Synthesis of 3,6-O-(o-xylylene)glucopyranosyl fluoride, an axial-rich glycosyl donor of β-glycosylation

Article abstract of DOI:10.1021/jo401395h

Despite the reported complete β-selectivity in glycosylation with 2,4-di-O-benzyl-3,6-O-(o-xylylene)glucopyranosyl fluoride, its preparation has been inefficient. This paper describes an improved route for the donor, including the formation of the 3,6-bri

Full text of DOI:10.1021/jo401395h

Note
pubs.acs.org/joc
Synthesis of 3,6‑O‑(o‑Xylylene)glucopyranosyl Fluoride, an Axial-Rich
Glycosyl Donor of β‑Glycosylation
Noriaki Asakura,† Atsushi Motoyama, Takuya Uchino, Kotaro Tanigawa, and Hidetoshi Yamada*
School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan
S
* Supporting Information
ABSTRACT: Despite the reported complete β-selectivity in
glycosylation with 2,4-di-O-benzyl-3,6-O-(o-xylylene)-
glucopyranosyl fluoride, its preparation has been inefficient.
This paper describes an improved route for the donor,
including the formation of the 3,6-bridge on 1,2,4-
orthoacetylglucose, the preparation of which was also refined,
along with a discovered feature that the 3,6-bridged glucose
prefers the furanose form. Although this feature made the
synthesis of the desired glucopyranosyl donor difficult,
application of thermal glycosylation solved the problem.
With a modifiable intermediate, the improved availability of
the donor would expand the applications.
ealization of advanced and stable stereoselectivity in
Rchemical glycosylation has been a fundamental challenge
for synthetic organic chemists for many years. Among the
variety of methods for realizing stereoselectivity, stereocontrol
on the basis of conformational locking of pyranose rings is one
developing area of research,1−3 Theoretical calculations have
also indicated the significance of the conformational control.4−7
Locking the conformation to the inverted form of pyranose
rings has been a typical approach.8−14 Ring inversion produces
carbohydrates possessing more axial substituents, which are
Despite the exhibited efficiency of 1 in β-glycosylation, its
preparation remained unpolished. The preparation required 13
steps from acetobromoglucose (3), including pyranose ring
opening as in 7 (Scheme 1), which made the formation of the
called axial-rich forms.15−19 To lock a conformation into an
axial-rich form, steric repulsion between bulky silyl groups has
often been applied.8−12,18−31 The axial-rich form has enhanced
the reactivity of glycosyl donors.18,19 In contrast, a reduction in
3,6-bridge possible, and reconstruction of the pyranose ring,
reactivity12,32 and migration of the silyl groups23 due to their
intense steric hindrance have also been observed in some
instances, which suggests a brittleness of the locking method of
conformation.
which was the transformation from 10 to 11.33,35 Therefore, a
rationalized synthetic route for 1 was indispensable to utilize
the β-glycosylation. In this study, we describe a drastic
rationalization of the synthesis of 1 along with new knowledge
that the equilibrium between the furanose and pyranose forms
is tilted toward the furanose form almost entirely when glucose
possesses an o-xylylene 3,6-bridge.
The rationalized synthetic route to 1 is summarized in
Scheme 2. A salient feature of this route is the employment of
1,2,4-orthoacetyl-D-glucose (13), the pyranose ring of which is
locked to the axial-rich conformation. This conformation allows
the formation of the 3,6-O-(o-xylylene) bridge without opening
of the pyranose ring. For ease of comparing the overall yield of
the new route with that of the previous one, the scheme
commences with 3, which is the precursor of ethyl orthoacetate
12.36 Although the transformation of 12 to 13 was known,37−42
We recently reported a completely β-selective glycosylation
based on the development of a new axial-rich glycosyl donor.33
This donor, 2,4-di-O-benzyl-3,6-O-(o-xylylene)glucopyranosyl
fluoride (1), reacts with various alcohols in a SnCl2−
AgB(C6F5)4 catalytic system to providing only the correspond-
ing glucosides β-2 through convergent isomerization from the
α-isomer to the β-isomer (eq 1).34 The one-way isomerization
was attributed to steric repulsion between the α-anomeric
oxygen and the axially oriented 2-oxygen. The orientation was
forced by the conformational lock due to the o-xylylenebridge.
This conformational locking system exhibited merits over the
system using silyl protecting groups because of its reduced
steric bulkiness and its structural robustness. In addition, the o-
xylylene group can be removed by hydrogenolytic cleavage
together with benzyl groups.
Received: June 27, 2013
Published: August 28, 2013
© 2013 American Chemical Society
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In the new route, the following three steps are noteworthy.
The first is the improvement in the synthesis of the known
compound 13, which allowed a 74% yield from 12 on a
reaction scale of 20 g. The second is the development of
optimized reaction conditions to give 14 through intra-
molecular formation of the o-xylylene bridge on 13 on a
reaction scale of 2 g, reducing the intermolecular formation of
o-xylylene ethers. The third is the removal of the orthoester
group of 14 by thermal glycosylation with p-methoxyphenol.
The following paragraphs describe details of the above.
Bochkov and co-workers first reported the synthesis of 13
through intramolecular transorthoesterification of 1,2-methyl-
orthoacetyl-D-glucopyranose catalyzed by p-toluenesulfonic
acid.37−41 However, the reproducibility and yield were low.
These problems were solved by the rational use of basic and
acidic properties of molecular sieves (M-sieve).42 However, this
synthetic method was too expensive for the large-quantity
synthesis of 13 because a 10 g scale reaction needed 100 g of
M-sieve 5A.
Scheme 1. Previous Synthetic Route to 1
In the present work, these problems were overcome by
application of the method for the synthesis of 1,2,4-
orthopivaloylxylose reported by Nakatsubo et al.46 The main
feature of this method is its reaction conditions, in which the
removal of the acetyl groups with DBU is followed by the
addition of p-TsOH to the crude deacetylated product without
removal of DBU. The mixing of DBU and p-TsOH might
generate suitable acidic conditions to prepare the 1,2,4-
orthopivaloyl moiety. Application of the reaction conditions
to 12 increased the efficiency of obtaining 13 to 83% and 74%
yield on 1 and 20 g scale reactions, respectively.
Scheme 2. New Synthetic Route to 1
The efficiency increase was also supported by the discovery
of an improved method for chromatographic purification of 13.
Compound 13 can be purified by recrystallization, but the yield
is poor.40 Although silica gel degrades 13 because the
orthoester moiety is prone to be hydrolyzed, pretreatment of
the silica gel with Et3N eliminated the degradation. As eluents, a
mixture of toluene and MeOH made the separation effective.
Elution with n-hexane/EtOAc required more than 3 times the
quantity of the eluent required with toluene/MeOH. The
improvement in chromatographic purification stabilized the
yield and reproducibility of this step.
In the formation of the o-xylylene bridge on 13, the order of
mixing the reagents and substrates and the rates of their
additions were important. The optimal reaction conditions
involved synchronized additions of a solution of α,α′-o-
dibromoxylene in DMF (0.1 mM) and a solution of 13 in
toluene (0.09 mM) to a stirred mixture of NaH in toluene
(0.12 M) at 85 °C. The rate of addition was 1 mL/min for both
solutions. This protocol stabilized the reproducibility of 14 to
give a yield of more than 70% when starting from 2 g of 13.
The following protocols provided 14 in poor yield with
significant amounts of byproducts, including dimers: (1)
reaction at lower temperature, (2) addition of a solution of
13 in DMF to a mixture of α,α′-o-dibromoxylene and NaH in
toluene, and (3) addition of a solution of α,α′-o-dibromoxylene
in DMF to a mixture of NaH and 13 in toluene.
For the preparation of 15, the unusual thermal glycosylation
was adopted to remove the orthoester. The adoption was due
to the exclusive production of the corresponding furanosyl
isomer when the orthoester was removed under common
hydrolysis conditions. Hence, the hydrolysis of 14 with
hydrochloric acid followed by acetylation provided furanose
17 (eq 1 in Scheme 3). The furanose structure was confirmed
we improved this step in terms of yield and reproducibility.
Tethering the 3,6-diol of 13 to the o-xylylene group gave 14.
The orthoester was cleaved to afford 15 through introduction
of the p-methoxyphenyl group followed by removal of the
remaining acetyl group. The reason for the adoption of this
unusual method for cleavage of the orthoester group will be
discussed later. Diol 15 was then benzylated to provide 16, the
p-methoxyphenyl group of which was removed by treatment
with cerium(IV) sulfate to produce 11.33 The use of
cerium(IV) sulfate as a one-electron oxidant gave a better
yield and purity of pyranose 11 than the use of ceric
ammonium nitrate, which is usually applied for oxidative
removal of the group.43−45 The yield of the fluorination of 11
was 96%. The advantages of this route over the previous one
are (1) the smaller number of steps, (2) the higher overall yield
(23% from 3), and (3) the creation of diol 15 as a synthetic
intermediate, which might allow variety in modification.
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enabled the cleavage of the 1,2,4-orthoester while keeping the
pyranose form intact. As a result, 1 was synthesized from 3 in
nine steps in 23% overall yield. The improved availability of 1
and the modifiable synthetic intermediate 15 should expand the
applications utilizing conformationally locked carbohydrates.
Scheme 3. Pyranose−Furanose Equilibrium of 3,6-O-(o-
Xylylene)glucose
EXPERIMENTAL SECTION
■
General Methods. All of the commercially available reagents were
used without further purification. When necessary, glassware was dried
under reduced pressure by heating with a heat gun and solvents were
distilled prior to use. Reaction mixtures were magnetically stirred.
Concentration was performed under reduced pressure.
Reactions were monitored by TLC and MS. Anhydrous MgSO4 was
used to dry the organic layers after extraction, and it was removed by
filtration through a cotton pad. The filtrate was concentrated and
subjected to further purification protocols if necessary. This sequence
is represented as “the general drying procedure” in the experimental
methods provided below.
TLC was performed on Merck precoated silica gel 60 F-254 plates.
Spots were visualized by exposure to UV light or by immersion into a
solution of 2% anisaldehyde and 5% H2SO4 in ethanol or a solution of
10% phosphomolybdic acid in ethanol, followed by heating at ca. 200
°C. Column chromatography (CC) was performed on Merck silica gel
60 (63−200 or 40−63 μm) or Kanto Chemical silica gel 60 N
(spherical, neutral, 40−50 or 63−210 μm). An Et3N-treated SiO2
column was prepared as follows. A slurry obtained by mixing SiO2 with
10% (v/v) Et3N/n-hexane was poured into a glass tube with a cotton
plug at the bottom. After sedimentation of SiO2, the solvent was eluted
off to the upper line of SiO2. The indicated eluent was then gently
added to replace the Et3N-containing n-hexane.
The melting points were uncorrected. Optical rotations were
determined with a 100 mm cell at 589 nm. IR spectra were recorded
with a spectrophotometer equipped with an ATR sampling unit, and
the major absorbance bands are reported in wavenumbers (cm−1).
The 1H NMR (400 MHz) data are indicated by chemical shifts (δ),
with the multiplicity, the coupling constant(s) (J), and the integration
in parentheses in that order. The multiplicities are abbreviated follows:
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The
13C NMR (100 MHz) data are reported as chemical shifts (δ) with the
by observed HMBC between C-1 and H-4 for both the α- and
β-isomers of 17. Molecular force field calculations confirmed
that the α-furanose was the most stable isomer, followed by the
β-furanose, among the four possible isomers of 3,6-O-(o-
xylylene)glucose (eq 2 in Scheme 3).47 The potential energies
of the pyranoses were clearly higher than those of the
furanoses.
The equilibrium between furanose and pyranose forms has
scarcely been discussed when glucose possesses a bridge
between the 3- and 6-oxygens. All that is known is that 3,6-
anhydroglucose prefers the furanose form (eq 3 in Scheme
3).48,49 Therefore, the result of the present study provides
fundamental knowledge for sugar chemistry, namely, that
glucose exists as the furanose form when the o-xylylene group
bridges the 3- and 6-oxygens, although this feature was adverse
to our synthesis.
hydrogen multiplicities obtained from DEPT spectra in parentheses.
The multiplicities are abbreviated as follows: s, C; d, CH; t, CH2; and
q, CH3. When the number of carbons is more than one, the number is
given in the parentheses after the H multiplicity.
If a pyranose form with a 3,6-O-(o-xylylene) bridge is desired,
the hydroxyl groups at the 1- and 4-positions should not be
unprotected at the same time (eq 2 in Scheme 3). The thermal
glycosylation of 14 with p-methoxyphenol (Scheme 2) was
discovered during efforts aimed at removing the orthoester
group while keeping its pyranose form intact. Thermal
glycosylation is a method of glycosylation that involves heating
a glycosyl donor and acceptor without solvent.50 Thus, heating
of a mixture of 14 and p-methoxyphenol cleaved the orthoester
part without the pyranose−furanose isomerization. The cleaved
orthoester group remained as an acetyl group on O-2. The
acetyl group was removed by methanolysis using M-sieve
4A42,51 to give diol 15 as a 1/3 mixture of anomers.
In summary, we have drastically improved the synthetic route
to 1, the glucosyl donor for the completely β-selective
glycosylation reaction. The o-xylylene bridge of 1 was
constructed on 1,2,4-orthoacetylglucose, which eliminated the
need for pyranose ring opening and reclosing processes
involved in the previous synthetic route. In addition, we
found that glucose prefers the furanose form when the 3- and 6-
oxygens are bridged by the o-xylylene group. This fact provided
fundamental chemical knowledge but also represented a major
problem for the synthesis of the desired pyranose derivative.
This problem was solved by thermal glycosylation, which
1,2,4-Orthoacetyl-α-D-glucopyranose (13). Synthesis on a 1 g
scale: A mixture of ethyl orthoacetate 12 (1.0 g, 2.66 mmol) and DBU
(405 mg, 2.66 mmol) in MeOH (20 mL) was stirred for 30 min at 25
°C. After concentration, the residue was dissolved in DCE (28 mL).
To this solution were added activated M-sieve 4A (710 mg) and p-
TsOH·H2O (19 mg, 99.9 μmol). After the mixture was refluxed for 6.5
h, NaHCO3 was added. The mixture was filtered through a cotton−
Celite pad. After concentration of the filtrate, the residue was purified
by CC (10 g of Et3N-treated SiO2, toluene/MeOH 25/1 to 10/1) to
give 1336 (449 mg, 83% yield) as a colorless syrup.
Synthesis on a 20 g scale: A mixture of ethyl orthoacetate 12 (20.5
g, 54.5 mmol) and DBU (12.4 g, 81.6 mmol) in MeOH (500 mL) was
stirred for 20 min at 25 °C. After concentration, the residue was
dissolved in DCE (545 mL). To this solution were added activated M-
sieve 4A (16.4 g) and p-TsOH·H2O (518 mg, 2.72 mmol). After the
mixture was refluxed for 18 h, it was filtered through a cotton−Celite
pad to remove M-sieve 4A. After concentration, the filtrate was
purified by CC (300 g of Et3N-treated SiO2, toluene/MeOH 25/1 to
10/1) to give 13 (8.23 g, 74% yield) as a colorless syrup.
1,2,4-Orthoacetyl-3,6-O-(o-xylylene)-α-D-glucopyranose
(14). To a stirred mixture of NaH (60% in mineral oil, 1.57 g; 942 mg
of NaH, 39.3 mmol) in toluene (330 mL) were added dropwise a
solution of α,α′-o-dibromoxylene (2.80 g, 10.6 mmol; caution: highly
lachrymatory and toxic by inhalation and in contact with skin) in DMF
(109 mL) and a solution of 1,2,4-orthoacetyl-α-D-glucopyranose (13)
(2.01 g, 9.79 mmol) in toluene (109 mL) at 85 °C. Two syringe
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1
pumps were used for these additions; the addition rate was 1 mL/min
for both, and thus, the addition required 109 min. The mixture was
further stirred for 1 h at 85 °C after the end of the addition. The
reaction was quenched by addition of H2O (150 mL). From this
aqueous mixture, the organic layer was separated and washed with
H2O. After the general drying procedure, the crude product was
purified by CC (40 g of Et3N-treated SiO2, n-hexane/EtOAc 15/1 to
10/1) to give 14 (2.21 g, 73% yield) as a white amorphous solid. Mp
131−133 °C; [α]2D4 +126.9 (c 1.09, CHCl3); IR 3009, 2953, 2899,
2859, 1134, 1082, 1048, 752 cm−1; 1H NMR (C6D6) δ 7.03−6.96 (m,
2H), 6.93−6.86 (m, 2H), 5.56 (d, J = 4.9 Hz, 1H), 5.52 (d, J = 10.1
Hz, 1H), 4.91 (d, J = 9.4 Hz, 1H), 4.61 (br d, J = 3.1 Hz, 1H), 4.47
(dd, J = 4.3, 2.1 Hz, 1 H), 4.18 (d, J = 10.1 Hz, 1 H), 4.11 (dd, J = 4.9,
2.1 Hz, 1H), 3.88 (d, J = 9.4 Hz, 1H), 3.85 (dd, J = 4.3, 1.8 Hz, 1H),
3.61 (dd, J = 14.2, 1.4 Hz, 1H), 3.53 (dd, J = 14.2, 3.1 Hz, 1H), 1.72
(s, 3 H); 13C NMR (C6D6) δ 138.0 (s), 136.7 (s), 128.7 (d), 128.7
(d), 127.8 (d), 127.4 (d), 119.9 (s), 98.1 (d), 79.7 (d), 74.8 (t), 74.1
(d), 72.3 (d), 71.9 (t), 70.5 (d), 69.3 (t), 20.9 (q); HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C16H18O6Na 329.1001, found 329.1010.
4-Methoxyphenyl 3,6-O-(o-Xylylene)-D-glucopyranoside
(15). A mixture of p-methoxyphenol (3.06 g, 24.6 mmol) and 1,2,4-
orthoacetyl-3,6-O-(o-xylylene)-α-D-glucopyranose (14) (1.44 g, 4.70
mmol) was heated to 100 °C. The melted mixture was stirred for 9 h
at 100 °C. After being cooled, the mixture was diluted with MeOH (25
mL). To the mixture, activated M-sieve 4A42 (4.5 g) was added. After
being refluxed for 12 h, the mixture was filtered through a cotton−
Celite pad to remove the M-sieve. After concentration, the residue was
purified by CC (45 g of SiO2, n-hexane/EtOAc 7/2 to 1/3) to give α-
15 (334 mg, 19% yield) and β-15 (853 mg, 47% yield), both as
colorless amorphous solids.
3063, 3029, 2903, 2872, 1455, 1215, 1113, 1044, 750 cm−1; H NMR
(CDCl3) δ 7.40−7.26 (m, 10H), 7.21−7.10 (m, 4H), 6.94 (d with
small long-range couplings, J = 9.2 Hz, 2H), 6.81 (d with small long-
range couplings, J = 9.2 Hz, 2H), 5.57 (d, J = 9.9 Hz, 1H), 5.27 (d, J =
6.6 Hz, 1H), 5.13 (d, J = 10.1 Hz, 1H), 4.81 (d, J = 12.1 Hz, 1H), 4.74
(d, J = 12.1 Hz, 1H), 4.70 (d, J = 11.7 Hz, 1H), 4.53 (d, J = 11.7 Hz,
1H), 4.45 (br s, 1H), 4.35 (d, J = 10.1 Hz, 1H), 4.30 (d, J = 9.9 Hz,
1H), 4.22 (br s, 1H), 4.01 (br d, J = 2.8 Hz, 1H), 3.90 (br d, J = 6.6
Hz, 1H), 3.83 (br d, J = 13.5 Hz, 1H), 3.79 (br d, J = 13.5 Hz, 1H),
3.77 (s, 3H); 13C NMR (CDCl3) δ 155.1 (s), 151.4 (s), 138.6 (s),
138.0 (s), 137.1 (s), 136.5 (s), 129.6 (d), 128.6 (d), 128.6 (d, 2C),
128.4 (d, 2C), 128.0 (d), 127.9 (d, 2C), 127.9 (d, 2C), 127.8 (d, 2C),
127.7 (d), 118.0 (d, 2C), 114.6 (d, 2C), 101.2 (d), 83.1 (d), 82.3 (d),
75.4 (d), 75.0 (t), 72.9 (t), 72.0 (t), 70.6 (t), 70.5 (t), 70.3 (d), 55.8
(q); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C35H36O7Na
591.2359, found 591.2345.
2,4-Di-O-benzyl-3,6-O-(o-xylylene)-D-glucopyranose (11). A
mixture of 4-methoxyphenyl glucoside 16 (194 mg, 341 μmol) and
Ce(SO4)2 (560 mg, 1.69 mmol) in CH3CN (5.0 mL) and H2O (2.5
mL) was stirred for 19 h at rt. The reaction was quenched by the
addition of 10% Na2S2O3(aq) (15 mL). The mixture was extracted
with EtOAc. The combined organic layers were successively washed
with H2O and brine. After the general drying procedure, the mixture
was purified by CC (10 g of SiO2, n-hexane/EtOAc 19/1 to 3/2) to
afford 11 (129 mg, 82% yield) and 16 (23.7 mg, 12% yield) as a white
solid and a yellow syrup, respectively.
Data for 11 (major isomer): mp 117−119 °C; [α]2D5 +97.5 (c 0.64,
CHCl3); IR 3409, 3029, 2903, 2870, 1455, 1115, 1028, 752, 698 cm−1;
1H NMR (CDCl3) δ 7.41−7.28 (m, 10H), 7.22−7.12 (m, 4H), 5.52
(d, J = 9.8 Hz, 1H), 5.09 (d, J = 10.1 Hz, 1H), 5.04 (d, J = 4.6 Hz,
1H), 4.80 (d, J = 11.9 Hz, 1H), 4.71 (d, J = 11.9 Hz, 1H), 4.67 (d, J =
11.9 Hz, 1H), 4.53 (d, J = 11.9 Hz, 1H), 4.40 (br dd, J = 3.0, 1.8 Hz,
1H), 4.34 (d, J = 10.1 Hz, 1H), 4.32 (d, J = 9.8 Hz, 1H), 4.18 (br d, J =
3.4 Hz, 1H), 3.96 (d, J = 3.0 Hz, 1H), 3.83 (br d, J = 13.6 Hz, 1H),
3.77 (dd, J = 13.6, 3.4 Hz, 1H), 3.59 (dd, J = 4.6, 1.8 Hz, 1H); 13C
NMR (CDCl3) δ 138.6 (s), 138.0 (s), 137.0 (s), 136.5 (s), 129.6 (d),
128.7 (d), 128.5 (d, 3C), 128.4 (d, 2C), 127.8 (d, 6C), 127.6 (d), 96.2
(d), 84.2 (d), 83.0 (d), 75.3 (d), 74.7 (t), 72.5 (t), 71.8 (t), 70.6 (t),
70.4 (t), 70.3 (d); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C28H30O6Na 485.1940, found 485.1941.
2,4-Di-O-benzyl-3,6-O-(o-xylylene)-D-glucopyranosyl fluo-
ride (1). A mixture of 11 (473 mg, 1.02 mmol) and N,N-
diethylaminosulfur trifluoride (DAST) (322 mg, 2.00 mmol) in
THF (20 mL) was stirred for 40 min at rt. MeOH (5 mL) was then
added, and the mixture was concentrated. The residue was dissolved in
EtOAc. The solution was successively washed with H2O, saturated
NaHCO3(aq), and brine. After the general drying procedure, the
mixture was purified by CC (15 g of SiO2, n-hexane/EtOAc 97/3 to 4/
1) to afford 1 (457 mg, 96% yield) as a mixture of anomers (α/β = 1/
6). The 1H and 13C NMR spectral data were identical to the reported
data.33
3,6-O-(o-Xylylene)-1,2,5-tri-O-acetyl-D-glucofuranose (17). A
mixture of orthoacetylglucopyranose 14 (100 mg, 327 μmol) in THF
(0.65 mL) and 1.0 M hydrochloric acid (1.3 mL) was stirred for 15
min at rt. After the addition of saturated NaHCO3(aq) (3 mL), the
aqueous mixture was extracted with EtOAc. The general drying
procedure provided a crude product that was used for the next
reaction without further purification. A mixture of the crude product,
pyridine (92 μL, 1.1 mmol), Ac2O (0.22 mL 2.3 mmol), and DMAP
(7.99 mg, 6.54 μmol) was stirred for 40 min at rt. After the addition of
1.0 M hydrochloric acid (5 mL), the aqueous mixture was extracted
with EtOAc. The combined organic layer was successively washed with
1 M hydrochloric acid, water, and brine. After the general drying
procedure, the mixture was purified by CC (2 g of SiO2, n-hexane/
EtOAc 8/1 to 6/1) to give 17 (100 mg, 74% yield, α/β = 1/1) as an
amorphous solid. A part of the anomeric mixture was separated by
HPLC (column, YMC-Pack R&D SIL, R-SIL-5, 250 mm × 20 mm;
eluent, n-hexane/EtOAc = 4/1; flow rate, 1.8 mL/min; detection, UV
254 nm; retention times, 35 min for α-17 and 28 min for β-17).
Data for α-15: mp 61−64 °C; [α]2D4 −40.3 (c 0.62, CHCl3); IR
3422, 2932, 2878, 1509, 1217, 1115, 1032, 758 cm−1; 1H NMR
(CDCl3) δ 7.33−7.20 (m, 4H), 6.96 (d with small long-range
couplings, J = 9.2 Hz, 2H), 6.80 (d with small long-range couplings, J =
9.2 Hz, 2H), 5.52 (d, J = 2.3 Hz, 1H), 5.02 (d, J = 9.9 Hz, 1H), 4.89
(d, J = 12.6 Hz, 1H), 4.74 (d, J = 12.6 Hz, 1H), 4.54 (d, J = 9.9 Hz,
1H), 4.39 (br dd, J = 7.3, 6.2 Hz, 1H), 4.33 (br d, J = 8.9 Hz, 1H),
4.15−4.07 (m, 4H), 3.91 (dd, J = 10.3, 6.2 Hz, 1H), 3.75 (s, 3H), 3.07
(d, J = 1.4 Hz, 1H); 13C NMR (CDCl3) δ 156.5 (s), 150.6 (s), 137.2
(s), 136.1 (s), 131.3 (d), 130.1 (d), 129.1 (d), 128.5 (d), 118.0 (d,
2C), 114.8 (d, 2C), 93.9 (d), 79.5 (d), 75.2 (d), 74.2 (t), 70.4 (d),
70.1 (t), 68.7 (t), 63.4 (d), 55.8 (q); HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C21H24O7Na 411.1420, found 411.1432.
Data for β-15: mp 88−90 °C; [α]2D4 −61.1 (c 1.04, CHCl3); IR
1
3407, 2907, 2874, 1509, 1217, 1111, 1090, 1051, 1036, 752 cm−1; H
NMR (CDCl3) δ 7.24−7.12 (m, 4H), 6.96 (d with small long-range
couplings, J = 9.2 Hz, 2H), 6.82 (d with small long-range couplings, J =
9.2 Hz, 2H), 5.44 (d, J = 10.3 Hz, 1H), 5.16 (d, J = 5.3 Hz, 1H), 5.15
(d, J = 10.3 Hz, 1H), 4.69 (m, 1H), 4.54 (d, J = 10.3 Hz, 1H), 4.42 (d,
J = 10.3 Hz, 1H), 4.13 (br dd, J = 3.9, 2.5 Hz, 1H), 4.07 (br dd, J = 8.5,
5.3 Hz, 1H), 3.99 (dd, J = 13.3, 3.9 Hz, 1H), 3.94 (dd, J = 13.3, 2.5 Hz,
1H), 3.86 (br d, J = 3.4 Hz, 1H), 3.77 (s, 3H), 2.84 (d, J = 8.5 Hz,
1H), 2.45 (d, J = 5.3 Hz, 1H); 13C NMR (CDCl3) δ 155.0 (s), 151.2
(s), 137.0 (s), 136.2 (s), 129.6 (d), 128.9 (d), 128.0 (d), 127.8 (d),
117.8 (d, 2C), 114.5 (d, 2C), 102.3 (d), 83.1 (d), 78.5 (d), 74.9 (t),
74.5 (d), 71.2 (t), 70.3 (t), 64.6 (d), 55.7 (q); HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C21H24O7Na 411.1420, found 411.1433.
4-Methoxyphenyl 2,4-Di-O-benzyl-3,6-O-(o-xylylene)-D-glu-
copyranoside (16). To a stirred solution of diol 15 (172 mg, 440
μmol) and NaH (60% in mineral oil, 120 mg; 72 mg of NaH, 3.0
mmol) in DMF (8.0 mL) was added BnBr (301 mg, 1.76 mmol) at rt.
After the mixture was stirred for 5 h at 80−85 °C, the reaction was
quenched by addition of saturated NH4Cl(aq) (2.0 mL). After dilution
of the mixture with H2O (40 mL), the aqueous mixture was extracted
with EtOAc. The combined organic layers were successively washed
with H2O and brine. After the general drying procedure, the mixture
was purified by CC (10 g of SiO2, n-hexane/EtOAc 19/1 to 4/1) to
afford 16 (194 mg, 77% yield) as a yellow syrup. Some fractions
contained the pure β-anomer (β-16), which allowed for its
characterization. Mp 68−70 °C; [α]2D4 +11.0 (c 1.29, CHCl3); IR
9485
dx.doi.org/10.1021/jo401395h | J. Org. Chem. 2013, 78, 9482−9487

The Journal of Organic Chemistry
Note
Data for α-17: mp 38−39 °C; [α]2D3 −26.9 (c 0.53, CHCl3); IR
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2925, 2852, 1740, 1435, 1368, 1217, 1124, 1051, 1005, 960, 886, 751
1
cm−1; H NMR (CDCl3) δ 7.33−7.22 (m, 4H), 6.05 (d, J = 2.1 Hz,
(14) Heuckendorff, M.; Pedersen, C. M.; Bols, M. J. Org. Chem. 2013,
78, 7234−7238.
1H), 5.42 (dd, J = 5.3, 2.1 Hz, 1H), 5.31 (ddd, J = 3.7, 3.7, 1.4 Hz,
1H), 5.07 (d, J = 11.0 Hz, 1H), 4.97 (d, J = 10.7 Hz, 1H), 4.79 (d, J =
10.7 Hz, 1H), 4.63 (d, J = 11.0 Hz, 1H), 4.56 (dd, J = 6.2, 1.4 Hz, 1H),
4.32 (dd, J = 6.2, 5.3 Hz, 1H), 3.91 (d, J = 3.7 Hz, 2H), 2.15 (s, 3H),
2.10 (s, 3H), 2.06 (s, 3H); 13C NMR (CDCl3) δ 170.5 (s), 170.1 (s),
169.9 (s), 137.1 (s), 135.6 (s), 130.3 (d), 130.1 (d), 128.9 (d), 128.4
(d), 98.9 (d), 81.4 (d), 80.8 (d), 80.1 (d), 75.2 (d), 73.9 (t), 73.6 (t),
69.9 (t), 21.6 (q), 21.1 (q), 21.0 (q); HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C20H24O9Na 431.1318, found, 431.1331.
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Data for β-17: mp 36−37 °C; [α]2D5 +54.5 (c 0.60, CHCl3); IR
2925, 1740, 1435, 1371, 1216, 1137, 1112, 1075, 1043, 1007, 930, 892,
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781, 732 cm−1; H NMR (CDCl3) δ 7.33−7.19 (m, 4H), 6.35 (d, J =
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4.6 Hz, 1H), 5.30−5.24 (m, 2H), 4.93 (d, J = 10.1 Hz, 1H), 4.88 (d, J
= 12.1 Hz, 1H), 4.77 (d, J = 10.1 Hz, 1H), 4.69−4.64 (m, 2H), 4.56
(dd, J = 7.6, 7.6 Hz, 1H), 3.87 (dd, J = 10.5, 6.2 Hz, 1H), 3.75 (dd, J =
10.5, 6.2 Hz, 1H), 2.11 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H); 13C NMR
(CDCl3) δ 170.4 (s), 170.1 (s), 169.6 (s), 136.9 (s), 135.6 (s), 130.9
(d), 130.0 (d), 129.0 (d), 128.6 (d), 92.5 (d), 80.2 (d), 76.3 (d), 75.4
(d), 74.0 (t), 73.4 (d), 73.0 (t), 67.9 (t), 21.3 (q), 21.1 (q), 20.7 (q);
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found, 431.1334.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(27) Marzabadi, C. H.; Anderson, J. E.; Gonzalez-Outeirino, J.;
Gaffney, P. R. J.; White, C. G. H.; Tocher, D. A.; Todaro, L. J. J. Am.
Chem. Soc. 2003, 125, 15163−15173.
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(28) Yamada, H.; Tanigakiuchi, K.; Nagao, K.; Okajima, K.; Mukae,
T. Tetrahedron Lett. 2004, 45, 9207−9209.
(29) Okajima, K.; Mukae, T.; Imagawa, H.; Kawamura, Y.; Nishizawa,
M.; Yamada, H. Tetrahedron 2005, 61, 3497−3506.
(30) Banaag, A. R.; Tius, M. A. J. Am. Chem. Soc. 2007, 129, 5328−
5329.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hidetosh@kwansei.ac.jp.
Present Address
†N.A.: Department of Chemistry, Graduate School of Science,
Osaka University, Toyonaka, Osaka 560-0043, Japan.
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Org. Lett. 2011, 13, 6126−6129.
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(33) Okada, Y.; Asakura, N.; Bando, M.; Ashikaga, Y.; Yamada, H. J.
Am. Chem. Soc. 2012, 134, 6940−6943.
Notes
The authors declare no competing financial interest.
(34) Abbreviations used in addition to those in “The Journal of
Organic Chemistry Guidelines for Authors (Updated July 2012).”:
BTF, benzotrifluoride; CC, column chromatography; DAST, N,N-
diethylaminosulfur trifluoride; M-sieve, molecular sieves.
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ACKNOWLEDGMENTS
■
JSPS A-STEP (Grant AS231Z04872D) and KAKENHI (Grant
22550047) partially supported this work.
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