Regioselective glycosylation of unprotected phenyl 1-thioglycopyranosides with phenylboronic acid as a transient masking group

Article abstract of DOI:10.1002/ejoc.201300723

A useful protocol is described for the regioselective glycosylation of the secondary alcohols in unprotected glycosyl acceptors. Phenyl 1-thioglycopyranosides derived from D-glucose, D-galactose, D-glucosamine, L-rhamnose, and L-fucose were treated with phenylboronic acid to install a temporary boronic ester, and then submitted to a Koenigs-Knorr glycosylation with perbenzoylated glucopyranosyl or galactopyranosyl bromides. Good yields for coupling to the 3-position in glucosides and galactosides were achieved, but lower yields were obtained with the other acceptors. With phenyl 1-thio-β-D-glucopyranoside, the coupling could also be achieved with a superarmed thiogalactoside donor. The product from a glucose-glucose coupling could be subjected to a second regioselective glycosylation at the 6-position. In the galactose series, a β(1→3)-linked galactotriose could be prepared in good yield by two consecutive glycosylations in one pot, where a free 2-hydroxy group ensures neighboring group participation in the second coupling. Unprotected phenyl 1-thioglycopyranosides are protected in situ with phenylboronic acid and regioselectively glycosylated under Koenigs-Knorr conditions. The product disaccharides can be used directly as donors or acceptors for an additional glycosylation reaction. Copyright

Full text of DOI:10.1002/ejoc.201300723

FULL PAPER
DOI: 10.1002/ejoc.201300723
Regioselective Glycosylation of Unprotected Phenyl 1-Thioglycopyranosides
with Phenylboronic Acid as a Transient Masking Group
Thomas Hauch Fenger[a] and Robert Madsen*[a]
Keywords: Boronic acids / Carbohydrates / Glycosylation / Protecting groups / Regioselectivity
A useful protocol is described for the regioselective glycosyl-
ation of the secondary alcohols in unprotected glycosyl ac-
were obtained with the other acceptors. With phenyl 1-thio-
β- -glucopyranoside, the coupling could also be achieved
D
ceptors. Phenyl 1-thioglycopyranosides derived from -gluc-
D
with a superarmed thiogalactoside donor. The product from
a glucose–glucose coupling could be subjected to a second
regioselective glycosylation at the 6-position. In the galact-
ose series, a β(1Ǟ3)-linked galactotriose could be prepared
in good yield by two consecutive glycosylations in one pot,
where a free 2-hydroxy group ensures neighboring group
participation in the second coupling.
ose, -galactose, -glucosamine, -rhamnose, and L-fucose
D
D
L
were treated with phenylboronic acid to install a temporary
boronic ester, and then submitted to a Koenigs–Knorr glyc-
osylation with perbenzoylated glucopyranosyl or galactopyr-
anosyl bromides. Good yields for coupling to the 3-position in
glucosides and galactosides were achieved, but lower yields
any special directing agents, 2-(trimethylsilyl)ethyl β-d-ga-
lactopyranoside has been glycosylated in good yield with a
number of glycosyl bromides under Koenigs–Knorr condi-
tions.[11] With unprotected gluco- and mannopyranosides,
however, the selectivity for the primary alcohol is lower. To
improve the regioselectivity, dibutyltin oxide has been intro-
duced to form 4,6-stannylene acetals with 2,3,4,6-unprotec-
ted hexopyranosides, and in this way enhance the reactivity
of the 6-position. Under these conditions, a number of β-
galacto- and β-glucopyranosides have been glycosylated at
the primary position in good yield with several donors.[12]
Other positions in 2,3,4,6-unprotected hexopyranosides,
however, are more difficult to glycosylate in high yield.
Methyl β-d-galactopyranoside has been shown to react at
its 3-position with a glycosyl bromide in the presence of
dibutyltin oxide and tetrabutylammonium fluoride. The tet-
rabutylammonium fluoride promotes a shift in regioselec-
tivity from the 6- to the 3-position.[13] Still, the isolated
yield of the (1Ǟ3)-linked disaccharide was only 40%.[13] p-
Methoxyphenylboronic acid has been used as an in situ
blocking agent for the 4- and 6-positions in hexopyranos-
ides.[14] With this reagent, the Koenigs–Knorr glycosylation
of methyl α-d-galactopyranoside and methyl β-d-galacto-
pyranoside with 2,3,4,6-tetra-O-pivaloyl-α-d-glucopyran-
osyl bromide (2 equiv.) gave 50 and 72% yields, respectively,
of the (1Ǟ3)-linked disaccharides.[14] With methyl α-d-
glucopyranoside and methyl β-d-glucopyranoside, however,
the yields and selectivities were poor, and mixtures of
(1Ǟ2)- and (1Ǟ3)-linked disaccharides were formed.[14]
The reactions were carried out by stirring the donor, the
acceptor and the arylboronic acid with molecular sieves
(3 Å) in dichloroethane for 16 h, followed by the addition
of silver(I) on silica–alumina.[14] Borinic acids have also
Introduction
The importance and diverse roles of glycans in biological
processes continue to be revealed in further detail in the
area of glycobiology.[1] This has led to the development of
an increasing number of therapeutic agents based on glyc-
ans,[2] and has created a high demand for structurally well-
defined carbohydrate oligomers. As a result, the chemical
synthesis of oligosaccharides has received significant atten-
tion over the past three decades.[3] During this period,
major progress has been made in the field in terms of glyc-
osyl donors and glycosylation strategies. Significant ad-
vances include the development of the trichloroacetimid-
ate[4] and thioglycoside[5] donors, as well as the armed–dis-
armed,[6] one-pot,[7,8] and solid-phase[8,9] strategies. How-
ever, the fundamental principle for forming a glycosidic
bond is the same today as in 1982,[10] i.e., a glycosyl donor
is activated with a promoter and coupled to a partially pro-
tected acceptor with only one free hydroxy group. Irrespec-
tive of the donor and the strategy used, this causes the syn-
thesis of a target oligosaccharide to involve a significant
number of steps, of which the majority are used for the
manipulation of protecting groups. A solution to this prob-
lem would come from the development of regioselective
glycosylations with unprotected glycosyl acceptors.
Some progress has been made in this area, but in most
cases, the more reactive 6-position is selectively glycosylated
in a 2,3,4,6-unprotected hexopyranoside. In the absence of
[a] Department of Chemistry, Technical University of Denmark,
2800 Kgs. Lyngby, Denmark
E-mail: rm@kemi.dtu.dk
Homepage: http://www.organic.kemi.dtu.dk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300723.
Eur. J. Org. Chem. 2013, 5923–5933
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T. H. Fenger, R. Madsen
FULL PAPER
been used to mediate regioselective glycosylations, but high Dioxane and THF were deemed to be too acid labile to
yields of disaccharides were only obtained if the 6-position use in some glycosylation reactions with silver triflate, and
of the acceptor was protected with a silyl group, or if the consequently DME was chosen to investigate the couplings.
acceptor was a 6-deoxy hexose.[15]
Thus, a Koenigs–Knorr glycosylation between the pre-
Thus, there is still room for further development in this formed 4,6-phenylboronate and 2,3,4,6-tetra-O-acetyl-α-d-
area, and more comprehensive studies are required to ex- galactopyranosyl bromide was studied in the presence of
plore the scope and limitations of this concept. A particular silver oxide, silver carbonate, and silver triflate. In each
challenge would be to glycosylate the secondary alcohols in case, the ratio between the donor and the acceptor was var-
2,3,4,6-unprotected hexopyranosides, and for this reason we ied, and the best result was obtained with silver triflate and
decided to explore the use of the cheaper phenylboronic 1.3 equiv. of the donor. This gave the (1Ǟ3)-linked disac-
acid as a transient blocking group. As in our recent study charide as the major coupling product, but it was not pos-
with dibutyltin oxide,[12a] phenyl 1-thioglycopyranosides sible to achieve a yield above 30%. The coupling appeared
were chosen as acceptors, since the products of the regiose- to be very selective for the 3-position, but the yield was not
lective couplings would then be thioglycoside building satisfactory. The low yield seems to be caused by water in
blocks, which are useful glycosyl donors in oligosaccharide the boronate; it was not possible to thoroughly dry the solid
synthesis. Thus, in this paper, we report full details of the under high vacuum due to the partial cleavage and sublima-
regioselective glycosylation of unprotected thiohexopyran- tion of phenylboronic acid.
osides using an in situ blocking strategy with phenylboronic
acid.
As a result, the formation of the boronate was carried
out in the presence of drying agents, and for these studies,
the more stable 2,3,4,6-tetra-O-benzoyl-α-d-glucopyranosyl
bromide was used as the donor (Table 1). In the first experi-
ment, the boronate was generated in DME solution over
Results and Discussion
Phenyl 1-thio-β-d-glucopyranoside (1) was chosen as the molecular sieves (3 Å), and then the glycosyl bromide and
acceptor for the initial experiments, since regioselective re- silver triflate were added. In the work-up, the boronate was
actions on glucose are usually more difficult than with removed with methanol and a weakly basic ion-exchange
other hexoses. When 1 was mixed with phenylboronic acid resin. This, however, gave only a 16% yield of the (1Ǟ3)-
in acetonitrile, a clear solution was immediately obtained, linked disaccharide (Table 1, entry 1), and it appeared that
and then the formation of a white precipitate was observed. water was still the main problem. Although the molecular
The solid was shown by NMR spectroscopy to be the 4,6- sieves were able to remove the water during the formation
phenylboronate of 1 (vide infra). It was not possible to dis- of the boronate, the glycosyl bromide is a better drying
solve the boronate effectively in toluene, diethyl ether, agent, and seemed to be drying the sieves in the subsequent
dichloromethane, or dichloroethane, but it was completely glycosylation. Therefore, the drying agent should be re-
soluble in dioxane, THF, and DME (1,2-dimethoxyethane). moved before the glycosylation. Indeed, with this modifica-
Table 1. Optimization of the regioselective glycosylation.[a]
Entry
Drying agent
Yield [%][b]
1[c]
2
3
MS (3 Å)
MS (3 Å)
MS (4 Å)
CaSO4
MS (3 Å)
MS (3 Å)
MS (3 Å)
16
52
19
41
68
61
66
4
5[d]
6[e]
7[f]
[a] Reaction conditions: PhB(OH)2 (0.14 mmol), acceptor 1 (0.14 mmol), drying agent, DME, room temp., 16 h, then drying agent re-
moved, donor 2 (0.18 mmol), AgOTf (0.18 mmol), 0 °C, 3 h, then MeOH, IRA 743. [b] Isolated yields. [c] Drying agent not removed
prior to glycosylation. [d] Freshly activated MS (3 Å) added in glycosylation. [e] As for entry 5 with PhBCl2 instead of PhB(OH)2. [f] As
for entry 5 with (PhBO)3 (0.33 equiv.) instead of PhB(OH)2.
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Regioselective Glycosylation of Unprotected Pyranosides
tion, the yield of the disaccharide increased to 52% Table 2. Koenigs–Knorr glycosylation of unprotected phenyl 1-
thioglycopyranosides.[a]
(Table 1, entry 2). Under the same conditions, 4 Å molecu-
lar sieves and CaSO4 gave lower yields (Table 1, entries 3–
4). A further improvement could be achieved by adding a
new fresh batch of activated sieves during the glycosylation;
this raised the yield to 68% (Table 1, entry 5). This is a quite
satisfactory result in light of the previous difficulties with
regioselective glycosylations on glucose.
Two other reagents for forming the boronate were also
investigated, namely dichlorophenylborane and the anhy-
dride of phenylboronic acid, i.e., triphenylboroxin. The for-
mer produces hydrogen chloride upon ester formation,
while the latter generates only 1 equiv. of water. Tri-
phenylboroxin is easily prepared by heating phenylboronic
acid in an oven at 110 °C.[16] With both reagents, the
boronate was formed from acceptor 1 in DME, and the
coupling reaction was performed as described in Table 1,
entry 5. This resulted in almost the same yield of the (1Ǟ3)-
linked disaccharide in both cases (Table 1, entries 6–7), and
so it was decided to continue the studies with phenylboronic
acid as the in situ blocking agent.
The structure of the 4,6-boronate formed from acceptor
1 was confirmed by NMR spectroscopy after the ester was
isolated from the DME solution (Figure 1). Distinct
changes in the chemical shifts of H-4 and H-6 were ob-
served, and in [D6]DMSO solution, the couplings to OH-2
and OH-3 were visible, whereas OH-4 and OH-6 were ab-
sent. Four additional phenyl thioglycosides were prepared,
and the boronates were formed in the same way and charac-
terized by NMR spectroscopy (Figure 1). Galactoside 4 and
aminoglucoside 5 both gave 4,6-boronates, while rhamnos-
ide 6 and fucoside 7 gave 2,3- and 3,4-esters, respectively.
Phenyl 1-thio-α-d-mannopyranoside was also converted
into its phenylboronate, but in this case, the ester was not
soluble in DME, and so no further studies were performed
with mannose.
Figure 1. Glycosyl acceptors, the corresponding boronates, and do-
nor 8.
With this information, the substrate scope could now be
[a] Reaction conditions: PhB(OH)2 (0.14 mmol), acceptor
investigated further under the optimized conditions from
(0.14 mmol), MS (3 Å), DME, room temp., 16 h, then donor
Table 1, entry 5. In addition to donor 2, the corresponding
galactosyl bromide 8 (Figure 1) was also included in the
(0.18 mmol), AgOTf (0.18 mmol), MS (3 Å), 0 °C, 3 h, then
MeOH, IRA 743. [b] Isolated yields.
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T. H. Fenger, R. Madsen
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study. When donor 8 was coupled with glucoside 1, the Table 3. Glycosylation of unprotected phenyl 1-thioglycopyranos-
ides with donors 18–20.
yield of the product was essentially the same as that of the
product obtained with donor 2 (Table 2, entry 1).
Better results were observed with both donors in cou-
pling reactions with galactoside 4, where 82 and 75% yields
of the (1Ǟ3)-linked disaccharides were obtained (Table 2,
entries 2–3). Glucosamine acceptor 5, on the other hand,
gave poor yields in the glycosylations (Table 2, entries 4–5).
This is most probably due to the lower reactivity of the
acceptor, since the 3-position in phthalimido-protected β-
glucosamines is known to be the least reactive.[17] With
rhamnoside 6, moderate yields of the (1Ǟ4)-linked disac-
charides were obtained, and fucoside 7 gave poor yields of
the (1Ǟ2)-linked products. These low yields may again be
attributed to the lower reactivity of the hydroxy group in
the acceptor.[18] No coupling products other than the iso-
lated disaccharides were formed in any of the reactions;
only donor-derived decomposition products and unreacted
acceptor were seen. Neither was any aglycon transfer of the
thiophenyl group from the acceptor to the donor observed.
The positions of the glycosidic linkages were established
from NMR spectroscopy. The free hydroxy groups were vis-
1
ible in the H NMR spectra, and deshielding of the carbon
signals was observed in the 13C NMR spectra.
In addition to glycosyl bromides, a thioglycoside and two
trichloroacetimidates were also tested as glycosyl donors.
Thioglycoside 18 was coupled in the presence of N-iodosuc-
[a] Isolated yields. [b] Reaction conditions: PhB(OH)2 (0.14 mmol),
acceptor (0.14 mmol), MS (3 Å), DME, room temp., 16 h, then 18
(0.16 mmol), NIS (0.17 mmol), AgOTf (0.02 mmol), MS (3 Å),
cinimide (NIS) and silver triflate, while imidates 19 and 20
were activated with triethylsilyl triflate (Figure 2). Thiogly-
coside 18 is a so-called superarmed donor,[19] and a selective
coupling to another thioglycoside should therefore be pos-
sible. Indeed, the glycosylation between 18 and glucoside
–30 °C, 15 min, then MeOH, IRA 743. [c] Reaction conditions:
PhB(OH)2 (0.14 mmol), acceptor (0.14 mmol), MS (3 Å), DME,
room temp., 16 h, then donor (0.17 mmol), TESOTf (0.03 mmol;
TES = triethylsilyl), MS (3 Å), 0 °C, 1 h, then MeOH, IRA 743.
1 gave a 66% yield of disaccharide 21 (Table 3, entry 1). fore serve as glycosyl donors for a further glycosylation re-
Unfortunately, the same coupling with galactoside 4 gave action in the same reaction vessel. As glucosides and galac-
only a 40% yield of the disaccharide product (Table 3, en- tosides had been identified as the most effective acceptors,
try 2), and similar results were obtained with the imidate these experiments were only performed with thioglycosides
donors (Table 3, entries 3–6). In all, the regioselective glyc- 1 and 4. The initially formed disaccharides have a free
osylations with phenylboronic acid have shown that good- hydroxy group at the 2-position, and the effectiveness of a
yielding reactions can be achieved at the 3-position in β- second glycosylation will therefore depend on the reactivity
glucosides and β-galactosides under Koenigs–Knorr condi- of the new acceptor. The first experiment was done in the
tions. This represents an improvement over the previous galactose series, and began with the Koenigs–Knorr cou-
procedure with p-methoxyphenylboronic acid, where a poor pling of bromide 8 and thioglycoside 4 (Scheme 1). Instead
yield was observed in the coupling with glucosides.[14]
of isolating the disaccharide as in Table 2, entry 3, the 4,6-
phenylboronate of methyl β-d-galactopyranoside was
formed separately and was then added to the reaction mix-
ture together with N-iodosuccinimide and triethylsilyl tri-
flate. This resulted in a second glycosylation, and galacto-
triose 23 was isolated in a satisfactory 66% yield after work-
up with methanol and a weakly basic ion-exchange resin.
Notably, the second glycosylation gave only the β-linked
product, which is consistent with earlier observations with
2-hydroxy glycosyl donors, and may indicate that neigh-
Figure 2. Thioglycoside donor 18 and imidate donors 19 and 20.
Finally, it was decided to investigate whether several con- boring group participation is occurring with the free
secutive glycosylations could be carried out using this hydroxy group and that the mechanism goes via an epox-
method to prepare trisaccharides and higher oligosac- ide.[20]
charides. First, an iterative approach was studied, since the
The same sequence was performed in the glucose series,
initially formed disaccharides (shown in Tables 1, 2, and 3) and began with the coupling of bromide 2 and thioglycoside
are protected with a phenylboronate group, and may there- 1 as described in Table 1, entry 5. The 4,6-phenylboronate
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Regioselective Glycosylation of Unprotected Pyranosides
Scheme 1. One-pot glycosylation in the galactose series.
Scheme 2. One-pot glycosylation in the glucose series.
of methyl β-d-glucopyranoside was then added to the reac- only to 28%, and it appears that the lower coupling yield
tion mixture, followed by N-iodosuccinimide and trieth- and reactivity of the acceptor in the glucose series have a
ylsilyl triflate (Scheme 2). This gave glucotriose 24 in 26% detrimental influence on the iterative strategy. Trisac-
isolated yield after the usual work-up. The phenylboronate charides 23–25 were subsequently acetylated and depro-
of methyl β-d-glucopyranoside was less soluble in DME tected in order to completely characterize the three glycans.
and required a slightly more dilute solution, and therefore
A different approach to consecutive glycosylations would
the sequence was repeated with the corresponding benzyl be to use the isolated disaccharide as an acceptor, and to
β-d-glucopyranoside. This, however, enhanced the yield carry out a regioselective glycosylation at the primary posi-
tion. Since the 3-position is occupied by a bulky monosac-
charide, it should be possible to achieve a high selectivity
for the 6-position. This was demonstrated with disaccharide
3, which underwent a Koenigs–Knorr glycosylation with
bromide 2 to give branched trisaccharide 26 in 70% yield
with no coupling to the other positions being observed
(Scheme 3). Inspired by the β-selective glycosylation with 2-
hydroxy glycosyl donors, a further glycosylation was carried
out with lactoside acceptor 28 to give pentasaccharide 29.
The new glycosidic linkage was formed with complete β-
selectivity, although the isolated yield was only 36%. When
the same coupling was repeated with acetyl-protected donor
27, the yield increased to 71%.
Conclusions
In summary, we have further developed the regioselective
glycosylation of unprotected glycosyl acceptors by the use
of transient protection with a boronic acid. Phenyl 1-
thiohexopyranosides were used as the acceptors, and good
coupling yields to the 3-position in glucose and galactose
substrates were achieved. This provides an easy route to
(1Ǟ3)-linked disaccharide thioglycosides, which are valu-
able building blocks for oligosaccharide synthesis. When the
Scheme 3. Regioselective glycosylation at the 6-position.
products were used as acceptors, an additional glycosyl-
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ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 134.74, 134.55, 131.61,
130.88, 129.68, 128.26, 128.02, 127.50, 88.08 (C-1), 76.52, 74.97,
73.30, 72.03, 64.15 ppm. HRMS: calcd. for C12H16O5S [M – C6H3B
+ Na]+ 295.0616; found 295.0614.
ation at the 6-position could be performed. Alternatively,
they could be used as donors in another glycosylation with
a transiently protected acceptor.
Phenyl 4,6-O-Phenylboranylidine-1-thio-β-D-galactopyranoside (4a):
1H NMR (300 MHz, [D6]DMSO): δ = 7.74 (d, J = 6.7 Hz, 2 H),
7.46 (t, J = 7.3 Hz, 1 H), 7.35 (t, J = 7.4 Hz, 4 H), 7.05 (t, J =
7.3 Hz, 1 H), 6.94 (t, J = 7.5 Hz, 2 H), 5.24 (d, J = 6.0 Hz, 1 H, 2-
OH), 5.21 (d, J = 6.6 Hz, 1 H, 3-OH), 4.73 (d, J = 9.5 Hz, 1 H, 1-
H), 4.35 (d, J = 2.9 Hz, 1 H, 4-H), 4.22 (d, J = 12.0 Hz, 1 H, 6-
H), 4.14–4.00 (m, 2 H, 5-H, 6-H), 3.56 (ddd, J = 9.4, 6.6, 3.0 Hz,
1 H, 3-H), 3.39 (dt, J = 9.2, 6.1 Hz, 1 H, 2-H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 134.46, 134.19, 131.42, 130.94, 129.26,
128.14, 127.08, 87.14 (C-1), 74.06, 71.88, 71.87, 68.36, 65.18 ppm.
HRMS: calcd. for C18H19BO5S [M + Na]+ 381.0944; found
381.0975.
Experimental Section
General Remarks: All reactions were performed under an argon
atmosphere. Molecular sieves (MS) were flame-dried before use.
Dichloromethane and 1,2-dimethoxyethane were dried with MS
(3 Å). Phenyl 1-thio-β-d-glucopyranoside (1),[21] 2,3,4,6-tetra-O-
benzoyl-α-d-glucopyranosyl bromide (2),[22] phenyl 1-thio-β-d-ga-
lactopyranoside (4),[21] phenyl 2-deoxy-2-phthalimido-1-thio-β-d-
glucopyranoside (5),[21] phenyl 1-thio-α-l-rhamnopyranoside (6),[23]
phenyl 1-thio-β-l-fucopyranoside (7),[23] 2,3,4,6-tetra-O-benz-
oyl-α-d-galactopyranosyl bromide (8),[24] ethyl 2-O-benzoyl-3,4,6-
tri-O-benzyl-1-thio-β-d-galactopyranoside (18),[25] 2,3,4,6-tetra-O-
benzoyl-α-d-glucopyranosyl trichloroacetimidate (19),[24] 2,3,4,6-
tetra-O-benzoyl-α-d-galactopyranosyl trichloroacetimidate (20),[24]
and benzyl 2,4,6-tri-O-benzyl-β-d-galactopyranosyl-(1Ǟ4)-2,3,6-
tri-O-benzyl-β-d-glucopyranoside (28)[26] were synthesized accord-
ing to literature procedures. Silver triflate was co-evaporated with
dry toluene and dried under high vacuum prior to use. TLC was
performed on aluminum plates coated with silica gel 60. The plates
were visualized with UV light or developed by dipping into a solu-
tion of cerium(IV) sulfate (2.50 g) and ammonium molybdate
(6.25 g) in sulfuric acid (10%; 250 mL) followed by heating. Col-
umn chromatography was carried out with HPLC grade solvents
on silica gel 60 (230–400 mesh). NMR spectra were recorded with
Bruker AC 200, Varian Mercury 300, or Varian Unity Inova 500
instruments. Chemical shifts were calibrated to the residual solvent
signal in CDCl3 (δH = 7.26 ppm, δC = 77.16 ppm) or to TMS. As-
Phenyl 2-Deoxy-4,6-O-phenylboranylidine-2-phthalimido-1-thio-β-D-
1
glucopyranoside (5a): H NMR (300 MHz, CDCl3): δ = 8.03–7.68
(m, 6 H), 7.53–7.21 (m, 8 H), 5.71 (d, J = 10.5 Hz, 1 H, 1-H), 4.56
(ddd, J = 10.1, 8.6, 3.5 Hz, 1 H, 3-H), 4.35 (t, J = 10.3 Hz, 1 H,
2-H), 4.31–4.22 (m, 1 H, 6-H), 4.01 (t, J = 10.1 Hz, 1 H, 6-H), 3.82
(t, J = 9.0 Hz, 1 H, 4-H), 3.79–3.67 (m, 1 H, 5-H), 2.83 (d, J =
3.6 Hz, 1 H, 3-OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.63,
167.75, 134.52, 134.31, 132.94, 131.86, 131.46, 129.23, 128.44,
127.89, 124.14, 123.57, 84.73 (C-1), 76.00, 72.59, 71.69, 64.08,
55.43 ppm. HRMS: calcd. for C20H19NO6S [M – C6H3B + Na]+
424.0831; found 424.0833.
Phenyl 2,3-O-Phenylboranylidine-1-thio-α-L-rhamnopyranoside (6a):
1H NMR (300 MHz, [D6]DMSO): δ = 7.76–7.68 (m, 2 H), 7.58–
7.49 (m, 3 H), 7.45–7.30 (m, 5 H), 5.91 (s, 1 H, 1-H), 5.65 (d, J =
6.4 Hz, 1 H, 4-OH), 4.72 (dd, J = 7.1, 1.1 Hz, 1 H, 2-H), 4.46 (t,
J = 7.3 Hz, 1 H, 3-H), 3.98–3.88 (m, 1 H, 5-H), 3.20–3.10 (m, 1 H,
4-H), 1.06 (d, J = 6.2 Hz, 3 H, 6-H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 135.25, 134.74, 133.41, 132.63, 129.84, 128.70,
128.33, 128.01, 84.46 (C-1), 79.73, 78.56, 76.01, 67.89, 18.04 ppm.
HRMS: calcd. for C12H16O4S [M – C6H3B + Na]+ 279.0667; found
279.0657.
1
signment of H and 13C resonances was based on COSY, HSQC,
and HMBC experiments. HRMS analysis was performed using an
Agilent 1100 LC system with a diode array detector and a Luna
C18 column (3 μm, 50 mmϫ2 mm). The LC was coupled to a
Micromass LCT orthogonal time-of-flight mass spectrometer
equipped with Lock Mass probe operating in positive electrospray
mode. Optical rotations were measured with a Perkin–Elmer 341
polarimeter. IR spectra were recorded with a Bruker Alpha-P
FTIR instrument.
Phenyl 3,4-O-Phenylboranylidine-1-thio-β-L
-fucopyranoside (7a): 1H
NMR (300 MHz, [D6]DMSO): δ = 7.79–7.70 (m, 2 H), 7.55–7.17
(m, 8 H), 5.94 (d, J = 5.8 Hz, 1 H, 2-OH), 4.91 (d, J = 7.6 Hz, 1
H, 1-H), 4.57–4.47 (m, 2 H, 3-H, 4-H), 4.13–4.03 (m, 1 H, 5-H),
3.52–3.44 (m, 1 H, 2-H), 1.29 (d, J = 6.5 Hz, 3 H, 6-H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 135.49, 135.22, 134.74, 132.42,
130.13, 129.66, 128.65, 128.01, 127.20, 86.77 (C-1), 79.99, 78.26,
72.35, 71.72, 17.07 ppm. HRMS: calcd. for C18H19BO4S
[M + Na]+ 365.0995; found 365.0942.
General Procedure for Koenigs–Knorr Glycosylation: Equimolar
amounts of phenyl thioglycopyranoside and phenylboronic acid
were dissolved in dry DME (5 mL) to give a 50 mg/mL glycoboron-
ate solution. MS (3 Å; 350 mg) were added, and the mixture was
stirred overnight or until dry, as monitored by NMR spectroscopy.
A decanted aliquot (1 mL) of this solution was added to a mixture
of the bromide donor (1.3 equiv.) and MS (3 Å; 175 mg) under ar-
gon, and the resulting suspension was stirred overnight. AgOTf
(1.3 equiv.) was added at 0 °C, and the reaction mixture was stirred
for 3 h (TLC: toluene/acetone, 3:1). CH2Cl2, MeOH, and Am-
berlite IRA 743 (250–300 mg) were then added, and the mixture
was stirred overnight. The suspension was filtered through Celite,
and the pad was flushed with CH2Cl2/MeOH (1:1 mixture). The
filtrate was concentrated and the residue was purified by flash
chromatography (toluene/acetone, 7:1).
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl-(1Ǟ3)-1-thio-β-
D
-glucopyranoside (3): Colorless solid. Rf = 0.38 (toluene/acetone,
3:1). [α]2D0 = +3.2 (c = 1, CDCl ). IR (neat): ν = 3493, 3064, 2962,
˜
3
2944, 2876, 1729, 1606, 1452, 1316, 1266, 1178, 1094, 1069, 1027,
1
710 cm–1. H NMR (500 MHz, CDCl3): δ = 8.08 (d, J = 7.3 Hz, 2
H), 7.98 (d, J = 7.3 Hz, 2 H), 7.93 (d, J = 7.3 Hz, 2 H), 7.83 (d, J
= 7.3 Hz, 2 H), 7.60–7.50 (m, 3 H), 7.45–7.35 (m, 9 H), 7.32–7.24
(m, 5 H), 5.95 (t, J = 9.7 Hz, 1 H, 3Ј-H), 5.62 (t, J = 9.7 Hz, 1 H,
4Ј-H), 5.54 (dd, J = 9.8, 8.1 Hz, 1 H, 2Ј-H), 5.06 (d, J = 8.0 Hz, 1
H, 1Ј-H), 4.77 (dd, J = 12.2, 2.4 Hz, 1 H, 6Ј-H), 4.47 (d, J = 9.8 Hz,
1 H, 1-H), 4.38 (dd, J = 12.2, 6.8 Hz, 1 H, 6Ј-H), 4.23 (ddd, J =
Phenyl 4,6-O-Phenylboranylidine-1-thio-β-
D-glucopyranoside (1a):
1H NMR (300 MHz, [D6]DMSO): δ = 7.79–7.69 (m, 2 H), 7.47–
7.40 (m, 3 H), 7.38–7.22 (m, 5 H), 5.64 (d, J = 6.2 Hz, 1 H, 2-OH), 9.5, 6.7, 2.5 Hz, 1 H, 5Ј-H), 3.92–3.86 (m, 1 H, 6-H), 3.76 (s, 1 H,
5.56 (d, J = 5.1 Hz, 1 H, 3-OH), 4.88 (d, J = 9.8 Hz, 1 H, 1-H),
4.15 (dd, J = 9.8, 5.0 Hz, 1 H, 6-H), 3.89 (t, J = 9.9 Hz, 1 H, 6-
H), 3.75 (td, J = 9.5, 5.0 Hz, 1 H, 5-H), 3.65 (t, J = 9.2 Hz, 1 H,
4-H), 3.46 (td, J = 8.7, 5.1 Hz, 1 H, 3-H), 3.23–3.14 (m, 1 H, 2-H)
4-OH), 3.74–3.69 (m, 1 H, 6-H), 3.57–3.48 (m, 2 H, 3-H, 4-H),
3.39–3.34 (m, 1 H, 5-H), 3.33–3.27 (m, 1 H, 2-H), 2.12 (d, J =
2.5 Hz, 1 H, 2-OH), 2.02 (t, J = 6.7 Hz, 1 H, 6-OH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.37, 165.91, 165.57, 165.45,
5928
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5923–5933

Regioselective Glycosylation of Unprotected Pyranosides
133.89, 133.70, 133.64, 133.60, 132.85, 131.62, 130.19, 130.13,
130.04, 129.99, 129.44, 129.31, 129.27, 128.85, 128.73, 128.63,
128.58, 128.52, 128.46, 125.53, 102.72 (C-1Ј), 89.68, 88.10 (C-1),
79.73, 73.00, 72.66, 72.17, 71.08, 69.60, 69.54, 63.25, 63.07 ppm.
HRMS: calcd. for C46H42O14S [M + Na]+ 873.2193; found
873.2222.
2.3 Hz, 1 H, 2-OH), 2.14 (dd, J = 8.9, 3.4 Hz, 1 H, 6-OH) ppm.
13C NMR (75 MHz, CDCl3): δ = 166.25, 166.04, 165.79, 165.72,
134.02, 133.79, 133.74, 133.66, 132.50, 132.42, 130.27, 130.00,
129.97, 129.44, 129.23, 129.19, 129.00, 128.95, 128.81, 128.75,
128.57, 128.11, 102.17 (C-1Ј), 88.28 (C-1), 84.25, 78.31, 72.10,
71.41, 70.22, 68.89, 68.46, 68.26, 62.72, 62.48 ppm. HRMS: calcd.
for C46H42O14S [M + Na]+ 873.2193; found 873.2213.
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl-(1Ǟ3)-1-thio-
β-
D
-glucopyranoside (9): Colorless solid. Rf = 0.47 (toluene/acetone,
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
2-phthalimido-1-thio-β- -glucopyranoside (12): Colorless solid. Rf =
0.51 (toluene/acetone, 3:1). [α]2D0 = +40.2 (c = 1, CDCl3). IR (neat):
D-glucopyranosyl-(1Ǟ3)-2-deoxy-
3:1). [α]2D0 = –23.4 (c = 1, CDCl ). IR (neat): ν = 3489, 3063, 2961,
D
˜
3
2914, 2886, 1726, 1602, 1452, 1315, 1265, 1178, 1095, 1069, 1026,
710 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.11–8.03 (m, 4 H), ν = 3480, 3063, 2956, 2943, 2881, 1777, 1714, 1602, 1584, 1451,
˜
7.98 (d, J = 7.3 Hz, 2 H), 7.79 (d, J = 7.3 Hz, 2 H), 7.63 (t, J =
7.5 Hz, 1 H), 7.59–7.36 (m, 11 H), 7.31–7.21 (m, 5 H), 5.99 (d, J
1386, 1316, 1262, 1178, 1091, 1069, 1026, 709 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 8.15–8.09 (m, 2 H), 7.89–7.85 (m, 2 H),
= 3.1 Hz, 1 H, 4Ј-H), 5.82 (dd, J = 10.4, 8.0 Hz, 1 H, 2Ј-H), 5.64 7.64–7.56 (m, 3 H), 7.52–7.43 (m, 6 H), 7.40–7.31 (m, 5 H), 7.28–
(dd, J = 10.4, 3.4 Hz, 1 H, 3Ј-H), 5.02 (d, J = 8.0 Hz, 1 H, 1Ј-H), 7.23 (m, 3 H), 7.21–7.14 (m, 5 H), 7.11 (t, J = 7.8 Hz, 2 H), 6.93
4.61 (dd, J = 11.6, 4.4 Hz, 1 H, 6Ј-H), 4.53–4.45 (m, 2 H, 6Ј-H, 1-
H), 4.41 (dd, J = 7.9, 4.4 Hz, 1 H, 5Ј-H), 3.99 (s, 1 H, 4-OH), 3.93–
(d, J = 7.3 Hz, 1 H), 5.76 (t, J = 9.7 Hz, 1 H, 3Ј-H), 5.52 (t, J =
9.7 Hz, 1 H, 4Ј-H), 5.44 (dd, J = 9.8, 8.0 Hz, 1 H, 2Ј-H), 5.40 (d,
3.86 (m, 1 H, 6-H), 3.74 (dt, J = 12.0, 6.2 Hz, 1 H, 6-H), 3.61–3.53 J = 10.5 Hz, 1 H, 1-H), 4.84 (d, J = 8.0 Hz, 1 H, 1Ј-H), 4.75 (dd,
(m, 2 H, 3-H, 4-H), 3.42–3.30 (m, 2 H, 2-H, 5-H), 2.18 (d, J = J = 12.3, 2.3 Hz, 1 H, 6Ј-H), 4.61 (dd, J = 10.2, 8.4 Hz, 1 H, 3-H),
2.5 Hz, 1 H, 2-OH), 2.10 (t, J = 6.7 Hz, 1 H, 6-OH) ppm. 13C
4.39–4.31 (m, 2 H, 2-H, 6Ј-H), 4.23 (ddd, J = 9.6, 7.1, 2.3 Hz, 1 H,
NMR (75 MHz, CDCl3): δ = 166.31, 165.77, 165.71, 165.65, 5Ј-H), 3.94 (dd, J = 11.8, 3.5 Hz, 1 H, 6-H), 3.79 (dd, J = 11.8,
134.04, 133.70, 133.65, 132.84, 131.64, 130.25, 130.17, 130.01,
129.99, 129.35, 129.31, 129.27, 128.94, 128.79, 128.73, 128.62,
128.57, 128.52, 128.46, 103.09 (C-1Ј), 90.01 (C-3), 88.11 (C-1),
79.68, 72.34, 71.62, 71.01, 70.06, 69.71, 68.21, 63.32, 62.78 ppm.
HRMS: calcd. for C46H42O14S [M + Na]+ 873.2193; found
873.2228.
5.5 Hz, 1 H, 6-H), 3.72 (t, J = 9.0 Hz, 1 H, 4-H), 3.54 (ddd, J =
9.3, 5.4, 3.7 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
168.86, 166.94, 166.33, 165.85, 165.28, 164.76, 134.31, 133.90,
133.70, 133.52, 133.04, 132.35, 132.11, 130.95, 130.26, 130.08,
129.89, 129.74, 129.33, 129.20, 128.71, 128.64, 128.59, 128.49,
128.43, 128.12, 123.73, 123.21, 101.58 (C-1Ј), 84.27 (C-1), 83.91 (C-
3), 79.88, 77.45, 73.08, 72.69, 72.03, 70.91, 69.19, 63.39, 63.00 ppm.
HRMS: calcd. for C54H45NO15S [M + Na]+ 1002.2402; found
1002.2405.
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl-(1Ǟ3)-1-thio-β-
D
-galactopyranoside (10): Colorless solid. Rf = 0.41 (toluene/acet-
one, 3:1). [α]2D0 = +14.8 (c = 1, CDCl ). IR (neat): ν = 3537, 3063,
˜
3
2950, 2888, 1728, 1601, 1452, 1315, 1266, 1178, 1107, 1093, 1069,
1027, 710 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.04 (d, J =
8.3 Hz, 2 H), 7.93 (dd, J = 11.3, 4.1 Hz, 4 H), 7.83 (d, J = 8.3 Hz,
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
oxy-2-phthalimido-1-thio-β- -glucopyranoside (13): Colorless solid.
Rf = 0.56 (toluene/acetone, 3:1). [α]2D0 = +147.7 (c = 1, CDCl3). IR
D-galactopyranosyl-(1Ǟ3)-2-de-
D
2 H), 7.61–7.14 (m, 17 H), 5.95 (t, J = 9.7 Hz, 1 H, 3Ј-H), 5.63 (t, (neat): ν = 3479, 3062, 2981, 2881, 1777, 1716, 1602, 1452, 1386,
˜
J = 9.7 Hz, 1 H, 4Ј-H), 5.50 (dd, J = 9.8, 7.9 Hz, 1 H, 2Ј-H), 5.16 1267, 1178, 1094, 1069, 1026, 711 cm–1. 1H NMR (500 MHz,
(d, J = 7.9 Hz, 1 H, 1Ј-H), 4.69 (dd, J = 12.2, 2.8 Hz, 1 H, 6Ј-H), CDCl3): δ = 8.10 (d, J = 7.2 Hz, 2 H), 8.04 (d, J = 7.2 Hz, 2 H),
4.49 (dd, J = 12.2, 6.0 Hz, 1 H, 6Ј-H), 4.45 (d, J = 9.7 Hz, 1 H, 1- 7.65–7.53 (m, 5 H), 7.52–7.41 (m, 7 H), 7.38–7.29 (m, 3 H), 7.28–
H), 4.22–4.16 (m, 1 H, 5Ј-H), 4.06 (s, 1 H, 4-H), 3.85 (dd, J = 11.3,
7.1 Hz, 1 H, 6-H), 3.78–3.71 (m, 1 H, 2-H), 3.64 (dd, J = 8.9, (t, J = 7.8 Hz, 2 H), 7.00 (d, J = 7.3 Hz, 1 H), 5.88 (d, J = 3.3 Hz,
3.2 Hz, 1 H, 3-H), 3.62–3.55 (m, 1 H, 6-H), 3.48–3.43 (m, 1 H, 5- 1 H, 4Ј-H), 5.74 (dd, J = 10.4, 8.0 Hz, 1 H, 2Ј-H), 5.46 (dd, J =
7.24 (m, 2 H), 7.21–7.16 (m, 3 H), 7.12 (t, J = 7.8 Hz, 2 H), 7.08
H), 2.69 (s, 1 H, 4-OH), 2.36 (s, 1 H, 2-OH), 2.16–2.10 (m, 1 H, 6- 10.4, 3.4 Hz, 1 H, 3Ј-H), 5.42 (d, J = 10.5 Hz, 1 H, 1-H), 4.85 (d,
OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.37, 165.95, 165.80,
165.44, 133.85, 133.71, 133.60, 132.51, 132.43, 130.09, 130.00,
129.55, 129.26, 129.18, 128.85, 128.78, 128.72, 128.58, 128.45,
J = 8.0 Hz, 1 H, 1Ј-H), 4.68–4.60 (m, 2 H, 3-H, 6Ј-H), 4.58 (s, 1
H, 4-OH), 4.47–4.35 (m, 3 H, 2-H, 5Ј-H, 6Ј-H), 3.99–3.91 (m, 1 H,
6-H), 3.84–3.76 (m, 2 H, 4-H, 6-H), 3.55 (ddd, J = 9.3, 5.2, 3.9 Hz,
128.08, 101.79 (C-1Ј), 88.35 (C-1), 83.91 (C-3), 78.33, 72.81, 72.56, 1 H, 5-H), 2.07 (t, J = 6.8 Hz, 1 H, 6-OH) ppm. 13C NMR
72.42, 69.66, 68.83, 68.53, 62.95, 62.64 ppm. HRMS: calcd. for (75 MHz, CDCl3): δ = 166.30, 165.59, 165.55, 164.95, 134.31,
C46H42O14S [M + Na]+ 873.2187; found 873.2196.
134.08, 133.92, 133.75, 133.55, 133.07, 132.23, 130.90, 130.24,
129.78, 129.75, 129.23, 129.20, 128.95, 128.74, 128.63, 128.47,
128.42, 128.16, 123.66, 123.14, 101.85 (C-1Ј), 84.23 (C-1), 84.12 (C-
3), 79.82, 72.48, 71.62, 70.99, 70.02, 68.10, 63.41, 62.85, 54.02 ppm.
HRMS: calcd. for C54H45NO15S [M + Na]+ 1002.2402; found
1002.2406.
Phenyl 2,3,4,6-Tetra-O-benzoyl-β- -galactopyranosyl-(1Ǟ3)-1-thio-
D
β-D-galactopyranoside (11): Colorless solid. Rf = 0.38 (toluene/acet-
one, 3:1). [α]2D0 = +92.4 (c = 1, CDCl ). IR (neat): ν = 3524, 3063,
˜
3
2963, 2925, 2894, 1725, 1601, 1451, 1315, 1266, 1177, 1108, 1094,
1
1069, 1027, 710 cm–1. H NMR (500 MHz, CDCl3): δ = 8.10 (d, J
= 7.2 Hz, 2 H), 8.01 (d, J = 7.2 Hz, 2 H), 7.94 (d, J = 7.3 Hz, 2 Phenyl 2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl-(1Ǟ4)-1-thio-α-
H), 7.78 (d, J = 7.3 Hz, 2 H), 7.63 (t, J = 7.5 Hz, 1 H), 7.57 (t, J
= 7.4 Hz, 1 H), 7.54–7.33 (m, 10 H), 7.25 (m, 5 H), 5.98 (d, J =
3.1 Hz, 1 H, 4Ј-H), 5.77 (dd, J = 10.4, 7.9 Hz, 1 H, 2Ј-H), 5.66 (dd,
L-rhamnopyranoside (14): Colorless solid. Rf = 0.51 (toluene/acet-
one, 3:1). [α]2D0 = –97.8 (c = 1, CDCl ). IR (neat): ν = 3500, 3063,
˜
3
2972, 2938, 2886, 1730, 1602, 1452, 1351, 1265, 1177, 1092, 1069,
J = 10.4, 3.4 Hz, 1 H, 3Ј-H), 5.11 (d, J = 7.9 Hz, 1 H, 1Ј-H), 4.63 1027, 709 cm–1. H NMR (300 MHz, CDCl3): δ = 8.08–7.97 (m, 4
(dd, J = 11.6, 7.5 Hz, 1 H, 6Ј-H), 4.48 (d, J = 11.6 Hz, 1 H, 6Ј-H), H), 7.92 (d, J = 7.1 Hz, 2 H), 7.82 (d, J = 7.1 Hz, 2 H), 7.60–7.47
4.47 (d, J = 9.9 Hz, 1 H, 1-H), 4.39–4.34 (m, 1 H, 5Ј-H), 4.08 (s, 1 (m, 3 H), 7.46–7.22 (m, 14 H), 5.93 (t, J = 9.6 Hz, 1 H, 3Ј-H), 5.67
H, 4-H), 3.88–3.82 (m, 1 H, 6-H), 3.78 (td, J = 9.4, 2.3 Hz, 1 H, (t, J = 9.7 Hz, 1 H, 4Ј-H), 5.55 (dd, J = 9.8, 8.0 Hz, 1 H, 2Ј-H),
1
2-H), 3.67 (dd, J = 8.9, 3.2 Hz, 1 H, 3-H), 3.60–3.53 (m, 1 H, 6-
5.41 (d, J = 1.1 Hz, 1 H, 1-H), 5.24 (d, J = 7.9 Hz, 1 H, 1Ј-H), 4.70
H), 3.50–3.44 (m, 1 H, 5-H), 2.81 (s, 1 H, 4-OH), 2.39 (d, J = (dd, J = 12.2, 3.0 Hz, 1 H, 6Ј-H), 4.48 (dd, J = 12.2, 5.6 Hz, 1 H,
Eur. J. Org. Chem. 2013, 5923–5933
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5929

T. H. Fenger, R. Madsen
6Ј-H), 4.23–4.14 (m, 2 H, 5-H, 5Ј-H), 4.06 (s, 1 H, 2-H), 3.85–3.76 1.34 (d, J = 6.5 Hz, 3 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3):
FULL PAPER
(m, 1 H, 3-H), 3.70 (t, J = 9.4 Hz, 1 H, 4-H), 2.75 (d, J = 5.2 Hz,
1 H, 3-OH), 2.60 (s, 1 H, 2-OH), 1.25 (d, J = 6.2 Hz, 3 H, 6-H)
δ = 166.17, 165.70, 165.62, 134.03, 133.79, 133.63, 133.43, 133.36,
131.58, 130.26, 130.05, 129.99, 129.45, 129.36, 129.27, 128.95,
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.36, 166.00, 165.46, 128.81, 128.78, 128.73, 128.56, 128.54, 128.46, 127.36, 125.53,
165.43, 134.00, 133.76, 133.52, 133.48, 131.69, 130.08, 129.99,
129.66, 129.29, 129.21, 128.94, 128.90, 128.82, 128.68, 128.55,
102.39 (C-1Ј), 85.75 (C-1), 80.85 (C-2), 74.24, 73.56, 72.43, 71.70,
70.85, 69.59, 68.26, 62.65, 16.84 ppm. HRMS: calcd. for
127.71, 101.18 (C-1Ј), 87.42 (C-1), 81.87 (C-4), 73.16, 72.78, 72.58, C46H42O13S [M + Na]+ 857.2244; found 857.2283.
72.53, 71.41, 69.82, 67.58, 63.11, 17.69 ppm. HRMS: calcd. for
Phenyl 2-O-Benzoyl-3,4,6-tri-O-benzyl-1-thio-β-
(1Ǟ3)-1-thio-β- -glucopyranoside (21): Glycoboronate 1a was
D-galactopyranosyl-(1Ǟ4)-1-thio- formed in DME as described above and an aliquot (1 mL) of this
D-galactopyranosyl-
C46H42O13S [M + Na]+ 857.2238; found 857.2245.
D
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
α-
L
-rhamnopyranoside (15): Colorless solid. Rf = 0.57 (toluene/acet-
solution (i.e., 50 mg, 0.14 mmol of glycoboronate 1a) was added to
a mixture of donor 18 (1.1 equiv.), N-iodosuccinimide (1.2 equiv.),
and MS (3 Å; 175 mg) under argon. The suspension was stirred
one, 3:1). [α]2D0 = –23.4 (c = 1, CDCl ). IR (neat): ν = 3514, 3062,
˜
3
2976, 2936, 2887, 1727, 1602, 1584, 1451, 1315, 1265, 1177, 1094,
1069, 1027, 709 cm–1. H NMR (500 MHz, CDCl3): δ = 8.10 (d, J overnight and then cooled to –30 °C. AgOTf (3–4 mg) was added,
1
= 7.3 Hz, 2 H), 8.04–7.98 (m, 4 H), 7.78 (d, J = 7.3 Hz, 2 H), 7.63
(t, J = 7.4 Hz, 1 H), 7.58–7.47 (m, 4 H), 7.45–7.35 (m, 7 H), 7.32–
7.22 (m, 5 H), 6.00 (d, J = 3.2 Hz, 1 H, 4Ј-H), 5.84 (dd, J = 10.3,
and the reaction mixture was stirred for 15 min at –30 °C (TLC:
toluene/acetone, 3:1). CH2Cl2, MeOH, and IRA 743 were then
added, and the mixture was stirred overnight. The suspension was
8.0 Hz, 1 H, 2Ј-H), 5.63 (dd, J = 10.4, 3.4 Hz, 1 H, 3Ј-H), 5.43 (s, filtered through Celite, and the pad was flushed with CH2Cl2/
1 H, 1-H), 5.19 (d, J = 8.0 Hz, 1 H, 1Ј-H), 4.62 (dd, J = 11.5,
7.1 Hz, 1 H, 6Ј-H), 4.48 (dd, J = 11.5, 5.6 Hz, 1 H, 6Ј-H), 4.36 (t,
MeOH (1:1 mixture). The filtrate was concentrated, and the residue
was purified by flash chromatography (toluene/acetone, 7:1) to give
J = 6.3 Hz, 1 H, 5Ј-H), 4.28–4.21 (m, 1 H, 5-H), 4.06 (s, 1 H, 2- 21 as a colorless solid. Rf = 0.54 (toluene/acetone, 3:1). [α]2D0 = +3.0
H), 3.85–3.80 (m, 1 H, 3-H), 3.73 (t, J = 9.4 Hz, 1 H, 4-H), 2.76
(d, J = 5.0 Hz, 1 H, 3-OH), 2.58 (s, 1 H, 2-OH), 1.33 (d, J = 6.2 Hz,
(c = 1, CDCl ). IR (neat): ν = 3461, 3063, 3031, 2915, 2876, 1709,
˜
3
1453, 1349, 1271, 1180, 1102, 1069, 741, 699 cm–1. 1H NMR
3 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.31, 165.78, (500 MHz, CDCl3): δ = 8.06–7.99 (m, 2 H), 7.61 (t, J = 7.4 Hz, 1
165.58, 134.04, 133.91, 133.80, 133.60, 131.67, 130.24, 130.00,
129.93, 129.51, 129.30, 129.25, 129.18, 128.91, 128.86, 128.73,
128.55, 127.71, 101.74 (C-1Ј), 87.39 (C-1), 82.41, 72.70, 72.07,
71.82, 71.38, 70.43, 68.44, 67.68, 62.55, 17.82 ppm. HRMS: calcd.
for C46H42O13S [M + Na]+ 857.2251; found 857.2244.
H), 7.47 (t, J = 7.7 Hz, 2 H), 7.42–7.15 (m, 20 H), 5.65 (dd, J =
10.0, 8.0 Hz, 1 H), 4.98 (d, J = 11.7 Hz, 1 H), 4.69–4.58 (m, 3 H),
4.56–4.40 (m, 4 H), 4.30 (s, 1 H), 3.91 (d, J = 2.2 Hz, 1 H), 3.87
(d, J = 11.0 Hz, 1 H), 3.74–3.65 (m, 4 H), 3.49 (t, J = 9.0 Hz, 1
H), 3.45–3.39 (m, 2 H), 3.38–3.29 (m, 2 H), 2.35 (d, J = 2.3 Hz, 1
H), 2.19 (s, 1 H, 6-OH) ppm. 13C NMR (75 MHz, CDCl3): δ =
165.97, 138.11, 137.53, 137.51, 133.47, 132.68, 132.01, 130.04,
130.01, 129.20, 128.70, 128.68, 128.64, 128.59, 128.35, 128.24,
128.13, 128.00, 102.87, 89.97, 87.46, 79.91, 79.57, 74.72, 74.31,
73.96, 72.47, 72.42, 72.38, 70.90, 69.87, 69.22, 63.40 ppm. HRMS:
calcd. for C46H48O11S [M + Na]+ 831.2809; found 831.2810.
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl-(1Ǟ2)-1-thio-β-
L
-fucopyranoside (16): Colorless solid. Rf = 0.59 (toluene/acetone,
3:1). [α]2D0 = –2.6 (c = 1, CDCl ). IR (neat): ν = 3496, 3064, 2937,
˜
3
2873, 1729, 1601, 1584, 1451, 1262, 1262, 1177, 1092, 1069, 1026,
1
708 cm–1. H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 7.9 Hz, 2
H), 7.97 (d, J = 7.9 Hz, 2 H), 7.94 (d, J = 7.9 Hz, 2 H), 7.81 (d, J
= 7.9 Hz, 2 H), 7.59 (t, J = 7.3 Hz, 1 H), 7.53 (t, J = 7.3 Hz, 1 H), Phenyl 2-O-Benzoyl-3,4,6-tri-O-benzyl-1-thio-β-
D-galactopyranosyl-
7.43 (m, 6 H), 7.28 (m, 4 H), 7.13–7.01 (m, 5 H), 5.97 (t, J = 9.7 Hz, (1Ǟ3)-1-thio-β- -galactopyranoside (22): Prepared from donor 18
D
1 H, 3Ј-H), 5.64 (t, J = 9.8 Hz, 1 H, 4Ј-H), 5.59 (dd, J = 12.3, and acceptor 4 as described above for 21. Colorless solid. Rf = 0.51
9.5 Hz, 1 H, 2Ј-H), 4.94 (d, J = 7.9 Hz, 1 H, 1Ј-H), 4.78–4.70 (m, (toluene/acetone, 3:1). [α]2D0 = +17.9 (c = 1, CDCl ). IR (neat): ν =
˜
3
1 H, 6Ј-H), 4.51 (d, J = 8.8 Hz, 1 H, 1-H), 4.44 (dd, J = 12.3,
3486, 3062, 3032, 2874, 1711, 1453, 1366, 1271, 1112, 1070, 1027,
1
6.6 Hz, 1 H, 6Ј-H), 4.23–4.17 (m, 1 H, 5Ј-H), 4.14 (s, 1 H, 3-OH), 739, 699 cm–1. H NMR (300 MHz, CDCl3): δ = 8.04–7.91 (m, 2
3.78 (s, 1 H, 4-H), 3.71–3.66 (m, 2 H, 2-H, 3-H), 3.57–3.51 (m, 1 H), 7.63–7.53 (m, 1 H), 7.48–7.40 (m, 4 H), 7.39–7.16 (m, 18 H),
H, 5-H), 2.35 (s, 1 H, 4-OH), 1.32 (d, J = 6.4 Hz, 3 H, 6-H) ppm. 5.60 (dd, J = 10.1, 7.9 Hz, 1 H), 4.96 (d, J = 11.6 Hz, 1 H), 4.73
13C NMR (75 MHz, CDCl3): δ = 166.25, 165.90, 165.40, 165.38,
133.90, 133.73, 133.56, 133.41, 133.30, 131.63, 130.27, 130.12,
130.09, 129.96, 129.46, 129.34, 128.79, 128.74, 128.56, 127.35,
(d, J = 7.9 Hz, 1 H, 1Ј-H), 4.63 (t, J = 12.3 Hz, 1 H), 4.52 (d, J =
12.3 Hz, 1 H), 4.48–4.41 (m, 3 H), 4.02 (s, 1 H), 3.97 (d, J = 2.7 Hz,
1 H), 3.94–3.86 (m, 1 H), 3.74–3.45 (m, 8 H), 2.81 (s, 1 H), 2.41
102.07 (C-1Ј), 85.78 (C-1), 80.67 (C-2), 74.21, 73.55, 73.05, 72.77, (d, J = 2.4 Hz, 1 H), 2.20 (m, 1 H) ppm. 13C NMR (75 MHz,
71.69, 70.84, 69.45, 62.75, 16.84 ppm. HRMS: calcd. for
CDCl3): δ = 166.08, 138.23, 137.80, 137.64, 133.47, 132.61, 132.45,
130.01, 129.97, 129.09, 128.76, 128.68, 128.63, 128.58, 128.23,
128.15, 128.10, 128.07, 127.96, 102.15 (C-1Ј), 87.93, 83.91, 79.67,
78.27, 74.87, 74.27, 73.87, 72.57, 72.33, 72.26, 69.06, 68.81, 68.38,
62.91 ppm. HRMS: calcd. for C46H48O11S [M + Na]+ 831.2810;
found 831.2852.
C46H42O13S [M + Na]+ 857.2238; found 857.2258.
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl-(1Ǟ2)-1-thio-
β-L-fucopyranoside (17): Colorless solid. Rf = 0.58 (toluene/acetone,
3:1). [α]2D0 = +75.2 (c = 1, CDCl ). IR (neat): ν = 3480, 3062, 2980,
˜
3
2877, 1728, 1602, 1451, 1315, 1264, 1163, 1095, 1069, 1026,
710 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.11–8.04 (m, 4 H), Methyl 2,3,4,6-Tetra-O-benzoyl-β-
D
-galactopyranosyl-(1Ǟ3)-β-
-galactopyranoside (23): Glycoboronate
4a was formed in DME as described above, and an aliquot (1 mL)
D-
8.00 (d, J = 7.2 Hz, 2 H), 7.78 (d, J = 7.2 Hz, 2 H), 7.63 (t, J =
7.5 Hz, 1 H), 7.58 (t, J = 7.4 Hz, 1 H), 7.54–7.39 (m, 5 H), 7.32–
galactopyranosyl-(1Ǟ3)-β-D
7.22 (m, 4 H), 7.19–7.15 (m, 1 H), 7.13–7.09 (m, 1 H), 7.05 (d, J of this solution (i.e., 50 mg, 0.14 mmol of glycoboronate 4a) was
= 4.3 Hz, 4 H), 5.99 (d, J = 3.3 Hz, 1 H, 4Ј-H), 5.87 (dd, J = 10.4,
8.0 Hz, 1 H, 2Ј-H), 5.66 (dd, J = 10.4, 3.4 Hz, 1 H, 3Ј-H), 4.92 (d,
added to a mixture of bromide 8 (120 mg, 0.18 mmol) and MS
(3 Å; 175 mg) under argon. The suspension was stirred overnight
J = 8.0 Hz, 1 H, 1Ј-H), 4.59–4.53 (m, 3 H, 1-H, 6Ј-H, 6Ј-H), 4.42– and then cooled to 0 °C. AgOTf (47 mg, 0.18 mmol) was added,
4.38 (m, 1 H, 5Ј-H), 4.37 (s, 1 H, 3-OH) 3.79 (s, 1 H, 4-H), 3.78– and the mixture was stirred for 1 h at 0 °C until TLC showed com-
3.70 (m, 2 H, 2-H, 3-H), 3.57 (m, 1 H, 5-H), 2.36 (s, 1 H, 4-OH),
plete product formation (toluene/acetone, 3:1). Then, a decanted
5930
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5923–5933

Regioselective Glycosylation of Unprotected Pyranosides
aliquot (1 mL) of a methyl β-d-galactopyranoside phenylboronate
solution in DME (i.e., 40 mg, 0.14 mmol of glycoboronate), N-
iodosuccinimide (38 mg, 0.17 mmol), and TESOTf (6.3 μL,
0.03 mmol) were added, and the mixture was stirred for 1.5 h (TLC,
H2O/iPrOH/EtOAc, 1:3:15). The reaction mixture was allowed to
warm to room temperature, CH2Cl2, MeOH, and IRA 743 were
added, and the mixture was stirred overnight. The suspension was
filtered through Celite, and the pad was flushed with CH2Cl2/
Methyl
glucopyranosyl-(1Ǟ3)-β-
2,3,4,6-Tetra-O-benzoyl-β-
D-glucopyranosyl-(1Ǟ3)-β-D-
D-glucopyranoside (24): Prepared from
bromide 2, thioglycoside 1, and methyl β-d-glucopyranoside [with
phenylboronate in DME (1.3 mL)], as described above for 23, to
give 24 as a colorless solid. Rf = 0.69 (H2O/iPrOH/EtOAc, 1:3:15).
[α]2D0 = +21.7 (c = 1, MeOH). IR (neat): ν = 3437, 3069, 2915, 2888,
˜
1729, 1602, 1584, 1452, 1266, 1092, 1070, 1044, 1027, 710 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 8.08 (d, J = 7.2 Hz, 2 H), 7.95 (d,
MeOH (1:1 mixture). The filtrate was concentrated, and the residue J = 7.3 Hz, 2 H), 7.93 (d, J = 7.3 Hz, 2 H), 7.82 (d, J = 7.4 Hz, 2
was purified by flash chromatography (H2O/iPrOH/EtOAc, 1:3:15)
to give 23 (86 mg, 66%) as a colorless solid. Rf = 0.52 (H2O/iPrOH/
H), 7.66–7.09 (m, 12 H), 5.92 (t, J = 9.4 Hz, 1 H), 5.63 (t, J =
9.4 Hz, 1 H), 5.54 (dd, J = 9.7, 8.2 Hz, 1 H), 5.04 (d, J = 8.1 Hz,
1 H), 4.77 (dd, J = 12.4, 2.2 Hz, 1 H), 4.44–4.30 (m, 2 H), 4.26–
4.17 (m, 2 H), 3.97–3.84 (m, 2 H), 3.83–3.62 (m, 3 H), 3.54 (s, 3
H), 3.57–3.27 (m, 7 H) ppm. 13C NMR (50 MHz, CD3OD): δ =
EtOAc, 1:3:15). [α]2D0 = +86.3 (c = 1, CDCl ). IR (neat): ν = 3411,
˜
3
3063, 2937, 2900, 1727, 1602, 1452, 1268, 1109, 1093, 1070, 1028,
1
711 cm–1. H NMR (300 MHz, CD3OD): δ = 8.10 (d, J = 7.2 Hz,
2 H), 8.04–7.93 (m, 4 H), 7.76 (d, J = 7.2 Hz, 2 H), 7.70–7.35 (m, 167.61, 167.05, 166.96, 166.77, 134.76, 134.44, 130.80, 130.59,
10 H), 7.26 (t, J = 7.8 Hz, 2 H), 5.99 (d, J = 2.8 Hz, 1 H), 5.85–
5.73 (m, 2 H), 5.36 (d, J = 7.4 Hz, 1 H), 4.72–4.52 (m, 2 H), 4.51–
4.40 (m, 2 H), 4.17 (d, J = 7.0 Hz, 1 H), 4.09–4.01 (m, 2 H), 3.76–
130.19, 129.52, 105.27, 104.91, 102.55, 87.99, 86.50, 77.61, 77.56,
75.12, 74.76, 74.28, 73.63, 73.26, 71.13, 70.06, 69.81, 64.22, 62.58,
57.29 ppm. HRMS: calcd. for C47H50O20 [M + Na]+ 957.2787;
3.39 (m, 10 H), 3.50 (s, 3 H) ppm. 13C NMR (75 MHz, CD3OD): found 957.2791.
δ = 166.29, 166.25, 166.02, 165.47, 133.75, 133.40, 129.72, 129.66,
Methyl
tri-O-acetyl-β-
2,3,4,6-Tetra-O-benzoyl-β-
D
-glucopyranosyl-(1Ǟ3)-2,4,6-
129.59, 129.53, 129.36, 129.01, 128.66, 128.53, 128.35, 128.28,
105.20, 104.16, 102.56, 83.70, 75.25, 75.00, 72.15, 71.31, 70.85,
70.45, 70.22, 69.94, 68.99, 68.93, 68.49, 62.33, 61.37, 61.28,
D-glucopyranosyl-(1Ǟ3)-2,4,6-tri-O-acetyl-β- -gluco-
D
pyranoside (24a): Trisaccharide 24 was acetylated with acetic anhy-
dride in pyridine to give 24a as a colorless solid. Rf = 0.34 (toluene/
56.00 ppm. HRMS: Calcd. for C47H50O20 [M
957.2787; found 957.2790.
+
Na]+ m/z,
acetone, 3:1). [α]2D0 = –34.4 (c = 0.5, CDCl ). IR (neat): ν = 3069,
˜
3
2965, 2874, 1738, 1452, 1372, 1264, 1223, 1093, 1069, 1044,
712 cm–1. H NMR (500 MHz, CDCl3): δ = 8.01 (d, J = 7.2 Hz, 2
1
Methyl 2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl-(1Ǟ3)-2,4,6-
H), 7.89–7.83 (m, 4 H), 7.78 (d, J = 7.2 Hz, 2 H), 7.56 (t, J =
7.4 Hz, 1 H), 7.52–7.46 (m, 2 H), 7.44–7.38 (m, 3 H), 7.38–7.30 (m,
4 H), 7.28–7.21 (m, 2 H), 5.89 (t, J = 9.7 Hz, 1 H, 3ЈЈ-H), 5.67 (t,
J = 9.7 Hz, 1 H, 4ЈЈ-H), 5.40 (dd, J = 9.7, 7.9 Hz, 1 H, 2ЈЈ-H), 5.00
(t, J = 9.5 Hz, 1 H, 4-H), 4.86 (d, J = 7.9 Hz, 1 H, 1ЈЈ-H), 4.84–
4.77 (m, 3 H, 2Ј-H, 2-H, 4Ј-H), 4.59 (dd, J = 12.1, 3.4 Hz, 1 H,
6ЈЈ-H), 4.53 (dd, J = 12.2, 4.7 Hz, 1 H, 6ЈЈ-H), 4.42 (d, J = 8.1 Hz,
1 H, 1Ј-H), 4.33–4.23 (m, 2 H, 1-H, 6-H), 4.17–4.09 (m, 3 H, 5ЈЈ-
H, 6Ј-H, 6Ј-H), 4.01 (dd, J = 12.3, 2.3 Hz, 1 H, 6-H), 3.89 (t, J =
9.3 Hz, 1 H, 3-H), 3.83 (t, J = 9.3 Hz, 1 H, 3Ј-H), 3.67–3.61 (m, 1
H, 5Ј-H), 3.56–3.50 (m, 1 H, 5-H), 3.44 (s, 3 H, OCH3), 2.12 (s, 3
H), 2.06 (s, 3 H), 2.05 (s, 3 H), 1.97 (s, 3 H), 1.95 (s, 3 H), 1.88 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.53, 171.35, 169.82,
169.78, 169.53, 169.16, 166.82, 166.59, 165.87, 165.76, 134.21,
134.08, 133.88, 130.49, 130.39, 130.03, 129.36, 129.26, 129.18,
129.13, 129.02, 128.85, 102.13, 102.09, 101.40, 79.57, 78.75, 77.93,
73.50, 73.13, 72.70, 72.56, 72.44, 70.27, 69.05, 68.85, 63.79, 62.77,
62.66, 57.33, 21.77, 21.50, 21.44, 21.31, 21.23, 21.17 ppm. HRMS:
calcd. for C59H62O26 [M + Na]+ 1209.3422; found 1209.3439.
tri-O-acetyl-β- -galactopyranosyl-(1Ǟ3)-2,4,6-tri-O-acetyl-β-
D
D
-gal-
actopyranoside (23a): For complete characterization, trisaccharide
23 was acetylated with acetic anhydride in pyridine to give 23a as
a colorless solid. Rf = 0.45 (toluene/acetone, 3:1). [α]2D0 = +59.6 (c
= 1, CDCl ). IR (neat): ν = 3064, 2983, 2968, 2873, 1733, 1452,
˜
3
1371, 1248, 1225, 1070, 712 cm–1. H NMR (500 MHz, CDCl3): δ
1
= 8.13 (d, J = 7.1 Hz, 2 H), 8.04 (d, J = 7.1 Hz, 2 H), 7.91 (d, J =
7.2 Hz, 2 H), 7.75 (d, J = 7.2 Hz, 2 H), 7.64 (t, J = 7.5 Hz, 1 H),
7.58 (t, J = 7.4 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 3 H), 7.47–7.40 (m,
3 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.24 (t, J = 7.8 Hz, 2 H), 5.94 (d,
J = 3.0 Hz, 1 H), 5.68 (dd, J = 10.4, 7.7 Hz, 1 H), 5.61 (d, J =
3.3 Hz, 1 H), 5.55 (dd, J = 10.5, 3.3 Hz, 1 H), 5.34 (d, J = 3.0 Hz,
1 H), 5.09 (dd, J = 9.9, 8.0 Hz, 1 H), 5.04 (dd, J = 10.1, 8.1 Hz, 1
H), 4.90 (d, J = 7.7 Hz, 1 H), 4.74 (dd, J = 11.2, 6.1 Hz, 1 H), 4.42
(d, J = 8.0 Hz, 1 H), 4.36 (dd, J = 11.2, 7.1 Hz, 1 H), 4.32–4.25
(m, 2 H), 4.21–4.03 (m, 4 H), 3.84–3.75 (m, 3 H), 3.73 (t, J =
6.1 Hz, 1 H), 3.47 (s, 3 H), 2.25 (s, 3 H), 2.09 (s, 3 H), 2.08 (s, 3
H), 2.07 (s, 3 H), 2.01 (s, 3 H), 1.48 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.86, 170.82, 170.16, 169.13, 168.66,
166.25, 165.82, 165.64, 164.88, 133.89, 133.60, 133.48, 130.32,
130.00, 129.58, 129.43, 129.19, 128.88, 128.80, 128.75, 128.52,
101.96, 101.86, 101.26, 75.75, 71.59, 71.47, 71.31, 70.99, 70.03,
69.94, 69.13, 69.11, 69.09, 67.80, 62.38, 62.19, 61.80, 56.84, 21.14,
21.12, 21.04, 21.01, 20.86, 20.06 ppm. HRMS: calcd. for C59H62O26
[M + Na]+ 1209.3422; found 1209.3452.
Methyl β-D-Glucopyranosyl-(1Ǟ3)-β-D-glucopyranosyl-(1Ǟ3)-β-D-
glucopyranoside (24b): Deprotection of 24a with sodium methoxide
in methanol gave 24b as a white solid. Rf = 0.50 (H2O/iPrOH/
EtOAc, 1:2:2). 1H NMR (500 MHz, D2O): δ = 4.59–4.55 (m, 2 H),
4.23 (d, J = 8.1 Hz, 1 H), 3.78–3.70 (m, 3 H), 3.64–3.50 (m, 5 H),
3.40 (s, 3 H), 3.38–3.28 (m, 7 H), 3.27–3.22 (m, 1 H), 3.21–3.15 (m,
2 H) ppm. 13C NMR (50 MHz, D2O): δ = 103.80, 103.64, 103.36,
85.29, 85.06, 76.83, 76.39, 74.28, 74.06, 73.66, 70.41, 68.98, 61.52,
58.06 ppm. 13C NMR spectroscopic data are consistent with litera-
ture values.[28]
Methyl β-D-Galactopyranosyl-(1Ǟ3)-β-D-galactopyranosyl-(1Ǟ3)-
β- -galactopyranoside (23b): Deprotection of 23a with sodium
D
methoxide in methanol gave 23b as a white solid. Rf = 0.24 (H2O/
iPrOH/EtOAc, 1:2:2). 1H NMR (300 MHz, D2O): δ = 4.50 (d, J =
7.5 Hz, 1 H, 1-H), 4.45 (d, J = 7.4 Hz, 1 H, 1-H), 4.21 (d, J = Benzyl
2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl-(1Ǟ3)-β-D-
7.9 Hz, 1 H, 1-H), 4.04 (d, J = 3.0 Hz, 2 H, 4-H, 4-H), 3.76 (d, J glucopyranosyl-(1Ǟ3)-β-D-glucopyranoside (25): Prepared from
= 3.1 Hz, 1 H, 4-H), 3.71–3.44 (m, 15 H), 3.42 (s, 3 H, CH3) ppm. bromide 2, thioglycoside 1, and benzyl β-d-glucopyranoside, as de-
13C NMR (50 MHz, D2O): δ = 104.40, 104.13, 103.57, 82.50, 82.13,
75.18, 74.80, 74.78, 72.63, 71.15, 70.34, 69.94, 68.64, 68.44, 61.04,
57.23 ppm. 13C NMR spectroscopic data are consistent with litera-
ture values.[27]
scribed above for 23, to give 25 as a colorless solid. Rf = 0.81 (H2O/
iPrOH/EtOAc, 1:3:15). [α]2D0 = +3.6 (c = 0.3, CDCl ). IR (neat): ν
˜
3
= 3467, 3064, 3033, 2907, 2884, 1730, 1601, 1451, 1264, 1093, 1070,
1
1049, 1027, 709, 687 cm–1. H NMR (300 MHz, CDCl3): δ = 8.07
Eur. J. Org. Chem. 2013, 5923–5933
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5931

T. H. Fenger, R. Madsen
FULL PAPER
(d, J = 7.7 Hz, 2 H), 7.94 (d, J = 7.6 Hz, 2 H), 7.92 (d, J = 7.6 Hz,
2 H), 7.82 (d, J = 7.7 Hz, 2 H), 7.61–7.22 (m, 17 H), 5.93 (t, J =
9.7 Hz, 1 H), 5.63 (t, J = 9.7 Hz, 1 H), 5.54 (dd, J = 9.8, 8.0 Hz, 1
by flash chromatography (toluene/acetone, 7:1) to give 26 (122 mg,
70%) as a colorless solid. Rf = 0.63 (toluene/acetone, 3:1). [α]2D0
=
+13.9 (c = 1, CDCl ). IR (neat): ν = 3498, 3064, 2961, 2887, 1727,
˜
3
H), 5.03 (d, J = 7.9 Hz, 1 H, 1-H), 4.87 (d, J = 11.9 Hz, 1 H, 1602, 1451, 1315, 1263, 1177, 1092, 1069, 1027, 708 cm–1. 1H NMR
CHH), 4.74 (dd, J = 12.4, 2.5 Hz, 1 H), 4.64 (d, J = 11.9 Hz, 1 H,
CHH), 4.42–4.32 (m, 2 H), 4.25–4.15 (m, 1 H), 3.92–3.82 (m, 2 H), 7.3 Hz, 2 H), 7.98 (d, J = 7.3 Hz, 2 H), 7.95–7.82 (m, 10 H), 7.60–
3.78–3.63 (m, 3 H), 3.55–3.25 (m, 8 H) ppm. 13C NMR (50 MHz,
7.49 (m, 5 H), 7.48–7.25 (m, 24 H), 5.92 (t, J = 9.7 Hz, 1 H, 3Ј-H),
CDCl3): δ = 166.09, 165.63, 165.36, 165.14, 136.85, 133.57, 133.31, 5.86 (t, J = 9.6 Hz, 1 H, 3ЈЈ-H), 5.66 (t, J = 9.7 Hz, 1 H, 4ЈЈ-H),
(500 MHz, CDCl3): δ = 8.08 (d, J = 7.3 Hz, 2 H), 8.02 (d, J =
129.82, 129.19, 129.01, 128.35, 128.02, 104.27, 102.40, 101.50,
87.86, 75.87, 75.28, 72.65, 72.48, 71.88, 71.38, 69.25, 69.10, 62.73,
62.43 ppm. HRMS: calcd. for C53H54O20 [M + Na]+ 1033.3101;
found 1033.3103.
5.60 (t, J = 9.7 Hz, 1 H, 4Ј-H), 5.54 (dd, J = 9.6, 8.0 Hz, 1 H, 2ЈЈ-
H), 5.50 (dd, J = 9.7, 8.1 Hz, 1 H, 2Ј-H), 4.96 (d, J = 8.0 Hz, 1 H,
1Ј-H), 4.92 (d, J = 7.9 Hz, 1 H, 1ЈЈ-H), 4.75 (dd, J = 12.2, 2.4 Hz,
1 H, 6Ј-H), 4.63 (dd, J = 12.1, 3.0 Hz, 1 H, 6ЈЈ-H), 4.44 (dd, J =
12.1, 5.2 Hz, 1 H, 6ЈЈ-H), 4.39–4.30 (m, 2 H, 1-H, 6Ј-H), 4.23–4.13
(m, 2 H, 5Ј-H, 6-H), 4.09–3.99 (m, 1 H, 5ЈЈ-H), 3.81 (dd, J = 12.0,
6.3 Hz, 1 H, 6-H), 3.46–3.35 (m, 2 H, 3-H, 5-H), 3.34–3.25 (m, 1
H, 4-H), 3.05 (t, J = 9.2 Hz, 1 H, 2-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.33, 166.30, 166.01, 165.90, 165.46, 165.28, 133.89,
133.66, 133.60, 133.42, 133.34, 132.82, 131.84, 130.22, 130.12,
130.03, 130.01, 129.80, 129.48, 129.43, 129.32, 129.10, 129.05,
128.86, 128.72, 128.65, 128.60, 128.53, 128.47, 102.63 (C-1Ј),
101.80 (C-1ЈЈ), 89.63, 88.15 (C-1), 79.88, 73.15, 72.91, 72.75, 72.35,
72.13, 72.05, 70.80, 70.03, 69.59, 69.16, 68.33, 63.29, 63.06 ppm.
HRMS: calcd. for C80H68O23S [M + Na]+ 1451.3764; found
1451.3836.
Benzyl 2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl-(1Ǟ3)-2,4,6-tri-
O-acetyl-β- -glucopyranosyl-(1Ǟ3)-2,4,6-tri-O-acetyl-β-
D
D
-gluco-
pyranoside (25a): Trisaccharide 25 was acetylated with acetic an-
hydride in pyridine to give 25a as a colorless solid. Rf = 0.21 (hept-
ane/EtOAc, 1:1). [α]2D0 = –38.8 (c = 0.3, CDCl ). IR (neat): ν =
˜
3
3066, 3032, 2966, 2879, 1739, 1602, 1584, 1452, 1371, 1264, 1224,
1093, 1069, 1045, 712 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.00
(d, J = 7.5 Hz, 2 H), 7.86 (d, J = 7.6 Hz, 2 H), 7.86 (d, J = 7.6 Hz,
2 H), 7.78 (d, J = 7.6 Hz, 2 H), 7.56 (t, J = 7.4 Hz, 1 H), 7.51–7.45
(m, 2 H), 7.43–7.30 (m, 9 H), 7.29–7.23 (m, 5 H), 5.88 (t, J =
9.7 Hz, 1 H, 3ЈЈ-H), 5.66 (t, J = 9.7 Hz, 1 H, 4ЈЈ-H), 5.39 (dd, J =
9.5, 8.1 Hz, 1 H, 2ЈЈ-H), 4.99 (t, J = 9.4 Hz, 1 H, 4Ј-H), 4.96–4.91
(m, 1 H, 2-H), 4.87–4.77 (m, 4 H, 1ЈЈ-H, 2Ј-H, 4-H, CHH), 4.61–
4.49 (m, 3 H, 6ЈЈ-H, 6ЈЈ-H, CHH), 4.39 (d, J = 8.1 Hz, 1 H, 1Ј-H),
4.36 (d, J = 8.0 Hz, 1 H, 1-H), 4.26 (dd, J = 12.4, 4.4 Hz, 1 H, 6Ј-
H), 4.17–4.11 (m, 3 H, 5ЈЈ-H, 6-H, 6-H), 3.99 (dd, J = 12.3, 2.1 Hz,
1 H, 6Ј-H), 3.88 (t, J = 9.3 Hz, 1 H, 3Ј-H), 3.81 (t, J = 9.3 Hz, 1
H, 3-H), 3.61 (dt, J = 9.4, 3.0 Hz, 1 H, 5-H), 3.52–3.47 (m, 1 H,
5Ј-H), 2.07 (s, 3 H), 2.06 (s, 3 H), 2.05 (s, 3 H), 1.96 (s, 3 H), 1.94
(s, 3 H), 1.88 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
171.03, 170.85, 169.32, 169.29, 169.01, 168.68, 166.34, 166.10,
165.38, 165.28, 137.03, 133.73, 133.59, 133.56, 133.40, 130.07,
130.01, 129.98, 129.92, 129.90, 129.55, 128.88, 128.78, 128.69,
128.67, 128.64, 128.54, 128.38, 128.17, 127.98, 101.60, 100.86,
99.20, 79.07, 78.20, 77.45, 73.14, 73.03, 72.70, 72.21, 72.07, 71.98,
71.96, 70.42, 69.79, 68.60, 68.35, 63.29, 62.30, 62.19, 21.21, 21.04,
20.95, 20.82, 20.74, 20.67 ppm. HRMS: calcd. for C65H66O26 [M +
Na]+ 1285.3735; found 1285.3743.
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
tetra-O-benzoyl-β- -glucopyranosyl-(1Ǟ6)]-2,4-di-O-acetyl-1-thio-
β- -glucopyranoside (27): Diol 26 (20 mg, 0.014 mmol) was dis-
D-glucopyranosyl-(1Ǟ3)-[2,3,4,6-
D
D
solved in pyridine (1 mL), and acetic anhydride (1 mL) was added.
The mixture was stirred until complete conversion was observed by
TLC (toluene/acetone, 3:1), then it was concentrated, and the resi-
due was purified by flash chromatography (toluene/acetone, 8:1) to
give 27 (20 mg, 94%) as a colorless solid. Rf = 0.73 (toluene/acet-
one, 3:1). [α]2D0 = +8.29 (c = 1, CDCl ). IR (neat): ν = 3063, 2959,
˜
3
2880, 1729, 1602, 1452, 1263, 1216, 1092, 1068, 1027, 709 cm–1. 1H
NMR (500 MHz, CDCl3): δ = 8.08–8.00 (m, 4 H), 7.95–7.78 (m,
12 H), 7.58–7.47 (m, 5 H), 7.46–7.25 (m, 24 H), 5.90 (t, J = 9.6 Hz,
1 H), 5.80 (t, J = 9.5 Hz, 1 H), 5.69–5.63 (m, 2 H), 5.64–5.57 (m,
1 H), 5.53–5.46 (m, 1 H), 5.43–5.34 (m, 1 H), 4.93 (d, J = 7.9 Hz,
1 H), 4.87 (d, J = 8.0 Hz, 1 H), 4.82 (t, J = 9.6 Hz, 1 H), 4.70 (t,
J = 9.6 Hz, 1 H), 4.66–4.56 (m, 2 H), 4.53–4.42 (m, 3 H), 4.16–
4.09 (m, 1 H), 4.05–3.98 (m, 1 H), 3.90 (t, J = 9.2 Hz, 1 H), 3.85–
3.71 (m, 2 H), 3.54 (dd, J = 12.3, 4.7 Hz, 1 H), 1.98 (s, 3 H), 1.92
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.76, 168.73,
166.30, 166.25, 166.12, 165.97, 165.45, 165.39, 165.34, 165.3,
133.72, 133.58, 133.48, 133.42, 133.39, 133.34, 131.75, 130.01,
129.96, 129.88, 129.73, 129.63, 129.55, 129.39, 129.06, 128.98,
128.85, 128.80, 128.73, 128.67, 128.55, 128.52, 128.49, 128.40,
128.21, 101.39, 100.67, 86.32 (C-1), 79.99, 78.46, 73.22, 73.13,
72.48, 72.36, 72.28, 72.09, 71.64, 69.95, 69.74, 68.69, 68.17, 63.19,
21.21, 20.79 ppm. HRMS: calcd. for C84H72O25S [M + Na]+
1535.3976; found 1535.8269.
Benzyl β-D-Glucopyranosyl-(1Ǟ3)-β-D-glucopyranosyl-(1Ǟ3)-β-D-
glucopyranoside (25b): Deprotection of 25a with sodium methoxide
in methanol gave 25b as a white solid. Rf = 0.77 (H2O/iPrOH/
EtOAc, 1:2:2). [α]2D0 = –27.5 (c = 1, MeOH). IR (neat): ν = 3379,
˜
2918, 2887, 1452, 1367, 1155, 1075, 1037 cm–1
.
1H NMR
(500 MHz, D2O): δ = 7.53–7.39 (m, 5 H), 4.96 (d, J = 11.6 Hz, 1
H), 4.77–4.73 (m, 3 H), 4.57 (d, J = 8.0 Hz, 1 H), 3.98–3.87 (m, 3
H), 3.81–3.68 (m, 5 H), 3.60–3.47 (m, 8 H), 3.43–3.33 (m, 2 H)
ppm. 13C NMR (50 MHz, D2O): δ = 139.18, 131.40, 131.16,
105.46, 105.18, 103.63, 87.00, 86.86, 78.66, 78.24, 76.11, 75.89,
75.58, 74.20, 72.24, 70.81, 63.36 ppm. HRMS: calcd. for C25H38O16
[M + Na]+ 617.2052; found 617.2053.
Benzyl 2,3,4,6-Tetra-O-benzoyl-β-
tetra-O-benzoyl-β- -glucopyranosyl-(1Ǟ6)]-β-
(1Ǟ3)-2,4,6-tri-O-benzyl-β- -galactopyranosyl-(1Ǟ4)-2,3,6-tri-O-
benzyl-β- -glucopyranoside (29): Trisaccharide 26 (62 mg,
D-glucopyranosyl-(1Ǟ3)-[2,3,4,6-
D
D
-glucopyranosyl-
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
D-glucopyranosyl-(1Ǟ3)-[2,3,4,6-
D
tetra-O-benzoyl-β- -glucopyranosyl-(1Ǟ6)]-1-thio-β-
D
D
-gluco-
D
pyranoside (26): Bromide 2 (97 mg, 0.15 mmol) was added to a mix-
ture of disaccharide 3 (104 mg, 0.12 mmol) and MS (3 Å; 175 mg)
in toluene (1 mL), and the solution was stirred for 1 h under argon.
The mixture was then cooled to 0 °C, AgOTf (44 mg, 0.17 mmol)
was added, and the resulting mixture was stirred for 1 h. Then
CH2Cl2 (1 mL), MeOH (1 mL), and Et3N (1 mL) were added, and
the mixture was stirred for a further 30 min. The mixture was fil-
tered through Celite and concentrated, and the residue was purified
0.044 mmol) was added to a mixture of lactoside 28 (55 mg,
0.057 mmol) and MS (3 Å; 175 mg) in CH2Cl2 (1 mL), and the
solution was stirred for 1 h under argon. The mixture was cooled to
–30 °C, and N-iodosuccinimide (13 mg, 0.057 mmol) and TESOTf
(2.0 μL, 0.009 mmol) were added. After 1 h, the reaction mixture
was diluted with CH2Cl2 (1 mL) and Et3N (1 mL). The mixture
was filtered through Celite and concentrated, and the residue was
purified by flash chromatography (heptane/EtOAc, 2:1) to give 29
5932
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5923–5933

Regioselective Glycosylation of Unprotected Pyranosides
A. V. Demchenko, Adv. Carbohydr. Chem. Biochem. 2009, 62,
161–250.
(36 mg, 36%) as a colorless solid. Rf = 0.55 (EtOAc/heptane, 1:1).
[α]2D0 = +15.6 (c = 1, CDCl ). IR (neat): ν = 3508, 3063, 3031, 2938,
˜
3
[4] R. R. Schmidt, W. Kinzy, Adv. Carbohydr. Chem. Biochem.
1994, 50, 21–123.
2914, 2870, 1732, 1602, 1452, 1265, 1093, 1069, 1027, 710 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 8.15–8.05 (m, 1 H), 8.02–7.77 (m,
14 H), 7.60–7.05 (m, 59 H), 5.97–5.80 (m, 2 H), 5.68–5.57 (m, 2
H), 5.56–5.40 (m, 2 H), 5.01 (dd, J = 10.7, 5.4 Hz, 1 H), 4.97–4.86
(m, 3 H), 4.83–4.61 (m, 7 H), 4.60–4.10 (m, 13 H), 4.05–3.82 (m,
4 H), 3.79–3.18 (m, 15 H), 3.08–2.97 (m, 1 H), 2.93–2.83 (m, 1 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 165.99, 165.66, 165.10,
165.07, 164.91, 164.74, 139.20, 139.03, 138.90, 138.57, 138.27,
138.13, 137.92, 137.49, 133.55, 133.26, 133.13, 104.24, 102.39,
102.08, 94.87, 88.01, 87.49, 82.88, 82.23, 81.66, 79.06, 78.14, 75.25,
74.96, 74.37, 73.29, 73.04, 72.65, 72.40, 71.97, 71.82, 70.82, 70.15,
70.13, 69.72, 69.46, 69.36, 68.84, 68.18, 67.73, 67.20, 63.08 ppm.
HRMS: calcd. for C135H126O34 [M + Na]+ 2313.8023; found
2313.8582.
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b) E. Kaji, N. Harita, Tetrahedron Lett. 2000, 41, 53–56; c) P. J.
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Kaji, T. Nishino, K. Ishige, Y. Ohya, Y. Shirai, Tetrahedron
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Benzyl 2,3,4,6-Tetra-O-benzoyl-β-
tetra-O-benzoyl-β- -glucopyranosyl-(1Ǟ6)]-2,4-di-O-acetyl-β-
glucopyranosyl-(1Ǟ3)-2,4,6-tri-O-benzyl-β- -galactopyranosyl-
(1Ǟ4)-2,3,6-tri-O-benzyl-β- -glucopyranoside (30): Trisaccharide
27 (51 mg, 0.034 mmol) was treated with lactoside 28 (45 mg,
0.046 mmol) as described above for 29 to give 30 (57 mg, 71%) as
a colorless solid. Rf = 0.67 (EtOAc/heptane, 1:1). [α]2D0 = –14.1 (c
D-glucopyranosyl-(1Ǟ3)-[2,3,4,6-
D
D-
D
D
= 1, CDCl ). IR (neat): ν = 3063, 3032, 2941, 2871, 1733, 1602,
˜
3
1495, 1452, 1367, 1268, 1214, 1092, 1068, 1027, 710 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.07–7.98 (m, 4 H), 7.93–7.73 (m, 12 H),
7.57–7.04 (m, 59 H), 5.95–5.79 (m, 2 H), 5.71–5.56 (m, 2 H), 5.52–
5.37 (m, 2 H), 5.01–4.80 (m, 7 H), 4.78–4.59 (m, 6 H), 4.54–4.44
(m, 4 H), 4.43–4.20 (m, 7 H), 4.18–3.99 (m, 2 H), 3.96–3.29 (m, 17
H), 1.93 (s, 3 H), 1.68 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 169.25, 167.31, 165.77, 165.71, 165.57, 165.39, 164.83, 164.74,
164.64, 138.89, 138.69, 138.29, 137.98, 137.90, 137.20, 133.17,
133.09, 132.98, 132.94, 132.83, 132.69, 129.46, 129.36, 129.19,
129.15, 129.01, 128.68, 128.44, 128.34, 128.25, 128.18, 128.10,
128.03, 127.96, 127.94, 127.88, 127.74, 127.61, 127.54, 127.48,
127.35, 127.26, 127.15, 127.08, 126.77, 102.18, 102.05, 100.82,
100.60, 100.56, 82.64, 81.43, 79.97, 79.94, 78.50, 76.90, 76.51,
76.06, 75.20, 75.00, 74.74, 74.66, 74.60, 73.31, 73.11, 72.83, 72.71,
72.58, 72.53, 72.36, 71.98, 71.71, 71.64, 71.35, 70.57, 69.15, 68.69,
67.90, 62.67, 62.60, 20.29 ppm. HRMS: calcd. for C139H130O36 [M
+ Na]+ 2397.8234; found 2397.6738.
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Supporting Information (see footnote on the first page of this arti-
1
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Financial support from the Lundbeck Foundation is gratefully ac-
knowledged. The authors thank Dr. Gyorgyi Osztrovszky for per-
forming the first experiment on this project.
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Received: May 17, 2013
Published Online: July 25, 2013
Eur. J. Org. Chem. 2013, 5923–5933
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5933