dd, 1H, J ) 2.5, 12.5 Hz, H-6a), 4.24
(dd, 1H, J ) 4.5, 12.5 Hz, H-6b), 4.14-4.09 (m, 1H, H-5), 3.66 (dd,
1H, J ) 3.5, 9.5 Hz, H-2), 3.62 (t, 1H, J ) 9.5 Hz, H-4), 2.03 (s, 3H,
COCH3), 1.99 (s, 3H, COCH3).
Methyl 3,6-di-O-acetyl-2,4-di-O-benzyl-r/â-D-glucopyranosyl-
(1f6)-2,3,4-tri-O-benzyl-r-D-glucopyranoside (24) (mixture as r/â
) 3/1): 1H NMR (500 MHz, CDCl3) δ 5.55 (t, 1H, J ) 9.5 Hz, H-3′-
R), 5.22 (t, 1H, J ) 9.0 Hz, H-3′-â), 4.96 (d, 1H, J ) 3.0 Hz, H-1′-R),
4.38 (d, 1H, J ) 8.5 Hz, H-1′-â), 3.36 (s, 3H, OCH3-R), 3.34 (s, 3H,
OCH3-â), 2.01 (s, 3H, COCH3-â), 2.00 (s, 3H, COCH3-R), 1.97 (s,
3H, COCH3-R), 1.86 (s, 3H, COCH3-â).
3,6-Di-O-acetyl-4-O-benzyl-2-O-(2-(phenylsulfanyl)ethyl)-r-D-glu-
copyranosyl trichloroacetimidate (25): 1H NMR (300 MHz, CDCl3)
δ 8.59 (s, 1H, dNH), 7.38-7.17 (m,10H, aromatic), 6.51 (d, 1H, J )
3.6 Hz, H-1), 5.56 (t, 1H, J ) 9.6 Hz, H-3), 4.60 (d, 1H, J ) 12.0 Hz,
CHHPh), 4.54 (d, 1H, J ) 12.0 Hz, CHHPh), 4.34-4.21 (m, 2H, H-6a,
H-6b), 4.14-4.09 (m, 1H, H-5), 3.86-3.49 (m, 4H, H-7a, H-7b, H-4,
H-2), 3.08-2.99 (m, 2H, H-8a, H-8b), 2.04 (s, 3H, COCH3), 2.03 (s,
3H, COCH3); 13C NMR (75 MHz, CDCl3) δ 170.49, 169.71, 161.24,
137.09, 135.76, 129.64, 129.46, 129.02, 128.60, 128.26, 128.22, 128.18,
128.07, 126.40, 126.32, 93.45, 77.84, 75.25, 74.55, 72.93, 71.19, 69.82,
62.38, 33.39, 21.11, 20.78.
Methyl 3,6-di-O-acetyl-4-O-benzyl-2-O-(2-(phenylsulfanyl)ethyl)-
r/â-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-r-D-glucopyrano-
side (26) (mixture as r/â ) 8/1): 1H NMR (500 MHz, CDCl3) δ 5.50
(t, 1H, J ) 10.0 Hz, H-3′-R), 5.17 (t, 1H, J ) 9.5 Hz, H-3′-â), 5.02 (d,
1H, J ) 3.5 Hz, H-1′-R), 4.31 (d, 1H, J ) 7.5 Hz, H-1′-â), 3.35 (s,
3H, OCH3-R), 3.33 (s, 3H, OCH3-â), 2.017 (s, 3H, COCH3-R), 2.006
(s, 3H, COCH3-â), 2.001 (s, 3H, COCH3-â), 1.99 (s, 3H, COCH3-R).
3,6-Di-O-acetyl-4-O-benzyl-2-O-{(1R)-phenyl-2-(phenylsulfanyl)-
ethyl}-r-D-glucopyranosyl Trichloroacetimidate (27). Compound 27
was synthesized according to the procedure described for the synthesis
of compound 8: colorless syrup; Rf ) 0.43 (dichloromethane/acetone
) 100/1); 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H, NH), 7.26-7.36
(m, 15H, aromatic), 5.79 (d, 1H, J ) 4.0 Hz, H-1), 5.68 (t, 1H, J )
10.0 Hz, H-3), 4.60 (d, 1H, J ) 11.0 Hz, CHHPh), 4.53 (d, 1H, J )
11.0 Hz, CHHPh), 4.50 (dd, 1H, J ) 5.0, 8.0 Hz, H-7), 4.23-4.16 (m,
2H, H-6a, H-6b), 4.03-4.00 (m, 1H, H-5), 3.65 (dd, 1H, J ) 4.0, 10.0
Hz, H-2), 3.60 (t, 1H, J ) 10.0 Hz, H-4), 3.25 (dd, 1H, J ) 8.0, 13.5
Hz, H-8a), 3.05 (dd, 1H, J ) 5.0, 13.5 Hz, H-8b), 2.08 (s, 3H, COCH3),
1.99 (s, 3H, COCH3).
Trimethylsilyl trifluoromethanesulfonate (3.6 µL, 0.02 mmol) was
added to the above solution at -50 °C. The reaction mixture was
allowed to warm slowly to 0 °C. The NMR spectra of 21 (1H, 1H
TOCSY 1D, HSQC, and HMBC) were recorded at -20 °C. 21: 1H
NMR (500 MHz, CD2Cl2) δ 7.89-7.87 (m, 2H, aromatic), 7.76-7.74
(m, 1H, aromatic), 7.65-7.62 (m, 2H, aromatic), 7.41-7.16 (m, 10H,
aromatic), 5.48 (t, 1H, J ) 9.5 Hz, H-3), 5.35 (d, 1H, J ) 11.0 Hz,
H-7), 5.30 (d, 1H, J ) 9.5 Hz, H-1), 4.56 (d, 1H, J ) 11.5 Hz, CHHPh),
4.50 (d, 1H, J ) 11.5 Hz, CHHPh), 4.32 (d, 1H, J ) 11.0 Hz, H-8eq),
4.16-4.08 (m, 3H, H-2, H-6a, H-6b), 3.81 (t, 1H, J ) 9.5 Hz, H-4),
3.77 (m, 1H, H-5), 3.66 (t, 1H, J ) 11.0 Hz, H-8ax), 1.96 (s, 3H,
COCH3), 1.95 (s, 3H, COCH3).
Methanol was added to the reaction mixture at the same temperature,
1
and the H NMR spectrum of 22 was recorded at 0 °C. 22: 1H NMR
(500 MHz, CD2Cl2) δ 7.39-7.18 (m, 15H, aromatic), 5.47 (t, 1H, J )
9.0 Hz, H-3), 4.84 (d, 1H, J ) 3.5 Hz, H-1), 4.44 (d, 1H, J ) 11.5 Hz,
CHHPh), 4.39 (d, 1H, J ) 11.5 Hz, CHHPh), 4.39 (t, 1H, J ) 5.5 Hz,
H-7), 4.27-4.11 (m, 2H, H-6a, H-6b), 3.81-3.77 (m, 1H, H-5), 3.40
(s, 3H, OCH3), 3.36-3.26 (m, 3H, H-2, H-4, H-8a), 3.10 (dd, 1H, J )
1
5.5, 14.0 Hz, H-8b), 1.96 (s, 3H, COCH3), 1.72 (s, 3H, COCH3); H
Methyl 3,6-di-O-acetyl-4-O-benzyl-2-O-{(1R)-phenyl-2-(phenyl-
sulfanyl)ethyl}-r/â-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-r-D-
NMR (300 MHz, CDCl3) δ 7.39-7.18 (m, 15H, aromatic), 5.49 (t,
1H, J ) 9.6 Hz, H-3), 4.94 (d, 1H, J ) 3.6 Hz, H-1), 4.49 (d, 1H, J
) 11.1 Hz, CHHPh), 4.42 (d, 1H, J ) 11.1 Hz, CHHPh), 4.40 (t, 1H,
J ) 6.3 Hz, H-7), 4.25-4.22 (m, 2H, H-6a, H-6b), 3.92-3.86 (m, 1H,
H-5), 3.44 (s, 3H, OCH3), 3.41-3.30 (m, 3H, H-2, H-4, H-8a), 3.10
(dd, 1H, J ) 4.8, 13.8 Hz, H-8b), 2.03 (s, 3H, COCH3), 1.66 (s, 3H,
COCH3).
The 1H NMR spectrum of 21 showed that the anomeric proton (H1)
signal (δ 6.58, d, J1,2 ) 2.5 Hz, R-configuration) was shifted to upfield
(δ 5.30, d, J1,2 ) 9.5 Hz, â-configuration). The change of anomeric
configuration indicate that the R-imidate donor 8 was completely
transformed to a new intermediate 21 after activation. H1, H7, H8eq,
1
glucopyranoside (28) (mixture as R/â ) 1/1): H NMR (500 MHz,
CDCl3) δ 5.59 (t, 1H, J ) 10.0 Hz, H-3′-R), 5.28 (t, 1H, J ) 9.0 Hz,
H-3′-â), 4.24 (d, 1H, J ) 6.5 Hz, H-1′-â), 4.23 (d, 1H, J ) 3.5 Hz,
H-1′-R), 2.04 (s, 3H, COCH3-R), 2.00 (s, 3H, COCH3-â), 1.98 (s, 3H,
COCH3-â), 1.95 (s, 3H, COCH3-R).
Acetyl 3,4,6-Tri-O-acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)-
ethyl}-r-D-galactopyranose (51). Boron trifluoride diethyl etherate
(190 µL, 1.5 mmol) was added to a solution of acetyl 3,4,6-tri-O-acetyl-
R-D-galactopyranose (348 mg, 1.0 mmol), acetic acid (1S)-phenyl-2-
(phenylsulfanyl)ethyl ester (408 mg, 1.5 mmol), and activated molecular
sieves (4 Å) in dichloromethane (5 mL) at 0 °C. After 20 min, the
9
12096 J. AM. CHEM. SOC. VOL. 127, NO. 34, 2005

General Strategy for Stereoselective Glycosylations
A R T I C L E S
1
reaction mixture was quenched with saturated aqueous NaHCO3 (10
mL). The organic phase was dried (MgSO4) and filtered, and the filtrate
was concentrated in vacuo. The residue was purified by silica gel
column chromatography (25% ethyl acetate in hexane) to afford 51
(504 mg, 90%): colorless syrup; Rf ) 0.37 (ethyl acetate/hexane, 1/2);
[R]20D ) -9.0° (c ) 4.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.36-
7.14 (m,10H, aromatic), 6.49 (d, 1H, J ) 3.6 Hz, H-1), 5.37-5.36 (m,
1H, H-4), 5.24 (dd, 1H, J ) 3.3, 10.2 Hz, H-3), 4.51 (dd, 1H, J ) 4.8,
9.6 Hz, H-7), 4.27-4.23 (m, 1H, H-5), 4.03-3.96 (m, 2H, H-6b, H-6a),
3.83 (dd, 1H, J ) 3.6, 10.2 Hz, H-2), 3.20 (dd, 1H, J ) 9.6, 13.8 Hz,
H-8a), 3.07 (dd, 1H, J ) 4.8, 13.8 Hz, H-8b), 2.18 (s, 3H, COCH3),
) +19.5° (c ) 0.2, CHCl3); H NMR (500 MHz, CDCl3) δ 8.13-
7.97 (m, 4H, aromatic), 7.57-7.19 (m, 21H, aromatic), 5.61 (t, 1H, J
) 9.0 Hz, H-2′), 5.49 (d, 1H, J ) 4.0 Hz, H-1′′), 5.11 (d, 1H, J ) 11.0
Hz, CHHPh), 5.08-5.06 (m, 1H, H-4′′), 5.05 (dd, 1H, J ) 3.0, 10.0
Hz, H-3′′), 4.77 (d, 1H, J ) 11.0 Hz, CHHPh), 4.64 (d, 1H, J ) 8.5
Hz, H-1′), 4.54 (dd, 1H, J ) 3.0, 10.0 Hz, H-7′′), 4.54-4.52 (m, 1H),
4.45 (dd, 1H, J ) 7.0, 10.0 Hz), 4.33 (m, 1H, H-4′), 4.21-4.18 (m,
1H), 4.04 (d, 1H, J ) 7.5 Hz, H-1), 4.03-4.02 (m, 1H, H-3′), 3.89-
3.78 (m, 4H, H-2′′, H-4), 3.72-3.68 (m, 2H), 3.46 (s, 3H, OCH3),
3.48-3.43 (m, 1H, H-3), 3.34-3.31 (m, 2H), 3.25 (t, 1H, J ) 9.0 Hz,
H-2), 3.20 (dd, 1H, J ) 3.0, 10.0 Hz, H-8a′′), 3.01 (dd, 1H, J ) 10.0,
14.0 Hz, H-8b′′), 1.93 (s, 3H, COCH3), 1.92 (s, 3H, COCH3), 1.77 (s,
3H, COCH3), 1.19 (s, 3H, COCH3); 13C NMR (75 MHz, CDCl3) δ
170.60, 169.95, 169.75, 169.45, 166.24, 164.79, 141.20, 138.12, 135.43,
133.51, 133.08, 129.83, 129.78, 129.54, 129.34, 129.09, 128.73, 128.63,
128.42, 128.32, 128.19, 127.98, 127.65, 126.71, 125.32, 102.60, 100.93,
96.22, 84.42, 80.75, 78.94, 77.22, 77.02, 77.01, 75.46, 72.78, 72.18,
71.17, 69.73, 67.61, 66.77, 65.83, 65.57, 62.89, 62.19, 60.48, 57.18,
43.54, 20.69, 20.49, 19.65; HR MALDI-TOF MS (m/z) calcd for
C62H67N3O21S [M + Na]+ 1244.3884, found 1244.3809.
1.99 (s, 3H, COCH3), 1.92 (s, 3H, COCH3), 1.76 (s, 3H, COCH3); 13
C
NMR (75 MHz, CDCl3) δ 170.38, 169.98, 169.97, 169.42, 140.06,
136.39, 129.28, 128.99, 128.95, 128.92, 128.88, 128.68, 128.38, 126.85,
126.75, 126.16, 89.61, 81.24, 71.55, 68.84, 68.33, 67.67, 61.26, 41.77,
21.171, 20.65, 20.48, 20.43; HR MALDI-TOF MS (m/z) calcd for
C28H32O10S [M + Na]+ 583.1614, found 583.1611.
3,4,6-Tri-O-acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)ethyl}-r-
D-galatopyranosyl Trichloroacetimidate (29). Hydrazinium acetate
(91 mg, 0.99 mmol) was added to a solution of 51 (504 mg, 0.9 mmol)
in DMF (5 mL) at room temperature. The reaction mixture was stirred
overnight and then quenched with saturated aqueous NaHCO3. The
aqueous layer was extracted with ethyl acetate (20 mL). The combined
organic phases were washed with saturated aqueous NH4Cl (20 mL),
dried (MgSO4), and filtered, and the filtrate was concentrated in vacuo.
The residue was purified by silica gel column chromatography (25%
ethyl acetate in hexane) to afford 3,4,6-tri-O-acetyl-2-O-{(1S)-phenyl-
2-(phenylsulfanyl)ethyl}-D-galactopyranose (52) (434 mg, 93%). Trichlo-
roacetonitrile (0.84 mL, 8.4 mmol) and 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (50 µL, 0.33 mmol) were added to a solution of 52 (434
mg, 0.84 mmol) in dichloromethane (10 mL) at 0 °C. The reaction
mixture was stirred at this temperature for 1 h and then concentrated
in vacuo. The residue was purified by silica gel column chromatography
Methyl 2,3,4,6-Tetra-O-acetyl-R-D-galatopyranosyl-(1f3)-4-O-
acetyl-2,6-di-O-benzoyl-â-D-galatopyranosyl-(1f4)-6-O-acetyl-3-O-
benzyl-2-deoxy-2-azido-â-D-glucopyranoside (33). To a solution of
the trisaccharide 32 (63 mg, 0.051 mmol) in acetic anhydride (3 mL)
was added boron trifluoride diethyl etherate (9.7 µL, 0.077 mmol) at
0 °C. The reaction mixture was stirred at the same temperature for 40
min and then quenched with aqueous saturated NaHCO3 (10 mL). After
dilution with DCM (10 mL), the reaction mixture was separated. The
organic phase was dried (MgSO4) and filtered, and the filtrate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography (25% ethyl acetate in hexane) to afford trisaccharide
33 (53 mg, 95%) as colorless syrup: Rf ) 0.24 (ethyl acetate/hexane,
1/1); [R]20D ) +41.8 ° (c ) 0.6, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 8.12-7.97 (m, 4H, aromatic), 7.63-7.28 (m, 11H, aromatic), 5.57
(dd, 1H, J ) 7.5, 9.0 Hz, H-2′), 5.46 (d, 1H, J ) 3.0 Hz, H-1′′), 5.21-
5.19 (m, 2H, H-2′′, H-4′′), 5.05 (d, 1H, J ) 11.0 Hz, CHHPh), 4.99
(dd, 1H, J ) 3.0, 10.0 Hz, H-3′′), 4.83 (d, 1H, J ) 11.0 Hz, CHHPh),
4.83-4.81 (m, 1H, H-4′), 4.70 (d, 1H, J ) 9.0 Hz, H-1′), 4.28-4.11
(m, 4H), 4.06 (d, 1H, J ) 7.5 Hz, H-1), 4.03 (dd, 1H, J ) 3.5, 10.0
Hz, H-3′), 3.98 (t, 1H, J ) 7.0 Hz), 3.86 (t, 1H, J ) 7.0 Hz), 3.83-
3.73 (m, 3H), 3.47 (s, 3H, OCH3), 3.43 (t, 1H, J ) 9.0 Hz), 3.40-3.27
(m, 2H), 2.16 (s, 3H, COCH3), 2.03 (s, 3H, COCH3), 2.02 (s, 3H,
COCH3), 1.98 (s, 3H, COCH3), 1.93 (s, 3H, COCH3), 1.87 (s, 3H,
COCH3); 13C NMR (75 MHz, CDCl3) δ 170.44, 170.13(2), 169.95,
169.63, 169.40, 165.87, 164.69, 138.23, 133.88, 133.46, 129.89, 129.77,
129.29, 128.83, 128.65, 128.54, 128.24, 127.29, 127.60, 102.65, 100.92,
93.74, 80.81, 77.22, 76.77, 75.14, 73.67, 72.68, 70.94, 67.63, 66.88,
66.66, 66.47, 65.72, 64.78, 61.69, 61.30, 61.15, 57.22, 20.77, 20.73,
20.66, 20.62, 20.52, 20.49; HR MALDI-TOF MS (m/z) calcd for
C52H59N3O23 [M + Na]+ 1116.3436, found 1116.3418.
(20% ethyl acetate in hexane) to afford 29 (505 mg, 91%): Rf ) 0.32
1
(ethyl acetate/hexane, 1/3); [R]20 ) -56.37° (c ) 3.0, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 8.66 (s, 1H, NH), 7.34-7.18 (m, 10H,
aromatic), 6.70 (d, 1H, J ) 3.3 Hz, H-1), 5.43-5.42 (m, 1H, H-4),
5.28 (dd, 1H, J ) 3.3, 10.5 Hz, H-3), 4.57 (dd, 1H, J ) 5.7, 7.8 Hz,
H-7), 441-4.37 (m, 1H, H-5), 4.11-3.99 (m, 2H, H-6a, H-6b), 3.94
(dd, 1H, J ) 3.3, 10.5 Hz, H-2), 3.21 (dd, 1H, J ) 7.8, 13.8 Hz, H-8a),
3.11 (dd, 1H, J ) 5.7, 13.8 Hz, H-8b), 1.99 (s, 3H, COCH3), 1.96 (s,
3H, COCH3), 1.69 (s, 3H, COCH3); 13C NMR (75 MHz, CDCl3) δ
170.33, 169.92, 169.84, 160.99, 140.26, 129.27, 129.02, 128.37, 128.25,
126.67, 126.14, 94.00, 81.41, 72.48, 69.10, 68.84, 67.71, 61.36, 41.86,
20.64, 20.45, 20.36; HR MALDI-TOF MS (m/z) calcd for C28H30Cl3-
NO9S [M+Na]+ 684.0604, found 684.0612.
Methyl 3,4,6-Tri-O-acetyl-2-O-{(1S)-phenyl-2-(phenylsulfanyl)-
ethyl}-r-D-galatopyranosyl-(1f3)-2,6-di-O-benzoyl-â-D-galatopyra-
nosyl-(1f4)-6-O-acetyl-3-O-benzyl-2-deoxy-2-azido-â-D-glucopyr-
anoside (32). Trimethylsilyl trifluoromethanesulfonate (9.0 µL, 0.05
mmol) was added to a solution of 29 (66 mg, 0.1 mmol) and activated
molecular sieves (4 Å) in DCM (10 mL) at 0 °C. After 5 min, phenyl
2,6-di-O-benzoyl-1-thio-â-D-galatopyranoside (30) (48 mg, 0.1 mmol)
was added to the reaction mixture at the same temperature. After the
temperature was raised gradually to room temperature over a period
of 4 h, methyl 6-O-acetyl-3-O-benzyl-2-deoxy-2-azido-â-D-glucopy-
ranoside (31) (70.3 mg, 0.2 mmol) and N-iodosuccinimide (45.0 mg,
0.2 mmol) were added at -78 °C. The reaction mixture was allowed
to warm gradually to room temperature over a period of 2 h and then
quenched with aqueous saturated NaHCO3 (10 mL). The organic phase
was washed with aqueous solution of sodium thiosulfate (1 M, 10 mL)
and then dried (MgSO4) and filtered, and the filtrate was concentrated
in vacuo. The residue was purified by silica gel column chromatography
(25% ethyl acetate in hexane) to afford the trisaccharide 32 (63 mg,
Acknowledgment. This research was supported by the NIH
Research Resource Center for Biomedical Complex Carbohy-
drates (Grant P41-RR-5351).
Supporting Information Available: General procedures,
experimental method for the preparation of compound 25 and
acetic acid (1S)-phenyl-2-phenylsulfanyl-ethyl ester, alternative
preparation of compound 8, 1H NMR spectra of all compounds,
and 1H, 1H-TOCSY, HSQC, and HMBC NMR spectra of
episulfonium ion 21. This material is available free of charge
via the Internet at http://pubs.acs.org.
52%) as a colorless syrup: Rf ) 0.32 (ethyl acetate/ hexane, 1/1); [R]20
JA052548H
D
9
J. AM. CHEM. SOC. VOL. 127, NO. 34, 2005 12097