Stereocontrolled O -glycosylation with palladium-catalyzed decarboxylative allylation

Article abstract of DOI:10.1021/jo502078c

The Pd-π-allyl intermediate in an electron-rich glycal system with poor reactivity is employed as an efficient glycosyl donor. Starting from glucal derived carbonate, various O-glycosides were formed via a palladium-catalyzed reaction through a tandem decarboxylation, proton abstraction, and nucleophilic addition, in good yields with excellent selectivity. Iterative glycosylation with the same strategy may provide an access to complex oligosaccharides.

Full text of DOI:10.1021/jo502078c

Article
pubs.acs.org/joc
Stereocontrolled O‑Glycosylation with Palladium-Catalyzed
Decarboxylative Allylation
Shaohua Xiang, Jingxi He, Yu Jia Tan, and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: The Pd-π-allyl intermediate in an electron-rich
glycal system with poor reactivity is employed as an efficient
glycosyl donor. Starting from glucal derived carbonate, various
O-glycosides were formed via a palladium-catalyzed reaction
through a tandem decarboxylation, proton abstraction, and nucleophilic addition, in good yields with excellent selectivity.
Iterative glycosylation with the same strategy may provide an access to complex oligosaccharides.
demonstrated in our previous studies.13b It was found that the
INTRODUCTION
■
driving force, release of CO2, made formation of Pd-π-allyl
The construction of glycosidic bonds with high efficiency and
species from carbonate substrates faster and more efficient.
selectivity has been and continues to be a challenging endeavor
Moreover, the resultant Pd-π-allyl intermediate can participate
in carbohydrate chemistry. Enormous progress has been made
in a subsequent intramolecular nucleophilic addition effi-
in the development of new strategies for expeditious glycosidic
ciently.13 We envisioned that this strategy has the potential in
linkage syntheses to construct glycoconjugates and oligosac-
the synthesis of other glycosides through an additional proton
charides due to their common occurrence in many bioactive
abstraction step in the presence of another nucleophile
natural products and their mimetics.1 Besides the continued
(Scheme 1).14 Herein, we describe our initial results of this
interest in traditional glycosyl donors, glycals are becoming
palladium-catalyzed intermolecular glycosylation from glucal
increasingly attractive as they can be transformed into 2,3-
derived allylic carbonates.
unsaturated glycosyl derivatives easily by a classic Ferrier
rearrangement.2 Moreover, the core structures can be function-
RESULTS AND DISCUSSION
alized readily to a variety of sugar scaffolds.3 Lewis acid
■
Compound 1, prepared from 4,6-para-methoxybenzylidene-
glucal and ethyl chloroformate, was selected as the model
substrate in our initial investigation. It was hypothesized that
the product of proton transfer in this case, ethanol, can be
promoted Ferrier rearrangement has demonstrated its capa-
bility on syntheses of such glycosides; however, only the α-
isomer can be furnished as the major product in most cases,
which limits their practical applicability.4 Therefore, the
development of other methods and strategies with impressive
yields and selectivities (particularly β-selectivity) remains
necessary and imperative.
Scheme 1. Palladium-Catalyzed O-Glycosylation
Compared to traditional methods, the reactions with Pd-π-
allyl donors are usually associated with good stereocontrol.
Recently, various convenient and efficient methods with metal
catalysts toward the syntheses of different glycosidic bonds with
excellent selectivity have been reported.5 However, both the
difficulty in formation and the poor reactivity of Pd-π-allyl
intermediates in electron-rich glycal systems prove to be an
impediment in further development of this methodology.6 The
addition of Et2Zn activator provided one way to solve this
problem, and another solution was employing electron-poor
cyclic pyranones as the starting materials.7,8 However, the
employment of a Pd-π-allyl intermediate in an electron-rich
glycal system as an efficient glycosyl donor without activator
has been only reported by Nguyen’s group with phenol type
acceptors.7b Under this situation, the decarboxylative allylation
(DcA), which has been well investigated by many pioneering
groups, such as Tunge,9 Trost,10 Stoltz,11 and others,12 from
more active allylic carbonates provided a viable alternative, as
Received: September 9, 2014
© XXXX American Chemical Society
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a
Table 1. Optimization of Reaction Conditions
b
c
entry
R
base
base loading
yield of 3 (%)
ratio (α:β)
yield of 4 (%)
1
Et
Et
tBu
Et
Et
Et
Et
Et
Et
Et
Et
20
69
55
79
92
80
23
45
62
90
93
45
ND
0:1
ND
1:3
0:1
0:1
2:3
6:1
5:1
0:1
0:1
1:1
68
21
25
2
NaOEt
NaOEt
K2CO3
Cs2CO3
DBU
1.2
1.2
1.2
1.2
1.2
1.2
0.1
0.2
0.5
2.0
2.0
3
4
5
6
7
NaH
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
d
12
a
Unless otherwise specified, all reactions were carried out with 0.1 mmol of 1, 0.2 mmol of 2a, 10% catalyst, and 20% ligand in toluene at 60 °C for
b
c
d
1
12 h. The ratios were determined by H NMR. Isolated yield. At the C-3 position, OCO2Et group was replaced by OAc.
1
Figure 1. Selectivities confirmed by H NMR.
removed with ease from the reaction system at high
temperature, inhibiting the formation of byproduct. For the
glycosyl acceptor, 3,4,5-trimethoxyphenol was first examined
due to its strong nucleophilicity. We initiated our study by
treating glucal carbonate 1 with 3,4,5-trimethoxyphenol 2a
under the same conditions established in our previous work on
intramolecular O-glycosylation.13b However, the desired
product 3a was formed in low yield and 68% of byproduct 4
was observed (entry 1, Table 1). Considering the low
nucleophilicity of the protonated phenol, sodium ethoxide
was added as the base to increase the nucleophilicity.
Gratifyingly, the yield of the product 3 increased significantly
to 69%. At the same time, the yield of the byproduct decreased
to 21%, although sodium ethoxide itself can serve as a
nucleophile to increase the potential of byproduct formation
(entry 2). A subsequent attempt to inhibit formation of
byproduct with a bulky group, tertiary butyl, was, however,
futile. Then, the effect of altering the base was examined. It was
found that Cs2CO3 is most efficient in increasing both the
chemical yield and the anomeric selectivity compared to other
bases, such as K2CO3, DBU, and NaH (entries 4−7). It should
be noted that this reaction is very sensitive to not only the
chemical properties but also the loading of the base. When less
than 0.5 equiv of base was used, the α-isomer was obtained as
the major product, while exclusive β-selectivity was afforded
with more than 0.5 equiv of base (entries 8−11). The substrate
with an OAc leaving group on the C-3 position was then
investigated, but only an α:β = 1:1 mixture was obtained in 45%
yield (entry 12). The ratios of the mixture can be determined
by the 1H NMR with ease, and selected results are summarized
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a
Scheme 2. Substrate Scope of Phenolic O-Glycosides
a
The reaction was conducted at 50 °C.
a
Table 2. Effects of Substituents on the Phenol and Temperature
b
c
entry
R
temperature (°C)
ratio (α:β)
yield of 3 (%)
1
2
3,4,5-trimethoxy
3,4,5-trimethoxy
4-methoxy
4-methoxy
4-fluoro
80
60
70
60
80
60
80
60
60
50
80
70
60
80
60
80
60
0:1
0:1
0:1
0:1
1:1
0:1
1:1
0:1
1:10
0:1
1:1
1:11
0:1
1:3
0:1
1:3
0:1
90
93
95
95
80
78
76
80
92
89
89
90
87
75
80
77
83
3
4
5
6
4-fluoro
7
4-phenyl
8
4-phenyl
9
H
10
11
12
13
14
15
16
17
H
4-methyl
4-methyl
4-methyl
3,4-dimethyl
3,4-dimethyl
3,5-dimethyl
3,5-dimethyl
a
Unless otherwise specified, all reactions were carried out with 0.1 mmol of compound 1, 0.2 mmol of compound 2, 0.2 mmol of Cs2CO3, 10%
b
c
1
catalyst, and 20% ligand in toluene for 12 h. The ratios were determined by H NMR. Isolated yield.
in Figure 1. Hence, our optimized conditions are concluded to
be 10% Pd2(dba)3 as the catalyst, 20% DtBPF (1,1′-bis(di-tert-
butylphosphino)ferrocene) as the ligand, 2.0 equiv of Cs2CO3
as the base, and toluene as the solvent at 60 °C for a reaction
time of 12 h.
With the optimized conditions in hand, we next turned our
attention to exploring the substrate tolerance of this reaction.
As detailed in Scheme 2, a more nucleophilic phenol with a
strong electron-donating group appended to the aromatic ring
gave the desired product in 95% yield (3b), while a slightly
lower yield was observed with a weaker electron-donating
group substituted phenol (3c). Under the optimized con-
ditions, unsubstituted phenol afforded the glycoside in good
yield with a ratio of α:β = 1:10. The pure product can be
furnished by decreasing the temperature to 50 °C, further
illustrating the sensitivity of the reaction in terms of
temperature (3d). This reaction was also tolerant to a fluoro
group on the aromatic ring, shown by the generation of
compound 3e in good yield. 4-Phenyl phenol and 2-naphthol
were then examined and were observed to give the desired
products 3f and 3g in moderate to good yields. The different
positions of the functionalities on a disubstituted phenol had
very little influence on this reaction and gave the O-glycosides
in good yields (3h−3j). It is worth noting that only the β-
isomer was produced in each reaction.
In the optimization section, we found that the selectivity of
the reaction was strongly influenced by the base loading.
Besides that, some results also suggested that the electronic
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Scheme 3. Effect of Substituents on the Phenol
a
Scheme 4. Substrate Scope of Aliphatic O-Glycosides
a
The reaction was conducted with 5a−5f (1.0 mmol) or 5g−5r (0.2 mmol) as the acceptor.
nature of the substituents on the phenol and the reaction
temperature are also important in controlling the stereo-
selectivities of this reaction. From the results detailed in Table
2, it is apparent that a lower reaction temperature always results
in higher selectivity. The good selectivity generally observed
with electron-rich phenol can be retained at higher temper-
atures, but electron-deficient phenol substrates can only afford
good selectivity at lower temperatures, such as 60 °C. Little
variation in yield is observed when the reaction temperature is
above 60 °C.
optimized reaction conditions, the byproduct 4 from ethoxide
addition was observed as the major product (Scheme 3). At the
same time, only a trace amount of desired products 3k and 3m
was detected and compound 3l was isolated in 10% yield as
inseparable mixtures with a ratio of α:β = 1:2.4, which could be
determined by 1H NMR. Noteworthy, the C-3 position
addition products 3′ were also isolated with yields of 18, 13,
and 20%, respectively.15 The difference in regioselectivity (C-1
or C-3) could be explained by the hard and soft acids and bases
(HSAB) principle.16 Further investigations revealed that, in
reactions involving phenols with strong electron-withdrawing
groups, such as 2-nitro phenol (2n) or 2,4,6-tribromo phenol
(2o), no desired product was observed.
Interestingly, the regioselectivity of the reaction could also be
affected by a glycosyl acceptor when electron-deficient phenol
was employed. For instance, when substrates 2k, 2l, and 2m
with an electron-withdrawing group were treated under the
D
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Scheme 5. Preparation of the Trisaccharide 9
Scheme 6. Plausible Mechanism
Having confirmed the efficiency of this reaction in syntheses
of phenolic O-glycosides, we next focused on its extension
toward aliphatic O-glycosides and attempted the synthesis of
disaccharides and oligosaccharides. The aliphatic alcohols were
first investigated and the results shown in Scheme 4
demonstrated that the reaction proceeds efficiently under the
optimized conditions (6a−6f) with the exception of sterically
hindered tertiary butanol (6c). It should be noted that 10 equiv
of alcohol was used in each reaction. Next, glucal with a free
hydroxyl group at different positions was employed. Notably,
the reaction with 3-OH glucals as the substrates proceeded
smoothly to form the desired glycosides, which cannot be
generated by intramolecular glycosylation (6g−6i). The bulky
glycosyl acceptor with a free hydroxyl group in the 4-position
gave the desired product with a much lower yield (6j). The 6-
OH glucal substrates afforded the desired products in good
yields (6k−6l), albeit with a ratio of α:β = 1:10 when PMB was
selected as the protecting group. Glucose type acceptors were
then examined, and gratifyingly, good to excellent yields with
excellent β-selectivity were observed (6m−6p). Galactose and
mannose type glycosides can also be prepared under this set of
conditions, with yields of 83% and 35%, respectively (6q−6r).
Encouraged by the above results, we next explored the
synthetic utility of this approach by the synthesis of
trisaccharide 9. As detailed in Scheme 5, starting from the
first glycosylation product 6l, intermediate 7 was obtained by a
deprotection in the presence of TBAF. In a parallel synthesis,
disaccharide carbonate 8 was prepared according to the
standard procedure for preparation of carbonates. Thereafter,
8 was treated under the optimized conditions with compound
5i as the glycosyl acceptor for the second glycosylation.
Fortunately, the desired product 9 was provided in 68% yield
with exclusive β-selectivity. The ease of access of trisaccharide 9
demonstrates the potential of this methodology in the synthesis
of more complex oligosaccharides.
On the basis of the results obtained and precedent work on
palladium-catalyzed reactions,13,14 we henceforth propose a
plausible mechanism involved in this intermolecular glyco-
sylation. As a traditional palladium-catalyzed decarboxylative
allylation reaction, starting from glucal carbonate compound I,
the palladium intermediate III is first generated by coordination
from the β-face and a subsequent decarboxylative reaction
(Scheme 6). In the absence of other nucleophiles, the
intramolecular product IV is then obtained through an
elimination of the Pd species. In the presence of an external
nucleophile, the reaction is intercepted by a proton transfer
between the ethoxide anion and the added nucleophile, yielding
Pd intermediate V. Thereafter, the desired β-product VI is
obtained with the elimination of the Pd species. Nevertheless,
besides the proton transfer, a nucleophile addition to the allyl
cation from the α-face, which can furnish the α-product, can
take place simultaneously at high temperature. Under such
conditions, a mixture of α- and β-product VII is thus observed.
E
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mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2 mL)
at 60 °C for 12 h gave a crude product that was further purified by
column chromatography (EA:Hexane = 1:6) to afford the desired
phenolic O-glycoside 3c (30.8 mg, 87%) as a white solid. mp 154−156
°C; [α]2D3 = +26.6 (c = 1.0 in CHCl3); IR (neat) ν: 3019, 1520, 1474,
CONCLUSION
■
In summary, we have reported a palladium-catalyzed
intermolecular glycosylation based on a decarboxylative
reaction. Various nucleophiles were tested in this reaction,
and the desired phenolic O-glycosides, aliphatic O-glycosides,
and disaccharides were formed in moderate to good yields with
excellent selectivity. The results also illustrate the sensitivity of
the reaction to the nature and loading of the base, reaction
temperature, and electronic nature of the substrates. In
addition, this method provides a practical and concise method
to synthesize some glycosides that cannot be prepared by the
intramolecular glycosylation. Moreover, by replacing the
complex carbonate substrates with readily available glucal
derivatives, preparation of complex carbonate substrates and
isolation of the related glycosides are more facile and
expeditious. The efficiency and practical applicability were
further proven by the iterative synthesis of a trisaccharide.
Further application of this methodology for the synthesis of
complex oligosaccharides is currently being explored in our
laboratory.
1
1423, 1215, 1032 cm−1; H NMR (400 MHz, CDCl3): δ 7.40−7.45
(m, 2H), 7.07−7.11 (m, 2H), 6.96−7.01 (m, 2H), 6.87−6.92 (m, 2H),
6.23 (d, J = 10.3 Hz, 1H), 5.88−5.91 (m, 1H), 5.82 (ddd, J1 = 10.3 Hz,
J2 = 2.5 Hz, J3 = 1.7 Hz, 1H), 5.57 (s, 1H), 4.38−4.42 (m, 1H), 4.25−
4.35 (m, 1H), 3.82−3.92 (m, 2H), 3.79 (s, 3H), 2.30 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3): δ 160.2, 154.6, 132.1, 132.0, 129.9, 129.7,
127.5, 127.3, 116.8 113.7, 102.0, 97.0, 74.7, 70.9, 69.0, 55.3, 20.6 ppm;
HRMS (ESI) calcd. for C21H22O5Na [M + Na]: 377.1365, found:
377.1359.
(4aR,6S,8aS)-2-(4-Methoxyphenyl)-6-phenoxy-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3]dioxine (3d). Following the general proce-
dure, the reaction with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3 (9.2
mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol), phenol 2d (18.8
mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2 mL)
at 60 °C for 12 h gave a crude product that was further purified by
column chromatography (EA:Hexane = 1:6) to afford the desired
phenolic O-glycoside 3d (30.3 mg, 89%) as a white solid.13b
(4aR,6S,8aS)-6-(4-Fluorophenoxy)-2-(4-methoxyphenyl)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (3e). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
phenol 2e (22.4 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in
toluene (2 mL) at 60 °C for 12 h gave a crude product that was further
purified by column chromatography (EA:Hexane = 1:6) to afford the
desired phenolic O-glycoside 3e (27.9 mg, 78%) as a white solid.13b
(4aR,6S,8aS)-6-(Biphenyl-4-yloxy)-2-(4-methoxyphenyl)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (3f). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
phenol 2f (34.0 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in
toluene (2 mL) at 60 °C for 12 h gave a crude product that was further
purified by column chromatography (EA:Hexane = 1:6) to afford the
desired phenolic O-glycoside 3f (33.3 mg, 80%) as a white solid.13b
(4aR,6S,8aS)-2-(4-Methoxyphenyl)-6-(naphthalen-2-yloxy)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (3g). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
phenol 2g (28.8 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in
toluene (2 mL) at 60 °C for 12 h gave a crude product that was further
purified by column chromatography (EA:Hexane = 1:6) to afford the
desired phenolic O-glycoside 3g (26.9 mg, 69%) as a white solid.13b
(4aR,6S,8aS)-6-(2,6-Dimethylphenoxy)-2-(4-methoxyphenyl)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (3h). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
phenol 2h (24.4 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in
toluene (2 mL) at 60 °C for 12 h gave a crude product that was further
purified by column chromatography (EA:Hexane = 1:6) to afford the
desired phenolic O-glycoside 3h (28.7 mg, 78%) as a white solid.13b
(4aR,6S,8aS)-6-(3,5-Dimethylphenoxy)-2-(4-methoxyphenyl)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (3i). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
phenol 2i (24.4 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in
toluene (2 mL) at 60 °C for 12 h gave a crude product that was further
purified by column chromatography (EA:Hexane = 1:6) to afford the
desired phenolic O-glycoside 3i (30.5 mg, 83%) as a white solid.13b
(4aR,6S,8aS)-6-(3,4-Dimethylphenoxy)-2-(4-methoxyphenyl)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (3j). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
phenol 2j (24.4 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in
toluene (2 mL) at 60 °C for 12 h gave a crude product that was further
purified by column chromatography (EA:Hexane = 1:6) to afford the
desired phenolic O-glycoside 3j (29.4 mg, 80%) as a white solid. mp
EXPERIMENTAL SECTION
■
General Procedure for Preparing Phenolic O-Glycosides. To
a mixture of DtBPF (0.02 mmol), Pd2(dba)3 (0.01 mmol), carbonate 1
(0.1 mmol), phenol 2 (0.2 mmol), and Cs2CO3 (0.2 mmol) was added
toluene (2 mL) under an atmosphere of argon. After stirring at 60 °C
for 12 h, the solvent was removed under reduced pressure to give a
crude product that was further purified by column chromatography to
afford the desired phenolic O-glycosides 3 with 69−95% yields.
(4aR,6S,8aS)-2-(4-Methoxyphenyl)-6-(3,4,5-trimethoxyphenoxy)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (3a). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
phenol 2a (36.8 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in
toluene (2 mL) at 60 °C for 12 h gave a crude product that was further
purified by column chromatography (EA:Hexane = 1:2) to afford
phenolic O-glycoside 3a (40.0 mg, 93%) as a white solid. mp 153−155
°C; [α]2D3 = +15.0 (c = 1.0 in CHCl3); IR (neat) ν: 3016, 2303, 1695,
1
1616, 1477, 1415, 1215, 1088 cm−1; H NMR (400 MHz, CDCl3): δ
7.41−7.44 (m, 2H), 6.86−6.93 (m, 2H), 6.36 (s, 2H), 6.26 (d, J = 10.3
Hz, 1H), 5.89−5.92 (m, 1H), 5.83 (ddd, J1 = 10.3 Hz, J2 = 2.4 Hz, J3 =
1.8 Hz, 1H), 5.59 (s, 1H), 4.39−4.44 (m, 1H), 4.26−4.34 (m, 1H),
3.79−3.94 (m, 14H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.2,
153.6, 153.1, 133.9, 132.3, 129.6, 127.5, 126.9, 113.7, 102.1, 97.2, 95.1,
74.6, 71.0, 68.9, 60.9, 56.1, 55.3 ppm; HRMS (ESI) calcd. for
C23H26O8Na [M + Na]: 453.1525, found: 453.1522.
(4aR,6S,8aS)-6-(4-Methoxyphenoxy)-2-(4-methoxyphenyl)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (3b). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
phenol 2b (24.8 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in
toluene (2 mL) at 60 °C for 12 h gave a crude product that was further
purified by column chromatography (EA:Hexane = 1:4) to afford
phenolic O-glycoside 3b (35.1 mg, 95%) as a white solid. mp 140−142
°C; [α]2D3 = +31.2 (c = 1.0 in CHCl3); IR (neat) ν: 3018, 2308, 1694,
1620, 1523, 1479, 1411, 1085, 1023 cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.43 (d, J = 8.7 Hz, 2H), 7.01−7.07 (m, 2H), 6.87−6.93
(m, 2H), 6.80−6.86 (m, 2H), 6.23 (d, J = 10.5 Hz, 1H), 5.80−5.86
(m, 2H), 5.58 (s, 1H), 4.37−4.42 (m, 1H), 4.28−4.34 (m, 1H), 3.83−
3.94 (m, 2H), 3.80 (s, 3H), 3.77 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 160.2, 155.3, 150.7, 132.0, 129.7, 127.5, 127.3, 118.4, 114.5,
113.7, 102.1, 97.8, 74.7, 70.9, 69.0, 55.6, 55.3 ppm; HRMS (ESI) calcd.
for C21H22O6Na [M + Na]: 393.1350, found: 393.1350.
(4aR,6S,8aS)-2-(4-Methoxyphenyl)-6-(p-tolyloxy)-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3]dioxine (3c). Following the general proce-
dure, the reaction with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3 (9.2
mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol), phenol 2c (21.6
F
dx.doi.org/10.1021/jo502078c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
107−109 °C; [α]2D3 = +29.9 (c = 1.0 in CHCl3); IR (neat) ν: 3022,
1614, 1517, 1476, 1423, 1382, 1217, 1126, 1088, 1023 cm−1; 1H NMR
(400 MHz, CDCl3): δ 7.40−7.45 (m, 2H), 7.01−7.06 (m, 1H), 6.81−
6.93 (m, 4H), 6.23 (d, J = 10.3 Hz, 1H), 5.88−5.93 (m, 1H), 5.79−
5.86 (m, 1H), 5.58 (s, 1H), 4.38−4.43 (m, 1H), 4.26−4.35 (m, 1H),
3.83−3.93 (m, 2H), 3.80 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3): δ 160.2, 154.9, 137.8, 131.9, 130.8, 130.3,
129.8, 127.5, 127.4, 118.4, 114.1 113.7, 102.1, 97.1, 74.8, 71.0, 69.0,
55.3, 20.0, 18.9 ppm; HRMS (ESI) calcd. for C22H24O5Na [M + Na]:
391.1521, found: 391.1517.
General Procedure for Preparing Compounds 3k′, 3l′, and
3m′. To a mixture of DtBPF (0.02 mmol), Pd2(dba)3 (0.01 mmol),
carbonate 1 (0.1 mmol), phenol 2 (0.2 mmol), and Cs2CO3 (0.2
mmol) was added toluene (2 mL) under an atmosphere of argon.
After stirring at 60 °C for 12 h, the solvent was removed under
reduced pressure to give a crude product that was further purified by
column chromatography to afford compound 3′ with 13−25% yields.
For these three substrates, compound 4 was obtained as the major
product and compound 3 was observed as a mixture.
2-((4aR,8R,8aS)-2-(4-Methoxyphenyl)-4,4a,8,8a-tetrahydro-
pyrano[3,2-d][1,3]dioxin-8-yloxy)phenol (3k′). Following the general
procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3
(9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol), phenol 2k
(24.4 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2
mL) at 60 °C for 12 h gave a crude product that was further purified
by column chromatography (EA:Hexane = 1:6) to afford compound
3k′ (7.4 mg, 20%) as a white solid. mp 122−124 °C; [α]2D3 = −123.5 (c
= 0.35 in CHCl3); IR (neat) ν: 3018, 1603, 1519, 1474, 1415, 1212,
1029 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.83 (dd, J1 = 7.8 Hz, J2 =
1.8 Hz, 1H), 7.47−7.55 (m, 1H), 7.33−7.40 (m, 2H), 7.13 (d, J = 8.4
Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.87 (dd, J1 = 9.6 Hz, J2 = 2.8 Hz,
2H), 6.46 (dd, J1 = 6.2 Hz, J2 = 1.2 Hz, 1H), 5.62 (s, 1H), 5.16−5.22
(m, 1H), 4.92 (dd, J1 = 6.2 Hz, J2 = 1.8 Hz, 1H), 4.43 (dd, J1 = 10.6
Hz, J2 = 5.1 Hz, 1H), 4.23 (dd, J1 = 10.3 Hz, J2 = 7.5 Hz, 1H), 4.06 (dt,
J1 = 10.2 Hz, J2 = 5.1 Hz, 1H), 3.90 (t, J = 10.4 Hz, 1H), 3.79 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 189.8, 160.5, 160.2, 145.8,
135.7, 129.3, 128.4, 127.3, 126.0, 121.5, 115.1, 113.6, 101.5, 99.8, 78.1,
73.6, 68.9, 68.2, 55.3 ppm; HRMS (ESI) calcd. for C21H21O6 [M + H]:
369.1338, found: 369.1337.
1H), 5.02−5.09 (m, 1H), 4.95 (dd, J1 = 6.2 Hz, J2 = 1.8 Hz, 1H), 4.40
(dd, J1 = 10.4 Hz, J2 = 5.0 Hz, 1H), 4.27 (dd, J1 = 10.2 Hz, J2 = 7.5 Hz,
1H), 4.00 (dt, J1 = 10.2 Hz, J2 = 5.1 Hz, 1H), 3.88 (t, J = 10.4 Hz, 1H),
3.79 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.0, 155.0,
145.3, 133.4, 129.5, 128.3, 127.3, 123.0, 117.4, 114.0, 113.5, 101.2,
100.7, 78.5, 75.0, 68.9, 68.2, 55.3 ppm; HRMS (ESI) calcd. for
C20H20O5Br [M + H]: 419.0494, found: 419.0493.
General Procedure for Preparing Aliphatic O-Glycosides. To
a mixture of DtBPF (0.02 mmol), Pd2(dba)3 (0.01 mmol), carbonate 1
(0.1 mmol), alcohol 5 (5a−5f, 1.0 mmol), and Cs2CO3 (0.2 mmol)
was added toluene (2 mL) under an atmosphere of argon. After
stirring at 60 °C for 12 h, the solvent was removed under reduced
pressure to give a crude product that was further purified by column
chromatography to afford the desired aliphatic O-glycosides 6a−6f
with 55−88% yields.
(4aR,6R,8aS)-6-Methoxy-2-(4-methoxyphenyl)-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3]dioxine (6a). Following the general proce-
dure, the reaction with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3 (9.2
mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol), methanol 5a (32.0
mg, 1.0 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2 mL)
at 60 °C for 12 h gave a crude product that was further purified by
column chromatography (EA:Hexane = 1:6) to afford the desired
aliphatic O-glycoside 6a (21.7 mg, 78%) as a white solid.13b
(4aR,6R,8aS)-6-Isopropoxy-2-(4-methoxyphenyl)-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3]dioxine (6b). Following the general proce-
dure, the reaction with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3 (9.2
mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol), isopropanol 5b
(60.1 mg, 1.0 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2
mL) at 60 °C for 12 h gave a crude product that was further purified
by column chromatography (EA:Hexane = 1:6) to afford the desired
aliphatic O-glycoside 6b (20.8 mg, 68%) as a white solid. mp 83−85
°C; [α]2D3 = +36.6 (c = 1.0 in CHCl3); IR (neat) ν: 3016, 1614, 1595,
1518, 1462, 1219, 1032 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.39−
7.45 (m, 2H), 6.86−6.91 (m, 2H), 6.09 (d, J = 10.3 Hz, 1H), 5.62−
5.69 (m, 1H), 5.60 (s, 1H), 5.37−5.41 (m, 1H), 4.30−4.36 (m, 1H),
4.26 (dd, J1 = 10.2 Hz, J2 = 4.5 Hz, 1H), 4.03 (septet, J = 6.2 Hz, 1H),
3.86 (t, J = 10.3 Hz, 1H), 3.80 (s, 3H), 3.70−3.77 (m, 1H), 1.26 (d, J
= 6.2 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 160.1, 130.8, 129.9, 129.1, 127.5, 113.7, 102.0, 97.3, 75.0,
71.0, 70.5, 69.1, 55.3, 23.6, 22.1 ppm; HRMS (ESI) calcd. for
C17H22O5Na [M + Na]: 329.1365, found: 329.1368.
(4aR,6R,8aS)-6-Butoxy-2-(4-methoxyphenyl)-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3]dioxine (6d). Following the general proce-
dure, the reaction with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3 (9.2
mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol), n-butanol 5d (74.1
mg, 1.0 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2 mL)
at 60 °C for 12 h gave a crude product that was further purified by
column chromatography (EA:Hexane = 1:6) to afford the desired
aliphatic O-glycoside 6d (23.0 mg, 72%) as a white solid. mp 76−78
°C; [α]2D3 = +43.4 (c = 1.0 in CHCl3); IR (neat) ν: 3017, 1614, 1517,
1422, 1248 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.39−7.44 (m, 2H),
6.86−6.92 (m, 2H), 6.12 (d, J = 10.3 Hz, 1H), 5.65−5.72 (m, 1H),
5.59 (s, 1H), 5.31−5.35 (m, 1H), 4.24−4.34 (m, 2H), 3.70−3.89 (m,
6H), 3.48−3.57 (m, 1H), 1.57−1.65 (m, 2H), 1.33−1.45 (m, 2H),
0.93 (t, J = 7.4 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.1,
131.1, 129.8, 128.5, 127.5, 113.7, 102.0, 98.6, 75.0, 70.4, 69.0, 68.0,
55.2, 31.7, 19.2, 13.8 ppm; HRMS (ESI) calcd. for C18H25O5 [M + H]:
321.1702, found: 321.1689.
3-((4aR,8R,8aS)-2-(4-Methoxyphenyl)-4,4a,8,8a-tetrahydro-
pyrano[3,2-d][1,3]dioxin-8-yloxy)phenol (3l′). Following the general
procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3
(9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol), phenol 2l
(24.4 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2
mL) at 60 °C for 12 h gave a crude product that was further purified
by column chromatography (EA:Hexane = 1:6) to afford compound
3l′ (4.8 mg, 13%) as a white solid. mp 129−131 °C; [α]2D3 = −33.2 (c
= 0.30 in CHCl3); IR (neat) ν: 3020, 1602, 1517, 1477, 1416, 1214,
1
1125 cm−1; H NMR (400 MHz, CDCl3): δ 7.50−7.54 (m, 1H),
7.35−7.50 (m, 4H), 7.22−7.26 (m, 1H), 6.83−6.89 (m, 2H), 6.42−
6.47 (m, 1H), 5.61 (s, 1H), 5.13−5.19 (m, 1H), 4.89 (dd, J1 = 6.2 Hz,
J2 = 1.6 Hz, 1H), 4.41 (dd, J1 = 10.6 Hz, J2 = 5.1 Hz, 1H), 4.17 (dd, J1
= 10.3 Hz, J2 = 7.5 Hz, 1H), 4.06 (dt, J1 = 10.2 Hz, J2 = 5.1 Hz, 1H),
3.89 (t, J = 10.4 Hz, 1H), 3.79 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 191.9, 160.2, 158.4, 145.5, 137.8, 130.1, 129.4, 127.4, 123.6,
123.2, 115.2, 113.6, 101.5, 100.0, 78.2, 72.7, 68.9, 68.2, 55.3 ppm;
HRMS (ESI) calcd. for C21H21O6 [M + H]: 369.1338, found:
369.1342.
(4aR,8R,8aS)-8-(2-Bromophenoxy)-2-(4-methoxyphenyl)-
4,4a,8,8a-tetrahydropyrano[3,2-d][1,3]dioxine (3m′). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
phenol 2m (34.6 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in
toluene (2 mL) at 60 °C for 12 h gave a crude product that was further
purified by column chromatography (EA:Hexane = 1:6) to afford
compound 3m′ (10.5 mg, 25%) as a white solid. mp 92−94 °C; [α]D23
= −60.8 (c = 0.75 in CHCl3); IR (neat) ν: 3023, 1603, 1514, 1216,
1179, 1133, 1027 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.53 (dd, J1 =
7.9 Hz, J2 = 1.4 Hz, 1H), 7.31−7.39 (m, 2H), 7.18−7.25 (m, 1H),
7.09−7.15 (m, 1H), 6.82−6.91 (m, 3H), 6.40−6.46 (m, 1H), 5.62 (s,
(4aR,6R,8aS)-6-(Cyclohexyloxy)-2-(4-methoxyphenyl)-4,4a,6,8a-
tetrahydropyrano[3,2-d][1,3]dioxine (6e). Following the general
procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
cyclohexanol 5e (100.2 mg, 1.0 mmol), and Cs2CO3 (65.2 mg, 0.2
mmol) in toluene (2 mL) at 60 °C for 12 h gave a crude product that
was further purified by column chromatography (EA:Hexane = 1:6) to
afford the desired aliphatic O-glycoside 6e (19.0 mg, 55%) as a white
solid. mp 108−110 °C; [α]2D3 = +33.7 (c = 1.0 in CHCl3); IR (neat) ν:
1
3016, 1616, 1252, 1085, 1029 cm−1; H NMR (400 MHz, CDCl3): δ
7.39−7.44 (m, 2H), 6.86−6.91 (m, 2H), 6.09 (d, J = 10.3 Hz, 1H),
5.63−5.70 (m, 1H), 5.56 (s, 1H), 5.41−5.46 (m, 1H), 4.31−4.37 (m,
G
dx.doi.org/10.1021/jo502078c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 4.26 (dd, J1 = 10.2 Hz, J2 = 4.5 Hz, 1H), 3.64−3.90 (m, 6H),
1.87−2.01 (m, 2H), 1.69−1.80 (m, 2H), 1.13−1.46 (m, 6H) ppm; 13C
NMR (100 MHz, CDCl3): δ 160.1, 130.7, 129.9, 129.3, 127.5, 113.7,
102.0, 97.1, 76.7, 75.1, 70.5, 69.1, 55.3, 33.7, 32.2, 25.5, 24.3, 24.1
ppm; HRMS (ESI) calcd. for C20H27O5 [M + H]: 347.1858, found:
347.1865.
65.8, 55.3, 27.4, 26.9, 22.7, 19.9 ppm; HRMS (ESI) calcd. for
C28H40O8NaSi [M + Na]: 555.2390, found: 555.2380.
tert-Butyl(((2R,3R,4S)-4-(tert-butyldimethylsilyloxy)-3-
((4aR,6S,8aS)-2-(4-methoxyphenyl)-4,4a,6,8a-tetrahydropyrano-
[3,2-d][1,3]dioxin-6-yloxy)-3,4-dihydro-2H-pyran-2-yl)methoxy)-
dimethylsilane (6j). Following the general procedure, the reaction
with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol),
carbonate 1 (33.6 mg, 0.1 mmol), compound 5j (74.9 mg, 0.2 mmol),
and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2 mL) at 60 °C for 12 h
gave a crude product that was further purified by column
chromatography (EA:Hexane = 1:20) to afford the desired
disaccharide 6j (34.1 mg, 55%) as a colorless oil. [α]2D3 = +20.0 (c =
1.0 in CHCl3); IR (neat) ν: 3015, 1650, 1614, 1522, 1254, 1082 cm−1;
1H NMR (400 MHz, CDCl3): δ 7.39−7.44 (m, 2H), 6.86−6.91 (m,
2H), 6.32 (dd, J1 = 6.2 Hz, J2 = 0.7 Hz, 1H), 6.10 (d, J = 10.3 Hz, 1H),
5.73 (ddd, J1 = 10.3 Hz, J2 = 2.4 Hz, J3 = 1.3 Hz, 1H), 5.54−5.58 (m,
2H), 4.70 (dd, J1 = 6.1 Hz, J2 = 3.5 Hz, 1H), 4.28−4.34 (m, 1H),
4.19−4.28 (m, 2H), 3.91−4.04 (m, 3H), 3.78−3.88 (m, 5H), 3.72
(ddd, J1 = 10.3 Hz, J2 = 8.4 Hz, J3 = 4.6 Hz, 1H), 0.87−0.94 (m, 18H),
0.09−0.13 (m, 6H), 0.05−0.09 (m, 6H) ppm; 13C NMR (100 MHz,
CDCl3): δ 160.1, 143.3, 131.1, 129.8, 128.4, 127.5, 113.7, 102.5, 102.0,
98.4, 78.0, 75.0, 74.8, 70.7, 69.0, 66.5, 61.5, 55.3, 25.9, 25.8, 18.3, 18.1,
−4.6(2C), −5.2, −5.3 ppm; HRMS (ESI) calcd. for C32H52O8NaSi2
[M + Na]: 643.3098, found: 643.3106.
(4aR,6R,8aS)-6-(((2R,3S,4R)-3,4-Bis(4-methoxybenzyloxy)-3,4-di-
hydro-2H-pyran-2-yl)methoxy)-2-(4-methoxyphenyl)-4,4a,6,8a-
tetrahydropyrano[3,2-d][1,3]dioxide (6k). Following the general
procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
compound 5k (77.3 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol)
in toluene (2 mL) at 60 °C for 12 h gave a crude product that was
further purified by column chromatography (EA:Hexane = 1:4) to
afford the desired disaccharide 6k (49.9 mg, 79%, α:β = 1:9) as a
yellow solid.13b
(4aR,6R,8aS)-6-(((2R,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-(4-
methoxybenzyloxy)-3,4-dihydro-2H-pyran-2-yl)methoxy)-2-(4-
methoxyphenyl)-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine
(6l). Following the general procedure, the reaction with DtBPF (9.5
mg, 0.02 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6
mg, 0.1 mmol), compound 5l (76.1 mg, 0.2 mmol), and Cs2CO3 (65.2
mg, 0.2 mmol) in toluene (2 mL) at 60 °C for 12 h gave a crude
product that was further purified by column chromatography
(EA:Hexane = 1:5) to afford the desired disaccharide 6l (55.1 mg,
88%) as a colorless oil.13b
(4aR,6R,8aS)-2-(4-Methoxyphenyl)-6-(((2R,3R,4S,5R,6S)-3,4,5-tris-
(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methoxy)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (6m). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
compound 5m (92.9 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2
mmol) in toluene (2 mL) at 60 °C for 12 h gave a crude product that
was further purified by column chromatography (EA:Hexane = 1:2) to
afford the desired disaccharide 6m (62.5 mg, 88%) as a white solid.13b
(4aR,6S,8aS)-6-((2R,3R,4S,5R,6S)-4,5-Bis(benzyloxy)-2-(benzyloxy-
methyl)-6-methoxytetrahydro-2H-pyran-3-yloxy)-2-(4-methoxy-
phenyl)-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (6n). Follow-
ing the general procedure, the reaction with DtBPF (9.5 mg, 0.02
mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1
mmol), compound 5n (92.9 mg, 0.2 mmol), and Cs2CO3 (65.2 mg,
0.2 mmol) in toluene (2 mL) at 60 °C for 12 h gave a crude product
that was further purified by column chromatography (EA:Hexane =
1:2) to afford the desired disaccharide 6n (51.8 mg, 73%) as a
colorless oil.13b
(4aR,6S,8aS)-6-((3aR,5R,6S,6aR)-5-((S)-2,2-Dimethyl-1,3-dioxo-
lan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yloxy)-2-
(4-methoxyphenyl)-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine
(6o). Following the general procedure, the reaction with DtBPF (9.5
mg, 0.02 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6
mg, 0.1 mmol), compound 5o (52.1 mg, 0.2 mmol), and Cs2CO3
(65.2 mg, 0.2 mmol) in toluene (2 mL) at 60 °C for 12 h gave a crude
product that was further purified by column chromatography
(4aR,6R,8aS)-6-(Benzyloxy)-2-(4-methoxyphenyl)-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3]dioxine (6f). Following the general proce-
dure, the reaction with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3 (9.2
mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol), benzyl alcohol 5f
(108.1 mg, 1.0 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2
mL) at 60 °C for 12 h gave a crude product that was further purified
by column chromatography (EA:Hexane = 1:6) to afford the desired
aliphatic O-glycoside 6f (31.1 mg, 88%) as a white solid.13b
General Procedure for Preparing Disaccharides. To a mixture
of DtBPF (0.02 mmol), Pd2(dba)3 (0.01 mmol), carbonate 1 (0.1
mmol), alcohol 5 (5g−5r, 0.2 mmol), and Cs2CO3 (0.2 mmol) was
added toluene (2 mL) under an atmosphere of argon. After stirring at
60 °C for 12 h, the solvent was removed under reduced pressure to
give a crude product that was further purified by column
chromatography to afford the desired disaccharides 6g−6r with 35−
89% yields.
(4aR,8R,8aS)-2-(4-Methoxyphenyl)-8-((4aR,6R,8aS)-2-(4-
methoxyphenyl)-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxin-6-
yloxy)-4,4a,8,8a-tetrahydropyrano[3,2-d][1,3]dioxine (6g). Follow-
ing the general procedure, the reaction with DtBPF (9.5 mg, 0.02
mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1
mmol), compound 5g (52.8 mg, 0.2 mmol), and Cs2CO3 (65.2 mg,
0.2 mmol) in toluene (2 mL) at 60 °C for 12 h gave a crude product
that was further purified by column chromatography (EA:Hexane =
1:3) to afford the desired disaccharide 6g (35.7 mg, 70%) as a white
solid.13b
(4aR,6R,8aS)-6-((2R,3S,4R)-3-(Benzyloxy)-2-(benzyloxymethyl)-
3,4-dihydro-2H-pyran-4-yloxy)-2-(4-methoxyphenyl)-4,4a,6,8a-
tetrahydropyrano[3,2-d][1,3]dioxide (6h). Following the general
procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
compound 5h (65.3 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol)
in toluene (2 mL) at 60 °C for 12 h gave a crude product that was
further purified by column chromatography (EA:Hexane = 1:4) to
afford the desired disaccharide 6h (31.5 mg, 55%) as a white solid. mp
94−96 °C; [α]2D3 = +54.6 (c = 0.7 in CHCl3); IR (neat) ν: 3016, 2303,
1
1614, 1596, 1523, 1466, 1218 cm−1; H NMR (400 MHz, CDCl3): δ
7.26−7.43 (m, 12H), 6.86−6.92 (m, 2H), 6.41−6.46 (m, 2H), 6.12 (d,
J = 10.3 Hz, 1H), 5.60 (ddd, J1 = 10.3 Hz, J2 = 2.4 Hz, J3 = 1.5 Hz,
1H), 5.48−5.53 (m, 2H), 4.83−4.91 (m, 2H), 4.55−4.66 (m, 3H),
4.45−4.51 (m, 1H), 4.18−4.26 (m, 2H), 4.08−4.15 (m, 1H), 3.85 (dd,
J1 = 7.9 Hz, J2 = 5.8 Hz, 1H), 3.69−3.82 (m, 7H) ppm; 13C NMR (100
MHz, CDCl3): δ 160.2, 144.9, 138.3, 138.0, 131.5, 129.8, 128.4(2C),
128.3, 127.9, 127.7, 127.6, 127.5, 113.7, 102.0, 99.8, 96.9, 75.0, 74.2,
73.4, 72.8, 70.6, 69.0, 68.5 ppm; HRMS (ESI) calcd. for C34H36O8Na
[M + Na]: 595.2308, found: 595.2331.
(4aR,8R,8aS)-2,2-Di-tert-butyl-8-((4aR,6R,8aS)-2-(4-methoxy-
phenyl)-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxin-6-yloxy)-
4,4a,8,8a-tetrahydropyrano[3,2-d][1,3,2]dioxasiline (6i). Following
the general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
compound 5i (57.3 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2 mmol)
in toluene (2 mL) at 60 °C for 12 h gave a crude product that was
further purified by column chromatography (EA:Hexane = 1:20) to
afford the desired disaccharide 6i (19.7 mg, 37%) as a colorless oil.
[α]2D3 = +57.4 (c = 0.44 in CHCl3); IR (neat) ν: 3016, 1655, 1608,
1523, 1258 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.39−7.45 (m, 2H),
6.86−6.92 (m, 2H), 6.27 (dd, J1 = 6.0 Hz, J2 = 1.4 Hz, 1H), 6.16 (d, J
= 10.3 Hz, 1H), 5.71−5.78 (m, 1H), 5.65−5.70 (m, 1H), 5.58 (s, 1H),
4.78 (dd, J1 = 6.0 Hz, J2 = 2.0 Hz, 1H), 4.25−4.36 (m, 3H), 4.16 (dd,
J1 = 10.3 Hz, J2 = 4.9 Hz, 1H), 4.09 (dd, J1 = 10.3 Hz, J2 = 7.3 Hz, 1H),
3.97 (t, J = 10.3 Hz, 1H), 3.72−3.88 (m, 6H), 1.08 (s, 9H), 1.00 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.2, 144.0, 131.4, 129.8,
129.3, 127.5, 113.7, 103.4, 102.0, 97.9, 75.0, 74.9, 74.0, 73.1, 71.0, 69.1,
H
dx.doi.org/10.1021/jo502078c | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
(EA:Hexane = 1:3) to afford the desired disaccharide 6o (39.5 mg,
78%) as a colorless oil.13b
(ddd, J1 = 9.3 Hz, J2 = 4.5 Hz, J3 = 2.3 Hz, 1H), 3.78−3.90 (m, 8H),
3.70−3.78 (m, 1H), 3.61 (dd, J1 = 9.4 Hz, J2 = 6.6 Hz, 1H), 1.76−1.84
(m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.2, 159.4, 144.4,
132.0, 130.3, 129.7, 129.6, 127.8, 127.5, 114.0, 113.7, 102.9, 102.0,
98.6, 76.5, 76.4, 74.8, 73.4, 70.6, 69.5, 68.9, 65.5, 55.3 ppm; HRMS
(ESI) calcd. for C28H32O9Na [M + Na]: 535.1944, found: 535.1943.
Ethyl(2R,3S,4R)-3-(4-methoxybenzyloxy)-2-(((4aR,6R,8aS)-2-(4-
methoxyphenyl)-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxin-6-
yloxy)methyl)-3,4-dihydro-2H-pyran-4-yl Carbonate (8). To a
solution of compound 7 (0.2 mmol) in DCM (5 mL) was added
pyridine (1.0 mmol) at 0 °C. Then, ethyl chloroformate (0.8 mmol)
was added slowly. The mixture was allowed to warm to room
temperature and stir overnight. After the reaction was completed, the
solvent was removed under reduced pressure. The residue was purified
by column chromatography (EA:Hexane = 1:4) on silica gel to provide
compound 8 (99.4 mg, 85%) as a colorless oil. [α]2D3 = +43.3 (c = 1.0
in CHCl3); IR (neat) ν: 3022, 1649, 1616, 1522, 1417, 1243, 1128
cm−1; 1H NMR (400 MHz, CDCl3): δ 7.40−7.48 (m, 2H), 7.26−7.34
(m, 2H), 6.87−6.95 (m, 4H), 6.47 (dd, J1 = 6.1 Hz, J2 = 0.8 Hz, 1H),
6.15−6.22 (m, 1H), 5.66−5.74 (m, 1H), 5.57 (s, 1H), 5.38−5.44 (m,
1H), 5.27−5.35 (m, 1H), 4.87 (dd, J1 = 6.1 Hz, J2 = 3.0 Hz, 1H),
4.70−4.78 (m, 1H), 4.60−4.68 (m, 1H), 4.20−4.34 (m, 4H), 4.10−
4.15 (m, 1H), 4.04 (dd, J1 = 10.9 Hz, J2 = 2.7 Hz, 1H), 3.79−3.94 (m,
9H), 3.71−3.79 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 160.1, 159.3, 154.6, 145.9, 131.9, 129.8, 129.7,
129.4, 127.7, 127.4, 113.8, 113.6, 101.9, 98.6, 98.5, 76.3, 74.8, 74.2,
73.0, 72.6, 70.5, 68.9, 65.0, 64.0, 55.2, 14.2 ppm; HRMS (ESI) calcd.
for C31H36O11Na [M + Na]: 607.2155, found: 607.2148.
tert-Butyl((2R,3R,4R)-3-(4-methoxybenzyloxy)-2-(((2R,5S,6R)-5-(4-
methoxybenzyloxy)-6-(((4aR,6R,8aS)-2-(4-methoxyphenyl)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxin-6-yloxy)methyl)-5,6-
dihydro-2H-pyran-2-yloxy)methyl)-3,4-dihydro-2H-pyran-4-yloxy)-
dimethylsilane (9). To a mixture of DtBPF (0.02 mmol), Pd2(dba)3
(0.01 mmol), carbonate 8 (0.1 mmol), compound 5i (0.2 mmol), and
Cs2CO3 (0.2 mmol) was added toluene (2 mL) under an atmosphere
of argon. After stirring at 60 °C for 12 h, the solvent was removed
under reduced pressure to give a crude product that was further
purified by column chromatography (EA:CH2Cl2 = 1:10) to afford the
desired trisaccharide 9 (59.5 mg, 68%) as a colorless oil. [α]2D3 = +49.3
(c = 1.0 in CHCl3); IR (neat) ν: 3025, 1652, 1616, 1517, 1130 cm−1;
1H NMR (400 MHz, CDCl3): δ 7.38−7.45 (m, 2H), 7.21−7.29 (m,
((2S,3R,4S,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-3-
((4aR,6S,8aS)-2-(4-methoxyphenyl)-4,4a,6,8a-tetrahydropyrano-
[3,2-d][1,3]dioxin-6-yloxy)tetrahydro-2H-pyran-2-yloxy)(tert-butyl)-
dimethylsilane (6p). Following the general procedure, the reaction
with DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol),
carbonate 1 (33.6 mg, 0.1 mmol), compound 5p (113.0 mg, 0.2
mmol), and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2 mL) at 60 °C
for 12 h gave a crude product that was further purified by column
chromatography (EA:Hexane = 1:4) to afford the desired disaccharide
6p (72.1 mg, 89%) as a colorless oil. [α]2D3 = +28.7 (c = 1.0 in CHCl3);
IR (neat) ν: 3016, 1650, 1614, 1520, 1252, 1214 cm−1; 1H NMR (400
MHz, CDCl3): δ 7.17−7.43 (m, 17H), 6.85−6.91 (m, 2H), 6.03 (d, J
= 10.3 Hz, 1H), 5.68−5.75 (m, 1H), 5.60−5.66 (m, 1H), 5.53 (s, 1H),
4.77−4.88 (m, 3H), 4.51−4.65 (m, 4H), 4.25−4.32 (m, 1H), 4.21 (dd,
J1 = 10.2 Hz, J2 = 4.5 Hz, 1H), 3.75−3.85 (m, 4H), 3.53−3.73 (m,
6H), 3.40−3.49 (m, 1H), 0.95 (s, 9H), 0.17 (s, 3H), 0.15 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 160.1, 138.3, 138.2, 138.0,
130.4, 129.8, 128.4(2C), 128.3, 127.9, 127.8, 127.7(2C), 127.5,
127.4(2C), 113.6, 101.9, 99.6, 97.0 84.6, 81.2, 78.2, 75.7, 74.9, 73.4,
70.8, 68.9(2C), 55.2, 25.7, 18.1, −4.1, −5.3 ppm; HRMS (ESI) calcd.
for C47H58O10NaSi [M + Na]: 833.3697, found: 833.3661.
(3aR,5R,5aS,8aS,8bR)-5-(((4aR,6R,8aS)-2-(4-Methoxyphenyl)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxin-6-yloxy)methyl)-
2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-
d]pyran (6q). Following the general procedure, the reaction with
DtBPF (9.5 mg, 0.02 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol),
carbonate 1 (33.6 mg, 0.1 mmol), compound 5q (52.1 mg, 0.2 mmol),
and Cs2CO3 (65.2 mg, 0.2 mmol) in toluene (2 mL) at 60 °C for 12 h
gave a crude product that was further purified by column
chromatography (EA:Hexane = 1:3) to afford the desired disaccharide
6q (42.0 mg, 83%) as a colorless oil.13b
(4aR,6S,8aS)-2-(4-Methoxyphenyl)-6-((2S,3S,4S,5R,6R)-2,4,5-tris-
(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-3-yloxy)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (6r). Following the
general procedure, the reaction with DtBPF (9.5 mg, 0.02 mmol),
Pd2(dba)3 (9.2 mg, 0.01 mmol), carbonate 1 (33.6 mg, 0.1 mmol),
compound 5r (108.1 mg, 0.2 mmol), and Cs2CO3 (65.2 mg, 0.2
mmol) in toluene (2 mL) at 60 °C for 12 h gave a crude product that
was further purified by column chromatography (EA:Hexane = 1:3) to
afford the desired disaccharide 6r (27.5 mg, 35%) as a colorless oil.
[α]2D3 = +77.3 (c = 1.0 in CHCl3); IR (neat) ν: 3014, 1649, 1612, 1523,
4H), 6.83−6.92 (m, 6H), 6.30 (dd, J1 = 6.2 Hz, J2 = 0.8 Hz, 1H),
6.06−6.13 (m, 1H), 5.96−6.06 (m, 1H), 5.80−5.89 (m, 1H), 5.59−
5.67 (m, 1H), 5.52 (s, 1H), 5.29−5.34 (m, 1H), 5.07−5.15 (m, 1H),
4.72−4.80 (m, 1H), 4.64 (dd, J1 = 6.1 Hz, J2 = 2.7 Hz, 1H), 4.47−4.62
(m, 3H), 4.29−4.35 (m, 1H), 4.19−4.26 (m, 2H), 4.01−4.09 (m, 2H),
3.88−4.00 (m, 3H), 3.64−3.82 (m, 13H), 3.55−3.61 (m, 1H), 0.91 (s,
9H), 0.10 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.1,
159.3(2C), 143.2, 131.4, 130.2, 130.1, 129.8, 129.5(2C), 128.7, 128.4,
128.2, 127.5, 113.9, 113.8, 113.7, 103.5, 102.0, 98.7, 96.0, 76.4, 76.3,
75.0, 74.9, 73.5, 70.5, 70.4, 69.0, 68.9, 68.8, 67.4, 66.5, 55.3, 55.2, 25.8,
17.9, −4.4, −4.6 ppm; HRMS (ESI) calcd. for C48H62O13Si [M + Na]:
897.3857, found: 897.3862.
1
1251, 1079 cm−1; H NMR (400 MHz, CDCl3): δ 7.23−7.43 (m,
20H), 7.14−7.19 (m, 2H), 6.86−6.92 (m, 2H), 6.13 (d, J = 10.3 Hz,
1H), 5.63−5.69 (m, 1H), 5.52−5.57 (m, 1H), 5.45 (s, 1H), 5.01−5.06
(m, 1H), 4.88 (d, J = 10.8 Hz, 1H), 4.69−4.76 (m, 2H), 4.61−4.69
(m, 2H), 4.46−4.58 (m, 3H), 4.05−4.16 (m, 3H), 3.93−3.99 (m, 1H),
3.87−3.93 (m, 1H), 3.70−3.87 (m, 6H), 3.60−3.69 (m, 1H), 3.47 (t, J
= 10.3 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.2,
138.4(2C), 138.3, 137.4, 132.2, 129.8, 128.4, 128.3(3C), 128.1, 127.9,
127.8, 127.6(2C), 127.5, 113.7, 101.9, 97.7(2C), 78.7, 75.1, 74.8, 73.4,
72.1, 71.8, 71.6, 70.6, 69.2, 68.7(2C), 55.3 ppm; HRMS (ESI) calcd.
for C48H50O10Na [M + Na]: 809.3302, found: 809.3300.
(4aR,6R,8aS)-6-(((2R,3S,6R)-6-Ethoxy-3-(4-methoxybenzyloxy)-
3,6-dihydro-2H-pyran-2-yl)methoxy)-2-(4-methoxyphenyl)-
4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine (Byproduct 10).
From the synthesis of trisaccharide 9, byproduct compound 10
(13.5 mg, 25%) was purified by column chromatography (EA:CH2Cl2
= 1:10) as a colorless oil. [α]2D3 = +66.4 (c = 1.0 in CHCl3); IR (neat)
Preparation of Trisaccharide 9. (2R,3S,4R)-3-(4-Methoxy-
benzyloxy)-2-(((4aR,6R,8aS)-2-(4-methoxyphenyl)-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3]dioxin-6-yloxy)methyl)-3,4-dihydro-2H-
pyran-4-ol (7). Compound 6l (0.5 mmol) was dissolved in THF (10
mL) under an atmosphere of N2, and the solution was cooled to 0 °C.
After stirring at 0 °C for 10 min, TBAF (1.0 M solution in THF, 0.7
mL) was added over a duration of 5 min. The mixture was then
allowed to warm to room temperature. After stirring for overnight, the
solvent was removed under reduced pressure to give a crude product
that was further purified by column chromatography (EA:Hexane =
1
ν: 3023, 1650, 1615, 1517, 1416, 1220, 1132 cm−1; H NMR (400
MHz, CDCl3): δ 7.38−7.46 (m, 2H), 7.21−7.29 (m, 2H), 6.83−6.94
(m, 4H), 6.09−6.16 (m, 1H), 5.92−6.05 (m, 1H), 5.79−5.87 (m, 1H),
5.67 (ddd, J1 = 10.3 Hz, J2 = 2.4 Hz, J3 = 1.5 Hz, 1H), 5.54 (s, 1H),
5.35−5.41 (m, 1H), 5.07−5.15 (m, 1H), 4.53−4.59 (m, 1H), 4.46−
4.53 (m, 1H), 4.21−4.30 (m, 2H), 3.87−4.00 (m, 4H), 3.67−3.86 (m,
9H), 3.51−3.62 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 160.2, 159.4, 131.5, 130.0, 129.8, 129.5, 129.1,
128.4, 128.2, 127.5, 113.8, 113.7, 102.0, 98.8, 95.9, 75.1, 75.0, 70.6,
70.5, 69.1, 69.0, 67.4, 63.7, 55.3, 15.1 ppm; HRMS (ESI) calcd. for
C30H36O9Na [M + Na]: 563.2257, found: 563.2257.
1:2) to afford compound 7 (230.6 mg, 90%) as a colorless oil. [α]D23
=
+57.5 (c = 1.0 in CHCl3); IR (neat) ν: 3020, 1652, 1616, 1521, 1244,
1215 cm−1; H NMR (400 MHz, CDCl3): δ 7.39−7.45 (m, 2H),
1
7.27−7.33 (m, 2H), 6.86−6.94 (m, 4H), 6.37 (dd, J1 = 6.0 Hz, J2 = 1.4
Hz, 1H), 6.13−6.21 (m, 1H), 5.70 (ddd, J1 = 10.3 Hz, J2 = 2.4 Hz, J3 =
1.5 Hz, 1H), 5.55 (s, 1H), 5.40−5.46 (m, 1H), 4.68−4.79 (m, 3H),
4.22−4.39 (m, 3H), 4.09 (dd, J1 = 10.8 Hz, J2 = 2.3 Hz, 1H), 3.97
I
dx.doi.org/10.1021/jo502078c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xuewei@ntu.edu.sg (X.-W.L.).
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the support by the Ministry of
Education (MOE2013-T3-1-004) and Nanyang Technological
University (RG6/13), Singapore.
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