Lewis acids as α-directing additives in glycosylations by using 2,3-O-carbonate-protected glucose and galactose thioglycoside donors based on preactivation protocol

Article abstract of DOI:10.1021/jo3002084

Catalytic or stoichiometric amounts of Lewis acids were found to be very effective α-directing additives in the stereoselective glycosylations of diverse 2,3-O-carbonate-protected glucose and galactose thioglycoside donors by preactivation protocol. The p

Full text of DOI:10.1021/jo3002084

Article
pubs.acs.org/joc
Lewis Acids as α-Directing Additives in Glycosylations by Using
2,3-O-Carbonate-Protected Glucose and Galactose Thioglycoside
Donors Based on Preactivation Protocol
Yiqun Geng, Qi Qin, and Xin-Shan Ye*
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Xue Yuan Road
No. 38, Beijing 100191, China
S
* Supporting Information
ABSTRACT: Catalytic or stoichiometric amounts of Lewis acids
were found to be very effective α-directing additives in the
stereoselective glycosylations of diverse 2,3-O-carbonate-
protected glucose and galactose thioglycoside donors by pre-
activation protocol. The poor stereoselectivities of 4,6-di-O-
acetyl-2,3-O-carbonate protected thioglycoside donors in glycosyl
coupling reactions were greatly improved, and excellent α-
stereoselectivities were achieved by the addition of 0.2 equiv of BF3·OEt2. On the other hand, the β-selectivities of 4,6-di-O-
benzyl-2,3-O-carbonate-protected thioglucoside donor toward glycosylations were reversed completely to the α-selectivities by
the use of 1 equiv of SnCl4, making the stereoselectivity controllable. Furthermore, the poor stereoselectivities of 4,6-di-O-benzyl-
2,3-O-carbonate-protected thiogalactoside donor in glycosylations were also improved by using SnCl4 as additive.
The preactivation protocol,23 which was developed as an
INTRODUCTION
Synthesis of oligosaccharides and glycoconjugates has a great
demand for biological research as well as carbohydrate-based
drug and vaccine discovery. Although much progress has been
■
effective strategy for iterative one-pot synthesis of oligosac-
charides in this laboratory,24 was found to have dramatic
influences on the stereoselectivies of glycosylations. Our recent
made in this field in the past decades,1−4 there are still no
work showed that, using this protocol, either α- or
β-stereoselective glycosylations of 2,3-N,O-oxazolidinone pro-
general methods for the routine preparation of this type of
compounds. The stereoselective introduction of a glycosidic
tected glucosamine and galactosamine thioglycoside donors can
be modulated just by different additives,15d,25 and highly
α-selective glycosylations of 3,4-O-carbonate protected 2-
deoxy- and 2,6-dideoxythioglycoside donors can be also
performed.19 Very recently, Mong and co-workers also reported
DMF as a good modulator to effect α-glycosylation by
preactivation procedure.26 Combination of the conformation-
constraining protecting group and preactivation protocol could
be an effective approach to stereoselective glycosylations and
might find wide applications to the oligosaccharide assembly.
Encouraged by the initial success in glucosamine, galactos-
amine, 2-deoxysugar, and 2,6-dideoxysugar donors, our next
goal was to extend the preactivation-based stereoselective
glycosylation protocol to glucose and galactose donors. We
wanted to develop an effective method for stereoselective
(especially α-selective) glycosylations of thioglucoside and
thiogalactoside donors. Considering the significant role played
by the conformation-constraining protecting groups, we
decided to use 2,3-O-carbonate as a fixed protecting group in
our thioglycoside donors, which was reported as an α-directing
bond is one of the key determinants.5 The formation of α/β-
anomers during glycosylations usually requires a time-
consuming separation process, thus decreasing the efficiency
of oligosaccharide assembly. Generally, the 1,2-trans glycosidic
bond is constructed by the neighboring group participation of
an acyl group at C-2 position of a glycosyl donor, while the
formation of 1,2-cis linked glycosides remains a difficult task in
many cases. The introduction of a nonparticipating neighboring
group at C-2 position is insufficient to guarantee stereoselective
cis-glycosylation reactions.
To improve the stereoselectivity (especially 1,2-cis-type) of
glycosylation reactions, many strategies have been developed.
These include the traditional methods such as anchimeric
assistance, anomeric effect, in situ anomerization of α-halide,6
heterogeneous catalysis,7 and the solvent effects of nitriles8,9 or
ethers.10 Recent progress in intramolecular aglycon delivery
approach,11,12 stereodirecting effects of the conformation-
constraining protecting groups such as benzylidene,13,14
oxazolidinone,15,16 carbonate,17−19 and the related mechanism
studies,20 as well as the participation of chiral auxiliary (S)-
(phenylthiomethyl)benzyl ether through β-sulfonium ion
intermediate21 has been also very encouraging. However,
there is still no general protocol to guarantee the stereo-
selectivities in one-pot multistep oligosaccharide assembly,22 in
which thioglycosides are usually employed as glycosyl donors.
agent with solvent assistance by the Boons group in 2001.17
A
similar glycosyl donor was reported by the Crich group to
show good β-selectivity in the absence of solvent effects.18c
Received: January 31, 2012
Published: May 18, 2012
© 2012 American Chemical Society
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These interesting findings also inspired us to find a way to
modulate the α/β selectivities of a single donor by changing
additives, like the additive-controlled stereoselective glycosylations
of glucosamine and galactosamine donors reported previously by
us.25b Herein we report the Lewis acid mediated α-selective
glycosylations of 2,3-O-carbonate-protected glucose and galactose
thioglycoside donors based on preactivation protocol.
was treated with sodium hydride (NaH) and p-methoxybenzyl
chloride (PMBCl) to provide compound 8. Removal of the
benzylidene group in 8 under acidic conditions in DCM/
MeOH (V/V, 1:1) afforded intermediate 9, which was con-
verted to compound 10 by acetylation and compound 12 by
benzylation, respectively. Subsequently, the removal of
p-methoxybenzyl groups of compound 10 and compound 12
followed by phosgenation led to 4,6-di-O-acetyl-2,3-O-carbo-
nate protected thioglucoside donor 2 and 4,6-di-O-benzyl-2,3-
O-carbonate protected donor 3, respectively. It is worth
mentioning that, in the synthetic routes of donors 2 and 3,
the p-methoxybenzyl group worked as a temporary protecting
group and the precursor of carbonate group, which was
somewhat unstable during the protecting group manipulations
and was introduced to the target molecules in the last step. In
the similar way, thiogalactoside donors 4−6 were prepared
starting from galactose derivative 1428 (Scheme 2).
RESULTS AND DISCUSSION
■
First, a series of 2,3-O-carbonate protected thioglycoside
donors 1−6 (Figure 1) were designed and prepared with
With glycosyl donors 1−6 in hand, we first investigated the
influence of protecting groups at 4,6-OH positions on the
stereochemical outcome toward glycosylations. A series of
couplings of acceptor 18a29 with diverse donors 1−6 by
preactivation protocol were carried out (Table 1). Benzene-
sulfinyl morpholine/triflic anhydride (BSM/Tf2O),30 diphenyl
sulfoxide/triflic anhydride (Ph2SO/Tf2O),31 or benzenesulfinyl
piperidine/triflic anhydride (BSP/Tf2O)32 worked as the
promoter system. It is worth mentioning that a preactivation
procedure is necessary for all glycosylations because we found
that none of donors 1−6 could be activated by the BSM (or
Ph2SO, BSP)/Tf2O system when using nonpreactivation
procedure. The promoter systems reacted preferentially with
the acceptor alcohol due to the disarmed nature of such trans-
carbonate-protected donors. Each donor was preactivated at
low temperature in anhydrous dichloromethane under argon
atmosphere, acceptor 18a was then added to the reaction
Figure 1. 2,3-O-Carbonate-protected glucose and galactose thioglyco-
side donors.
different protecting groups at 4,6-OH positions, including the
rigid benzylidene group, the electron-donating benzyl group,
and the electron-withdrawing acetyl group. Among them, the
similar structure of donor 3 was reported to show moderate to
excellent β-selectivities toward glycosylations.18c
The synthesis of thioglucoside donors 1−3 started from the
same glucose derivative 727 (Scheme 1). Donor 1 was obtained
through phosgenation of compound 7 in the presence of pyri-
dine using dichloromethane (DCM) as solvent. Compound 7
a
Scheme 1. Preparation of Thioglucoside Donors 1−3
a
Reagents and conditions: (a) triphosgene, Py, CH2Cl2, 81% for 1, 76% for 2, 86% for 3; (b) PMBCl, NaH, DMF, 88%; (c) p-TsOH, CH2Cl2/
MeOH (1:1), 90%; (d) Ac2O, Py, DMAP, 100%; (e) TFA, CH2Cl2, 97%; (f) BnBr, NaH, DMF, 94%; (g) DDQ, CH2Cl2/H2O (10:1), 88%.
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a
anomeric ratio were determined based on the isolated products.
As shown in Table 1, 4,6-O-benzylidene protected donors 1
and 4 were not able to be activated by any promoters, even at
room temperature (entries 1 and 4), due to the strong
“disarming” effects of both benzylidene and carbonate
groups.18c At −72 °C, 4,6-di-O-acetyl-protected donors 2 and
5 were completely activated only by Ph2SO/Tf2O,33 which is
nearly the most powerful promoter for the activation of
thioglycoside donors. More reactive 4,6-O-benzyl protected
donors 3 and 6 were fully activated by BSM/Tf2O at −72 °C.
The glycosylations of acceptor 18a with donors 2, 3, 5, and 6
went well with good yields but poor stereoselectivities except
for donor 3, which showed excellent β-selectivity. It seemed
that even with closely related structures, donors with different
protecting groups at 4,6-OH showed quite different stereo-
selectivities, which was consistent with the results reported by
the Boons17 and Crich groups.18c Under our preactivation
protocol, the more important α-selectivity was not achieved as
expected by using carbonate protecting groups.
Scheme 2. Preparation of Thiogalactoside Donors 4−6
a
Reagents and conditions: (a) triphosgene, Py, CH2Cl2, 83% for 4,
75% for 5, 83% for 6; (b) PMBCl, NaH, DMF, 85%; (c) p-TsOH,
CH2Cl2/MeOH (1:1), 90%; (d) Ac2O, Py, DMAP, 100%; (e) TFA,
CH2Cl2, 93%; (f) BnBr, NaH, DMF, 95%; (g) DDQ, CH2Cl2/H2O
(10:1), 86%.
However, based on our experiences in developing the
additive-controlled stereoselective glycosylation strategy,25b
there is still possibility for us to find suitable additives to
improve the poor selectivities of such donors. So our next goal
focused on looking for effective stereoselectivity-directing
mixture after the complete consumption of donor as indicated
by TLC monitoring. After that, the reaction mixture was
allowed to warm up to room temperature to accomplish the
glycosidic bond formation. In each case, both the yield and the
Table 1. Glycosylations of Acceptor 18a with Various 2,3-O-Carbonate Protected Glycosyl Donors 1−6
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Table 2. Effects of Different Lewis Acids on the Stereochemical Outcome in the Glycosylation of Acceptor 18a with Donor 2
a
b
c
The yield was determined on the basis of isolated products. The anomeric ratio was determined by isolated products. The anomeric ratio was
d
1
determined by integration of H NMR spectrum of the crude product. The crude product was not isolated furthermore to give the yield.
additives in the glycosylation reactions of 2,3-O-carbonate-
protected donors. In the beginning, the β-directing additive
2,4,6-tri-tert-butylpyrimidine (TTBP), α-directing additive
thiophene, bifunctional additives TBAI, and dimethyl sulfide,
which worked well in the stereoselective glycosylations of
glucosamine and galactosamine donors,25b were checked.
Unfortunately, they did not work at all in this case.
Our previous work and related mechanism studies by other
research groups34,35 suggested that the good α-selectivity of 2,3-
N,O-oxazolidinone protected aminosugar donors arose from
the in situ anomerization of β-glycosidic bonds under the mild
acidic reaction conditions. Obviously, the same mild acidic
conditions in the glycosylation of 2,3-O-carbonate-protected
donor 2 was not enough to promote the anomerization process.
We then decided to use Lewis acid as additive in this
glycosylation reaction to assist the anomerization process from
β-glycoside to its α-anomer. Some Lewis acids were screened,
their effects on the stereochemical outcome in the coupling of 2
with 18a were investigated, and the results are listed in Table 2.
In each coupling reaction, Lewis acid was added after the
preactivation of donor 2 by Ph2SO/Tf2O at −72 °C and the
addition of acceptor 18a. Fortunately, it was found that a
catalytic amount of BF3·OEt2 (entry 25) or AgBF4 (entry 30) as
well as 1 equiv of AgPF6 (entry 31) significantly improved the
stereoselectivity of this reaction, and excellent α-selectivity was
realized. We also found that the yields were reduced when
adding larger amounts of Lewis acid (entries 22−24, 27−29),
but no hydrolysis products were observed under these
conditions. The decrease of yields could probably arise from
the degradation of the disaccharide.
Considering the high cost and sensibility to moisture of AgBF4
or AgPF6, we preferred BF3·OEt2 as an effective α-directing
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Table 3. BF3·OEt2 as an Effective α-Directing Additive in the Glycosylations of a Series of Acceptors 18a−g with Donor 2 or 5
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Table 3. continued
a
b
c
Yield based on the recovery of the acceptor. The reaction was carried out without adding BF3·OEt2 as additive. α-Selectivity was obtained by
d
using 2 equiv of BF3·OEt2 as additive. α-Selectivity was obtained by using 1 equiv of BF3·OEt2 as additive.
additive in the glycosylations of 2,3-O-carbonate-protected
donors. The generality of such an additive on both glycosyl
acceptors and donors was then checked. Either thioglucoside
donor 2 or similar thiogalactoside donor 5 was preactivated in
dry dichloromethane at −72 °C and reacted with a series of
representative glycosyl acceptors 18a−g29,36−41 (Table 3).
Generally, excellent α-selectivities were obtained in moderate to
high yields by using BF3·OEt2 as additive in the glycosylation
reactions. In most cases, 0.2 equiv of BF3·OEt2 was quite
enough, except for the coupling of donor 2 or 5 with acceptor
18d (2 equiv, entries 4 and 10) as well as the coupling of donor
2 with 18g (1 equiv, entry 7). We reasoned that the good
α-selectivities resulted from the Lewis acid-mediated anomeri-
zation of the β-glycosidic bonds to the α-linked ones, which are
thermodynamically favored. That is, even α/β mixtures were
obtained at first, β-linked disaccharides anomerized immedi-
ately through endocyclic C1−O5 bond cleavage assisted by
Lewis acid BF3·OEt2. It seemed that both 2,3-O-carbonate
group and Lewis acid are determining factors in this case. It is
worth mentioning that the β-configuration of the glycosidic
bond at the anomeric carbon of acceptor 18f was kept during
the process of glycosylation and anomerization of new
glycosidic bond (entries 6 and 12). Meanwhile, we realized
that the cleavage of the exocyclic C−O bond, which is the
glycosidic bond of the product, might occur competitively. This
may be explained by the fact that the use of even catalytic
amounts of BF3·OEt2 in the coupling of donor 2 or 5 with
acceptor 18c led to disaccharide 24 or 29 (entries 3 and 9) in
poor yield (less than 10%). The newly formed α-1,4-glycosidic
bond in both cases might be sensitive to Lewis acid and easily
cleaved. However, unlike the others, the α-selectivities of both
glycosylations were good even without any additives, perhaps
due to the less nucleophilic property of 4-OH in the acceptor
or the in situ anomerization under the mild acidic reaction
conditions.
One limitation of the 4,6-O-acetyl-protected donor was its
lower reactivity due to the “disarming” effects of both acetyl
groups and carbonate group. Thus, moderate yield was
achieved in the coupling reaction of donor 2 with the less
nucleophilic acceptor 18b (entry 2, Table 3). Therefore, we
decided to extend the Lewis acid-assisted α-selective glyco-
sylation protocol to the more reactive 4,6-O-benzyl-protected
donor 3. According to our preliminary investigation (entry 3,
Table 1), which is consistent with the reported work by Crich
et al.,18c the glycosylation of donor 3 without any additive is
β-selective. Hopefully the initially formed β-glycosidic bond
could anomerize to the α-bond in the presence of proper Lewis
acid, making the stereoselectivities of this donor toward
glycosylations controllable just by modulating the additive.
The coupling of donor 3 with acceptor 18a was chosen as the
model reaction, and the effects of different Lewis acids on the
stereochemical outcome were investigated (Table 4). First,
Lewis acids such as BF3·OEt2 (entries 2−5), AgBF4 (entries 6−
7), and AgPF6 (entries 8−9), which were quite effective
α-directing additives in the glycosylations of donor 2 or 5, were
checked. It was found that good α-stereoselectivity was
obtained only when a large amount of BF3·OEt2 was used,
and the yield was moderate (entry 5). So we got a hint that the
electron-donating effects of benzyl groups at 4,6-OH resulted in
reduced tendency of anomerization from the initially formed
disaccharide 20β to its anomer 20α. During the process of
searching for a more powerful Lewis acid as our α-directing
additive, we found that strong Lewis acids such as TiCl4
(entries 10−11), HfCl4 (entry 12), BCl3 (entry 13), and
GaCl3 (entry 23) only gave rise to the cleavage of glycosidic
bonds or debenzylation or decomposition of sugars but did not
assist the anomerization process. Relatively mild ones such as
SnF4 (entry 18) and BiCl3 (entry 24) had no effect at all. Only
the addition of appropriate amount of SnCl4 (entry 14) or
AlCl3 (entry 21) resulted in the total reversal of the
β-stereoselectivity to α-stereoselectivity. Compared with AlCl3,
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Table 4. Effects of Different Lewis Acids on the Stereochemical Outcome in the Glycosylation of Acceptor 18a with Donor 3
SnCl4 performed better, with advantages of less influence on
the coupling yield, fewer side reactions, and smaller amount
needed.
only gave rise to the cleavage of glycosidic bond, leading to
decomposition of the product.
Although the stereoselectivity was quite poor in the case of
similar benzyl-protected thiogalactoside donor 6, we want to
use SnCl4 as additive to improve the α-selectivity through the
same anomerization mechanism, and the results are listed in
Table 6. As expected, the additive worked well. Except for the
coupling of donor 6 with the 4-OH acceptor 18b (entries 3 and
4, from 1.5:1 without any additives to 3:1 with 3 equiv of
SnCl4), the stereoselectivities of all glycosylations were
improved to good to excellent α-selectivities by using SnCl4
as additive.
In the end, in order to support our assumption of the in situ
anomerization process, β-disaccharide 19β and 20β were
treated with a catalytic amount of BF3·OEt2 or a stoichiometric
amount of SnCl4 at −72 °C in dichloromethane, respectively
(Scheme 3). The reaction mixture was allowed to warm up to
room temperature, and an efficient anomerization was
observed, providing the α-linked disaccharides 19α and 20α
in around 85% yield. The experimental results demonstrated
that the anomerization indeed occurred after the glycosylation,
probably through an endocyclic C−O bond cleavage assisted by
the Lewis acid.
Because of the good performance of its α-directing effect in
the glycosylation of donor 3, we next investigated the generality
of SnCl4 as additive. As we reasoned the total reversal of
β-selectivity to α-selectivity may come from the endocyclic
C−O bond cleavage assisted by SnCl4, we slightly optimized
the protocol this time. Acceptor was added after donor 3 was
preactivated completely by BSM/Tf2O at −72 °C, and then the
reaction mixture was warmed slowly to accomplish the new
glycosidic bond formation. After the full consumption of
acceptor and the formation of disaccharide (usually at low
temperature below −20 °C) as indicated by TLC monitoring,
SnCl4 (neat liquid) was then added to perform the
anomerization process. As shown in Table 5, in most cases,
1−3 equiv of SnCl4 worked well as an effective α-directing
additive in the couplings of donor 3 with different acceptors
18a−g. In this way, the stereochemical outcome of donor 3
toward glycosylations can be modulated by means of additive,
that is, β-selectivity was obtained in the absence of SnCl4
whereas α-selectivity was obtained in the presence of it.
However, this protocol did not work well in the coupling
reactions of donor 3 with the 4-OH acceptors 18b and 18c
(entries 4 and 6). No stereoselectivity was observed when even
5 equiv of SnCl4 was used in the glycosylation of acceptor 18b
with donor 3. In the case of acceptor 18c, the presence of SnCl4
CONCLUSION
In this context, we developed a Lewis acid mediated α-stereo-
selective glycosylation protocol of 2,3-O-carbonate-protected
■
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Table 5. Additive SnCl4-Controlled Stereoselective Glycosylations of Different Acceptors 18a−g with Donor 3
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Table 5. continued
Table 6. SnCl4-Mediated α-Selective Glycosylations of Different Acceptors 18a,b,d,e with Donor 6
thioglucoside and thiogalactoside donors based on preactiva-
tion strategy. BF3·OEt2 was found to be an effective α-directing
additive in the glycosylations of a series of representative
acceptors with 4,6-di-O-acetyl-2,3-O-carbonate-protected thio-
glucoside donor 2 and thiogalactoside donor 5. Poor
stereoselectivities were greatly improved to nearly α-only
selectivities by the addition of catalytic amount of BF3·OEt2.
Meanwhile, the β-stereoselectivity of 4,6-di-O-benzyl-2,3-O-
carbonate-protected thioglucoside donor 3 toward glycosyla-
tions with different acceptors was totally reversed to the
α-selectivity by the use of stoichiometric Lewis acid SnCl4 as
additive, making the stereochemical outcome predictable and
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p-Tolyl 4,6-O-Benzylidene-2,3-di-O-p-methoxybenzyl-1-thio-β-D-
glucopyranoside (8). Compound 7 (10.0 g, 26.7 mmol) was dissolved
in dry DMF (100 mL) and stirred at −15 °C, and NaH (4.28 g,
107 mmol, 60% w/w in mineral oil) was added in three portions,
followed by the dropwise addition of p-methoxybenzyl chloride
(10.9 mL, 80.2 mmol). After being stirred for 30 min at −15 °C, the
reaction mixture was warmed to room temperature and stirred for 6 h.
The reaction mixture was poured into ice-cooled water and extracted
with dichloromethane (2 × 200 mL). The combined organic layer was
dried, filtered, and concentrated under reduced pressure. The residue
was purified through recrystallization in petroleum ether/ethyl acetate
to give 8 (14.4 g, 88%) as a foam: Rf = 0.5 (petroleum ether/ethyl
acetate, 2:1); [α]D −2.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.25−7.50 (m, 11H), 7.11 (d, 1H, J = 8.1 Hz), 6.82−6.90 (m, 4H),
5.57 (s, 1H), 4.86 (d, 1H, J = 10.8 Hz), 4.79 (d, 1H, J = 10.2 Hz), 4.73
(d, 1H, J = 9.9 Hz), 4.71 (d, 1H, J = 10.8 Hz), 4.66 (d, 1H, J = 9.6
Hz), 4.37 (dd, 1H, J = 5.1, 10.5 Hz), 3.81 (s, 3H), 3.78 (s, 3H), 3.68−
3.81 (m, 2H), 3.65 (t, 1H, J = 9.3 Hz), 3.38−3.47 (m, 2H), 2.34 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 159.2, 138.0, 137.2,
132.9, 130.4, 130.2, 129.8, 129.71, 129.68, 129.1, 128.9, 128.2, 125.9,
113.73, 113.72, 101.0, 88.4, 82.6, 81.4, 80.0, 75.4, 74.9, 70.1, 68.6,
55.22, 55.17, 21.1; HRMS (ESI) calcd for C36H39O7S [M + H]+
615.2411, found 615.2436.
Scheme 3. Anomerization Reaction of β-Disaccharides 19β
and 20β
controllable. For the similar thiogalactoside donor 6, poor
stereoselectivities in glycosylations were also improved by
adding SnCl4. It was suggested that the good α-selectivities in
all cases may come from one mechanism, that is, no matter
what the initial stereoselectivities are, the newly formed
β-glycosidic bonds in the glycosylations of such donors can
anomerize to their thermodynamically more stable α-anomers,
through the endocyclic C−O bond cleavage assisted by an
appropriate Lewis acid. It is worth to mention that, the
anomerization process relies on the conformation-constraining
2,3-O-carbonate group, just like the 2,3-N,O-oxazolidinone
group in the glucosamine and galactosamine donors reported
before. Further exploration of new additives which may
modulate the stereoselectivity of glycosylations, and the
extension of this protocol to other types of sugars is still
under investigation.
p-Tolyl 2,3-Di-O-p-methoxybenzyl-1-thio-β-D-glucopyranoside
(9). p-TsOH (2.75 g, 16.0 mmol) was added to the solution of
compound 8 (14.0 g, 22.8 mmol) in 200 mL of dichloromethane−
methanol (v/v = 1:1). The reaction mixture was stirred at rt for 5 h,
neutralized with Et3N (2 mL), and concentrated to dryness under
reduced pressure. The residue was purified by column chromatog-
raphy (petroleum ether/acetone, 1:1) to give 9 (10.8 g, 90%) as a
foam: Rf = 0.1 (petroleum ether/ethyl acetate, 1:1). Compound 9 was
used for the next reaction directly.
EXPERIMENTAL SECTION
■
General Methods. All chemicals were purchased as reagent grade
and used without further purification, unless otherwise noted.
Dichloromethane, pyridine, and DMF were distilled over calcium
hydride. Methanol was distilled from magnesium. All reactions were
carried out under anhydrous conditions with freshly distilled solvents,
unless otherwise noted. Reactions were monitored by analytical thin-
layer chromatography on silica gel 60 F254 precoated on aluminum
plates. Spots were detected under UV (254 nm) and/or by staining
with acidic ceric ammonium molybdate. Solvents were evaporated
under reduced pressure and below 40 °C (bath). Column
p-Tolyl 4,6-Di-O-acetyl-2,3-di-O-p-methoxybenzyl-1-thio-β-D-
glucopyranoside (10). To a stirred solution of compound 9 (5.00 g,
9.50 mmol) in pyridine (50 mL) with a catalytic amount of DMAP
was added acetic anhydride (9.00 mL, 95.0 mmol) at 0 °C. The
reaction mixture was warmed to room temperature, stirred for 3 h, and
then concentrated under reduced pressure. The residue was purified
by column chromatography (petroleum ether/ethyl acetate, 3:1) to
give 10 (5.80 g, 100%) as a foam: Rf = 0.25 (petroleum ether/ethyl
1
acetate, 1.5:1); H NMR (300 MHz, CDCl3) δ 7.47 (d, 2H, J = 8.1
Hz), 7.34 (d, 2H, J = 8.7 Hz), 7.09−7.18 (m, 4H), 6.84−6.90 (m, 4H),
4.99 (t, 1H, J = 9.6 Hz), 4.82 (d, 1H, J = 9.9 Hz), 4.75 (d, 1H, J = 11.1
Hz), 4.64 (d, 1H, J = 9.6 Hz), 4.57 (d, 1H, J = 11.4 Hz), 4.57 (d, 1H,
J = 9.9 Hz), 4.20 (dd, 1H, J = 5.4, 12.0 Hz), 4.10 (dd, 1H, J = 2.7, 12.3
Hz), 3.81 (s, 3H), 3.79 (s, 3H), 3.61 (t, 1H, J = 9.0 Hz), 3.52−3.56
(m, 1H), 3.48 (t, 1H, J = 8.7 Hz), 2.34 (s, 3H), 2.08 (s, 3H), 1.93 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 170.7, 169.6, 159.4, 159.2, 138.1,
132.9, 130.2, 130.0, 129.6, 129.4, 129.3, 113.84, 113.82, 87.8, 83.4,
80.2, 75.8, 75.2, 75.0, 69.8, 63.6, 55.3 (2C), 21.1, 20.8 (2C); HRMS
(ESI) calcd for C33H38O9SNa [M + Na]+ 633.2129, found 633.2147.
p-Tolyl 4,6-Di-O-acetyl-1-thio-β-D-glucopyranoside (11). TFA
(20 mL) was added to the solution of compound 10 (5.80 g, 9.50 mmol)
in 100 mL of dichloromethane at −20 °C. The reaction mixture was
stirred at the same temperature for 30 min, diluted with dichloro-
methane, quenched with 100 mL of saturated NaHCO3, and extracted
with dichloromethane (2 × 120 mL). The combined organic layer was
dried, filtered and concentrated under reduced pressure. The residue
was purified by column chromatography (petroleum ether/ethyl
acetate, 1:2) to give 11 (3.41 g, 97%) as a foam: Rf = 0.1 (petroleum
ether/ethyl acetate, 1:1.5). Compound 11 was used for the next
reaction directly.
1
chromatography was performed on silica gel (200−300 mesh). H
NMR spectra were recorded on a spectrometer. Chemical shifts (in
ppm) were referenced to tetramethylsilane (δ = 0 ppm) in deuterated
chloroform. 13C NMR spectra were obtained by using the same NMR
spectrometers and were calibrated with CDCl3 (δ = 77.00 ppm). Mass
spectra were recorded using a spectrometer. Elemental analysis data
were recorded on an elemental analyzer.
Preparation of 2,3-O-Carbonate-Protected Glycosyl Donors
1−6. p-Tolyl 4,6-O-Benzylidene-2,3-O-carbonyl-1-thio-β-D-gluco-
pyranoside (1). Triphosgene (0.94 g, 3.21 mmol) in 5 mL of
dichloromethane was added dropwise to a solution of p-tolyl 4,6-O-
benzylidene-1-thio-β-D-glucopyranoside27 (2.00 g, 5.35 mmol) and
pyridine (2.6 mL) in dichloromethane (25 mL) at −20 °C. The
reaction mixture was stirred vigorously for 30 min at the same
temperature. After consumption of the starting material by TLC
detection, the reaction was quenched by satd NH4Cl solution (20 mL)
and extracted with dichloromethane (2 × 25 mL). The combined
organic layer was dried, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(petroleum ether/acetone, 6:1) to give 1 (1.73 g, 81%) as a foam:
Rf = 0.2 (petroleum ether/ethyl acetate, 2:1); [α]D −16.0 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.43−7.48 (m, 4H), 7.35−
p-Tolyl 4,6-Di-O-acetyl-2,3-O-carbonyl-1-thio-β-D-glucopyrano-
side (2). Triphosgene (0.95 g, 3.24 mmol) in 5 mL of dichloromethane
was added dropwise to the solution of compound 11 (2.00 g,
5.40 mmol) and pyridine (2.61 mL, 32.4 mmol) in dichloromethane
(25 mL) at −20 °C. The reaction mixture was stirred vigorously for
about 20−30 min at the same temperature. After most of the starting
material was consumed by TLC detection, the reaction was quenched
by satd NH4Cl aqueous solution (20 mL) and extracted with
7.38 (m, 3H), 7.18 (d, 2H, J = 8.0 Hz), 5.55 (s, 1H), 4.89 (d, 1H, J =
9.6 Hz), 4.46 (dd, 1H, J = 10.0, 10.8 Hz), 4.40 (dd, 1H, J = 4.8, 10.8
Hz), 3.93 (dd, 1H, J = 8.4, 9.6 Hz), 3.88 (t, 1H, J = 10.0 Hz), 3.83 (dd,
1H, J = 9.6, 10.8 Hz), 5.57−3.61 (m, 1H), 2.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 152.5, 140.0, 136.0, 135.3, 130.0, 129.4, 128.4,
126.0, 124.7, 101.3, 83.6, 80.8, 78.3 (2C), 72.8, 68.2, 21.2; HRMS
(ESI) calcd for C21H20O6SNa [M + Na]+ 423.0873, found 423.0875.
5264
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Article
dichloromethane (2 × 25 mL). The combined organic layer was dried,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (petroleum ether/ethyl acetate,
3:1 to 1:2) to give 2 (1.63 g, 76%) as a foam and the recovered starting
material 11. Compound 2: Rf = 0.2 (petroleum ether/ethyl acetate,
1.5:1); [α]D −8.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48
(d, 2H, J = 8.0 Hz), 7.16 (d, 2H, J = 8.0 Hz), 5.17 (t, 1H, J = 9.6 Hz),
4.83 (d, 1H, J = 9.2 Hz), 4.34 (t, 1H, J = 10.0 Hz), 4.29 (dd, 1H, J =
2.0, 12.4 Hz), 4.18 (dd, 1H, J = 4.4, 12.4 Hz), 3.81 (dd, 1H, J = 9.6,
11.2 Hz), 3.76 (td, 1H, J = 2.4, 4.4 Hz), 2.38 (s, 3H), 2.11 (s, 3H),
2.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.4, 168.9, 152.2,
140.1, 135.6, 129.9, 124.2, 82.3, 81.9, 77.1, 75.6, 67.2, 61.6, 21.2, 20.7,
20.5; MS (ESI) 397 [M + H]+. Anal. Calcd for C18H20O8S: C, 54.54;
H, 5.09. Found: C, 54.34; H, 5.07.
p-Tolyl 4,6-Di-O-benzyl-2,3-di-O-p-methoxybenzyl-1-thio-β-D-
glucopyranoside (12). NaH (1.52 g, 38.0 mmol, 60% w/w in mineral
oil) was added in two portions to the solution of compound 9 (5.00 g,
9.50 mmol) in DMF (60 mL) at −15 °C, followed by the dropwise
addition of benzyl bromide (4.00 mL, 33.3 mmol). After being stirred
for 30 min at the same temperature, the reaction mixture was warmed
to room temperature, stirred for 3 h, then poured into ice-cooled
water. The aqueous layer was extracted with dichloromethane (2 ×
100 mL). The combined organic layer was dried, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (petroleum ether/ethyl acetate, 10:1) to give
12 (6.30 g, 94%) as a foam: Rf = 0.6 (petroleum ether/ethyl acetate,
2:1); 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 2H, J = 8.0 Hz), 7.19−
7.36 (m, 14H), 7.02 (d, 2H, J = 8.0 Hz), 6.82−6.89 (m, 4H), 4.84 (d,
1H, J = 10.8 Hz), 4.82 (d, 1H, J = 10.4 Hz), 4.77 (d, 1H, J = 10.4 Hz),
4.67 (d, 1H, J = 9.6 Hz), 4.56−4.60 (m, 3H), 4.52 (d, 1H, J = 12.0
Hz), 3.79 (s, 3H), 3.78 (s, 3H), 3.76 (d, 1H, J = 1.6 Hz), 3.71 (dd, 1H,
J = 4.8, 10.8 Hz), 3.67 (t, 1H, J = 8.8 Hz), 3.60 (t, 1H, J = 9.2 Hz),
3.43−3.47 (m, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
159.3, 159.2, 138.3, 138.1, 137.6, 132.6, 130.6, 130.3, 129.8, 129.6,
129.4, 128.4, 128.3, 127.8, 127.7, 127.6, 127.4, 113.8, 87.6, 86.4, 80.5,
79.0, 77.8, 75.4, 75.0, 73.3, 69.0, 55.23, 55.21, 21.1; HRMS (ESI) calcd
for C43H46O7SNa [M + Na]+ 729.2856, found 729.2859.
Hz), 4.76 (d, 1H, J = 11.6 Hz), 4.58 (d, 1H, J = 12.0 Hz), 4.50 (d, 2H,
J = 11.6 Hz), 4.32 (dd, 1H, J = 10.0, 11.2 Hz), 3.87 (t, 1H, J = 9.6 Hz),
3.73−3.80 (m, 3H), 3.58−3.62 (m, 1H), 2.32 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 153.0, 139.5, 138.0, 136.8, 135.2, 129.8, 128.4, 128.3,
128.1, 128.0, 127.7, 127.6, 125.1, 85.4, 82.3, 80.1, 76.1, 73.6, 73.5, 72.9,
68.2, 21.2; HRMS (ESI) calcd for C28H28O6S Na [M + Na]+ 515.1499,
found 515.1500.
Donors 4−6 were prepared starting from galactoside derivative
14,28 following the same procedure as described in the preparation of
donors 1-3.
p-Tolyl 4,6-O-Benzylidene-2,3-O-carbonyl-1-thio-β-D-galactopyr-
anoside (4). The crude product was purified by column chromatog-
raphy (petroleum ether/ethyl acetate, 3:1) to give 4 (83%) as a foam:
1
Rf = 0.3 (petroleum ether/ethyl acetate, 1:1); H NMR (300 MHz,
CDCl3) δ 7.58−7.60 (m, 2H), 7.27−7.41 (m, 5H), 7.15 (d, 1H, J = 7.8
Hz), 5.52 (s, 1H), 4.90 (d, 1H, J = 9.3 Hz), 4.58−4.59 (m, 1H), 4.41−
4.50 (m, 2H), 4.35 (dd, 1H, J = 2.4, 10.4 Hz), 4.09 (dd, 1H, J = 1.5,
12.6 Hz), 3.64 (d, 1H, J = 1.2 Hz), 2.38 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 152.6, 139.6, 136.7, 135.8, 129.9, 129.5, 128.2, 126.4, 124.4,
100.7, 82.9, 81.1, 72.4, 71.7, 69.9, 69.7, 21.3; HRMS (ESI) calcd for
C21H20O6SNa [M + Na]+ 423.0873, found 423.0886.
p-Tolyl 4,6-Di-O-acetyl-1-thio-β-D-galactopyranoside (16).
Through acetylation and removal of p-methoxybenzyl groups, compound
16 was prepared from the known compound 15.42 The crude product
was purified by column chromatography (petroleum ether/ethyl
acetate, 1:1) to give 16 (93%, two steps) as a foam: Rf = 0.1
(petroleum ether/ethyl acetate, 1:1.5); 1H NMR (300 MHz, CDCl3) δ
7.47 (d, 2H, J = 7.8 Hz), 7.13 (d, 2H, J = 8.1 Hz), 5.34 (d, 1H, J = 3.0
Hz), 4.50 (d, 1H, J = 9.6 Hz), 4.16 (d, 2H, J = 6.9 Hz), 3.80−3.90 (m,
2H), 3.65 (t, 1H, J = 9.0 Hz), 2.58 (s, 1H), 2.56 (s, 1H), 2.35 (s, 3H),
2.11 (s, 3H), 2.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.1,
170.6, 138.4, 133.0, 129.7, 128.2, 88.8, 74.7, 73.2, 69.6, 69.4, 62.2, 21.1,
20.7(2C); HRMS (ESI) calcd for C17H22O7SNa [M + Na]+ 393.0978,
found 393.0980.
p-Tolyl 4,6-Di-O-acetyl-2,3-O-carbonyl-1-thio-β-D-galactopyra-
noside (5). The crude product was purified by column chromatog-
raphy (petroleum ether/ethyl acetate, 5:1) to give 5 (75%) as a foam:
Rf = 0.3 (petroleum ether/ethyl acetate, 1.5:1); [α]D −9.6 (c 2.4,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H, J = 8.0 Hz), 7.16
(d, 2H, J = 8.0 Hz), 5,62 (dd, 1H, J = 1.2, 2.0 Hz), 4.90 (d, 1H, J = 9.6
Hz), 4.40 (dd, 1H, J = 2.4, 11.2 Hz), 4.30 (dd, 1H, J = 9.2, 11.2 Hz),
4.18 (d, 2H, J = 6.4 Hz), 4.04 (td, 1H, J = 1.2, 7.2 Hz), 2.37 (s, 3H),
2.10 (s, 3H), 2.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.3,
169.1, 152.2, 139.6, 134.6, 129.8, 125.8, 84.5, 80.2, 75.5, 74.0, 65.5,
61.3, 21.2, 20.6, 20.4; MS (ESI) 397 [M + H]+. Anal. Calcd for
C18H20O8S: C, 54.54; H, 5.09. Found: C, 54.28; H, 5.10.
p-Tolyl 4,6-Di-O-benzyl-1-thio-β-D-galactopyranoside (17).
Through benzylation and removal of p-methoxybenzyl groups,
compound 17 was prepared from the known intermediate 15. The
crude product was purified by column chromatography (petroleum
ether/ethyl acetate, 1.5:1) to give 17 (82%, two steps) as a foam: Rf =
0.1 (petroleum ether/ethyl acetate, 1.5:1); [α]D −5.0 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.44 (d, 2H, J = 8.0 Hz), 7.25−7.36
p-Tolyl 4,6-Di-O-benzyl-1-thio-β-D-glucopyranoside (13). Com-
pound 12 (3.00 g, 4.25 mmol) was resolved in the mixed solution of
dichloromethane (80 mL) and water (8 mL), followed by the addition
of DDQ (5.79 g, 25.5 mmol) at room temperature. The reaction
mixture was stirred for 1 h, quenched by 100 mL of saturated
NaHCO3, and extracted with dichloromethane (2 × 120 mL). The
combined organic layer was dried, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (petroleum ether/ethyl acetate, 1.5:1) to give 13 (1.74 g, 88%)
1
as a foam: Rf = 0.1 (petroleum ether/ethyl acetate, 1.5:1); H NMR
(300 MHz, CDCl3) δ 7.46 (d, 2H, J = 8.1 Hz), 7.26−7.36 (m, 10H),
7.06 (d, 2H, J = 8.1 Hz), 4.77 (d, 1H, J = 11.1 Hz), 4.63 (d, 1H, J =
12.0 Hz), 4.62 (d, 1H, J = 11.4 Hz), 4.55 (d, 1H, J = 12.0 Hz), 4.43 (d,
1H, J = 9.9 Hz), 3.66−3.82 (m, 3H), 3.45−3.50 (m, 2H), 3.32 (t, 1H,
J = 9.0 Hz), 2.68 (br.s, 1H), 2.60 (br.s, 1H), 2.32 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 138.4, 138.2, 138.1, 133.5, 129.7, 128.5, 128.3,
128.0, 127.9, 127.7, 127.6, 87.8, 79.1, 78.1, 77.1, 74.6, 73.4, 71.9, 69.0,
21.1; HRMS (ESI) calcd for C27H30O5SNa [M + Na]+ 489.1706,
found 489.1713.
(m, 10H), 7.06 (d, 2H, J = 8.0 Hz), 4.72 (d, 1H, J = 11.6 Hz), 4.67 (d,
1H, J = 11.6 Hz), 4.53 (d, 1H, J = 11.6 Hz), 4.47 (d, 1H, J = 12.0 Hz),
4.44 (d, 1H, J = 9.2 Hz), 3.91 (d, 1H, J = 3.2 Hz), 3.59−3.73 (m, 5H),
2.51 (d, 1H, J = 8.0 Hz), 2.36−2.40 (m, 1H), 2.32 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 138.4, 137.9, 137.8, 132.7, 129.6, 128.6, 128.4,
128.3, 127.8, 127.63, 127.56, 88.6, 77.5, 76.0, 75.3, 74.9, 73.5, 70.2,
68.5, 21.1; HRMS (ESI) calcd for C27H30O5SNa [M + Na]+ 489.1706,
found 489.1708.
p-Tolyl 4,6-Di-O-benzyl-2,3-O-carbonyl-1-thio-β-D-glucopyrano-
side (3). Triphosgene (0.64 g, 2.20 mmol) in 3 mL of dichloromethane
was added dropwise to the solution of compound 13 (1.70 g,
3.65 mmol) and pyridine (1.76 mL, 22.0 mmol) in dichloromethane
(20 mL) at −20 °C. The reaction mixture was stirred vigorously for
about 20 min. After the starting material was completely consumed by
TLC detection, the reaction was quenched by 15 mL of satd NH4Cl
solution and extracted with dichloromethane (2 × 20 mL). The
combined organic layer was dried, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (petroleum ether/ethyl acetate, 8:1) to give 3 (1.54 g, 86%) as a
foam: Rf = 0.5 (petroleum ether/ethyl acetate, 2:1); [α]D 2.0 (c 1.0,
p-Tolyl 4,6-Di-O-benzyl-2,3-O-carbonyl-1-thio-β-D-galactopyra-
noside (6). The crude product was purified by column chromatog-
raphy (petroleum ether/ethyl acetate, 8:1) to give 6 (83%) as a foam:
Rf = 0.4 (petroleum ether/ethyl acetate, 2:1); [α]D −11.0 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H, J = 8.0 Hz),
7.25−7.35 (m, 8H), 7.19−7.21 (m, 2H), 7.10 (d, 2H, J = 8.0 Hz), 4.82
(d, 1H, J = 9.6 Hz), 4.75 (d, 1H, J = 12.0 Hz), 4.43−4.53 (m, 4H),
4.30 (dd, 1H, J = 2.0, 11.2 Hz), 4.22 (s, 1H), 3.80 (t, 1H, J = 6.0 Hz),
3.62−3.69 (m, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H, J = 8.0 Hz),
7.22−7.37 (m, 10H), 7.06 (d, 2H, J = 8.0 Hz), 4.77 (d, 1H, J = 10.0
5265
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152.8, 139.1, 137.6, 137.1, 134.3, 129.8, 128.4, 128.3, 127.90, 127.86,
127.7, 127.6, 126.4, 84.4, 83.2, 78.2, 74.2, 73.60, 73.56, 71.9, 68.0, 21.2;
MS (ESI) 515 [M + Na]+. Anal. Calcd for C28H28O6S: C, 68.27; H,
5.73. Found: C, 68.24; H, 5.62.
HRMS (ESI) calcd for C39H44O14Na [M + Na]+ 759.2623, found
759.2625.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→2)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (25α). The coupling
of donor 2 with acceptor 18d38 afforded 25α (70%, α/β > 20:1) as a
colorless glassy solid: Rf = 0.5 (petroleum ether/ethyl acetate, 1:1);
[α]D +10.0 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25−7.35
(m, 13H), 7.11−7.12 (m, 2H), 5.34 (d, 1H, J = 2.8 Hz), 5.24 (t, 1H,
J = 10.0 Hz), 4.98 (d, 1H, J = 11.2 Hz), 4.87 (d, 1H, J = 3.6 Hz),
4.75−4.80 (m, 2H), 4.67 (d, 1H, J = 11.2 Hz), 4.64 (d, 1H, J = 12.0
Hz), 4.53 (d, 1H, J = 10.8 Hz), 4.51 (d, 1H, J = 12.0 Hz), 4.24 (dd,
1H, J = 2.8, 11.2 Hz), 3.84−4.02 (m, 5H), 3.67−3.79 (m, 4H), 3.42 (s,
3H), 2.03 (s, 3H), 1.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.4, 168.8, 152.5, 138.2, 137.80, 137.76, 128.4, 127.9, 127.8, 127.7,
127.1, 96.5, 92.4, 80.0, 78.4, 76.74, 76.68, 76.6, 76.4, 75.4, 75.0, 70.3,
70.1, 68.2, 67.6, 60.7, 55.4, 20.6, 20.5; HRMS (ESI) calcd for
C39H44O14K [M + K]+ 775.2363, found 775.2362.
General Procedure for the BF3·OEt2-Mediated α-Selective
Glycosylations of Donor 2 or 5 with Acceptors 18a−g. Triflic
anhydride (10.2 μL, 0.060 mmol, 1.4 equiv) was added to a stirred
solution of 2 or 5 (22.2 mg, 0.056 mmol, 1.3 equiv), Ph2SO (2.2 mg,
0.060 mmol, 1.4 equiv), and activated 4 Å molecular sieves (300 mg)
in dichloromethane (3.0 mL) at −72 °C under nitrogen atmosphere.
The reaction mixture was stirred for 3−5 min. After disappearance of
donor detected by TLC, a solution of the acceptor alcohol 18a
(20.0 mg, 0.043 mmol, 1.0 equiv) or 18b−g in dichloromethane (0.2 mL)
was added dropwise to the preactivated system, followed by the
addition of BF3·OEt2. The reaction mixture was stirred and slowly
warmed to room temperature, and then quenched by Et3N (0.1 mL).
The precipitate was filtered off, and the filtrate was concentrated. The
crude product was purified by column chromatography on silica gel to
give the disaccharides. The yields were calculated on the basis of the
isolated products.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→3)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (26α). The coupling
of donor 2 with acceptor 18e39 afforded 26α (78%) as a colorless
glassy solid: Rf = 0.2 (petroleum ether/ethyl acetate, 1.5:1); [α]D
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (19α). The coupling
of donor 2 with acceptor 18a29 afforded 19α (76%, α/β > 20:1) as a
foam: Rf = 0.4 (petroleum ether/ethyl acetate, 1:1); [α]D +23.6 (c 1.4,
1
+18.7 (c 1.5, CHCl3); H NMR (500 MHz, CDCl3) δ 7.25−7.38 (m,
13H), 7.14−7.16 (m, 2H), 5.69 (d, 1H, J = 3.5 Hz), 5.22 (t, 1H, J =
10.0 Hz), 4.82 (d, 1H, J = 3.5 Hz), 4.73 (dd, 1H, J = 10.0, 11.5 Hz),
4.65 (d, 2H, J = 12.0 Hz), 4.62 (d, 1H, J = 11.5 Hz), 4.51 (d, 1H, J =
12.5 Hz), 4.50 (d, 1H, J = 11.5 Hz), 4.48 (d, 1H, J = 10.5 Hz), 4.10−
4.21 (m, 3H), 3.86 (dd, 1H, J = 2.0, 13.0 Hz), 3.65−3.77 (m, 5H),
3.55 (dd, 1H, J = 3.5, 10.0 Hz), 3.38 (s, 3H), 2.07 (s, 3H), 2.03 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 168.9, 152.9, 137.5 (2C),
137.3, 128.6, 128.53, 128.45, 128.40, 128.3, 128.1, 127.9, 127.8, 127.6,
97.1, 94.4, 78.4, 77.5, 77.4, 76.9, 74.6, 73.7, 72.2, 69.9, 69.6, 67.8, 60.7,
55.1, 20.61, 20.58; HRMS (ESI) calcd for C39H44O14Na [M + Na]+
759.2623, found 759.2625.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.28−7.38 (m, 15H), 5.35
(d, 1H, J = 2.8 Hz), 5.28 (t, 1H, J = 10.0 Hz), 5.00 (d, 1H, J = 10.8
Hz), 4.93 (d, 1H, J = 11.6 Hz), 4.80 (d, 2H, J = 11.2 Hz), 4.66 (d, 1H,
J = 12.0 Hz), 4.60 (dd, 1H, J = 10.0, 11.6 Hz), 4.60 (d, 1H, J = 11.6
Hz), 4.56 (d, 1H, J = 3.6 Hz), 4.20 (dd, 1H, J = 2.8, 11.6 Hz), 4.14
(dd, 1H, J = 4.4, 12.4 Hz), 4.09 (td, 1H, J = 2.0, 12.4 Hz), 4.00 (t, 1H,
J = 9.2 Hz), 3.87 (dd, 1H, J = 4.4, 11.6 Hz), 3.74−3.83 (m, 3H), 3.52
(dd, 1H, J = 3.6, 9.6 Hz), 3.46 (t, 1H, J = 9.6 Hz), 3.36 (s, 3H), 2.12
(s, 3H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 168.9,
152.7, 138.6, 138.1, 138.0, 128.5, 128.4, 128.1, 127.9, 127.8, 127.6,
98.1, 94.7, 82.0, 80.1, 76.8, 76.5, 75.7, 74.6, 73.5, 69.9 (2C), 68.1, 67.1,
61.2, 55.3, 20.6, 20.5; MS (ESI) 759 [M + Na]+. Anal. Calcd for
C39H44O14: C, 63.58; H, 6.02. Found: C, 63.54; H, 6.02.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-β-D-glucopyranoside (27α). The coupling
of donor 2 with acceptor 18f40 afforded 27α (75%) as a colorless
glassy solid: Rf = 0.2 (petroleum ether/ethyl acetate, 1.5:1); [α]D
1
+16.7 (c 0.6, CHCl3); H NMR (400 MHz, CDCl3) δ 7.25−7.36 (m,
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (23α). The coupling
of donor 2 with acceptor 18b36 afforded 23α (51%) as a colorless
glassy solid: Rf = 0.4 (petroleum ether/ethyl acetate, 1:1); [α]D +25.0
(c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28−7.34 (m, 15H),
5.86 (d, 1H, J = 3.2 Hz), 5.25 (t, 1H, J = 10.0 Hz), 5.04 (d, 1H, J =
10.4 Hz), 4.75 (d, 1H, J = 12.4 Hz), 4.73 (d, 1H, J = 10.4 Hz), 4.67 (t,
1H, J = 10.0 Hz), 4.63 (d, 1H, J = 12.0 Hz), 4.61 (d, 1H, J = 3.2 Hz),
4.60 (d, 1H, J = 12.0 Hz), 4.54 (d, 1H, J = 12.0 Hz), 4.14 (dd, 1H, J =
3.2, 11.6 Hz), 4.04 (dd, 1H, J = 3.6, 12.4 Hz), 3.96−4.00 (m, 1H),
3.80−3.84 (m, 3H), 3.74−3.77 (m, 1H), 3.67 (d, 2H, J = 2.0 Hz), 3.54
(dd, 1H, J = 3.6, 9.6 Hz), 3.41 (s, 3H), 2.10 (s, 3H), 2.01 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.3, 168.8, 152.7, 138.3, 137.8 (2C),
128.53, 128.46, 128.4, 128.11, 128.06, 127.8, 127.6, 127.4, 97.8, 95.1,
81.2, 80.2, 76.4, 76.3, 75.3, 73.6, 73.3, 70.5, 69.3, 69.1, 68.0, 61.1, 55.5,
20.61, 20.56; HRMS (ESI) calcd for C39H45O14 [M + H]+ 737.2804,
found 737.2803. Anal. Calcd for C39H44O14: C, 63.58; H, 6.02. Found:
C, 63.53; H, 6.17.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→4)-2,3,6-tri-O-benzyl-α-D-galactopyranoside (24α). The cou-
pling of donor 2 with acceptor 18c37 in the absence of BF3·OEt2
afforded 24α (77%) as a colorless oil: Rf = 0.3 (petroleum ether/ethyl
acetate, 1:1); [α]D +13.6 (c 1.1, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.25−7.42 (m, 15H), 5.27 (t, 1H, J = 10.0 Hz), 5.27 (d, 1H,
J = 4.0 Hz), 4.83 (d, 1H, J = 12.0 Hz), 4.80 (d, 1H, J = 12.5 Hz), 4.77
(d, 1H, J = 12.5 Hz), 4.70 (d, 1H, J = 3.5 Hz), 4.70 (d, 1H, J = 11.0
Hz), 4.68 (dd, 1H, J = 10.5, 12.0 Hz), 4.51 (s, 2H), 4.22 (d, 1H, J = 3.0
Hz), 4.10−4.16 (m, 2H), 3.88−3.91 (m, 2H), 3.80−3.85 (m, 2H),
3.59 (t, 1H, J = 9.0 Hz), 3.48 (dd, 1H, J = 5.5, 9.0 Hz), 3.42 (dd, 1H,
J = 2.0, 13.0 Hz), 3.36 (s, 3H), 2.12 (s, 3H), 2.00 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.3, 168.9, 152.8, 138.1, 138.0, 137.3, 128.6,
128.48, 128.46, 128.1, 128.01, 127.95, 127.7, 98.3, 95.7, 77.2, 76.9,
76.0, 75.5, 73.5, 73.3, 73.0, 69.9, 67.74, 67.68, 66.7, 60.4, 55.5, 20.6;
15H), 5.39 (d, 1H, J = 2.8 Hz), 5.31 (t, 1H, J = 10.0 Hz), 4.96 (d, 1H,
J = 11.2 Hz), 4.91 (d, 1H, J = 10.8 Hz), 4.89 (d, 1H, J = 11.6 Hz), 4.78
(d, 1H, J = 11.2 Hz), 4.71 (d, 1H, J = 10.8 Hz), 4.65 (dd, 1H, J = 10.4,
11.6 Hz), 4.59 (d, 1H, J = 11.6 Hz), 4.31 (d, 1H, J = 7.6 Hz), 4.18−
4.25 (m, 2H), 4.12 (dd, 1H, J = 2.0, 12.4 Hz), 3.87−3.91 (m, 2H),
3.82 (dd, 1H, J = 4.8, 11.6 Hz), 3.67 (t, 1H, J = 8.8 Hz), 3.55 (s, 3H),
3.46−3.47 (m, 2H), 3.41 (dd, 1H, J = 8.0, 9.2 Hz), 2.11 (s, 3H), 2.08
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.4, 168.9, 152.7, 138.4,
138.3, 137.9, 128.5, 128.40, 128.39, 128.1, 127.99, 127.97, 127.9,
127.71, 127.68, 104.7, 94.5, 84.6, 82.2, 77.0. 76.9, 76.5, 75.6, 74.8, 74.7,
74.2, 70.0, 68.0, 67.0, 61.2, 57.1, 20.7, 20.5; HRMS (ESI) calcd for
C39H44O14Na [M + Na]+ 759.2623, found 759.2640.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→6)-2,3,4-tri-O-benzoyl-α-D-glucopyranoside (28α). The coupling
of donor 2 with acceptor 18g41 afforded 28α (55%) as a foam: Rf = 0.3
1
(petroleum ether/ethyl acetate, 1:1); H NMR (400 MHz, CDCl3) δ
7.89−7.99 (m, 4H), 7.54−7.87 (m, 2H), 7.43−7.53 (m, 2H), 7.36−
7.42 (m, 5H), 7.28−7.32 (m, 2H), 6.16 (t, 1H, J = 9.6 Hz), 5.62 (t,
1H, J = 10.0 Hz), 5.33 (d, 1H, J = 3.2 Hz), 5.23−5.31 (m, 3H), 4.89
(dd, 1H, J = 10.0, 11.2 Hz), 3.92−4.35 (m, 6H), 3.81 (dd, 1H, J = 2.0,
11.2 Hz), 3.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 169.1,
166.4, 165.3, 165.1, 152.7, 133.6, 133.4, 133.0, 129.9, 129.7, 129.6,
129.2, 129.1, 128.9, 128.8, 128.5, 128.2, 99.0, 94.9, 78.0, 76.8, 74.1,
72.7, 69.9, 68.0, 67.8, 65.9, 65.5, 62.0, 56.2, 20.7, 20.5; HRMS (ESI)
calcd for C39H39O17 [M + H]+ 779.2182, found 779.2182.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-galactopyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (21α). The coupling
of donor 5 with acceptor 18a afforded 21α (81%) as a colorless glassy
solid: Rf = 0.4 (petroleum ether/ethyl acetate, 1:1); [α]D +20.0 (c 0.7,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28−7.39 (m, 15H), 5.56 (s,
1H), 5.35 (d, 1H, J = 2.4 Hz), 5.00 (d, 1H, J = 10.8 Hz), 4.90 (d, 1H,
J = 11.2 Hz), 4.80 (d, 1H, J = 10.8 Hz), 4.80 (d, 1H, J = 12.4 Hz), 4.66
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Article
(d, 1H, J = 12.0 Hz), 4.61 (dd, 1H, J = 2.4, 12.0 Hz), 4.59 (d, 1H, J =
11.6 Hz), 4.56 (d, 1H, J = 3.6 Hz), 4.55 (dd, 1H, J = 2.8, 12.0 Hz),
4.12 (dd, 1H, J = 5.6, 10.4 Hz), 3.97−4.06 (m, 3H), 3.73−3.85 (m,
3H), 3.51 (dd, 1H, J = 3.2, 9.6 Hz), 3.43 (t, 1H, J = 10.0 Hz), 3.36 (s,
3H), 2.14 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.2, 169.1, 152.1, 138.6, 138.14, 138.06, 128.5, 127.9, 127.8, 127.6,
98.0, 95.6, 82.0, 80.1, 76.9, 75.7, 74.6, 74.2, 74.1, 73.5, 69.8, 68.3, 67.2,
66.6, 61.3, 55.3, 20.6, 20.5; HRMS (ESI) calcd for C39H45O14 [M +
H]+ 737.2804, found 737.2804. Anal. Calcd for C39H44O14: C, 63.58;
H, 6.02. Found: C, 63.30; H, 6.17.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-galactopyranosyl)-
(1→4)-2,3,6-tri-O-benzyl-α-D-galactopyranoside (29α). The cou-
pling of donor 5 with acceptor 18c in the absence of BF3·OEt2
afforded major product 29α (75%, α/β = 15:1) as a colorless oil: Rf =
0.3 (petroleum ether/ethyl acetate, 1.5:1); [α]D +18.3 (c 1.2, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.29−7.40 (m, 15H), 5.55 (s, 1H),
5.29 (d, 1H, J = 2.4 Hz), 4.76−4.81 (m, 3H), 4.67−4.73 (m, 3H),
4.47−4.54 (m, 3H), 4.37 (t, 1H, J = 7.6 Hz), 4.19 (d, 1H, J = 2.4 Hz),
3.94 (t, 1H, J = 10.8 Hz), 3.86−3.89 (m, 2H), 3.77 (dd, 1H, J = 3.2,
10.0 Hz), 3.58 (t, 1H, J = 9.2 Hz), 3.49 (dd, 1H, J = 5.6, 8.8 Hz), 3.41
(dd, 1H, J = 5.2, 11.2 Hz), 3.36 (s, 3H), 2.11 (s, 3H), 1.92 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 169.9, 169.2, 153.0, 138.2, 138.0, 137.4,
128.6, 128.42, 128.39, 128.3, 128.01, 127.98, 127.9, 127.7, 127.6, 98.2,
96.6, 75.9, 75.3, 74.6, 74.1, 73.5, 73.3, 72.9, 68.0, 67.8, 66.8, 66.4, 60.3,
55.5, 20.56, 20.55; HRMS (ESI) calcd for C39H44O14Na [M + Na]+
759.2623, found 759.2625.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α- and β-D-galactopyr-
anosyl)-(1→2)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (30α and
30β). The coupling of donor 5 with acceptor 18d afforded a mixture
of 30α and 30β (68%, α/β = 5:1). For 30α: colorless glassy solid; Rf =
0.5 (petroleum ether/ethyl acetate, 1:1); [α]D +30.0 (c 1.1, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.27−7.37 (m, 13H), 7.15−7.17 (m,
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-galactopyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-β-D-glucopyranoside (32α). The coupling
of donor 5 with acceptor 18f afforded 32α (76% yield) as a colorless
glassy solid: Rf = 0.25 (petroleum ether/ethyl acetate, 1.5:1); [α]D
1
+17.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.25−7.36 (m,
15H), 5.58 (br.s, 1H), 5.42 (d, 1H, J = 2.4 Hz), 4.95 (d, 1H, J = 10.8
Hz), 4.91 (d, 1H, J = 11.2 Hz), 4.88 (d, 1H, J = 11.2 Hz), 4.78 (d, 1H,
J = 10.8 Hz), 4.70 (d, 1H, J = 10.8 Hz), 4.66 (dd, 1H, J = 2.4, 12.0
Hz), 4.59 (d, 1H, J = 11.2 Hz), 4.58 (dd, 1H, J = 3.6, 12.0 Hz), 4.30
(d, 1H, J = 7.6 Hz), 4.08−4.17 (m, 2H), 4.02 (dd, 1H, J = 5.6, 10.0
Hz), 3.89 (d, 1H, J = 11.2 Hz), 3.80−3.84 (m, 1H), 3.64−3.69 (m,
1H), 3.54 (s, 3H), 3.45−3.47 (m, 2H), 3.41 (dd, 1H, J = 8.0, 9.2 Hz),
2.15 (s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9,
169.2, 152.8, 138.4, 138.3, 137.9, 128.5, 128.4, 128.1, 127.93, 127.86,
127.7, 104.6, 95.5, 84.6, 82.2, 76.9, 75.6, 74.8, 74.7, 74.3, 74.2, 74.1,
68.4, 67.2, 66.6, 61.2, 57.1, 20.6, 20.5; HRMS (ESI) calcd for
C39H44O14Na [M + Na]+ 759.2623, found 759.2629.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-galactopyranosyl)-
(1→6)-2,3,4-tri-O-benzoyl-α-D-glucopyranoside (33α). The coupling
of donor 5 with acceptor 18g afforded 33α (60% yield) as a foam: Rf =
0.1 (petroleum ether/ethyl acetate, 1.5:1); [α]D +18.0 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.98 (d, 2H, J = 7.6 Hz), 7.94 (d, 2H,
J = 7.2 Hz), 7.88 (d, 2H, J = 7.6 Hz), 7.50−7.56 (m, 2H), 7.36−7.45
(m, 5H), 7.26−7.32 (m, 2H), 6.16 (t, 1H, J = 10.0 Hz), 5.68 (s, 1H),
5.65 (t, 1H, J = 10.0 Hz), 5.37 (d, 1H, J = 2.4 Hz), 5.24−5.30 (m, 2H),
5.01 (dd, 1H, J = 2.8, 12.0 Hz), 4.67 (dd, 1H, J = 2.8, 12.0 Hz), 4.26
(dd, 1H, J = 2.4, 10.0 Hz), 4.17 (t, 1H, J = 6.4 Hz), 4.06 (dd, 1H, J =
5.6, 11.2 Hz), 3.92−3.98 (m, 2H), 3.80 (dd, 1H, J = 1.6, 11.2 Hz), 3.48
(s, 3H), 2.16 (s, 3H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.2, 169.2, 165.8, 165.7, 165.5, 152.8, 133.7, 133.4, 133.2, 129.9,
129.8, 129.7, 129.1, 129.0, 128.64, 128.57, 128.4, 128.3, 97.1, 95.6,
74.24, 74.18, 71.9, 70.3, 69.0, 68.7, 68.0, 67.0, 66.9, 61.5, 55.8, 20.5,
20.4; HRMS (ESI) calcd for C39H38O17Na [M + Na]+ 801.2001, found
801.2010.
General Procedure for the SnCl4-Modulated α/β-Selective
Glycosylations of Donor 3 or 6 with Acceptors 18a−g. Protocol
A (in the absence of SnCl4): Triflic anhydride (9.50 μL, 0.056 mmol,
1.3 equiv) was added to a stirred solution of 3 or 6 (25.4 mg,
0.052 mmol, 1.2 equiv), BSM (11.8 mg, 0.056 mmol, 1.3 equiv), and
activated 4 Å molecular sieves (300 mg) in dichloromethane (3.0 mL)
at −72 °C under nitrogen atmosphere. The reaction mixture was
stirred for 3−5 min. After the disappearance of donor detected by
TLC, a solution of the acceptor alcohol 18a (20.0 mg, 0.043 mmol,
1.0 equiv) or 18b−g in dichloromethane (0.2 mL) was added
dropwise to the preactivated system. The reaction mixture was stirred
and slowly warmed to room temperature, and then quenched by Et3N
(0.1 mL). The precipitate was filtered off and the filtrate was
concentrated. The crude product was purified by column chromatog-
raphy on silica gel to give the disaccharides. Protocol B (in the
presence of SnCl4): Triflic anhydride (9.50 μL, 0.056 mmol, 1.3 equiv)
was added to a stirred solution of 3 or 6 (25.4 mg, 0.052 mmol,
1.2 equiv), BSM (11.8 mg, 0.056 mmol, 1.3 equiv), and activated 4 Å
molecular sieves (300 mg) in dichloromethane (3.0 mL) at −72 °C
under nitrogen atmosphere. The reaction mixture was stirred for 3−5
min. After the disappearance of donor detected by TLC, a solution of
the acceptor alcohol 18a (20.0 mg, 0.043 mmol, 1.0 equiv) or 18b−g
in dichloromethane (0.2 mL) was added dropwise to the preactivated
system. The reaction was monitored by TLC. SnCl4 (1−3 equiv) was
added after disappearance of the acceptor at about −40 °C to −20 °C.
The reaction mixture was warmed up to room temperature to
accomplish the anomerization process, and then quenched by Et3N
(0.1 mL). The precipitate was filtered off and the filtrate was
concentrated. The crude product was purified by column chromatog-
raphy on silica gel to give the disaccharides.
2H), 5.34 (d, 1H, J = 2.8 Hz), 5.10 (s, 1H), 4.99 (d, 1H, J = 11.2 Hz),
4.86 (d, 1H, J = 3.6 Hz), 4.81 (d, 1H, J = 10.8 Hz), 4.67 (d, 1H, J =
11.6 Hz), 4.65 (d, 1H, J = 12.0 Hz), 4.50−4.56 (m, 3H), 4.40 (dd, 1H,
J = 2.8, 12.0 Hz), 4.09−4.12 (m, 1H), 3.97−4.02 (m, 2H), 3.76−3.83
(m, 4H), 3.68−3.72 (m, 2H), 3.42 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 170.1, 169.0, 152.6, 138.4, 137.78,
137.76, 128.6, 128.44, 128.41, 128.1, 128.0, 127.9, 127.8, 127.7, 96.4,
92.9, 80.4, 78.6, 75.8, 75.4, 75.0, 74.03, 73.96, 73.6, 70.3, 68.5, 68.2,
66.6, 61.0, 55.3, 20.6, 20.5; HRMS (ESI) calcd for C39H44O14Na [M +
Na]+ 759.2623, found 759.2626. For 30β: foam; Rf = 0.4 (petroleum
1
ether/ethyl acetate, 1:1); [α]D +3.8 (c 0.8, CHCl3); H NMR (400
MHz, CDCl3) δ 7.27−7.38 (m, 13H), 7.15−7.17 (m, 2H), 5.58 (br.s,
1H), 5.02 (d, 1H, J = 8.0 Hz), 4.85 (d, 1H, J = 3.6 Hz), 4.85 (d, 2H,
J = 10.8 Hz), 4.82 (d, 1H, J = 10.8 Hz), 4.63 (d, 1H, J = 12.0 Hz), 4.55
(dd, 1H, J = 4.4, 12.4 Hz), 4.51 (d, 1H, J = 11.2 Hz), 4.50 (d, 1H, J =
12.0 Hz), 4.20 (dd, 1H, J = 6.4, 11.6 Hz), 4.12 (dd, 1H, J = 2.8, 12.0
Hz), 4.07 (dd, 1H, J = 6.4, 11.2 Hz), 4.03 (t, 1H, J = 9.6 Hz), 3.93 (td,
1H, J = 1.2, 6.4 Hz), 3.65−3.79 (m, 5H), 3.42 (s, 3H), 2.16 (s, 3H),
2.06 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.3, 169.1, 152.4,
138.1, 138.0, 137.8, 128.5, 128.4, 128.2, 127.9, 127.85, 127.80, 101.7,
99.1, 81.1, 81.0, 78.3, 77.8, 75.9, 75.5, 75.1, 73.5, 72.9, 70.1, 68.2, 65.2,
61.2, 55.2, 20.7, 20.5; HRMS (ESI) calcd for C39H44O14Na [M + Na]+
759.2623, found 759.2618.
Methyl (4,6-Di-O-acetyl-2,3-O-carbonyl-α-D-galactopyranosyl)-
(1→3)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (31α). The coupling
of donor 5 with acceptor 18e afforded 31α (77% yield) as a colorless
glassy solid: Rf = 0.2 (petroleum ether/ethyl acetate, 1.5:1); [α]D
1
+47.8 (c 0.9, CHCl3); H NMR (400 MHz, CDCl3) δ 7.27−7.37 (m,
13H), 7.14 (d, 2H, J = 7.2 Hz), 5.70 (s, 1H), 5.34 (s, 1H), 4.76 (d, 1H,
J = 3.2 Hz), 4.60−4.67 (m, 3H), 4.46−4.53 (m, 5H), 4.37 (t, 1H, J =
6.4 Hz), 4.15 (t, 1H, J = 7.6 Hz), 4.07 (dd, 1H, J = 6.4, 11.2 Hz),
3.65−3.77 (m, 5H), 3.55 (dd, 1H, J = 3.2, 10.0 Hz), 3.35 (s, 3H), 2.09
(s, 3H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.3, 169.2,
153.0, 137.52, 137.46 (2C), 128.64, 128.57, 128.5, 128.43, 128.40,
128.1, 127.9, 127.8, 127.6, 97.3, 95.1, 78.5, 77.9, 76.5, 74.6, 74.33,
74.28, 73.7, 72.5, 69.9, 68.1, 67.9, 66.8, 61.1, 55.1, 20.6, 20.5; HRMS
(ESI) calcd for C39H45O14 [M + H]+ 737.2804, found 737.2803. Anal.
Calcd for C39H44O14: C, 63.58; H, 6.02. Found: C, 63.43; H, 6.05.
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-β-D-glucopyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (20β). The coupling
of donor 3 with acceptor 18a by protocol A afforded 20β (86% yield)
as a foam: Rf = 0.3 (petroleum ether/ethyl acetate, 1.5:1). Compound
20β is a known compound, and its spectroscopic data coincide with
the previous report.18c
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The Journal of Organic Chemistry
Article
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (20α). The coupling
of donor 3 with acceptor 18a by protocol B afforded 20α (80% yield)
as a colorless glassy solid: Rf = 0.25 (petroleum ether/ethyl acetate,
74.5, 73.5, 73.4, 72.8, 72.6, 70.2, 68.2, 67.0, 55.3; HRMS (ESI) calcd
for C49H52O12K [M + K]+ 871.3090, found 871.3082.
Methyl (4,6-di-O-benzyl-2,3-O-carbonyl-β-D-glucopyranosyl)-
(1→3)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (37β). The coupling
of donor 3 with acceptor 18e by protocol A afforded 37β (84% yield)
as a glassy solid: Rf = 0.3 (petroleum ether/ethyl acetate, 1.5:1); [α]D
1
1.5:1); [α]D +21.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
7.20−7.37 (m, 25H), 5.32 (d, 1H, J = 2.8 Hz), 4.99 (d, 1H, J = 10.8
Hz), 4.90 (d, 1H, J = 11.6 Hz), 4.80 (d, 1H, J = 4.0 Hz), 4.76−4.79
(m, 2H), 4.63−4.70 (m, 2H), 4.53−4.59 (m, 3H), 4.47 (d, 1H, J =
11.2 Hz), 4.42 (d, 1H, J = 12.0 Hz), 4.12 (dd, 1H, J = 2.8, 11.6 Hz),
3.96−4.01 (m, 2H), 3.66−3.84 (m, 5H), 3.51−3.57 (m, 2H), 3.48 (t,
1H, J = 8.0 Hz), 3.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.6,
138.6, 138.1 (2C), 137.7, 137.0, 128.5, 128.42, 128.39, 128.37, 128.1,
128.03, 127.96, 127.92, 127.89, 127.79, 127.75, 127.7, 127.6, 98.0,
95.0, 82.0, 80.12, 80.07, 77.2, 75.7, 74.7, 74.5, 73.5 (2C), 72.8, 72.4,
69.9, 67.4, 66.7, 55.2; HRMS (ESI) calcd for C49H52O12K [M + K]+
871.3090, found 871.3095.
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α- and β-D-glucopyra-
nosyl)-(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (34α and
34β). The coupling of donor 3 with acceptor 18b by either protocol
A or protocol B afforded a mixture of 34α and 34β. Both of them are
known compounds, and their spectroscopic data coincide with the
previous report.18c
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α- and β-D-glucopyra-
nosyl)-(1→4)-2,3,6-tri-O-benzyl-α-D-galactopyranoside (35α and
35β). The coupling of donor 3 with acceptor 18c by protocol A
afforded an inseparable anomeric mixture of 35α and 35β (85% yield,
α/β = 1:10) as a colorless glassy solid, and the anomeric ratio was
determined by integration of the 1H NMR spectrum: Rf = 0.4
(petroleum ether/ethyl acetate, 1.5:1); 1H NMR (400 MHz, CDCl3) δ
7.20−7.40 (m, 30H), 5.29 (d, 0.1H, J = 3.2 Hz, H-1α’), 5.16 (d, 1H, J =
7.2 Hz, H-1β’), 4.94 (d, 1H, J = 11.6 Hz), 4.83 (d, 1H, J = 12.0 Hz),
4.77 (d, 1H, J = 11.6 Hz), 4.79 (d, 1H, J = 12.0 Hz), 4.62 (t, 1H, J =
3.6 Hz), 4.61 (d, 1H, J = 11.6 Hz), 4.47−4.51 (m, 3H), 4.43 (d, 1H, J
= 12.0 Hz), 4.34 (d, 1H, J = 12.0 Hz), 4.19−4.23 (m, 1H), 3.85−4.01
(m, 7H), 3.62−3.68 (m, 2H), 3.54−3.59 (m, 2H), 3.36−3.38 (m, 1H),
3.37 (s, 3H), 3.35 (s, 0.3H); HRMS (ESI) calcd for C49H52O12Na [M
+ Na]+ 855.3351, found 855.3359.
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-β-D-glucopyranosyl)-
(1→2)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (36β). The coupling
of donor 3 with acceptor 18d by protocol A afforded 36β (90% yield)
as a foam: Rf = 0.3 (petroleum ether/ethyl acetate, 1.5:1); [α]D +13.8
(c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.22−7.38 (m, 23H),
7.15−7.17 (m, 2H), 4.99 (d, 1H, J = 4.0 Hz), 4.89 (d, 1H, J = 7.6 Hz),
4.86 (d, 1H, J = 10.8 Hz), 4.85 (d, 1H, J = 11.2 Hz), 4.81 (d, 1H, J =
10.8 Hz), 4.78 (d, 1H, J = 11.6 Hz), 4.62 (d, 1H, J = 12.0 Hz), 4.56 (d,
1H, J = 12.0 Hz), 4.52 (d, 1H, J = 11.2 Hz), 4.50 (d, 1H, J = 12.4 Hz),
4.49 (d, 1H, J = 12.0 Hz), 4.47 (d, 1H, J = 12.0 Hz), 4.11−4.13 (m,
2H), 4.01 (t, 1H, J = 9.2 Hz), 3.93−3.98 (m, 1H), 3.63−3.79 (m, 7H),
3.52 (ddd, 1H, J = 2.0, 4.0, 8.4 Hz), 3.38 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 153.2, 138.2, 138.0, 137.9, 137.7, 136.7, 128.5, 128.43,
128.37, 128.1, 128.0, 127.9, 127.80, 127.77, 127.71, 127.66, 100.6,
99.3, 83.3, 81.2, 80.5, 77.8, 77.7, 77.0, 75.9, 75.0, 73.7, 73.6, 73.5, 72.9,
70.1, 68.3, 68.1, 55.2; HRMS (ESI) calcd for C49H53O12 [M + H]+
833.3532, found 833.3532. Anal. Calcd for C49H52O12: C, 70.66; H,
6.29. Found: C, 70.38; H, 6.14.
1
+13.6 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ 7.16−7.36 (m,
25H), 5.32 (d, 1H, J = 7.6 Hz), 5.00 (d, 1H, J = 11.2 Hz), 4.76 (d, 1H,
J = 11.2 Hz), 4.72 (d, 1H, J = 11.6 Hz), 4.60 (d, 1H, J = 12.0 Hz), 4.58
(d, 1H, J = 4.0 Hz), 4.54 (d, 1H, J = 12.0 Hz), 4.50 (d, 1H, J = 11.2
Hz), 4.44 (d, 1H, J = 12.0 Hz), 4.27 (d, 1H, J = 12.0 Hz), 4.41 (d, 1H,
J = 11.2 Hz), 4.31 (d, 1H, J = 12.0 Hz), 4.27 (t, 1H, J = 9.2 Hz), 4.14
(dd, 1H, J = 9.6, 11.2 Hz), 4.01−4.06 (m, 2H), 3.57−3.72 (m, 7H),
3.48 (td, 1H, J = 2.8, 8.4 Hz), 3.34 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 153.6, 138.6, 138.0, 137.9, 137.5, 136.8, 128.6, 128.5,
128.33, 128.27, 128.2, 128.14, 128.08, 128.0, 127.8, 127.64, 127.58,
127.5, 127.4, 99.9, 97.4, 83.7, 80.31, 80.26, 78.5, 75.7, 74.7, 73.8, 73.6,
73.43, 73.36, 73.0, 69.8, 68.4, 67.9, 55.2; MS (ESI) 855 [M + Na]+.
Anal. Calcd for C49H52O12: C, 70.66; H, 6.29. Found C, 70.52; H, 6.26.
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→3)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (37α). The coupling
of donor 3 with acceptor 18e by protocol B afforded 37α (78% yield)
as a glassy solid: Rf = 0.25 (petroleum ether/ethyl acetate, 1.5:1); [α]D
1
+18.9 (c 2.8, CHCl3); H NMR (400 MHz, CDCl3) δ 7.13−7.36 (m,
25H), 5.70 (d, 1H, J = 3.2 Hz), 4.78−4.83 (m, 1H), 4.76 (d, 1H, J =
12.0 Hz), 4.75 (d, 1H, J = 2.8 Hz), 4.69 (d, 1H, J = 10.8 Hz), 4.64 (d,
1H, J = 12.0 Hz), 4.44−4.54 (m, 6H), 4.27 (d, 1H, J = 12.0 Hz), 4.11−
4.16 (m, 2H), 4.03 (d, 2H, J = 6.0 Hz), 3.75 (dd, 1H, J = 2.8, 10.4 Hz),
3.64−3.73 (m, 3H), 3.49 (dd, 1H, J = 3.6, 10.0 Hz), 3.31−3.37 (m,
2H), 3.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.9, 137.9,
137.52, 137.49, 137.4, 137.1, 128.8, 128.6, 128.5, 128.44, 128.36,
128.3, 128.1, 128.0, 127.91, 127.85, 127.8, 127.7, 127.6, 97.2, 94.7,
80.4, 78.5, 77.7, 77.5, 74.7, 74.6, 73.7, 73.3, 72.8, 72.7, 72.1, 69.7, 68.0,
66.9, 55.1; HRMS (ESI) calcd for C49H56NO12 [M + NH4]+ 850.3797,
found 850.3795. Anal. Calcd for C49H52O12: C, 70.66; H, 6.29. Found:
C, 70.38; H, 6.32.
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-β-D-glucopyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-β-D-glucopyranoside (38β). The coupling
of donor 3 with acceptor 18f by protocol A afforded 38β (87% yield)
as a colorless glassy solid: Rf = 0.4 (petroleum ether/ethyl acetate,
1
1.5:1); [α]D +8.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
7.22−7.34 (m, 25H), 4.93 (d, 1H, J = 11.2 Hz), 4.90 (d, 1H, J = 11.6
Hz), 4.88 (d, 1H, J = 11.2 Hz), 4.77 (d, 2H, J = 12.0 Hz), 4.76 (d, 1H,
J = 7.2 Hz), 4.69 (d, 1H, J = 10.8 Hz), 4.58 (d, 1H, J = 11.6 Hz), 4.55
(d, 1H, J = 10.0 Hz), 4.51 (d, 1H, J = 11.2 Hz), 4.49 (d, 1H, J = 12.0
Hz), 4.31 (d, 1H, J = 7.6 Hz), 4.21 (dd, 1H, J = 9.6, 11.6 Hz), 4.14 (d,
1H, J = 11.2 Hz), 4.03 (dd, 1H, J = 8.0, 12.0 Hz), 3.95 (t, 1H, J = 9.2
Hz), 3.63−3.70 (m, 4H), 3.57 (s, 3H), 3.38−3.58 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 153.4, 138.48, 138.45, 138.2, 137.8, 136.8, 128.5,
128.43, 128.41, 128.35, 128.14, 128.07, 128.0, 127.83, 127.78, 127.75,
127.63, 127.60, 104.7, 100.0, 84.6, 83.4, 82.3, 77.93, 77.88, 77.2, 75.6,
74.9, 74.7, 74.5, 74.0, 73.6, 72.9, 68.8, 68.2, 57.2; HRMS (ESI) calcd
for C49H56NO12 [M + NH4]+ 850.3797, found 850.3796.
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-β-D-glucopyranoside (38α). The coupling
of donor 3 with acceptor 18f by protocol B afforded 38α (81% yield,
α/β > 20:1) as a colorless glassy solid: Rf = 0.35 (petroleum ether/
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→2)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (36α). The coupling
of donor 3 with acceptor 18d by protocol B afforded 36α (85% yield)
as a foam: Rf = 0.15 (petroleum ether/ethyl acetate, 1.5:1); [α]D +27.1
(c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.22−7.34 (m, 18H),
7.07−7.18 (m, 7H), 5.34 (d, 1H, J = 2.8 Hz), 4.87 (d, 1H, J = 3.6 Hz),
4.73−4.86 (m, 5H), 4.63 (d, 1H, J = 12.0 Hz), 4.51 (d, 1H, J = 12.0
Hz), 4.50 (d, 2H, J = 11.6 Hz), 4.44 (d, 1H, J = 11.2 Hz), 4.33 (d, 1H,
J = 12.4 Hz), 4.18 (dd, 1H, J = 2.8, 11.6 Hz), 4.04 (t, 1H, J = 9.6 Hz),
3.97 (t, 1H, J = 9.2 Hz), 3.82−3.87 (m, 2H), 3.73−3.78 (m, 2H),
3.65−3.70 (m, 2H), 3.50 (dd, 1H, J = 2.8, 11.2 Hz), 3.41 (s, 3H)
3.39−3.42 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 153.5, 138.0,
137.9, 137.8, 137.7, 137.2, 128.4, 128.3, 127.92, 127.89, 127.87, 127.8,
127.72, 127.67, 127.6, 96.6, 92.6, 80.19, 80.15, 78.2, 76.6, 75.9, 74.9,
1
ethyl acetate, 1.5:1); H NMR (400 MHz, CDCl3) δ 7.20−7.35 (m,
25H), 5.37 (d, 1H, J = 2.8 Hz), 4.94 (d, 1H, J = 10.8 Hz), 4.90 (d, 1H,
J = 11.2 Hz), 4.87 (d, 1H, J = 12.0 Hz), 4.78 (d, 2H, J = 10.0 Hz), 4.71
(dd, 1H, J = 10.0, 12.0 Hz), 4.69 (d, 1H, J = 11.2 Hz), 4.59 (d, 1H, J =
12.4 Hz), 4.57 (d, 1H, J = 11.2 Hz), 4.47 (d, 1H, J = 12.8 Hz), 4.44 (d,
1H, J = 12.4 Hz), 4.29 (d, 1H, J = 8.0 Hz), 4.16 (dd, 1H, J = 3.2, 12.0
Hz), 4,01 (t, 1H, J = 9.2 Hz), 3.61−3.88 (m, 7H), 3.50 (s, 3H), 3.45
(d, 2H, J = 9.6 Hz), 3.40 (t, 1H, J = 8.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 153.6, 138.4 (2C), 137.9, 137.7, 137.1, 128.44, 128.42,
128.40, 128.38, 128.1, 128.0, 127.91, 127.87, 127.85, 127.7, 127.6,
104.6, 94.4, 84.6, 82.2, 80.1, 77.2, 77.1, 75.6, 74.8, 74.5, 74.3, 73.5,
72.7, 72.2, 67.4, 66.6, 57.1; HRMS (ESI) calcd for C49H56NO12 [M +
NH4]+ 850.3797, found 850.3799.
5268
dx.doi.org/10.1021/jo3002084 | J. Org. Chem. 2012, 77, 5255−5270

The Journal of Organic Chemistry
Article
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-β-D-glucopyranosyl)-
(1→6)-2,3,4-tri-O-benzoyl-α-D-glucopyranoside (39β). The coupling
of donor 3 with acceptor 18g by protocol A afforded major product
39β (83% yield, α/β = 1:5) as a foam: Rf = 0.25 (petroleum ether/
CDCl3) δ 153.4, 138.3, 138.1, 137.9, 137.6, 137.0, 128.5, 128.44,
128.37, 128.3, 128.13, 128.11, 128.08, 128.0, 127.9, 127.8, 127.7,
127.6, 127.5, 127.4, 97.8, 96.0, 81.4, 80.1, 75.7, 75.4, 74.1, 73.9, 73.5,
73.3, 73.1, 72.9, 71.2, 69.3, 69.2, 68.0, 55.4; HRMS (ESI) calcd for
C49H52O12Na [M + Na]+ 855.3351, found 855.3358. For 40β: Rf = 0.3
1
ethyl acetate, 1:1); H NMR (400 MHz, CDCl3) δ 7.93−7.98 (m,
1
4H), 7.86 (d, 2H, J = 7.2 Hz), 7.49−7.52 (m, 2H), 7.34−7.43 (m,
5H), 7.26−7.33 (m, 10H), 7.22−7.24 (m, 2H), 6.17 (t, 1H, J = 10.0
Hz), 5.46 (t, 1H, J = 10.0 Hz), 5.22−5.27 (m, 1H), 5.24 (d, 1H, J = 3.6
Hz), 4.93 (d, 1H, J = 7.6 Hz), 4.78 (d, 1H, J = 11.2 Hz), 4.56 (d, 1H,
J = 12.4 Hz), 4.51 (d, 1H, J = 11.2 Hz), 4.46 (d, 1H, J = 12.4 Hz),
4.27−4.34 (m, 2H), 4.04 (dd, 1H, J = 2.0, 11.6 Hz), 3.99 (dd, 1H, J =
7.6, 11.6 Hz), 3.95 (t, 1H, J = 9.2 Hz), 3.82 (dd, 1H, J = 6.8, 11.6 Hz),
3.66−3.73 (m, 2H), 3.57−3.61 (m, 1H), 3.48 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 165.8, 165.7, 165.4, 153.4, 137.8, 136.8, 133.5, 133.3,
133.1, 129.91, 129.87, 129.6, 129.2, 129.1, 128.8, 128.4, 128.3, 128.12,
128.10, 127.7, 100.0, 96.8, 83.2, 78.0, 73.9, 73.5, 72.9, 72.0, 70.3, 69.7,
69.0, 68.4, 68.1, 55.6; HRMS (ESI) calcd for C49H47O15 [M + H]+
875.2910, found 875.2910.
(petroleum ether/ethyl acetate, 1.5:1); [α]D −1.3 (c 1.5, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.18−7.21 (m, 5H), 7.25−7.35 (m, 20H),
4.86 (d, 1H, J = 10.8 Hz), 4.78 (d, 1H, J = 10.8 Hz), 4.78 (d, 1H, J =
13.2 Hz), 4.77 (d, 1H, J = 12.4 Hz), 4.73 (d, 1H, J = 11.2 Hz), 4.62 (d,
1H, J = 12.0 Hz), 4.59 (d, 1H, J = 3.6 Hz), 4.50 (d, 1H, J = 11.2 Hz),
4.49 (d, 1H, J = 7.6 Hz), 4.37 (dd, 1H, J = 8.0, 12.0 Hz), 4.30 (d, 1H,
J = 12.0 Hz), 4.29 (d, 1H, J = 11.6 Hz), 4.22 (d, 1H, J = 11.6 Hz), 4.06
(s, 1H), 3.80−3.89 (m, 3H), 3.71 (d, 1H, J = 9.6 Hz), 3.60 (dd, 1H,
J = 1.6, 10.8 Hz), 3.50 (dd, 1H, J = 3.6, 9.2 Hz), 3.46 (t, 1H, J = 8.4
Hz), 3.43 (dd, 1H, J = 2.4, 12.0 Hz), 3.35−3.40 (m, 1H), 3.37 (s, 3H),
3.20 (dd, 1H, J = 4.8, 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ 153.2,
139.2, 138.1, 137.8, 137.7, 137.3, 128.8, 128.5, 128.42, 128.39, 128.10,
128.05, 128.02, 127.97, 127.9, 127.84, 127.81, 127.7, 127.5, 127.2,
100.6, 98.4, 80.9, 79.9, 79.0, 78.1, 76.1, 75.3, 74.9, 73.8, 73.6, 73.4,
71.4, 69.3, 67.5, 67.1, 55.3; HRMS (ESI) calcd for C49H56NO12 [M +
NH4]+ 850.3797, found 850.3796. Anal. Calcd for C49H52O12: C,
70.66; H, 6.29. Found: C, 70.38; H, 6.40.
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α-D-glucopyranosyl)-
(1→6)-2,3,4-tri-O-benzoyl-α-D-glucopyranoside (39α). The coupling
of donor 3 with acceptor 18g by protocol B afforded 39α (79% yield,
α/β > 20:1) as a foam: Rf = 0.3 (petroleum ether/ethyl acetate, 1:1);
1H NMR (400 MHz, CDCl3) δ 7.96−7.99 (m, 2H), 7.86−7.92 (m,
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α- and β-D-galactopyr-
anosyl)-(1→2)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (41α and
41β). The coupling of donor 6 with acceptor 18d by protocol B
afforded a mixture of 41α and 41β (78% yield, α/β = 5:1), both of
them as colorless glassy solids. For 41α: Rf = 0.4 (petroleum ether/
ethyl acetate, 1.5:1); [α]D +17.6 (c 2.1, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.19−7.36 (m, 23H), 7.12−7.14 (m, 2H), 5.32 (d, 1H, J =
2.8 Hz), 4.92 (d, 1H, J = 11.2 Hz), 4.86 (d, 1H, J = 3.6 Hz), 4.78 (d,
1H, J = 10.8 Hz), 4.70−4.75 (m, 3H), 4.63 (d, 1H, J = 12.0 Hz), 4.49−
4.53 (m, 3H), 4.45 (d, 1H, J = 11.2 Hz), 4.38 (d, 1H, J = 12.0 Hz),
4.32 (d, 1H, J = 12.0 Hz), 4.01−4.05 (m, 1H), 3.98 (t, 1H, J = 8.8 Hz),
3.84 (dd, 1H, J = 3.6, 10.0 Hz), 3.81 (br.s, 1H), 3.74−3.77 (m, 2H),
3.65−3.70 (m, 2H), 3.47 (dd, 1H, J = 6.0, 9.6 Hz), 3.38−3.42 (m,
1H), 3,41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.3, 138.5,
138.0, 137.88, 137.85, 137.1, 128.41, 128.39, 128.3, 128.1, 127.9,
127.8, 127.74, 127.65, 127.6, 127.5, 96.6, 93.1, 80.8, 78.4, 77.1, 75.8,
75.6, 74.9, 74.3, 73.8, 73.6, 73.1, 72.9, 70.5, 70.3, 68.3, 67.8, 55.3;
HRMS (ESI) calcd for C49H52O12Na [M + Na]+ 855.3351, found
855.3356. For 41β: Rf = 0.3 (petroleum ether/ethyl acetate, 1.5:1);
4H), 7.48−7.53 (m, 2H), 7.23−7.44 (m, 17H), 6.14 (t, 1H, J = 10.0
Hz), 5.57 (t, 1H, J = 10.0 Hz), 5.29 (d, 1H, J = 2.8 Hz), 5.26 (d, 1H,
J = 3.6 Hz), 5.22 (t, 1H, J = 3.6 Hz), 4.87 (dd, 1H, J = 9.6, 11.6 Hz),
4.81 (d, 1H, J = 11.6 Hz), 4.52 (d, 1H, J = 12.0 Hz), 4.50 (d, 1H, J =
12.0 Hz), 4.39 (d, 1H, J = 12.0 Hz), 4.23−4.27 (m, 1H), 4.18 (dd, 1H,
J = 3.2, 12.0 Hz), 4.02 (t, 1H, J = 9.2 Hz), 3.95 (dd, 1H, J = 5.6, 11.2
Hz), 3.73−3.78 (m, 2H), 3.67 (dd, 1H, J = 3.2, 10.8 Hz), 3.53 (dd,
1H, J = 2.0, 10.8 Hz), 3.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
165.8 (2C), 165.3, 153.5, 137.7, 137.1, 133.5, 133.4, 133.1, 129.93,
129.89, 129.7, 129.6, 129.1, 129.0, 128.7, 128.5, 128.44, 128.40, 128.3,
128.0, 127.8, 97.0, 94.7, 80.1, 77.1, 74.6, 73.5, 72.8, 72.6, 72.0, 70.3,
69.2, 68.2, 67.3, 67.0, 55.7; HRMS (ESI) calcd for C49H50NO15 [M +
NH4]+ 892.3180, found 892.3183.
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α-D-galactopyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (22α). The coupling
of donor 6 with acceptor 18a by protocol B afforded 22α (78% yield)
as a colorless glassy solid: Rf = 0.4 (petroleum ether/ethyl acetate,
1
1.5:1); [α]D +15.0 (c 1.2, CHCl3); H NMR (400 MHz, CDCl3) δ
1
[α]D +2.7 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ 7.24−7.38
7.22−7.37 (m, 25H), 5.30 (d, 1H, J = 2.8 Hz), 4.99 (d, 1H, J = 10.8
Hz), 4.88 (d, 1H, J = 11.2 Hz), 4.79 (d, 1H, J = 10.8 Hz), 4.79 (d, 1H,
J = 12.0 Hz), 4.78 (d, 1H, J = 11.2 Hz), 4.73 (dd, 1H, J = 2.8, 12.0
Hz), 4.65 (d, 1H, J = 12.0 Hz), 4.63 (dd, 1H, J = 2.0, 12.0 Hz), 4.58
(d, 1H, J = 11.2 Hz), 4.54 (d, 1H, J = 3.6 Hz), 4.52 (d, 1H, J = 11.6
Hz), 4.46 (d, 1H, J = 11.6 Hz), 4.40 (d, 1H, J = 11.6 Hz), 4.20 (s, 1H),
3.99 (t, 1H, J = 9.2 Hz), 3.89 (t, 1H, J = 6.4 Hz), 3.74 (dd, 1H, J = 4.8,
12.0 Hz), 3.79 (s, 1H), 3.71−3.76 (m, 1H), 3.58 (dd, 1H, J = 3.6, 8.8
Hz), 3.50−3.53 (m, 2H), 3.44 (t, 1H, J = 9.6 Hz), 3.34 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 153.4, 138.6, 138.1, 137.6, 137.1, 128.5,
128.42, 128.38, 128.1, 128.0, 127.91, 127.85, 127.74, 127.69, 127.6,
98.0, 95.6, 82.0, 80.1, 77.1, 75.7, 74.8, 74.5, 73.9, 73.5, 72.9, 70.6, 69.9,
67.9, 66.9, 55.2; HRMS (ESI) calcd for C49H56NO12 [M + NH4]+:
850.3797, found 850.3796. Anal. Calcd for C49H52O12: C, 70.66; H,
6.29. Found: C, 70.40; H, 6.43.
(m, 23H), 7.14−7.16 (m, 2H), 4.94 (d, 1H, J = 8.0 Hz), 4.86 (d, 1H,
J = 10.8 Hz), 4.84 (d, 1H, J = 10.8 Hz), 4.82 (d, 1H, J = 3.6 Hz), 4.82
(d, 1H, J = 9.6 Hz), 4.79 (d, 1H, J = 11.2 Hz), 4.65 (dd, 1H, J = 8.0,
12.0 Hz), 4.62 (d, 1H, J = 11.6 Hz), 4.53 (d, 1H, J = 12.0 Hz), 4.50 (d,
1H, J = 11.6 Hz), 4.49 (d, 1H, J = 12.0 Hz), 4.46 (d, 1H, J = 12.0 Hz),
4.43 (d, 1H, J = 12.0 Hz), 4.16 (brs, 1H), 4.02 (dd, 1H, J = 2.4, 12.0
Hz), 4.01 (t, 1H, J = 9.6 Hz), 3.72−3.78 (m, 3H), 3.60−3.68 (m, 4H),
3.53 (dd, 1H, J = 4.8, 8.4 Hz), 3.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 153.1, 138.3, 138.1, 137.9, 137.4, 137.0, 128.51, 128.45,
128.4, 128.2, 128.13, 128.12, 128.0, 127.9, 127.8, 127.73, 127.71,
101.6, 99.3, 81.4, 81.3, 80.1, 77.9, 75.8, 75.05, 75.01, 73.9, 73.6, 73.5,
71.4, 70.1, 68.4, 67.7, 55.2; HRMS (ESI) calcd for C49H52O12Na [M +
Na]+ 855.3351, found 855.3353.
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α-D-galactopyranosyl)-
(1→3)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (42α). The coupling
of donor 6 with acceptor 18e by protocol B afforded 42α (71% yield,
α/β > 20:1) as a foam: Rf = 0.45 (petroleum ether/ethyl acetate,
Methyl (4,6-Di-O-benzyl-2,3-O-carbonyl-α- and β-D-galactopyr-
anosyl)-(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (40α and
40β). The coupling of donor 6 with acceptor 18b by protocol B
afforded a mixture of 40α and 40β (73% yield, α/β = 3:1), both of
them are colorless glassy solids. For 40α: Rf = 0.4 (petroleum ether/
1
1.5:1); [α]D +9.1 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ
7.21−7.35 (m, 23H), 7.11−7.14 (m, 2H), 5.68 (d, 1H, J = 3.2 Hz),
4.75 (dd, 1H, J = 3.2, 12.0 Hz), 4.74 (d, 1H, J = 11.2 Hz), 4.68 (d, 1H,
J = 11.6 Hz), 4.65 (d, 1H, J = 12.4 Hz), 4.65 (dd, 1H, J = 2.4, 14.8
Hz), 4.64 (d, 1H, J = 3.2 Hz), 4.61 (d, 1H, J = 12.0 Hz), 4.53 (d, 1H,
J = 12.0 Hz), 4.51 (d, 1H, J = 11.2 Hz), 4.50 (d, 1H, J = 12.0 Hz), 4.44
(d, 1H, J = 10.8 Hz), 4.36 (d, 1H, J = 11.6 Hz), 4.31 (d, 1H, J = 11.6
Hz), 4.25 (t, 1H, J = 7.2 Hz), 4.11−4.16 (m, 2H), 3.75 (dd, 1H, J =
2.4, 10.8 Hz), 3.63−3.71 (m, 3H), 3.48−3.53 (m, 3H), 3.29 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 153.7, 138.0, 137.7, 137.5 (2C),
137.3, 128.6, 128.48, 128.46, 128.41, 128.39, 128.3, 128.2, 128.10,
1
ethyl acetate, 1.5:1); [α]D +5.0 (c 1.4, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.23−7.34 (m, 23H), 7.18−7.0 (m, 2H), 5.85 (d, 1H, J = 3.2
Hz), 4.99 (d, 1H, J = 10.4 Hz), 4.76 (d, 1H, J = 2.8 Hz), 4.75 (d, 2H,
J = 10.8 Hz), 4.70 (dd, 1H, J = 3.2, 12.0 Hz), 4.62 (d, 2H, J = 12.0
Hz), 4.58 (d, 1H, J = 3.2 Hz), 4.53 (d, 1H, J = 12.0 Hz), 4.48 (d, 1H, J
= 11.6 Hz), 4.40 (d, 1H, J = 12.0 Hz), 4.34 (d, 1H, J = 12.0 Hz), 4.28
(d, 1H, J = 11.6 Hz), 4.08 (s, 1H), 3.96 (t, 1H, 8.8 Hz), 3.76−3.84 (m,
3H), 3.58−3.65 (m, 2H), 3.52 (dd, 1H, J = 3.2, 9.6 Hz), 3.45 (t, 1H,
7.6 Hz), 3.40 (s, 3H), 3.35−3.38 (m, 1H); 13C NMR (100 MHz,
5269
dx.doi.org/10.1021/jo3002084 | J. Org. Chem. 2012, 77, 5255−5270

The Journal of Organic Chemistry
Article
128.05, 128.0, 127.9, 127.8, 127.7, 127.6, 97.5, 95.5, 78.5, 78.2, 77.5,
77.2, 74.6 (2C), 73.9, 73.7, 73.11 (2C), 73.05, 70.1, 69.8, 68.0, 67.5,
55.0; HRMS (ESI) calcd for C49H52O12Na [M + Na]+ 855.3351, found
855.3355.
7259. (d) Crich, D.; Navuluri, C. Angew. Chem., Int. Ed. 2010, 49,
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(23) The “preactivation” protocol was conducted in a manner where
the glycosyl donor was completely activated and consumed (by TLC
detection) prior to the addition of a glycosyl acceptor.
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ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xinshan@bjmu.edu.cn.
Notes
The authors declare no competing financial interest.
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4949−4958. (b) Geng, Y.; Ye, X.-S. Synlett 2010, 2506−2512.
(26) Lu, S.-R.; Lai, Y.-H.; Chen, J.-H.; Liu, C.-Y.; Mong, K.-K. T.
Angew. Chem., Int. Ed. 2011, 50, 7315−7320.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 21102008) and the
“973” grant from the Ministry of Science and Technology of
China (2012CB822100).
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