Stannylene-mediated regioselective 6-O-glycosylation of unprotected phenyl 1-thioglycopyranosides

Article abstract of DOI:10.1002/ejoc.201300026

A straightforward procedure is described for the synthesis of (1→6)-linked saccharides by regioselective glycosylation of unprotected glycosyl acceptors. Phenyl 1-thioglycopyranosides derived from D-glucose, D-galactose and D-mannose were treated with dibutyltin oxide to introduce a stannylene acetal, and then subjected to selective glycosylation at the 6-position with the Koenigs-Knorr protocol. Peracylated glycosyl bromides of D-glucose, D-galactose, D-mannose and D-glucosamine were employed as the donors to give the corresponding (1→6)-linked disaccharides in moderate to good yields. The best results were obtained with glycosyl donors and acceptors derived from D-glucose and D-galactose. Fully acylated disaccharide thioglycosides could also serve as glycosyl donors for the regioselective coupling. Brominolysis and subsequent Koenigs-Knorr coupling with the stannylene acetal of phenyl 1-thio-β-D-glucopyranoside gave rise to the corresponding (1→6)-linked trisaccharides in moderate yields. Unprotected phenyl 1-thioglycopyranosides are activated with dibutyltin oxide and regioselectively glycosylated at the 6-position with peracylated glycosyl bromides under Koenigs-Knorr conditions. Copyright

Full text of DOI:10.1002/ejoc.201300026

FULL PAPER
DOI: 10.1002/ejoc.201300026
Stannylene-Mediated Regioselective 6-O-Glycosylation of Unprotected Phenyl
1-Thioglycopyranosides
Agnese Maggi[a] and Robert Madsen*[a]
Keywords: Carbohydrates / Glycosylation / Protecting groups / Regioselectivity / Stannanes
A straightforward procedure is described for the synthesis of
(1Ǟ6)-linked saccharides by regioselective glycosylation of
unprotected glycosyl acceptors. Phenyl 1-thioglycopyran-
sponding (1Ǟ6)-linked disaccharides in moderate to good
yields. The best results were obtained with glycosyl donors
and acceptors derived from D-glucose and D-galactose. Fully
osides derived from
D
-glucose,
D
-galactose and
D
-mannose
acylated disaccharide thioglycosides could also serve as glyc-
osyl donors for the regioselective coupling. Brominolysis and
subsequent Koenigs–Knorr coupling with the stannylene
were treated with dibutyltin oxide to introduce a stannylene
acetal, and then subjected to selective glycosylation at the 6-
position with the Koenigs–Knorr protocol. Peracylated glyc-
acetal of phenyl 1-thio-β-D-glucopyranoside gave rise to the
osyl bromides of
D-glucose,
D-galactose,
D-mannose and
D-
corresponding (1Ǟ6)-linked trisaccharides in moderate
glucosamine were employed as the donors to give the corre-
yields.
During the past two decades, there have been several
studies on the glycosylation of unprotected glycosyl ac-
ceptors. These investigations have been carried out both in
the absence[9–11] and in the presence[12–18] of special addi-
tives in order to control the regioselectivity. In the absence
of any additional reagents, the direct Koenigs–Knorr
glycosylation of unprotected 2-(trimethylsilyl)ethyl β-d-ga-
lactopyranoside with several glycosyl bromides gave the 6-
linked saccharides in 75–90% yield.[9] Similar regioselectiv-
ity, however, could not be achieved with unprotected gluco-
and mannopyranosides. Glycosylation of unprotected β-py-
ranosides of glucose and N-acetylglucosamine gave near
statistical mixtures of all possible glycosylation products.[10]
Glycosylation of unprotected α-mannopyranosides gave
mainly the 6-linked disaccharides and the 3,6-linked trisac-
charides, but the isolated yields were modest.[11]
Several additives based on tin and boron have been ex-
amined in an attempt to further direct the glycosylations.
Dibutyltin oxide-mediated coupling of unprotected methyl
β-d-galactopyranoside with different donors gave the 6-
linked disaccharides in good yields.[12,13] A notable shift in
regioselectivity to the 3-linked disaccharide could be
achieved in the presence of fluoride, although the isolated
yield was modest.[14] On the other hand, treatment of
methyl β-d-glucopyranoside with dibutyltin oxide, 2,3,4,6-
tetra-O-benzyl-α-d-glucopyranosyl bromide and tetrabut-
ylammonium iodide furnished the 6-linked disaccharide in
a mere 44% yield.[12] Under similar conditions, unprotected
methyl β-lactoside gave a 58% yield of the 6Ј-linked trisac-
charide in a reaction with bis(tributyltin) oxide and 2,3,4,6-
tetra-O-benzyl-α-d-galactopyranosyl bromide.[15]
Introduction
Complex carbohydrates constitute a major class of cell-
surface molecules, and play a crucial role in numerous bio-
logical processes such as cell recognition events, cellular ad-
hesion and communication, as well as protein structure and
function.[1] The growing interest towards a better under-
standing of these processes has stimulated a large number
of studies in the field of glycobiology and has increased the
demand for structurally defined oligosaccharides.[2]
Chemical synthesis is the most widespread and versatile
protocol to access pure and well-defined oligosaccharides,
and a vast array of glycosylation methods are available.[3]
In addition, contemporary glycosylation strategies such as
solid-phase,[4,5] one-pot[5,6] and armed/disarmed[7] ap-
proaches continue to be further developed. As a result, the
synthesis of almost any oligosaccharide is possible, al-
though certain glycosidic linkages may still pose a challeng-
ing task. However, regardless of the glycosylation strategy,
modern oligosaccharide synthesis continues to employ mul-
tiple protecting groups to mask hydroxy groups that are not
involved in the glycosylations.[8] This causes the synthesis
of a target oligosaccharide to be a rather time-consuming
process, since a majority of the reactions are used for pro-
tection and deprotection of the hydroxy groups. An obvious
solution to this problem would be to develop regioselective
glycosylations with unprotected carbohydrates.
[a] Department of Chemistry, Technical University of Denmark,
2800 Kgs. Lyngby, Denmark
Fax: +45-4593-3968
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.201300026.
With a special diarylborinic acid as the additive,
Koenigs–Knorr glycosylation of methyl α-d-galactopyran-
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A. Maggi, R. Madsen
FULL PAPER
oside and α-d-mannopyranoside proceeded selectively at the vestigated. Addition of 2,4,6-collidine to the reaction gave
3- and the 6-positions to afford the corresponding trisac- 58% yield, but the product turned out to be orthoester 4
charides in good yields.[16] Very recently, another diaryl bor- (Entry 2). It is well known that a base can cause orthoester
inic acid was used to catalyze the regioselective Koenigs– formation in the silver triflate-promoted glycosylation with
Knorr glycosylation of unprotected acceptors, although no 2-O-acyl glycosyl bromides.[21] The orthoester may consti-
acceptor with a free primary hydroxy group was investi- tute the kinetic product, and the base may prevent the sub-
gated.[17] With p-methoxyphenylboronic acid as the addi- sequent rearrangement into the 1,2-trans glycoside. The
tive, an in-situ masking of the 4- and the 6-hydroxy groups weaker base 1,1,3,3-tetramethylurea (TMU) has shown
took place, and Koenigs–Knorr glycosylations on methyl β- promising results for generating the 1,2-trans glycoside ex-
d-galactopyranoside could be directed to the 3-position in clusively,[22] but in our case the coupling led to a mixture
good yield.[18] With methyl β-d-glucopyranoside, however, of several products which were not further identified (Entry
poor regioselectivity was observed under the same condi- 3). Molecular sieves were then investigated in order to re-
tions.[18]
move traces of water and methanol which may still have
In all, the chemical glycosylation of unprotected carbo- been present after the stannylene acetal formation. Gratify-
hydrates is still in its infancy and there is room for much ingly, the yield of the β(1Ǟ6)-linked disaccharide increased
development in this area. Most of the studies so far have to 56%, and the reaction was allowed to proceed for 6 h
briefly investigated different methods for controlling the re- where no further conversion was observed (Entry 4). An
gioselectivity, but more comprehensive studies are needed additional improvement was achieved by using a slightly
to fully understand the scope and limitations. We decided larger excess of the donor, which produced disaccharide 3
to compare the regioselective glycosylation of several un- as the sole product in 85% yield (Entry 5). This is a remark-
protected phenyl 1-thioglycopyranosides, since this would able result given the previous difficulties with regioselective
provide an easy route to a number of thioglycoside building glycosylations on glucopyranosides.
blocks that could be useful glycosyl donors. Dibutyltin ox-
Table 1. Optimization of the regioselective glycosylation.[a]
ide was selected for directing the glycosylations because
stannylene acetals have been widely applied in carbohydrate
chemistry for controlling regioselective esterifications and
alkylations of diols and polyols.[19]
Results and Discussion
Phenyl thioglycosides are easily prepared from the corre-
sponding peracetylated monosaccharides by reaction with
thiophenol and boron trifluoride etherate.[20] In addition,
the unprotected phenyl thioglycosides of glucose, galactose
and mannose are all crystalline and therefore easily avail-
able on a large scale. Phenyl 1-thio-β-d-glucopyranoside (1)
was selected as the test substrate for optimizing the glyc-
osylation, because regioselective couplings to glucose have
proven notoriously difficult. The Koenigs–Knorr procedure
was chosen as the coupling method due to the high reactiv-
ity of glycosyl halides, and to avoid any simultaneous acti-
vation of the thiophenyl group in the acceptor. Therefore,
2,3,4,6-tetra-O-benzoyl-α-d-glucopyranosyl bromide (2)
was selected as the donor for the optimization.
Entry
Additive
Time
Product
Yield[b]
1
2
3
–
3 h[c]
3 h
3 h
6 h
6 h
6 h
3
4
–
3
3
3
42%
58%
–
56%
85%
32%
collidine
TMU
MS (4 Å)
MS (4 Å)
MS (4 Å)
4
5[d]
6[e]
[a] Reaction conditions: Bu2SnO (0.75 mmol), acceptor
1
(0.5 mmol), MeOH, reflux, 3 h, then donor 2 (0.75 mmol), AgOTf
(1.1 mmol), additive, CH2Cl2, –30 °C to 10 °C, time. [b] Isolated
yield. [c] No improvement in yield with 6 h reaction time. [d] With
0.9 mmol of 2 and AgOTf. [e] In the absence of Bu2SnO and with
dioxane instead of CH2Cl2.
First, the stannylene acetal was installed by refluxing ac-
ceptor 1 with dibutyltin oxide in methanol until a clear
solution was obtained. The solvent was removed and re-
placed with dichloromethane. Notably, acceptor 1 was solu-
The importance of the stannylene acetal was verified by
ble in dichloromethane after attachment of the stannylene attempting the direct Koenigs–Knorr coupling between 1
acetal. The Koenigs–Knorr coupling was then investigated and 2 in the absence of the acetal. This only led to decom-
under different conditions (Table 1). Soluble silver triflate position of the donor and no reaction occurred with the
was chosen as the promoter because silver carbonate gave acceptor. The poor solubility of acceptor 1 in dichlorometh-
essentially no conversion. In the absence of any other addi- ane, however, could account for this result, and the cou-
tives, the glycosylation produced the β(1Ǟ6)-linked disac- pling between 1 and 2 was therefore repeated in dioxane
charide 3 as the sole product in 42% yield after 3 h (Entry where 1 was completely soluble. In this case, however, only
1). No improvement was observed by increasing the reac- 32% of disaccharide 3 was isolated (Entry 6), which was
tion time to 6 h, and different additives were therefore in- lower than the other yields in Table 1. As a result, the opti-
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Tin-Mediated Glycosylation
mized conditions for the glycosylation employed 1.8 equiv. Table 2. Koenigs–Knorr glycosylation of unprotected phenyl 1-thi-
oglycopyranosides.[a]
of the donor in the presence of molecular sieves. With this
protocol in hand, our attention then turned to other donors
and acceptors in order to explore the scope and limitations
of the reaction.
Perbenzoylated galactopyranosyl and mannopyranosyl
bromides 5 and 6 and peracetylated trichloroacetamido glu-
copyranosyl bromide 7 were selected as additional donors
(Figure 1). When these were treated with acceptor 1, the
(1Ǟ6)-linked disaccharides were obtained in 71%, 33% and
52% yields, respectively (Table 2, Entries 1–3). A longer re-
action time was required for glucosamine donor 7 because
TLC analysis of the reaction showed simultaneous forma-
tion of a minor second product which was only slowly con-
verted into the desired disaccharide. This second product
was not isolated, but TLC comparison with an authentic
sample[23] showed it to be the corresponding oxazoline of
7 which is a known intermediate in glycosylations with 2-
trichloroacetamido glycosyl donors.[23]
Figure 1. Glycosyl donors 5–7.
Next, the four glycosyl donors were treated with phenyl
1-thio-β-d-galactopyranoside (11) and -α-d-mannopyran-
oside (12) as the acceptors (Figure 2). With the former,
good yields were obtained of the (1Ǟ6)-linked disac-
charides when 2, 5 and 7 were employed as the donors,
while mannosyl bromide 6 gave a low yield (Table 2, Entries
4–7). With 12 as the acceptor, moderate yields of the (1Ǟ6)-
linked disaccharides were achieved in the glycosylations
with 2, 5 and 7 (Entries 8–10). The reaction between 2 and
12 was repeated in the presence of 2.5 equiv. of dibutyltin
oxide and 3.5 equiv. of 2, but these conditions only led to a
slightly lower yield of the disaccharide. The coupling be-
tween mannose donor 6 and acceptor 12 was also studied,
but in this case a complex mixture of products was obtained
which was not further investigated (result not shown). Ex-
cept for this case, the reactions in Table 2 did not show any
other coupling products than the desired disaccharides to-
gether with unreacted acceptor and decomposed donor.
Thorough drying of the acceptor stannylene acetal and the
use of molecular sieves ensured that methanol was com-
pletely removed, and the reactions were not accompanied
by methyl glycoside formation.
[a] Reaction conditions: Bu2SnO (0.75 mmol), acceptor (0.5 mmol),
MeOH, reflux, 3 h, then donor (0.9 mmol), AgOTf (0.9 mmol), 4 Å
MS, CH2Cl2, –30 °C to 10 °C, 6 h. [b] Isolated yield. [c] Reaction
Figure 2. Glycosyl acceptors 11 and 12.
Eur. J. Org. Chem. 2013, 2683–2691
time 22 h.
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Maggi, R. Madsen
FULL PAPER
The structures of the disaccharides were unequivocally Koenigs–Knorr glycosylation with bromide 2 in the pres-
elucidated by NMR spectroscopy and mass spectrometry. ence of molecular sieves produced a mixture of several cou-
The position of the interglycosidic linkages were verified pling products, and no attempts were made to further im-
from the deshielding of the 13C NMR signal due to the prove this result. Instead, it was decided to use a disaccha-
additional substituent.[14] In fact, for all disaccharides, the ride as the donor and to study the glycosylation of unpro-
C-6 carbon atoms resonate at a considerably lower mag- tected monosaccharide acceptors.
netic field (69.2–68.6 ppm) as compared to those of the un-
For these studies a thioglycoside disaccharide was se-
protected acceptors (62.7–61.2 ppm). A further confirm- lected as the donor because it may then be possible to use
ation was obtained by HMBC analysis, which showed cor- the products from Tables 1 and 2 for an additional glycosyl-
relations between the anomeric H-1Ј and the two H-6 pro- ation with an unprotected acceptor. Therefore, disaccharide
tons in the disaccharides. When glucose, galactose and gluc- 3 was converted into the corresponding perbenzoylated de-
osamine were used as the donors, the β-linkages in the rivative 20, which was investigated in two different glycosyl-
disaccharides were established from the JH-1Ј,H-2Ј coupling ation reactions. In the first approach, disaccharide 20 was
constants. With mannose as the donor the α-linkages were directly activated with dimethyl disulfide and triflic anhy-
verified from the JC-1Ј,H-1Ј coupling constants which were dride[27] and coupled with the stannylene acetal of methyl
around 175 Hz.[24]
β-d-glucopyranoside (21) (Scheme 1). Initially, the coupling
The best results in Table 2 were obtained with glucose was carried out by activating the donor at –40 °C in the
and galactose substrates as the donor and the acceptor, presence of the stannylene acetal of the acceptor. However,
while mannose substrates gave lower yields. It is not clear this only afforded trisaccharide 22 in 5% yield, which was
why mannose gives inferior results both as a donor and as probably due to tin acetal decomposition, because a con-
an acceptor. Previously, glycosylation of the 6-position in siderable amount of unreacted acceptor was detected by
unprotected hexopyranosides had only been achieved in TLC. As a result, the conditions were altered by premixing
good yield with β-d-galactopyranosides.[9,12,13] This is also donor 20 with dimethyl disulfide and triflic anhydride for
observed with acceptor 11 in Table 2, entries 4, 5 and 7. 10 min before adding the stannylene acetal of the acceptor.
Good-yielding glycosylation of the 6-position in unprotec- This now led to complete consumption of acceptor 21, and
ted gluco- and mannopyranosides has never been described. trisaccharide 22 was isolated as the sole product in 35%
The results in Tables 1 and 2 show that a β-d-glucopyrano- yield. Although this was a considerable improvement, it was
side can now be selectively glycosylated in good yield with still not a completely satisfactory result. Unfortunately,
certain donors, while an α-d-mannopyranoside is still a attempts to further optimize the coupling by prolonging the
problematic acceptor.
reaction time or the time for pre-activating the donor only
All the couplings are believed to proceed by formation led to similar yields. Changing the promoter to N-iodosuc-
of the 4,6-stannylene acetal of the acceptor which is then cinimide and triethylsilyl triflate gave no coupling, but in-
glycosylated at the most reactive 6-position. With galactose stead silylation of the acceptor was observed.
and mannose acceptors, stannylene acetals can also be
formed at the 3,4- and the 2,3-positions, respectively. In
fact, benzylation and benzoylation of methyl β-d-galacto-
pyranoside and α-d-mannopyranoside in the presence of di-
butyltin oxide takes place predominately at the 3-posi-
tion.[25] However, benzyl bromide and benzoyl chloride are
sterically less encumbered than a glycosyl bromide. In ad-
dition, equilibriums are known to exist between the dif-
ferent stannylene acetals,[19] and together with the steric de-
mand of the donor, this is believed to explain the exclusive
glycosylation of the primary position in the acceptors.[14]
A
similar regioselectivity dependence on the size of the elec-
trophile has been observed when unprotected lactosides are
reacted in the presence of dibutyltin oxide. Allylation with
allyl bromide gives the 3Ј-O-allylated product, while sil- Scheme 1. Glycosylation of methyl β-d-glucopyranoside.
ylation with the more bulky tert-butyldimethylsilyl chloride
affords exclusively the 6Ј-O-silylated compound.[26]
Therefore, a second glycosylation approach was investi-
With the successful preparation of several disaccharides gated where thioglycoside 20 was first converted into the
we decided to extend the investigations to the synthesis of corresponding glycosyl bromide and then coupled under
trisaccharides. A disaccharide would then be employed Koenigs–Knorr conditions. The advantage of this strategy
either as the donor or as the unprotected acceptor. The lat- is that a thioglycoside could now be used as the acceptor,
ter approach was examined first with benzyl β-lactoside as and for this reason thioglucoside 1 was selected as the other
the acceptor. The stannylene acetal was introduced as de- coupling partner. Accordingly, donor 20 was treated with
scribed in Table 1, and the resulting complex was found to 0.5 equiv. of bromine followed by addition of silver triflate
be soluble in dichloromethane. However, the subsequent and the stannylene acetal of glucoside 1. With a donor:ac-
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Tin-Mediated Glycosylation
ceptor ratio of 2:1, this gave rise to trisaccharide 23 in 40%
yield (Table 3, Entry 1). The same glycosylation was also
performed with disaccharides 24 and 25 as donors (Fig-
ure 3) to afford trisaccharides 26 and 27 in 46% and 57%
yield, respectively (Table 3, Entries 2 and 3). In all three
cases, small amounts of byproducts were observed by TLC,
but were not further characterized. These experiments illus-
trate that the strategy can be extended to disaccharide do-
nors, although at the expense of a slightly lower coupling
yield.
Experimental Section
General: All reactions were performed under an argon atmosphere.
Molecular sieves (MS) were flame dried before use. Dichlorometh-
ane was dried with 3 Å MS. Methanol was distilled from sodium
and then dried with 3 Å MS. Phenyl 1-thio-β-d-glucopyranoside
(1),[20] phenyl 1-thio-β-d-galactopyranoside (11),[28] phenyl 1-thio-
α-d-mannopyranoside (12),[29] methyl 1-thiolactoside,[30] 2,3,4,6-
tetra-O-benzoyl-α-d-glucopyranosyl bromide (2),[31] 2,3,4,6-tetra-
O-benzoyl-α-d-galactopyranosyl bromide (5),[32] 2,3,4,6-tetra-O-
benzoyl-α-d-mannopyranosyl bromide (6),[33] 3,4,6-tri-O-acetyl-2-
deoxy-2-trichloroacetamido-α-d-glucopyranosyl bromide (7)[23]
and phenyl 1-thio-N-trichloroacetyllactosamine hexaacetate (25)[34]
were synthesized according to literature procedures. TLC was per-
formed on aluminum plates coated with silica gel 60. Visualization
was carried out by UV and by dipping in 20% solution of sulfuric
acid in ethanol followed by heating. Flash column chromatography
was performed with silica gel 60 (40–63 μm). NMR spectra were
recorded with a Varian Mercury 300 or a Varian Unity Inova 500
instrument. Chemical shifts are measured relative to the residual
solvent signal in CDCl3 (δH = 7.26 ppm, δC = 77.0 ppm) or TMS.
Assignment of 1H and 13C resonances were based on COSY, HSQC
and HMBC experiments. HRMS analyses were performed with an
Agilent 1100 LC system with a diode array detector and equipped
with a Luna C18 column (3 μm, 50 mmϫ2 mm). The LC was cou-
pled to a Micromass LCT orthogonal time-of-flight mass spec-
trometer equipped with a Lock Mass probe and operating in posi-
tive electrospray mode. Optical rotations were measured with a Per-
kin–Elmer 241 polarimeter. Melting points were measured with a
Stuart SMP30 apparatus.
Table 3. Koenigs–Knorr glycosylation of phenyl 1-thio-β-d-gluco-
pyranoside (1).[a]
Tin-Mediated Glycosylation with Peracylated Glycosyl Bromide
(Method A): A suspension of the unprotected phenyl 1-thiohexo-
pyranoside (0.5 mmol) and Bu2SnO (0.75 mmol) in MeOH
(3.0 mL) was refluxed until a clear solution was obtained (3 h). The
solvent was evaporated in vacuo followed by drying at high vacuum
for 2 h to give the stannylene derivative as a colorless foam. The
bromide donor (0.9 mmol) and 4 Å MS (500 mg) were added to a
solution of the stannylene derivative in CH2Cl2 (5 mL). The sus-
pension was stirred at –30 °C for 30 min. AgOTf (0.9 mmol) was
then added, and the mixture was stirred in the dark while the tem-
perature was allowed to reach 10 °C. After 6 h the mixture was
filtered, diluted with CH2Cl2, washed once with 2 m aqueous HCl,
once with saturated aqueous NaHCO3 and once with water. The
organic layer was dried (MgSO4), filtered and concentrated. The
crude product was purified by column chromatography (toluene/
acetone, 8:2Ǟ6:4) to afford the pure disaccharide.
[a] Reaction conditions: (i) Bu2SnO (0.37 mmol), 1 (0.25 mmol),
MeOH, reflux, 3 h; (ii) donor (0.5 mmol), Br2 (0.25 mmol),
CH2Cl2, room temp., then activated 1, AgOTf (0.5 mmol), 4 Å MS,
CH2Cl2, –40 °C to 10 °C, 6 h. [b] Isolated yield.
Tin-Mediated Glycosylation with Peracylated Thioglycoside in the
Presence of Bromine (Method B): The thioglycoside donor
(0.5 mmol) was dissolved in CH2Cl2 (2 mL), and a 1 m solution of
Br2 in CH2Cl2 (0.25 mL, 0.25 mmol) was added at room tempera-
ture. The orange solution was stirred at room temperature until it
turned yellow (from 1 h to 16 h). The solution was then added via
syringe at –40 °C to a suspension of the stannylene derivative of the
acceptor (0.25 mmol, prepared as reported in method A), AgOTf
(0.75 mmol) and 4 Å MS (250 mg) in CH2Cl2 (3 mL). The mixture
was stirred for 6 h in the dark while the temperature was allowed
to reach 10 °C. Then solids were filtered off, and the filtrate was
diluted with CH2Cl2 and successively washed with 2 m aqueous
HCl, saturated aqueous NaHCO3 and water. The organic layer was
dried (MgSO4), filtered and concentrated. The crude product was
purified by silica gel column chromatography (toluene/acetone,
8:2Ǟ6:4) to afford the pure trisaccharide.
Figure 3. Glycosyl donors 24 and 25.
Conclusions
In summary, we have further developed the stannylene-
mediated regioselective glycosylation of unprotected glyc-
osyl acceptors. The best results were achieved with glycosyl
donors and acceptors derived from glucose and galactose,
while mannose substrates gave lower yields. With phenyl 1-
thiohexopyranosides as the acceptors, the approach gives
easy access to several (1Ǟ6)-linked disaccharide thioglycos-
ides which are useful building blocks in oligosaccharide
synthesis.
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Phenyl 2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl-(1Ǟ6)-1-thio-β- tween 1 and 7 was performed according to method A and stopped
D
-glucopyranoside (3): The coupling between 1 and 2 was per-
after 22 h to afford disaccharide 10 as a colorless solid (183 mg,
52%). [α]2D5 = –29.3 (c = 0.9, CHCl3). Rf = 0.3 (CH2Cl2/MeOH,
9:1). 1H NMR (300 MHz, CDCl3): δ = 7.54–7.50 (m, 2 H, Ar),
7.34–7.32 (m, 3 H, Ar), 7.07 (d, J = 9.3 Hz, 1 H, NH), 5.28 (t, J
= 10.2 Hz, 1 H, 3Ј-H), 5.11 (t, J = 9.9 Hz, 1 H, 4Ј-H), 4.77 (d, J =
8.4 Hz, 1 H, 1Ј-H), 4.50 (d, J = 9.6 Hz, 1 H, 1-H), 4.27–4.15 (m, 2
H, 6Ј-Ha, 6Ј-Hb), 4.10–4.06 (m, 1 H, 6-Ha), 4.03–3.97 (m, 1 H, 2Ј-
formed according to method A to afford disaccharide 3 as a color-
less foam (362 mg, 85%). [α]2D5 = +9.5 (c = 0.8, CHCl3). Rf = 0.4
(CH2Cl2/MeOH, 9:1). 1H NMR (300 MHz, CDCl3): δ = 7.94–7.15
(m, 25 H, Ar), 5.79 (t, J = 9.6 Hz, 1 H, 3Ј-H), 5.61 (t, J = 9.6 Hz,
1 H, 4Ј-H), 5.44 (t, J = 9.6 Hz, 1 H, 2Ј-H), 4.87 (d, J = 7.9 Hz, 1
H, 1Ј-H), 4.61 (dd, J = 3.0, 12.3 Hz, 1 H, 6Ј-Ha), 4.35 (m, 2 H, 1-
H, 6Ј-Hb), 4.00 (m, 2 H, 5Ј-H, 6-Ha), 3.79 (dd, J = 3.0, 11.5 Hz, 1 H), 3.82 (dd, J = 5.4, 12.0 Hz, 1 H, 6-Hb), 3.74–3.67 (m, 1 H, 5Ј-
H, 6-Hb), 3.35 (m, 3 H, 2-H, 3-H, 4-H), 3.19 (br. t, 1 H, 5-H) H), 3.57–3.45 (m, 3 H, 3-H, 5-H, 4-H), 3.31 (t, J = 9.9 Hz, 1 H, 2-
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.3, 165.7, 165.5, 165.1
H), 2.08, 2.05, 2.03 (s, 9 H, 3ϫCH3) ppm. 13C NMR (75 MHz,
(4ϫC=O), 133–127 (Ar), 101.2 (C-1Ј), 87.6 (C-1), 78.8 (C-5), 77.6 CDCl3): δ = 171.0, 170.8, 169.5 (3ϫC=O), 162.0 (NH-C=O),
(C-4), 72.7 (C-3Ј), 72.1, 71.9 (C-2, C-3), 71.8 (C-5Ј), 70.3 (C-2Ј), 132.7–128.3 (Ar), 100.7 (C-1Ј), 92.1 (CCl3), 87.8 (C-1), 78.7, 77.6,
69.5 (C-6), 69.2 (C-4Ј), 62.7 (C-6Ј) ppm. HRMS: calcd. for
71.9 (C-5Ј), 71.7 (C-3Ј), 71.6 (C-2), 69.8, 68.9 (C-6), 68.3 (C-4Ј),
61.8 (C-6Ј), 55.8 (C-2Ј), 20.8, 20.6, 20.5 (3ϫCH3) ppm. HRMS:
calcd. for C26H32Cl3NO13S [M + Na]+ 726.0552; found 726.0556.
C46H42O14S [M + Na]+ 873.2187; found 873.2177.
3,4,6-Tri-O-benzoyl-1,2-O-(phenyl
1-thio-β-D-glucopyranosid-6-
yloxy-1-benzylidene)-α- -glucopyranose (4): The coupling between
D
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl-(1Ǟ6)-1-thio-β-
1 and 2 was performed according to method A in the presence of
2,4,6-collidine (1.12 mmol), and the reaction was stopped after 3 h
to afford a mixture (280 mg) containing 90% of orthoester 4 and
10% of 2,4,6-collidine. Rf = 0.4 (CH2Cl2/MeOH, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 7.90–6.99 (m, 25 H, Ar), 5.91 (d, J =
4.5 Hz, 1 H, 1Ј-H), 5.67 (br. s, 1 H, 3Ј-H), 5.39 (d, J = 9.0 Hz, 1
H, 4Ј-H), 4.73 (br. s, 1 H, 2Ј-H), 4.45–4.24 (m, 3 H, 1-H, 6Ј-Ha, 6Ј-
Hb), 4.06–4.00 (m, 1 H, 5-H), 3.80–3.16 (m, 10 H, 2-H, 3-H, 4-H,
5-H, 6-Ha, 6-Hb) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.9,
165.1, 164.4 (3ϫC=O), 134.6–120.9 (Ar, C-7), 97.6 (C-1Ј), 87.4 (C-
1), 77.8, 77.7, 77.5, 71.8, 71.5 (C-2Ј), 70.2, 68.8 (C-3Ј), 68.3 (C-4Ј),
67.3 (C-5Ј), 63.9 ppm. HRMS: calcd. for C46H42O14S [M + Na]+
873.2187; found 873.2198.
D
-galactopyranoside (13): The coupling between 11 and 2 was per-
formed according to method A to afford disaccharide 13 as a color-
less foam (326 mg, 76%). [α]2D5 = +5.1 (c = 0.7, CHCl3). Rf = 0.4
(CH2Cl2/MeOH, 9:1). 1H NMR (300 MHz, CDCl3): δ = 7.99–7.19
(m, 25 H, Ar), 5.80 (t, J = 9.6 Hz, 1 H, 3Ј-H), 5.61 (t, J = 9.6 Hz,
1 H, 4Ј-H), 5.41 (dd, J = 8.1, 9.6 Hz, 1 H, 2Ј-H), 4.86 (d, J =
8.1 Hz, 1 H, 1Ј-H), 4.72 (dd, J = 3.3, 12.3 Hz, 1 H, 6Ј-Ha), 4.37–
4.29 (m, 2 H, 6Ј-Hb, 1-H), 4.07–4.01 (m, 1 H, 5Ј-H), 3.98–3.92 (m,
1 H, 6-Ha), 3.91–3.85 (m, 2 H, 4-H, 3-H), 3.60–3.50 (m, 2 H, 5-H,
2-H), 3.40 (dd, J = 3.6, 9.0 Hz, 1 H, 6-Hb) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.4, 165.7, 165.2, 165.1 (4ϫC=O), 133.5–
128.2 (Ar), 101.1 (C-1Ј), 88.5 (C-1), 77.1 (C-5), 74.3 (C-3), 72.7 (C-
5Ј), 72.4 (C-3Ј), 71.6 (C-2Ј), 69.9 (C-4Ј), 69.2 (C-2), 68.0 (C-4), 67.8
(C-6), 62.4 (C-6Ј) ppm. HRMS: calcd. for C46H42O14S [M + Na]+
873.2187; found 873.2185.
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl-(1Ǟ6)-1-thio-
β-D-glucopyranoside (8): The coupling between 1 and 5 was per-
formed according to method A to afford disaccharide 8 as a glassy
solid (303 mg, 71%). [α]2D5 = +37.8 (c = 1, CHCl3). Rf = 0.4
(CH2Cl2/MeOH, 9:1). 1H NMR (300 MHz, CDCl3): δ = 8.00–7.12
(m, 25 H, Ar), 5.92 (br. s, 1 H, 4Ј-H), 5.72 (m, 1 H, 2Ј-H), 5.52
(dd, J = 3.0, 10.0 Hz, 1 H, 3Ј-H), 4.86 (d, J = 7.8 Hz, 1 H, 1Ј-H),
4.58 (dd, J = 6.6, 11.4 Hz, 1 H, 6Ј-Ha), 4.37–4.31 (m, 2 H, 6Ј-Hb,
1-H), 4.22–4.10 (m, 2 H, 6-Ha, 5Ј-H), 3.84 (dd, J = 6.0, 11.0 Hz, 1
H, 6-Hb), 3.39–3.30 (m, 3 H, 2-H, 3-H, 4-H), 3.17 (br. t, 1 H, 5-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.1, 165.5, 165.4,
165.4 (4ϫC=O), 133–128 (Ar), 101.6 (C-1Ј), 87.8 (C-1), 78.5 (C-
5), 77.5 (C-4), 71.6 (C-5Ј), 71.5, 70.4, 71.4 (C-3Ј), 69.7 (C-2Ј), 69.3
(C-6), 68.0 (C-4Ј), 61.9 (C-6Ј) ppm. HRMS: calcd. for C46H42O14S
[M + Na]+ 873.2187; found 873.2184.
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
D-galactopyranosyl-(1Ǟ6)-1-thio-
β- -galactopyranoside (14): The coupling between 11 and 5 was
D
performed according to method A to afford disaccharide 14 as a
glassy solid (266 mg, 62%). [α]2D5 = +54.2 (c = 0.9, CHCl3). Rf =
1
0.5 (CH2Cl2/MeOH, 9:1). H NMR (300 MHz, CDCl3): δ = 7.98–
7.13 (m, 25 H, Ar), 5.91 (d, J = 3.3 Hz, 1 H, 4Ј-H), 5.73–5.67 (m,
1 H, 2Ј-H), 5.50 (dd, J = 3.3, 10.0 Hz, 1 H, 3Ј-H), 4.86 (d, J =
8.1 Hz, 1 H, 1Ј-H), 4.56 (dd, J = 6.6, 11.4 Hz, 1 H, 6Ј-Ha), 4.41–
4.33 (m, 2 H, 6Ј-Hb, 1-H), 4.22 (t, J = 6.6 Hz, 1 H, 5Ј-H), 4.03–
3.92 (m, 1 H, 6-Ha), 3.88 (br. s, 1 H, 6-Hb), 3.56 (m, 2 H, 5-H, 4-H),
3.42–3.05 (m, 2 H, 3-H, 2-H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 166.1, 165.5, 165.4, 165.3 (4ϫC=O), 133.6–127.9 (Ar), 101.5 (C-
1Ј), 88.5 (C-1), 74.2 (C-2), 74.2 (C-3), 71.5 (C-3Ј), 71.5 (C-5Ј), 69.8
(C-5), 69.6 (C-2Ј), 68.5 (C-6), 68.2 (C-4), 68.1 (C-4Ј), 61.9 (C-6Ј)
ppm. HRMS: calcd. for C46H42O14S [M + Na]+ 873.2187; found
873.2187.
Phenyl 2,3,4,6-Tetra-O-benzoyl-α-
D-mannopyranosyl-(1Ǟ6)-1-thio-
β- -glucopyranoside (9): The coupling between 1 and 6 was per-
D
formed according to method A to afford disaccharide 9 as a color-
less foam (140 mg, 33%). [α]2D5 = –35.9 (c = 1, CHCl3). Rf = 0.4
(CH2Cl2/MeOH, 9:1). 1H NMR (300 MHz, CDCl3): δ = 8.03–7.00
(m, 25 H, Ar), 6.06 (t, J = 10.2 Hz, 1 H, 4Ј-H), 5.85 (dd, J = 2.7,
9.6 Hz, 1 H, 3Ј-H), 5.71 (br. s, 1 H, 2Ј-H), 5.05 (s, 1 H, 1Ј-H), 4.64–
4.49 (m, 3 H, 1-H, 5Ј-H, 6Ј-Ha), 4.34 (dd, J = 3.6, 12.6 Hz, 1 H,
6Ј-Hb), 3.91 (br. s, 2 H, 6-Ha, 6-Hb), 3.64–3.58 (m, 2 H, 3-H, 5-H),
3.54–3.48 (br. d, 1 H, 4-H), 3.45–3.37 (m, 1 H, 2-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.2, 165.7, 166.4, 166.3 (4ϫC=O),
Phenyl 2,3,4,6-Tetra-O-benzoyl-α-
D-mannopyranosyl-(1Ǟ6)-1-thio-
β- -galactopyranoside (15): The coupling between 11 and 6 was
D
performed according to method A to afford disaccharide 15 as a
colorless foam (97 mg, 23%). [α]2D5 = –26.5 (c = 0.9, CHCl3). Rf =
1
0.3 (CH2Cl2/MeOH, 9:1). H NMR (300 MHz, CDCl3): δ = 8.12–
7.15 (m, 25 H, Ar), 6.06 (t, J = 9.9 Hz, 1 H, 3Ј-H), 5.85 (dd, J =
3.0, 10.0 Hz, 1 H), 5.68 (br. s, 1 H), 5.08 (s, 1 H, 1Ј-H), 4.64–4.52
(m, 3 H, 1-H, 6Ј-Ha, 6-Ha), 4.30 (dd, J = 4.5, 12.0 Hz, 1 H, 6Ј-Hb),
4.18–4.15 (m, 1 H), 4.01 (br. s, 1 H, 6-Hb), 3.89–3.85 (m, 1 H), 3.78
(dd, J = 5.0, 10.5 Hz, 1 H), 3.69–3.63 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.2, 165.6, 165.4, 165.3 (4ϫC=O), 133.8–
128.3 (Ar), 97.4 (JC,H = 176.7 Hz, C-1Ј), 89.4 (JC,H = 154.5 Hz, C-
1), 76.8, 74.7, 70.3, 70.2, 69.8, 68.9 (C-6), 68.7, 67.3, 66.4, 62.6 (C-
6Ј) ppm. HRMS: calcd. for C46H42O14S [M + Na]+ 873.2187; found
873.2192.
133.4–128.3 (Ar), 97.4 (JC,H = 173.5 Hz, C-1Ј), 88.2 (JC,H
=
156.0 Hz, C-1), 78.4 (C-5), 78.1 (C-3), 72.1 (C-2), 70.4 (C-3Ј), 70.2
(C-4), 70.1 (C-2Ј), 68.7 (C-5Ј), 67.2 (C-6), 66.5 (C-4Ј), 62.6 (C-6Ј)
ppm. HRMS: calcd. for C46H42O14S [M + Na]+ 873.2187; found
873.2202.
Phenyl 3,4,6-Tri-O-acetyl-2-deoxy-2-trichloroacetamido-β-
D-gluco-
pyranosyl-(1Ǟ6)-1-thio-β- -glucopyranoside (10): The coupling be-
D
2688
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2683–2691

Tin-Mediated Glycosylation
Phenyl 3,4,6-Tri-O-acetyl-2-deoxy-2-trichloroacetamido-β-
pyranosyl-(1Ǟ6)-1-thio-β-D-galactopyranoside (16): The coupling
D
-gluco-
71.5, 71.5 (C-3Ј), 68.8 (C-6), 68.3 (C-4Ј), 68.0, 61.8 (C-6Ј), 55.8 (C-
2Ј), 21.0, 20.9, 20.8 (3ϫCH3) ppm. HRMS: calcd. for
C26H32Cl3NO13S [M + Na]+ 726.0552; found 726.0554.
between 11 and 7 was performed according to method A and
stopped after 22 h to afford disaccharide 16 as a colorless solid
(230 mg, 66%). [α]2D5 = –21.8 (c = 1, CHCl3). Rf = 0.3 (CH2Cl2/
MeOH, 9:1). 1H NMR (300 MHz, CDCl3): δ = 7.52–7.49 (m, 2 H,
Ar), 7.34–7.29 (m, 3 H, Ar), 6.95 (d, J = 9.3 Hz, 1 H, NH), 5.24
(t, J = 10.5 Hz, 1 H, 3Ј-H), 5.08 (t, J = 9.9 Hz, 1 H, 4Ј-H), 4.74
(d, J = 7.8 Hz, 1 H, 1Ј-H), 4.52 (d, J = 9.9 Hz, 1 H, 1-H), 4.26–
4.15 (br. m, 2 H, 6Ј-Ha, 6Ј-Hb), 4.00–3.94 (br. m, 3 H, 2Ј-H), 3.90–
3.85 (br. m, 1 H, 6-H), 3.75–3.59 (br. m, 7 H, 5Ј-H, 2-H), 2.07,
2.04, 2.01 (s, 9 H, 3ϫCH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 171.0, 170.8, 169.5 (3ϫC=O), 162.3 (HN-C=O), 132.7, 132.0,
129.2, 128.1 (Ar), 100.6 (C-1Ј), 92.1 (CCl3), 88.8 (C-1), 77.5, 74.4,
71.9, 71.6 (C-3Ј), 69.8 (C-5Ј), 68.7, 68.4 (C-6), 68.3 (C-4Ј), 61.8 (C-
6Ј), 55.7 (C-2Ј), 20.8, 20.6, 20.5 (3ϫCH3) ppm. HRMS: calcd. for
C26H32Cl3NO13S [M + Na]+ 726.0552; found 726.0540.
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
D-glucopyranosyl-(1Ǟ6)-2,3,4-tri-
O-benzoyl-1-thio-β- -glucopyranoside (20): Disaccharide 3 (1.8 g,
D
2.1 mmol ) was dissolved in pyridine (4.2 mL), and benzoyl chlor-
ide (2.5 mL, 21 mmol) was added at 0 °C. The mixture was stirred
at room temperature overnight. CH2Cl2 was added, followed by
water. After separation, the organic phase was washed twice with
saturated aqueous NaHCO3 and twice with water. The organic
layer was dried with MgSO4 and concentrated in vacuo to leave an
amorphous solid which was crystallized from toluene/pentane to
give the title compound as a white crystalline solid (1.929 g, 80%).
[α]2D5 = +63.2 (c = 0.9, CHCl3). Rf = 0.7 (toluene/acetone, 9:1). M.p.
193–197 °C. 1H NMR (300 MHz, CDCl3): δ = 8.05–7.15 (m, 40 H,
Ar), 5.79–5.69 (m, 2 H, 3Ј-H, 3-H), 5.52 (t, J = 9.5 Hz, 1 H, 4Ј-H),
5.42 (t, J = 9.0 Hz, 1 H, 2Ј-H), 5.28 (t, J = 9.9 Hz, 1 H, 2-H), 5.18
(t, J = 9.6 Hz, 1 H, 4-H), 4.88 (d, J = 8.4 Hz, 1 H, 1Ј-H), 4.84 (d,
J = 10.2 Hz, 1 H, 1-H), 4.52 (dd, J = 3.0, 12.6 Hz, 1 H, 6Ј-Ha),
4.33 (dd, J = 4.8, 12.6 Hz, 1 H, 6Ј-Hb), 3.99–3.92 (m, 2 H, 5Ј-H,
5-H), 3.89 (br. s, 2 H, 6-Ha, 6-Hb) ppm. 13C NMR (75 MHz,
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
D-glucopyranosyl-(1Ǟ6)-1-thio-α-
D-mannopyranoside (17): The coupling between 12 and 2 was per-
formed according to method A to afford disaccharide 17 as an
amorphous solid (209 mg, 49%). [α]2D5 = +104 (c = 0.5, CHCl3). Rf
= 0.4 (CH2Cl2/MeOH, 9:1). 1H NMR (300 MHz, CDCl3): δ = CDCl3): δ = 166.0, 165.8, 165.6, 165.3, 165.2, 165.1, 164.9
8.03–7.24 (m, 25 H, Ar), 5.82 (t, J = 9.0 Hz, 1 H, 3Ј-H), 5.60 (t, J
= 9.0 Hz, 1 H, 4Ј-H), 5.48 (br. d, 1 H, 2Ј-H), 5.42 (br. s, 1 H, 1-
H), 4.85 (d, J = 8.0 Hz, 1 H, 1Ј-H), 4.58 (dd, J = 4.0, 12.0 Hz, 1
H, 6Ј-Ha), 4.36 (dd, J = 6.0, 12.0 Hz, 1 H, 6Ј-Hb), 4.11–4.03 (br.
m, 4 H), 3.89 (dd, J = 5.0, 11.1 Hz, 1 H, 6-Hb), 3.69–3.63 (m, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.3, 165.7, 165.4, 165.1
(4ϫC=O), 133–127 (Ar), 101.0 (C-1Ј), 87.7 (C-1), 72.6 (C-3Ј), 72.2
(C-2Ј), 72.0, 71.9 (3ϫC), 69.4 (C-5Ј), 69.0 (C-6), 68.3 (C-5), 62.8
(C-6Ј) ppm. HRMS: calcd. for C46H42O14S [M + Na]+ 873.2187;
found 873.2197.
(7ϫC=O), 134.5–128.4 (Ar), 100.9 (C-1Ј), 85.9 (C-1), 78.4 (C-5),
74.0 (C-3), 72.9 (C-3Ј), 72.2 (C-5Ј), 71.8 (C-2Ј), 70.5 (C-2), 69.6
(C-4), 69.5 (C-4Ј), 68.2 (C-6), 62.8 (C-6Ј) ppm. HRMS: calcd. for
C67H54O17S [M + Na]+ 1185.2974; found 1185.3017.
Methyl
2,3,4,6-Tetra-O-benzoyl-β-
D-glucopyranosyl-(1Ǟ6)-2,3,4-
tri-O-benzoyl-β-D-glucopyranosyl-(1Ǟ6)-β-D-glucopyranoside (22):
A solution of Me2S2–Tf2O (1 m, 1.12 mL, 1.12 mmol, prepared fol-
lowing a reported procedure[27]) in CH2Cl2 was added to a suspen-
sion of donor 20 (0.75 mmol) and 4 Å MS (1.0 g) in CH2Cl (2 mL).
The mixture was stirred for 10 min at –40 °C. At this point, the
Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
D-galactopyranosyl-(1Ǟ6)-1-thio- stannylene derivative of acceptor 21 (0.5 mmol, prepared as re-
α- -mannopyranoside (18): The coupling between 12 and 5 was per-
formed according to method A (reaction temperature –70 °C to
D
ported in method A) was dissolved in CH2Cl2 (3 mL) and added
via syringe to the activated donor at –40 °C. The reaction mixture
was stirred for one hour, allowing the temperature to reach –10 °C,
and quenched by addition of excess Et3N (9 mmol), diluted with
10°) to afford disaccharide 18 as a glassy solid (162 mg, 38%).
[α]2D5 = +120.4 (c = 1, CHCl3). Rf = 0.5 (CH2Cl2/MeOH, 9:1). H
1
NMR (300 MHz, CDCl3): δ = 8.00–7.13 (m, 25 H, Ar), 5.91 (d, J = CH2Cl2, filtered and successively washed with 2 m aqueous HCl,
3.3 Hz, 1 H, 4Ј-H), 5.73 (m, 1 H, 2Ј-H), 5.56 (dd, J = 3.6, 10.8 Hz, 1 saturated aqueous NaHCO3 and water. The organic layer was dried
H, 3Ј-H), 5.45 (d, J = 1.2 Hz, 1 H, 1-H), 4.83 (d, J = 7.2 Hz, 1 H, with MgSO4 and concentrated in vacuo. The residue was subjected
1Ј-H), 4.59 (dd, J = 6.3, 11.4 Hz, 1 H, 6Ј-Ha), 4.33 (dd, J = 5.7, to silica gel column chromatography (toluene/acetone, 8:2Ǟ6:4) to
11.4 Hz, 1 H, 6Ј-Hb), 4.26–4.20 (br. t, 1 H, 5Ј-H), 4.15–4.02 (m, 3
H), 3.92 (dd, J = 4.2, 12.0 Hz, 1 H, 6-H), 3.66–3.56 (m, 2 H), 2.63
(br. s, 3 H, 3ϫOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.1,
afford the pure trisaccharide 22 as a colorless foam (224.5 mg,
35%). [α]2D5 = –10.2 (c = 1, CHCl3). Rf = 0.5 (toluene/acetone, 1:1).
1H NMR (300 MHz, CDCl3): δ = 7.98–7.15 (m, 35 H, Ar), 5.84 (t,
165.6, 165.5, 165.4 (4ϫC=O), 133.7–127.4 (Ar), 102.2 (C-1Ј), 87.8 J = 9.3 Hz, 1 H, 3ЈЈ-H), 5.73 (t, J = 9.9 Hz, 1 H, 3Ј-H), 5.61 (t, J
(C-1), 72.0 (C-3), 71.9, 71.7 (C-5Ј), 71.5, 71.2 (C-3Ј), 69.9 (C-2Ј),
69.4 (C-6), 68.3, 68.0 (C-4Ј), 61.9 (C-6Ј) ppm. HRMS: calcd. for
C46H42O14S [M + Na]+ 873.2187; found 873.2191.
= 10.2 Hz, 1 H, 4ЈЈ-H), 5.47 (t, J = 9.0 Hz, 1 H, 2ЈЈ-H), 5.35 (t, J
= 9.0 Hz, 1 H, 2Ј-H), 5.23 (t, J = 9.3 Hz, 1 H, 4Ј-H), 5.03 (d, J =
7.8 Hz, 1 H, 1ЈЈ-H), 4.69 (d, J = 7.5 Hz, 1 H, 1Ј-H), 4.58 (dd, J =
3.3, 12.6 Hz, 1 H, 6ЈЈ-Ha), 4.41 (dd, J = 4.8, 12.6 Hz, 1 H, 6ЈЈ-Hb),
4.11–4.07 (m, 2 H, 5ЈЈ-H, 6-Ha), 4.04 (d, J = 7.8 Hz, 1-H), 3.95–
3.84 (m, 3 H, 6Ј-Ha, 6Ј-Hb, 5Ј-H), 3.68–3.63 (m, 1 H, 6-Hb), 3.50–
3.43 (m, 1 H, 3-H), 3.41–3.37 (m, 2 H, 5-H, 4-H), 3.29–3.24 (m, 1
H, 2-H), 3.19 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 166.2, 166.1, 165.6, 165.3, 165.2, 165.1, 165.0 (7ϫC=O), 133.4–
128.2 (Ar), 103.2 (C-1), 101.3 (C-1ЈЈ), 100.7 (C-1Ј), 76.4 (C-3), 74.8
(C-5), 74.4 (C-5Ј), 73.6 (C-2), 72.8 (C-3ЈЈ), 72.5 (C-3Ј), 72.3 (C-5ЈЈ),
71.8 (C-2ЈЈ), 71.3 (C-2Ј), 70.7 (C-4), 69.5 (C-4Ј), 69.4 (C-4ЈЈ), 68.4
(C-6), 68.1 (C-6Ј), 62.8 (C-6ЈЈ), 56.7 (OCH3) ppm. HRMS: calcd.
for C68H62O23 [M + Na]+ 1269.3574; found 1269.3647.
Phenyl 3,4,6-Tri-O-acetyl-2-deoxy-2-trichloroacetamido-β-
D-gluco-
pyranosyl-(1Ǟ6)-1-thio-α- -mannopyranoside (19): The coupling
D
between 12 and 7 was performed according to method A and
stopped after 22 h to afford disaccharide 19 as a white solid
(170 mg, 48%). [α]2D5 = +63.2 (c = 0.9, CHCl3). Rf = 0.3 (CH2Cl2/
MeOH, 9:1). 1H NMR (300 MHz, CDCl3): δ = 7.38–7.35 (m, 2 H,
Ar), 7.26–7.19 (m, 4 H, Ar, NH), 5.49 (s, 1 H, 1-H), 5.23 (t, J =
9.3 Hz, 1 H, 3Ј-H), 5.04 (t, J = 9.6 Hz, 1 H, 4Ј-H), 4.74 (d, J =
9.0 Hz, 1 H, 1Ј-H), 4.21–4.07 (m, 4 H, 6Ј-Ha, 6Ј-Hb, 4-H, OH),
4.01–3.82 (m, 3 H, 2Ј-H, 6-Ha, 6-Hb), 3.80–3.65 (br. m, 2 H, 5Ј-H,
OH), 3.63–3.40 (m, 3 H, 5-H, 3-H, OH), 2.00, 1.97, 1.95 (s, 9 H,
3ϫCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.9, 170.8,
169.4 (3ϫC=O), 162.5 (NH-C=O), 133.7, 131.0, 129.2, 127.5 (Ar),
Phenyl
2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl-(1Ǟ6)-2,3,4-
tri-O-benzoyl-β-D-glucopyranosyl-(1Ǟ6)-1-thio-β-D-glucopyranoside
100.8 (C-1Ј), 92.2 (CCl3), 87.8 (C-1), 72.0 (C-5Ј), 71.9 (C-5), 71.9, (23): The coupling between 1 and 20 was performed according to
Eur. J. Org. Chem. 2013, 2683–2691
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2689

A. Maggi, R. Madsen
FULL PAPER
method B to afford trisaccharide 23 as a glassy solid (133 mg,
40%). [α]2D5 = –13.7 (c = 1, CHCl3). Rf = 0.6 (toluene/acetone, 6:4).
1H NMR (300 MHz, CDCl3): δ = 8.01–7.13 (m, 40 H, Ar), 5.87 (t,
J = 10.5 Hz, 1 H, 3Ј-H), 5.71 (t, J = 9.6 Hz, 1 H, 3ЈЈ-H), 5.59 (t, J
7.53–7.14 (m, 6 H, Ar, NH), 5.34 (d, J = 3.6 Hz, 1 H), 5.19–5.07
(m, 2 H, 3Ј-H), 4.96 (dd, J = 3.6, 11.1 Hz, 1 H), 4.63 (d, J = 8.1 Hz,
1 H, 1Ј-H), 4.57–4.49 (m, 3 H, 1ЈЈ-H, 1-H), 4.12–3.76 (m, 10 H),
3.62–3.38 (m, 5 H), 3.36–3.28 (br. t, 1 H, 2-H), 2.14, 2.10, 2.05,
= 10.2 Hz, 1 H, 4Ј-H), 5.47 (dd, J = 8.1, 10.5 Hz, 1 H, 2Ј-H), 5.35 2.04, 1.96 (s, 18 H, 6ϫCH3) ppm. 13C NMR (75 MHz, CDCl3): δ
(dd, J = 8.1, 9.6 Hz, 1 H, 2ЈЈ-H), 5.26–5.18 (m, 1 H, 4ЈЈ-H), 5.00
(d, J = 8.1 Hz, 1 H, 1Ј-H), 4.67 (d, J = 8.1 Hz, 1 H, 1ЈЈ-H), 4.54
(dd, J = 3.0, 12.3 Hz, 1 H, 6Ј-Ha), 4.45 (d, J = 9.9 Hz, 1 H, 1-H),
= 170.7, 170.6, 170.4, 170.1, 170.0, 169.3 (6ϫC=O), 162.3 (HN-
C=O), 132.6–128.3 (Ar), 101.2 (C-1Ј), 100.8 (C-1ЈЈ), 92.2 (CCl3),
87.8 (C-1), 78.9, 77.7, 75.9, 72.8, 71.9, 71.8, 70.7, 70.6, 69.8, 69.1,
4.38 (dd, J = 4.8, 12.3 Hz, 1 H, 6Ј-Hb), 4.11–3.78 (br. m, 6 H, 5ЈЈ- 68.6, 66.6, 61.8, 60.6, 55.4, 20.9, 20.7, 20.6, 20.5 (6ϫCH3) ppm.
H, 5Ј-H, 6ЈЈ-Ha, 6ЈЈ-Hb, 6-Ha, 6-Hb), 3.71–3.66 (m, 1 H, 5-H), 3.55–
3.41 (br. m, 3 H, 3-H, 4-H, OH), 3.28 (t, J = 9.3 Hz, 1 H, 2-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.1, 166.0, 165.6, 165.4,
165.2, 165.1, 165.0 (7ϫC=O), 133.5–127.8 (Ar), 101.4 (C-1Ј), 100.7
(C-1ЈЈ), 88.2 (C-1), 78.6, 77.8, 74.3, 72.7 (C-3Ј), 72.6 (C-3ЈЈ), 72.2
(C-2Ј), 71.9 (C-2ЈЈ), 71.8 (C-2), 71.5, 70.3 (C-4Ј), 69.6 (C-4ЈЈ), 69.4,
68.6 (C-6Ј, C-6), 68.3, 62.8 (C-6ЈЈ) ppm. HRMS: calcd. for
C73H64O22S [M + Na]+ 1347.3502; found 1347.3566.
HRMS: calcd. for C38H48Cl3NO21S [M + Na]+ 1014.1397; found
1014.1431.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all products.
Acknowledgments
Methyl 2,3,4,6-Tetra-O-benzoyl-β-
D-galactopyranosyl-(1Ǟ4)-2,3,6-
Financial support from the Lundbeck Foundation is gratefully
acknowledged. We thank Dr. Gyorgyi Osztrovszky for performing
the first experiment on this project.
tri-O-benzoyl-1-thio-β- -glucopyranoside (24): Methyl 1-thiolactos-
D
ide (2 g, 5.4 mmol ) was dissolved in pyridine (5 mL), and benzoyl
chloride (6.3 mL, 54 mmol) was added at 0 °C. The mixture was
stirred at room temperature overnight and worked up as described
above. The residue was purified by silica gel column chromatog-
raphy (toluene/acetone, 10:0Ǟ9:1) to afford the title compound as
a colorless foam (5.3 g, 89%). [α]2D5 = +52.2 (c = 1.1, CHCl3). Rf =
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1
0.8 (toluene/acetone, 9:1). H NMR (300 MHz, CDCl3): δ = 7.95–
7.05 (m, 35 H, Ar), 5.76 (t, J = 9.6 Hz, 1 H, 3-H), 5.67–5.62 (m, 2
H, 2Ј-H, 4Ј-H), 5.43 (t, J = 8.7 Hz, 1 H, 2-H), 5.30 (dd, J = 3.9,
10.2 Hz, 1 H, 3Ј-H), 4.80 (d, J = 7.5 Hz, 1 H, 1Ј-H), 4.54 (d, J =
9.9 Hz, 1 H, 1-H), 4.51–4.39 (m, 2 H, 6-Ha, 6-Hb), 4.17 (t, J =
9.9 Hz, 1 H, 4-H), 3.85–3.59 (m, 4 H, 6Ј-Ha, 6Ј-Hb, 5Ј-H, 5-H),
2.09 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.7,
165.7, 165.4, 165.3, 165.3, 165.2, 164.7 (7ϫC=O), 133.6–128.2
(Ar), 100.9 (C-1Ј), 83.2 (C-1), 75.8 (C-4), 73.9 (C-3), 71.7 (C-3Ј),
71.3, 69.8, 69.8 67.4 (C-5, C-5Ј, C-4Ј, C-2Ј, C-2), 62.5 (C-6), 60.9
(C-6Ј), 11.6 (CH3) ppm. HRMS: calculated for C62H52O17S [M +
Na]+ 1123.2817; found 1123.2835.
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Phenyl 2,3,4,6-Tetra-O-benzoyl-β-
D
-galactopyranosyl-(1Ǟ4)-2,3,6-
tri-O-benzoyl-β- -glucopyranosyl-(1Ǟ6)-1-thio-β-
D
D-glucopyranoside
(26): The coupling between 1 and 24 was performed according to
method B to afford trisaccharide 26 as a glassy solid (152 mg,
46%). [α]2D5 = +23.5 (c = 1, CHCl3). Rf = 0.7 (toluene/acetone, 1:1).
1H NMR (300 MHz, CDCl3): δ = 7.96–7.05 (m, 40 H, Ar), 5.72–
5.63 (m, 3 H, 2ЈЈ-H, 3Ј-H, 4ЈЈ-H), 5.38–5.30 (m, 2 H, 2Ј-H, 3ЈЈ-H),
4.82 (d, J = 8.1 Hz, 1 H, 1ЈЈ-H), 4.70 (d, J = 8.1 Hz, 1 H, 1Ј-H),
4.58–4.52 (br. d, 1 H, 6Ј-Ha), 4.38 (dd, J = 4.2, 12.9 Hz, 1 H, 6Ј-
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H), 3.95 (br. d, 1 H, 6-Ha), 3.84 (t, J = 6.0 Hz, 1 H, 5-H), 3.76–
3.70 (br. d, 1 H, 6-Hb), 3.69–3.63 (m, 3 H, 5Ј-H, 6ЈЈ-Ha, 6ЈЈ-Hb),
3.40–3.29 (m, 3 H, 3-H, 4-H, 5ЈЈ-H), 3.14 (t, J = 9.0 Hz, 1 H, 2-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 165.9, 165.6, 165.4, 165.3,
165.3, 165.2, 164.8 (7ϫC=O), 133.5–128.2 (Ar), 101.0 (C-1ЈЈ),
100.9 (C-1Ј), 87.8 (C-1), 78.6, 77.6, 75.8 (C-4Ј), 73.1 (C-5Ј), 72.7,
71.8, 71.7 (C-2), 71.7, 71.3 (C-5Ј), 70.5, 69.9, 69.0 (C-6), 67.5, 62.0
(C-6Ј), 60.9 (C-6ЈЈ) ppm. HRMS: calcd. for C73H64O22S
[M + Na]+ 1347.3502; found 1347.3559.
Phenyl 2,3,4,6-Tetra-O-acetyl-β-
O-acetyl-2-deoxy-2-trichloroacetamido-β-
(1Ǟ6)-1-thio-β- -glucopyranoside (27): The coupling between 1 and
D
-galactopyranosyl-(1Ǟ4)-3,6-di-
D
-glucopyranosyl-
D
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25 was performed according to method B to afford trisaccharide
27 as a glassy solid (141 mg, 57%). [α]2D5 = –14.4 (c = 1, CHCl3).
1
Rf = 0.5 (toluene/acetone, 4:6). H NMR (300 MHz, CDCl3): δ =
2690
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2683–2691

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Published Online: March 13, 2013
Eur. J. Org. Chem. 2013, 2683–2691
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2691