Total synthesis of cucurbitoside-like phenolic glycosides by double fluorous and acyl mixture synthesis

Article abstract of DOI:10.1016/j.tet.2011.08.087

The first and simultaneous total syntheses of cucurbitosides A, B, G, and I, seguinosides C and D, and two unnatural analogs were achieved using the technique of fluorous mixture synthesis. The eight precursors of cucurbitoside-like phenolic glycosides we

Full text of DOI:10.1016/j.tet.2011.08.087

Tetrahedron 67 (2011) 8276e8292
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Total synthesis of cucurbitoside-like phenolic glycosides by double fluorous
and acyl mixture synthesis
,
a
a
b
b
a
Masaru Kojima a , Yutaka Nakamura , Kazuki Komori , Shoji Akai , Ken-ichi Sato , Seiji Takeuchi
*
a Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan
b Material and Life Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2011
Received in revised form 29 August 2011
Accepted 29 August 2011
Available online 3 September 2011
The first and simultaneous total syntheses of cucurbitosides A, B, G, and I, seguinosides C and D, and two
unnatural analogs were achieved using the technique of fluorous mixture synthesis. The eight precursors
of cucurbitoside-like phenolic glycosides were prepared by glycosylation of a mixture of two glucopyr-
anosyl acceptors bearing different fluorous benzyl groups with a mixture of four apiofuranosyl donors
bearing benzoyl, 3-methylbutyryl, 4-benzyloxybenzoyl, and 4-nitrobenzoyl groups, followed by a single
run of HPLC with serially connected FluophaseÒ RP and InertsilÒ ODS-3 columns. Finally, the individual
pure disaccharide precursors were detagged to yield the eight cucurbitoside-like phenolic glycosides.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Acylated phenolic glycosides
Fluorous
Mixture synthesis
1. Introduction
a mixture of structurally similar phenolic glycosides.4a,b,5 Koike and
co-workers have utilized repetitive preparative reverse-phase
New acylated phenolic glycosides, cucurbitosides AeM (Fig. 1),
were isolated from the seeds of Cucurbita moschata and Cucurbita
HPLC for the isolation of cucurbitosides AeM on the basis of the
difference in hydrophobicity of phenolic glycosides.1 These reverse-
phase HPLC experiments also demonstrated that the chromato-
graphic behavior of phenolic glycosides on an ODS silica gel is de-
pendent upon the structure of substituents on the sugar chain.
These results suggest that these acyl groups are a suitable tool for
sorting acyl-tagged molecules. Thus, benzoyl, 3-methylbutyryl, 4-
hydroxybenzoyl, and 4-aminobenzoyl groups can be used as sort-
ing tags for a solution-phase mixture synthesis of acylated target
compounds.
In 2001, Curran and co-workers reported a fluorous mixture
synthesis as the first solution-phase mixture synthetic technique
using sorting tags for the simultaneous preparation of individual
pure products via intermediate mixtures.6 In summary, a series of
organic substrates are tagged with a series of fluorous tags of dif-
ferent chain lengths. The tagged compounds are mixed and un-
dergo a series of reactions as if they were a single compound. The
components of the final mixture of the tagged products are then
separated (demixed) depending upon their fluorine atom contents
by chromatography over fluorous silica gel, prior to detagging, to
give individually pure target products. Fluorous mixture synthesis
has been shown to be a powerful technique for preparing small
molecule libraries, studying structureeactivity relationships, and
assigning structures of natural products.7 The high efficiency and
practicality of the methodology have attracted many researchers’
interest.
pepo.1 Cucurbitosides possess a
b-D-apiofuranosyl-(1/2)-b-D-glu-
copyranose sugar chain and an ester linkage with various acyl
moieties at C-50 of apiofuranose. Various pharmacological studies
have demonstrated that the water extracted from the seeds of C.
moschata exhibits hepatoprotective effect.2 Although this extracted
water possesses beneficial biological properties, the biological ac-
tivity of one family of its water-soluble constituents, the cucurbi-
tosides, has not yet been evaluated. Apiofuranose-containing
glycosides, such as saponins, flavinoids, or phenolic glycosides play
crucial roles in the biochemistry of plants.3 Among them, segui-
nosides AeK and M-leaf movement factor (LMF) and kelampayo-
sides A and B are structurally similar to cucurbitosides, and most of
them possess interesting biological activities.4 Therefore, a chem-
ical synthesis of cucurbitosides is an important step in elucidating
the relationship between the structures and biological activities of
these natural products.
In the isolation and structure assignment of naturally occurring
phenolic glycosides, a reverse-phase HPLC with an ODS column has
been often used at the last stage to separate the components of
* Corresponding author. Fax: þ81 025 25 5021; e-mail address: masaru@nu-
pals.ac.jp (M. Kojima).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.087

M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
8277
Fig. 1. Structures of cucurbitoside-like phenolic glycosides.
In addition, Curran and Wilcox have recently reported a double
mixture synthetic method for preparing 16 stereoisomers of the
natural product murisolin via one-pot reactions by the combination
of four fluorous tags and four oligoethylene glycol (OEG) tags.8 First,
on the basis of the properties of OEG tags, the 16 components of the
mixture were separated into four fractions by flash column chro-
matography.9 Each of these four fractions was then further demixed
by fluorous HPLC with a FluoroFlashÒ PF-C8 column. A double
mixture synthesis combining fluorous tags and acyl tags is con-
sidered to be a good approach for an efficient and expeditious
synthesis of cucurbitoside-like phenolic glycosides because of the
following reasons. First, these natural products have a high degree
of structure similarity. Second, the chemical reactions of acyl-
tagged compounds with fluorous-tagged compounds can be con-
ducted with a traditional solution-phase synthetic technique, and
the mixture of fluorous- and acyl-tagged compounds can be dem-
ixed with fluorous and octadecyl stationary phases.
two acceptors and the mixture of the four donors are mixed and
then glycosylated. The resulting mixture of the eight components,
M-3, is demixed into two fractions by fluorous HPLC depending
upon the lengths of the perfluoroalkyl chains. These two fractions,
each containing four components, are then demixed by reverse-
phase HPLC with an ODS column. The separation depends upon
We describe herein the double fluorous and acyl mixture syn-
theses of eight cucurbitoside-like phenolic glycosides using two
fluorous benzyl groups and four acyl groups from D-glucose and L-
ribose.
2. Results and discussion
2.1. Synthetic plan of cucurbitoside-like phenolic glycosides
Our synthetic plan of the double mixture synthesis to provide
the eight cucurbitoside-like phenolic glycosides 1aeh is shown in
Scheme 1. The plan is based on our previous study of the total
synthesis of cucurbitoside A.10
A mixture (M-1) of two fluorous-tagged phenyl
anosyl acceptors, in which the structure of aglycones differed, is
prepared from -glucose. In the previous study, the fluorous N-
b-D-glucopyr-
D
phenylcarbamoyl (FCar) group was introduced into the C-3 hy-
droxyl group on glucopyranoside, because this fluorous-protecting
group can be removed selectively without damaging other acyl
groups. Herein, we replaced the FCar group with fluorous benzyl
(FBn) group to minimize steps required to remove the protecting
groups at the last stage of the synthesis. Another component of the
cucurbitoside-like phenolic glycosides, a mixture (M-2) of the four
acyl-tagged
D-apiofuranosyl donors, is prepared from L-ribose.
Benzoyl, 3-methylbutyryl, 4-benzyloxybenzoyl, and 4-nitrobenzoyl
groups are chosen as the acyl-protecting groups for the C-50 hy-
droxyl group on D-apiofuranose and are utilized as sorting tags for
demixing the mixture into its individual pure components
according to the structure of the acyl groups. To accomplish the
total synthesis of the eight target compounds, the mixture of the
Scheme 1. Strategy for the double mixture synthesis with four fluorous and two acyl
tags.

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M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
the structure of the acyl groups. The components are finally
deprotected to provide the eight cucurbitoside-like phenolic
glycosides.
derivative have been published.14 However, it was reported by
Zhu’s and Gin’s groups that the acetal group on apiofuranose could
not be removed without the acid hydrolysis of glycosidic linkages of
the oligosaccharide.15 Therefore, we chose the benzylidene group
as the protecting group for the C-2 and C-3 hydroxyl groups on
apiose because the protecting group can be regioselectively in-
troduced into -ribose and removed under mild neutral conditions.
Acetalization of -ribose with benzaldehyde in the presence of
a catalytic amount of camphorsulfonic acid gave 2,3-O-benzyli-
dene- -ribose 15 as a single stereoisomer. K2CO3-catalyzed aldol
condensation of 15 with formaldehyde gave the corresponding 2-C-
hydroxymethyl derivative 16 in 92% yield. Reduction of 16 followed
by oxidative cleavage with sodium periodate afforded 2,3-O-ben-
D-
2.2. Preparation of phenyl
and 14b
b-D-glucopyranosyl acceptors 14a
L
L
Fluorous-protecting reagents 4-(3-perfluoroalkyl)propyl benzyl
bromides 5a and 5b were prepared via fluorous methyl benzoate11
by the route shown in Scheme 2. Compound 3a, which was pre-
pared in two steps from fluorous phosphonium salt 2a and methyl
4-formylbenzoate, was converted into fluorous benzyl alcohol 4a
with LiAlH4. Bromination of 4a with PPh3 and CBr4 in CH2Cl2 gave
the crystalline and non-lachrymatory fluorous benzyl bromide 5a
in excellent yield. Fluorous benzyl bromide 5b was also synthesized
via a similar route starting from fluorous phosphonium salt 2b.
L
zylidene- -apiofuranose 17 in 87% yield. In the last two steps prior
D
to the double mixture synthesis, the primary hydroxyl group of 17
was selectively acylated with benzoyl chloride, 3-methylbutyryl
chloride, 4-benzyloxybenzoyl chloride, and 4-nitrobenzoyl chlo-
ride and then the hydroxyl group at C-1 underwent tri-
chloroacetimidation. The results of the selective acylation followed
by trichloroacetimidation are shown in Table 1. For example,
compound 17 was reacted with benzoyl chloride in the presence of
pyridine at ꢀ78 ꢁC in CH2Cl2 to give the corresponding benzoylated
derivative 18a in 78% yield (entry 1). Likewise, 3-methylbutyry-
lated, 4-benzyloxybenzoylated and 4-nitrobenzoylated derivatives
18bed were obtained in 78%, 53%, and 71% yields, respectively
(entries 2e4).16 Since 4-benzyloxybenzoyl chloride was insoluble in
CH2Cl2 at ꢀ78 ꢁC, the yield of product 18c was lower than those of
18a, 18b, and 18d. Next, these compounds 18aed were converted
into their corresponding imidates 19aed in high yields by treat-
ment with trichloroacetonitrile and 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) in CH2Cl2 at 0 ꢁC (entries 1e4).
Scheme 2. Preparation of fluorous benzyl bromides 5a and 5b.
2.4. Double mixture synthesis, analysis, and separation of
eight disaccharides 20aeh
As shown in Scheme 3, the C6F13Bn-protected phenyl
pyranosyl acceptor 14a was prepared from the fluorous benzyl
bromide 5a and 1,2:5,6-di-O-isopropylidene- -glucofuranose (6)
b-D-gluco-
a-D
Using the fluorous-tagged acceptors and acyl-tagged donors
successfully prepared thus far, we attempted a solution-phase
mixture synthesis of cucurbitoside-like phenolic glycosides. A
mixture of two acceptors 14a and 14b were glycosylated with
a mixture of four donors 19aed. The reaction was carried out in
anhydrous CH2Cl2 at ꢀ20 ꢁC in the presence of a catalytic amount of
in an eight-step synthesis. C6F13Benzyl bromide 5a was reacted with
6 to give the 3-O-C6F13benzyl derivative 7a in 84% yield. Acid hy-
drolysis of 7a using 80% aq trifluoroacetic acid followed by acetyla-
tion with acetic anhydride gave the tetra-O-acetylated compound
8a, which was then reacted with benzylamine. The crude product
was purified by silica gel column chromatography to provide 2,3,4-
tri-O-acetate 9a in 65% yield. Trichloroacetimidation of 9a followed
ꢀ
trimethylsilyl trifluoromethane sulfonate and molecular sieves 4 A
(Scheme 5). After purification of the crude product by FSPE, M-3,
including the eight structural isomers, was analyzed by HPLC with
a FluophaseÒ RP column,17 InertsilÒ ODS-3 column,18 and standard
silica gel TLC to determine the optimal separation conditions.
Identification of individual peaks or spots was accomplished by
comparing the retention times or Rf values of some components in
the mixture with those of the corresponding pure disaccharides
that were prepared individually. When a FluophaseÒ RP column
was used, all four C6F13Bn-tagged disaccharides 20aed were eluted
before all four C8F13Bn-tagged disaccharides 20eeh, as expected
(Fig. 2a). Interestingly, the retention times of the 3-
methylbutyrylated disaccharides 20b and 20f were largely differ-
ent from those of the three disaccharides bearing benzoyl, 4-
nitrobenzoyl, and 4-benzyloxybenzoyl groups, although the per-
fluoroalkyl chain length was the same. Besides the interaction be-
tween perfluoroalkyl chain and the fluorinated stationary phase,
the disaccharides 20b and 20f would be strongly retained by the
hydrophobic interaction of the 3-methylbutyryl group, which is the
only aliphatic substituent in the four acyl-protecting groups, with
the fluorinated stationary phase. Next, to demix M-3 according to
the difference of hydrophobicity of the acyl groups, HPLC analysis
with an InertsilÒ ODS-3 column was carried out. The resulting HPLC
trace is shown in Fig. 2b. The eight components of M-3 were sep-
arated into two groups of four peaks. The first four peaks were
by glycosylation with 4-(benzyloxy)phenol (10) gave phenyl b-D-
glucopyranoside 12a in 93% yield. Acetyl groups were removed from
12a with sodium methoxide to give 13a. Finally, benzylidenation of
13a with benzaldehyde dimethylacetal in the presence of a catalytic
amount of p-toluenesulfonic acid monohydrate gave the desired
glycosyl acceptor 14a in 66% yield. Therefore, compound 14a was
successfully prepared from 5a in 34% overall yield. In these reaction
steps, fluorous solid-phase extraction (FSPE) was utilized for the
speedy purification of the fluorous intermediates.12 In FSPE, the re-
action mixture was loaded onto a FluoroFlashÒ column and eluted
with 80% aq methanol to remove the non-fluorous compounds.13
Then, the desired fluorous compound was eluted with a fluo-
rophilic solvent, such as methanol. Next, the glycosyl acceptor 14b,
bearing 4-(benzyloxyethyl)phenol (11) as the aglycone, was pre-
pared using a C8F17benzyl group via a similar route. As a result, the
desired compound 14b was synthesized in 37% overall yield from 5b.
2.3. Preparation of apiofuranosyl donors 19aed
Other components of cucurbitoside-like phenolic glycosides,
four
D-apiofuranosyl donors 19aed, were prepared from L-ribose in
a five-step synthesis, as shown in Scheme 4. Numerous synthetic
methods of apiose and its 2,3-O-isopropylidene-protected

M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
8279
Scheme 3. Preparation of fluorous-tagged phenyl b-D-glucopyranosyl acceptors 14a and 14b.
assigned to the four disaccharides 20aed with C6F13Bn-tag. The
second four peaks were assigned to the four disaccharides 20eeh
with C8F17Bn-tag. The four acyl-tagged disaccharides of the first and
second groups were eluted in the same order. The first peaks were
due to the 4-nitrobenzoylated disaccharides 20d and 20h. The
second peaks were due to the benzoylated disaccharides 20a
and 20e. The third peaks were due to the 3-methylbutyrylated
disaccharides 20b and 20f, but the peak of impurity was ob-
served and overlapped with the peak of disaccharide 20b. The
fourth peaks were due to the 4-benzyloxybenzoylated di-
saccharides 20c and 20g. However, the retention times of com-
pounds 20c and 20h were very close. Finally, TLC analysis of M-3 on
a standard silica gel showed three major spots with Rf values of
0.52, 0.48, and 0.41 and one minor spot with Rf value of 0.34 (Fig. 3).
Scheme 4. Preparation of acyl-tagged apiofuranosyl donors 19aed.

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M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
in a single step by using serially connected FluophaseÒ RP and
Table 1
InertsilÒ ODS-3 columns instead of two independent HPLC purifi-
cation steps (Fig. 4a). For comparison, the separation result
obtained using only an InertsilÒ ODS-3 column was also listed
(Fig. 4b). When the serially connected FluophaseÒ RP and InertsilÒ
ODS-3 columns were used, the eight components of M-3 were
cleanly separated with large differences in their retention times.
Compared with the separation result obtained using only the ODS
column, the difference between the retention times of compounds
20c and 20h was particularly improved.
Selective acylation and trichloroacetimidation
Entry Acyl
chloride
R
Yield of Yield of
selective trichloroacetimidation
acylation (%)
(%)
O
O
Benzoyl
chloride
1
18a: 78 19a: 93
3-Methylbutyryl
chloride
2
3
18b: 78 19b: 86
18c: 53 19c: 83
O
O
4-Benzyloxybenzoyl
chloride
B
nO
4-Nitrobenzoyl
chloride
4
18d: 71 19d: 81
N
O2
Fig. 3. Using hexane/EtOAc (5:1) as the mobile phase and a normal-phase silica gel
TLC, M-3 was developed four times. The compounds were detected by dipping the
plate into Hanessian’s (Cerium Molybdate) stain followed by heating. Lane a: M-3, Lane
b: the samples of synthetic 20a, Lane c: the samples of synthetic 20b, Lane d: the
samples of synthetic 20c, Lane e: the samples of synthetic 20d. When 20e, 20f, 20g,
and 20h were used as the standard samples, a similar separation result was obtained
from TLC analysis.
Fig. 2. HPLC analysis of M-3. (a) FluophaseÒ column (4.6 mmꢂ150 mm), CH3CN/H2O
gradient (80% CH3CN/H2O to 100% CH3CN over 40 min), flow rate 1.0 mL/min, UV
detection at 254 nm (b) InertsilÒ column (4.6 mmꢂ250 mm), CH3CN/H2O gradient
(90% CH3CN/H2O to 100% CH3CN over 40 min), flow rate 1.0 mL/min, UV detection at
254 nm.
The high and middle spots (Rf values of 0.52 and 0.48) corre-
sponded to the samples of the 3-methylbutyrylated and benzoy-
lated disaccharides, respectively. However, the low spot (Rf
value of 0.41) was a mixture of the 4-nitrobenzoylated and 4-
benzyloxybenzoylated disaccharides. Therefore, it was predicted
that the four acyl-tagged disaccharides would be difficult to sepa-
rate on the basis of polarity of acyl groups by standard silica gel
chromatography. Considering the results obtained from separa-
tions by HPLC and TLC analyses, HPLC purification of M-3 with
a FluophaseÒ RP column followed by purification with an InertsilÒ
ODS-3 column would provide the individual compounds. However,
this is a time-consuming method. Therefore, we tried to separate
the eight components of M-3 into its individual pure compounds
Fig. 4. HPLC analysis of M-3. (a)
A
serially connected FluophaseÒ column
(4.6 mmꢂ150 mm) and InertsilÒ ODS-3 column (4.6 mmꢂ250 mm), CH3CN/H2O gra-
dient (90% CH3CN/H2O to 100% CH3CN over 120 min), flow rate 1.0 mL/min, UV de-
tection at 254 nm. (b) InertsilÒ ODS-3 column (4.6 mmꢂ250 mm), CH3CN/H2O
gradient (90% CH3CN/H2O to 100% CH3CN over 120 min), flow rate 1.0 mL/min, UV
detection at 254 nm.

M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
8281
Usually, FluophaseÒ RP column easily separates more than four
fluorous compounds depending upon their fluorine atom contents.
The separation of each component is enhanced with increasing the
length of the column. InertsilÒ ODS-3 column is suitable for sepa-
rating the compounds with the acyl groups. The separation of each
component is also enhanced with increasing the column length.
Therefore, we will be able to control the ability of the serially
connected columns to separate more than eight components of the
product mixture with changing their length independently. How-
ever, it may be impossible for us to separate the components of the
product mixture only with the InertsilÒ ODS-3 column when the
components of the product mixture increase more than 16, for
example.
hydrogenolysis (Scheme 6). The crude products were purified by
semi-preparative HPLC to provide the six cucurbitoside-like phe-
nolic glycosides 1aec and 1eef in high yields (entries 1e3 and 5e7
of Table 2). However, the hydrogenolysis of disaccharides 20d and
20h with a catalytic amount of palladium hydroxide on carbon
(Pd(OH)2/C) in THF/MeOH was unsuccessful. In this case, an amino
group on the aromatic ring that was initially generated by the re-
duction of the nitro group would have acted as a catalyst poison,
inhibiting deprotection of the other protecting groups. Therefore,
we examined hydrogenolysis of the compounds 20d and 20h under
acidic conditions in order to promote the activity of the Pd(OH)2/C
catalyst. When 0.1 M HCl was used as an acid, the yields of these
final products 1d and 1h were increased to 55% and 33%, re-
Scheme 5. Double mixture synthesis.
The mixture of fluorous- and acyl-tagged compounds was then
preparatively demixed to provide its eight components in pure
form. M-3 (80.6 mg) was injected into the serially connected
FluophaseÒ RP and InertsilÒ ODS-3 columns, and the columns were
eluted over 120 min with a gradient from 90% CH3CN/H2O to 100%
CH3CN (Fig. 5). After these eight major fractions were collected and
concentrated, the pure compounds 20a, 20b, 20c, 20d, 20e, 20f,
20g, and 20h were obtained in 8.4 mg, 8.5 mg, 9.5 mg, 8.8 mg,
10.6 mg, 8.6 mg, 8.0 mg, and 9.1 mg, respectively (Scheme 6). MS
analysis and 1D (1H and 13C) and 2D (1He1H COSY) NMR data of the
products demonstrated that compounds 20aeh were the desired
disaccharides. In addition, no noticeable peaks due to impurities
were observed in the 1H and 13C NMR spectra of the compounds.
2.5. Total synthesis of eight cucurbitoside-like phenolic
glycosides 1aeh
Fig. 5. HPLC chromatogram from the preparative demixing of M-3, obtained using
serially connected FluophaseÒ (21.2 mmꢂ250 mm) and InertsilÒ ODS-3
(20.0 mmꢂ250 mm) columns, CH3CN/H2O gradient (90% CH3CN/H2O to 100% CH3CN
over 120 min), flow rate 19.0 mL/min, UV detection at 254 nm.
The benzylidene groups and the standard and fluorous benzyl
groups of disaccharides 20aec and 20eeg were removed by

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M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
Scheme 6. Demix of eight protected disaccharides 20aeh.
Table 2
Hydrogenolysis and optical rotation
OH
O
Pd(OH)2, H2 gas
THF–MeOH,rt
HO
HO
R2O
O
20a-h
O
R1
O
HO OH
1a-h
cucurbitoside-like phenolic glycosides
Entry
Product
Yield (%)
Optical rotationc
Synthetic sample
R1
R2
Natural product
1
2
3
4
5
6
7
8
Seguinoside C (1a)
Analog I (1b)
Seguinoside D (1c)
Analog II (1d)
Cucurbitoside A (1e)
Cucurbitoside G (1f)
Cucurbitoside B (1g)
Cucurbitoside l (1h)
OH
OH
OH
OH
Benzoyl
3-Methylbutyryl
4-Hydroxybenzoyl
4-Aminobenzoyl
Benzoyl
3-Methylbutyryl
4-Hydroxybenzoyl
4-Aminobenzoyl
80
Quant.
ꢀ87.8 (c 0.59)
ꢀ88.7 (c 1.1)
ꢀ67.4 (c 0.43)
ꢀ64.7 (c 0.62)
ꢀ76.2 (c 1.0)
ꢀ83.8 (c 0.29)
ꢀ68.8 (c 0.42)
ꢀ63.7 (c 0.51)
ꢀ86.3 (c 0.58)
d
Quant.
ꢀ67.1 (c 0.39)
d
55a
CH2CH2OH
90
93
ꢀ76.1 (c 1.1)
ꢀ81.3 (c 0.25)
ꢀ65.9 (c 0.4)
ꢀ57.1 (c 0.44)
CH2CH2OH
CH2CH2OH
CH2CH2OH
Quant.
33b
a
EtOAc/MeOH was used as solvent instead of THF/MeOH. In addition, aq HCl (0.1 M) was used as an additive.
aq HCl (0.1 M) was used as an additive.
The optical rotation of 1a was measured in pyridine. The other seven compounds, 1beh, were measured in methanol.
b
c
spectively (entries 4 and 8). An improvement in the yields of the
two independent HPLC separations, a single HPLC separation con-
ducted with two serially connected columns was achieved in
a shorter time and at a lower cost. This method could also be ap-
plied to the synthesis of 16 structural isomers of phenolic glyco-
sides in a single-step reaction of four fluorous benzyl-tagged
acceptors with the four acyl-tagged donors. The work is currently
underway.
From the realistic point of view, it may be considered to be more
practical to synthesize the final products independently from each
of the two acceptors and the four donors, because the reaction of
the acceptor with the donor is the final step to the precursor of the
target product. However, if final precursors are obtained via several
steps after mixing the acceptors and donors, the method described
here is more practical than that carrying out the steps for each
acceptor and donor independently. This report is on a theoretical
work to examine an ability of acyl tags as a partner for a fluorous
mixture synthesis.
two final products is in progress. The 1H, 13C NMR data, and other
physical data obtained from synthetic 1a, 1c, 1e, 1f, 1g, and 1h
agreed well with the previously reported values for the corre-
sponding natural products. In addition, the 1H and 13C NMR spectra
of synthetic 1a, 1e, and 1f were identical to those of natural
seguinoside C, cucurbitosides A and G, samples kindly supplied by
Professor K. Koike and Associate Professor W. Li. Two unnatural
cucurbitoside-like phenolic glycosides were fully characterized by
the usual spectroscopic techniques.
3. Conclusion
We have simultaneously synthesized six natural and two un-
natural cucurbitoside-like phenolic glycosides using the technique
of double mixture synthesis. Besides fluorous tags, the acyl groups
connected to the C-50 hydroxyl group of these natural products
were also utilized as sorting tags for separation. A mixture of pro-
tected disaccharides was obtained by a single glycosylation of two
fluorous-tagged acceptors with four acyl-tagged donors. It was also
demonstrated that the eight precursors of the cucurbitoside-like
phenolic glycosides were cleanly separated by a single HPLC puri-
fication with serially connected FluophaseÒ RP and InertsilÒ ODS-3
columns depending upon the lengths of their perfluoroalkyl chains
and the hydrophobicity of their acyl groups. In comparison with
4. Experimental section
4.1. General
Melting points were measured using a Yanaco Model MP-J3
micro-melting point apparatus, and are uncorrected. IR spectra
were recorded using a JASCO FT/IR-460 spectrometer on KBr pellets

M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
8283
or liquid film on NaCl. 1H and 13C NMR spectra were measured with
Bruker Avance DPX-250 and JEOL JNM-ECA600 spectrometers in
CDCl3 or CD3OD solution with tetramethylsilane as an internal
standard. Thin-layer chromatography (TLC) was performed on
Merck Silica gel 60 F254 plates. Flash column chromatography was
and the residue was purified by short silica gel column chroma-
tography (hexane) to give benzyl bromide 5a (620 mg, 98% yield) as
colorless solids. The product 5a was used for the next reaction
without further purification.
performed on silica gel 60 N (spherical, neutral) (40e100
m
m,
4 . 2 . 4 . 4 - ( 4 , 4 , 5 , 5 , 6 , 6 , 7 , 7 , 8 , 8 , 9 , 9 , 1 0 , 1 0 , 11 , 11 , 11 -
Heptadecafluoroundecyl)benzyl bromide (5b). To a solution of ben-
zyl alcohol 4b (1.0 g, 1.76 mmol) in dry CH2Cl2 (20 mL) were added
triphenylphosphine (600 mg, 2.29 mmol) and carbon tetrabromide
(759 mg, 2.29 mmol). After stirring for 1 h at room temperature, the
solvent was evaporated, and the residue was purified by short silica
gel column chromatography (hexane) to give benzyl bromide 5b
(1.09 g, 98% yield) as colorless solids. The product 5b was used for
the next reaction without further purification.
Kanto). Analytical high-performance liquid chromatography
(HPLC) was performed with an SHIMADZU LC-10ATvp system,
consisting of an LC-10ATvp pump, an FCV-10ALvp low-pressure
gradient unit, a DGU-14A degasser, an SPD-10AV UV-VIS detector,
and a CTO-10ACvp column oven. Semi-preparative HPLC was per-
formed on an SHIMADZU system equipped with an LC-6AD binary
pump, an SCL-10Avp system controller, an SPD-20AV UV/VIS de-
tector, and a DGU-20A3 degasser. Specific rotations were measured
in 1.0 dm tubes using a PerkineElmer 241 polarimeter in CHCl3,
CH3OH or pyridine. ESI-TOF mass spectra were recorded with JEOL
JMS-T100LC AccuTOF mass spectrometer.
4.2.5. 3-O-[4-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl)benzyl]-
1,2:5,6-di-O-isopropylidene-
a-D-glucofuranose (7a). To a solution of
1,2:5,6-di-O-isopropyridene-a-D-glucofuranose (6) (664 mg,
4.2. Preparation of phenyl
and 14b
b
-
D
-glucopyranosyl acceptors 14a
2.55 mmol) in dry THF (10 mL) was added sodium hydride (55%
dispersion in paraffin liquid, 223 mg, 5.11 mmol) at 0 ꢁC under ar-
gon. After stirring for 30 min at the same temperature, tetrabutyl
ammonium iodide (79 mg, 0.213 mmol) was added, and then a so-
lution of benzyl bromide 5a (1.13 g, 2.13 mmol) in THF (20 mL) was
added dropwise to the solution. After stirring for 16 h at room
temperature, the reaction mixture was poured into saturated aq
NH4Cl solution (30 mL), and the aqueous layer was extracted with
EtOAc (30 mLꢂ3). The combined organic layer was successively
washed with water (10 mL) and brine (10 mL), dried over Na2SO4,
filtered, and concentrated. The residue was purified by silica gel
column chromatography (hexane/EtOAc¼6:1 v/v) to give 7a (1.34 g,
88% yield) as colorless amorphous solids: Rf¼0.59 (hexane/
4.2.1. 4-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl)benzyl
alcohol
(4a). To suspension of lithium aluminum hydride (92 mg,
a
2.4 mmol) in dry THF (5 mL) was added dropwise a solution of
methyl ester 3a (1.0 g, 2.0 mmol) in dry THF (10 mL) with dropping
funnel at 0 ꢁC under argon. After stirring for 1 h at the same tem-
perature, the reaction mixture was warmed to room temperature
and stirred for an additional 1 h. The reaction was quenched with
saturated aq Na2SO4 solution (1 mL). The resulting suspension was
then filtered through Celite and the filtrate was dried over Na2SO4,
filtered, and concentrated. The residue was purified by silica gel
column chromatography (hexane/EtOAc¼3:1 v/v) to give alcohol
4a (900 mg, 95% yield) as colorless amorphous solids: Rf¼0.27
EtOAc¼2:1 v/v); ½a D15
ꢃ
ꢀ11.9 (c 0.202, CHCl3); IR (KBr, disk):
n
2989 cmꢀ1, 2938 cmꢀ1, 2879 cmꢀ1 (CH3); 1H NMR (250 MHz,
(hexane/EtOAc¼3:1 v/v); IR (KBr, disk):
n
3365 cmꢀ1 (OH); 1H NMR
CDCl3):
d
7.29, 7.16 (4H, each d, J¼8.0 Hz, eC6H4e), 5.89 (1H, d,
(250 MHz, CDCl3):
d
7.31, 7.18 (4H, each d, J¼8.0 Hz, eC6H4e), 4.67
J1,2¼3.7 Hz, H-1), 4.67, 4.61 (2H, each d, JAB¼11.8 Hz, C6H4CH2), 4.58
(2H, d, J1,OH¼5.8 Hz, CH2OH), 2.71 (2H, t, J¼7.4 Hz,
(1H, d, J2,1¼3.7 Hz, H-2), 4.37 (1H, ddd, J5,4¼7.8 Hz, J5,6¼6.1 Hz,
0
CH2CH2CH2C6F13), 2.19e1.88 (4H, m, CH2CH2CH2C6F13), 1.60 (1H, t,
J5,6 ¼5.9 Hz, H-5), 4.15 (1H, dd, J4,5¼7.8 Hz, J4,3¼3.1 Hz, H-4), 4.11
OH); 13C NMR (63 MHz, CDCl3):
d
140.1, 139.0, 128.5, 127.4, 65.1,
(1H, dd, J6,5¼6.1 Hz, J6,6 ¼8.6 Hz, H-6), 4.02 (1H, d, J3,2¼3.1 Hz, H-3),
0
4.00 (1H, dd, J6 ,5¼5.9 Hz, J6 ,6¼8.6 Hz, H-60), 2.71 (2H, t, J¼7.5 Hz,
0
0
34.7, 30.3 (t, JCF¼22.5 Hz), 21.9; ESI-HRMS calcd for C16H13F13ONa
m/z [MþNa]þ: 491.0657. Found: 491.0639.
CH2CH2CH2C6F13), 2.19e1.88 (4H, m, CH2CH2CH2C6F13), 1.49, 1.43,
1.37, 1.31 (12H, each s, CH3ꢂ4); 13C NMR (63 MHz, CDCl3):
d 140.3,
4 . 2 . 2 . 4 - ( 4 , 4 , 5 , 5 , 6 , 6 , 7 , 7 , 8 , 8 , 9 , 9 , 1 0 , 1 0 , 11 , 11 , 11 -
Heptadecafluoroundecyl)benzyl alcohol (4b). To a suspension of
lithium aluminum hydride (153 mg, 4.0 mmol) in dry THF (10 mL)
was added dropwise a solution of methyl ester 3b (2.0 g, 3.4 mmol)
in dry THF (15 mL) with dropping funnel at 0 ꢁC under argon. After
stirring for 1 h at the same temperature, the reaction mixture was
warmed to room temperature and stirred for an additional 1 h. The
reaction was quenched with saturated aq Na2SO4 solution (1 mL).
The resulting suspension was then filtered through Celite and the
filtrate was dried over Na2SO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography (hexane/
EtOAc¼3:1 v/v) to give alcohol 4b (1.9 g, 99% yield) as colorless
amorphous solids: Rf¼0.27 (hexane/EtOAc¼3:1 v/v); IR (KBr, disk):
135.7,128.4,128.0,111.8,109.0,105.3, 82.7, 81.7, 81.3, 72.5, 72.2, 67.4,
34.7, 30.3 (t, JCF¼22.3 Hz), 26.8, 26.7, 26.2, 25.4, 21.8; ESI-HRMS
calcd for C28H31F13O6Na m/z [MþNa]þ: 733.1811. Found: 733.1784.
4 . 2 . 6 . 3 - O - [ 4 - ( 4 , 4 , 5 , 5 , 6 , 6 , 7 , 7 , 8 , 8 , 9 , 9 ,10 ,10 ,11,11,11 -
Heptadecafluoroundecyl)benzyl]-1,2:5,6-di-O-isopropylidene-
a
-
D
-
glucofuranose (7b). To a solution of 1,2:5,6-di-O-isopropyridene-
a
-
D-glucofuranose (6) (549 mg, 2.11 mmol) in dry THF (10 mL) was
added sodium hydride (55% dispersion in paraffin liquid, 184 mg,
4.22 mmol) at 0 ꢁC under argon. After stirring for 30 min at the
same temperature, tetrabutyl ammonium iodide (65 mg,
0.176 mmol) was added, and then a solution of benzyl bromide 5b
(1.11 g, 1.76 mmol) in THF (20 mL) was added dropwise to the so-
lution. After stirring for 16 h at room temperature, the reaction
mixture was poured into saturated aq NH4Cl solution (30 mL), and
the aqueous layer was extracted with EtOAc (30 mLꢂ3). The com-
bined organic layer was successively washed with water (10 mL)
and brine (10 mL), dried over Na2SO4, filtered, and concentrated.
The residue was purified by silica gel column chromatography
(hexane/EtOAc¼6:1) to give 7b (1.26 g, 88% yield) as colorless
needles: mp 67.5e69.9 ꢁC (MeOH); Rf¼0.59 (hexane/EtOAc¼2:1 v/
n
3324 cmꢀ1 (OH); 1H NMR (250 MHz, CDCl3):
d 7.31, 7.17 (4H, each
d, J¼8.0 Hz, eC6H4e), 4.66 (2H, s, CH2OH), 2.71 (2H, t, J¼7.5 Hz,
CH2CH2CH2C8F17), 2.19e1.88 (4H, m, CH2CH2CH2C8F17), 1.72 (1H, br
s, OH); 13C NMR (63 MHz, CDCl3):
d 140.1, 139.0, 128.5, 127.4, 65.1,
34.7, 30.3 (t, JCF¼22.5 Hz), 21.9; ESI-HRMS calcd for C18H13F17ONa
m/z [MþNa]þ: 591.0593. Found: 591.0631.
4.2.3. 4-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl)benzyl bromide
(5a). To a solution of benzyl alcohol 4a (558 mg, 1.19 mmol) in dry
CH2Cl2 (12 mL) were added triphenylphosphine (406 mg,
1.55 mmol) and carbon tetrabromide (514 mg, 1.55 mmol). After
stirring for 1 h at room temperature, the solvent was evaporated,
v); ½a 1D1
ꢃ
ꢀ12.04 (c 1.03, CHCl3); IR (KBr, disk):
n 2988, 2937,
7.29, 7.16 (4H, each
2878 cmꢀ1 (CH3); 1H NMR (250 MHz, CDCl3):
d
d, J¼8.0 Hz, eC6H4e), 5.90 (1H, d, J1,2¼3.7 Hz, H-1), 4.67, 4.61 (2H,
each d, JAB¼11.8 Hz, C6H4CH2), 4.58 (1H, d, J2,1¼3.7 Hz, H-2), 4.37

8284
M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
0
(1H, ddd, J5,4¼7.7 Hz, J5,6¼6.0 Hz, J5,6 ¼5.9 Hz, H-5), 4.15 (1H, dd,
toluene. The residue was dried in vacuo. The crude product 8b was
used for the next reaction without further purification. To a solution
of the crude product 8a in dry THF (6 mL) was added benzylamine
0
J4,5¼7.7 Hz, J4,3¼3.2 Hz, H-4), 4.12 (1H, dd, J6,5¼6.0 Hz, J6,6 ¼8.5 Hz,
0
H-6), 4.02 (1H, d, J3,2¼3.2 Hz, H-3), 4.01 (1H, dd, J6 ,5¼5.9 Hz,
J6 ,6¼8.5 Hz, H-60), 2.71 (2H, t, J¼7.5 Hz, CH2CH2CH2C8F17),
(101 mL, 0.93 mmol). After stirring for 48 h at room temperature, the
0
2.19e1.88 (4H, m, CH2CH2CH2C8F17), 1.49, 1.43, 1.38, 1.31 (12H, each
solvent was removed by evaporation. The residue was then dis-
solved in EtOAc (20 mL). The organic layer was successively washed
with 1 M aq HCl solution (5 mL), water (5 mL) and brine (5 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography (hexane/
s, CH3ꢂ4); 13C NMR (63 MHz, CDCl3):
d 140.3, 135.7, 128.4, 128.0,
111.8, 109.0, 105.3, 82.7, 81.7, 81.3, 72.5, 72.2, 67.4, 34.7, 30.3 (t,
JCF¼22.3 Hz), 26.8, 26.7, 26.2, 25.4, 21.8; ESI-HRMS calcd for
C30H31F17O6Na m/z [MþNa]þ: 833.1747. Found: 833.1720.
EtOAc¼3:2 v/v) to give hemiacetal 9b (342 mg, 65% yield,
a
/
b
¼3:1)
4.2.7. 2,4,6-Tri-O-acetyl-3-O-[4-(4,4,5,5,6,6,7,7,8,8,9,9,9-
as a colorless syrup: Rf¼0.18 (hexane/EtOAc¼3:2 v/v); ½a D18
ꢃ
þ17.1 (c
tridecafluorononyl)benzyl]-
a/
b-
D
-glucopyranose (9a). To a solution
0.21, CHCl3); IR (KBr, disk): n
3461 cmꢀ1 (OH), 1746 cmꢀ1 (C]O); 1H
of 7a (625 mg, 0.88 mmol) in CH2Cl2 (1.5 mL) was added 80% aq TFA
solution (1.5 mL). After stirring for 5 h at room temperature, the
reaction mixture was carefully poured into saturated aq NaHCO3
solution (10 mL), and the aqueous layer was extracted with EtOAc
(10 mLꢂ5). The combined organic layers were dried over Na2SO4,
filtered, and concentrated. The residue was then dried in vacuo. The
residue was redissolved in pyridine (5 mL), and acetic anhydride
(5 mL) was added. After stirring for 11 h at room temperature, the
reaction mixture was poured into MeOH at 0 ꢁC and stirred for
10 min. The mixture was evaporated and co-evaporated with tolu-
ene. The residue was dried in vacuo. The crude product 8a was used
for the next reactionwithout further purification. To a solution of the
NMR (250 MHz, CDCl3)
a
-anomer:
d
7.20, 7.14 (4H, each d, J¼8.3 Hz,
eC6H4e), 5.46 (1H, dd, J1,2¼3.6 Hz, H-1), 5.10 (1H, dd, J4,3¼9.6 Hz,
J4,5¼9.1 Hz, H-4), 4.88 (1H, dd, J2,1¼3.6 Hz, J2,3¼10.0 Hz, H-2), 4.69,
4.58 (2H, each d, J¼11.6 Hz, C6H4CH2), 4.22e4.00 (3H, m, H-5, 6, 60),
4.04 (1H, dd, J3,2¼10.0 Hz, J3,4¼9.3 Hz, H-3), 2.69 (2H, t, J¼7.4 Hz,
CH2CH2CH2C8F17), 2.19e1.86 (4H, m, CH2CH2CH2C8F17), 2.08, 2.07,
1.97 (9H, each s, COCH3ꢂ3);
b
-anomer:
d
5.14e5.06 (1H, m, H-4,
overlapped with H-4 signal of
overlapped with H-2 signal of
a
-anomer), 4.91e4.84 (1H, m, H-2,
a
-anomer), 4.67e4.56 (3H, m, H-1,
-anomer), 4.26e4.07
(2H, m, H-6, 60, overlapped with H-5, 6, 60 signals of
-anomer), 3.73
C6H4CH2, overlapped with C6H4CH2 signal of
a
a
(1H, t, J3,2¼9.3 Hz, J3,4¼9.3 Hz, H-3), 3.64 (1H, ddd, J5,4¼10.0 Hz,
J5,6¼2.6 Hz, J5,6 ¼5.0 Hz, H-5),1.98 (3H, s, COCH3); 13C NMR (63 MHz,
0
crude product 8a in dry THF (8 mL) was added benzylamine (144
mL,
1.32 mmol). After stirring for 48 h at room temperature, the solvent
was removed by evaporation. The residue was then dissolved in
EtOAc (20 mL). The organic layer was successively washed with 1 M
aq HCl solution (5 mL), water (5 mL) and brine (5 mL). The organic
layer was dried over Na2SO4, filtered, and concentrated. The residue
was purified by silica gel column chromatography (hexane/
CDCl3) a-anomer: d 171.0,170.1,169.5,140.1,136.2,128.4,127.9, 90.3,
76.9, 74.6, 73.5, 69.9, 67.7, 62.3, 34.7, 30.3 (t, JCF¼22.6 Hz), 21.8, 20.8,
20.68, 20.67; -anomer: 171.0, 170.9, 169.4, 140.4, 135.8, 128.4,
b
d
128.0, 95.8, 79.7, 75.3, 74.1, 72.3, 69.7; ESI-HRMS calcd for
C30H29F17O9Na m/z [MþNa]þ: 879.1438. Found: 879.1438.
EtOAc¼3:2 v/v) to give hemiacetal 9a (482 mg, 72% yield,
a
/
b
¼7:1)
4.2.9. 4-(Benzyloxy)phenyl 2,4,6-tri-O-acetyl-3-O-[4-(4,4,5,5,6,6,7,7,
8,8,9,9,9-tridecafluorononyl)benzyl]-b-D-glucopyranoside (12a). To
a solution of hemiacetal 9a (1.90 g, 2.51 mmol) in dry CH2Cl2
as a colorless syrup: Rf¼0.18 (hexane/EtOAc¼3:2 v/v); ½a D19
ꢃ
þ20.8 (c
1.0, CHCl3); IR (KBr, disk):
n
3452 cmꢀ1 (OH), 1747 cmꢀ1 (C]O); 1H
NMR (250 MHz, CDCl3)
a
-anomer:
d
7.20, 7.14 (4H, each d, J¼8.3 Hz,
(20 mL) was added trichloroacetonitrile (3.0 mL, 30.14 mmol) and
eC6H4e), 5.46 (1H, dd, J1,2¼3.7 Hz, J1,OH¼3.8 Hz, H-1), 5.10 (1H, dd,
J4,3¼9.6 Hz, J4,5¼9.7 Hz, H-4), 4.87 (1H, ddd, J2,1¼3.7 Hz, J2,3¼9.9 Hz,
J2,OH¼1.3 Hz, H-2), 4.69, 4.60 (2H, each d, J¼11.6 Hz, C6H4CH2),
4.22e4.09 (3H, m, H-5, 6, 60), 4.04 (1H, dd, J3,2¼9.9 Hz, J3,4¼9.6 Hz, H-
3), 3.24 (1H, dd, JOH,1¼3.8 Hz, JOH, 2¼1.3 Hz, OH), 2.70 (2H, t, J¼7.4 Hz,
CH2CH2CH2C6F13), 2.18e1.89 (4H, m, CH2CH2CH2C6F13), 2.08, 2.07,
1,8-diazabicyclo[5.4.0]undec-7-ene (105 m
L, 0.703 mmol) at 0 ꢁC
under argon. After stirring for 10 min, the mixture was directly
chromatographed on a silica gel column (hexane/EtOAc¼4:1 v/v)
to give the trichloroacetimidate.
chloroacetimidate, phenol 10 (754 mg, 3.77 mmol), and MS-4 A
A
suspension of tri-
ꢀ
(2.0 g) in dry CH2Cl2 (40 mL) was stirred for 30 min at room
1.97 (9H, each s, COCH3ꢂ3);
b
-anomer:
d
5.13e5.05 (1H, m, H-4,
temperature under argon. BF3$Et2O complex (158 mL, 1.26 mmol)
overlapped with H-4 signal of
overlapped with H-2 signal of
a
-anomer), 4.91e4.84 (1H, m, H-2,
was then added at ꢀ20 ꢁC. After stirring for 1 h at the same
temperature, the reaction mixture was quenched with an excess
amount of triethylamine and filtered through Celite. The filtrate
was washed with saturated aq NaHCO3 solution (10 mL) and brine
(10 mL), dried over Na2SO4, filtered, and concentrated. The residue
was loaded onto a fluorous reverse-phase silica gel (FluoroFlashÒ)
column and the column was eluted successively with 80% aq
MeOH and EtOAc. The EtOAc fraction was concentrated to give
a
-anomer), 4.67e4.56 (3H, m, H-1,
-anomer), 4.24e4.07
(2H, m, H-6, 60, overlapped with H-5, 6, 60 signals of
-anomer), 3.73
C6H4CH2, overlapped with C6H4CH2 signal of
a
a
(1H, t, J3,2¼9.3 Hz, J3,4¼9.3 Hz, H-3), 3.64 (1H, ddd, J5,4¼10.0 Hz,
J5,6¼2.6 Hz, J5,6 ¼5.0 Hz, H-5),1.98 (3H, s, COCH3); 13C NMR (63 MHz,
0
CDCl3) a-anomer: d 170.9,170.1,169.4,140.2,136.2,128.4,127.9, 90.4,
76.9, 74.6, 73.4, 69.9, 67.8, 62.3, 34.7, 30.3 (t, JCF¼22.3 Hz), 21.8, 20.8,
20.73, 20.69; -anomer: 171.6, 170.8, 169.4, 140.4, 135.8, 128.4,
b
d
phenyl b-D-glucoside 12a (2.20 g, 93% yield) as colorless solids: mp
128.0, 95.9, 79.6, 75.4, 74.2, 72.3, 69.7; ESI-HRMS calcd for
116.9e119.7 ꢁC (MeOH/EtOAc); Rf¼0.38 (hexane/EtOAc¼3:2 v/v);
C28H29F13O9Na m/z [MþNa]þ: 779.1502. Found: 779.1494.
½
a 2D3
ꢃ
ꢀ8.04 (c 1.02, CHCl3); IR (KBr, disk):
n
1745 cmꢀ1 (C]O); 1H
d 7.43e7.27 (5H, m, PhH), 7.19, 7.14 (4H,
NMR (250 MHz, CDCl3):
4.2.8. 2,4,6-Tri-O-acetyl-3-O-[4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
heptadecafluoroundecyl)benzyl]-a/b-D-glucopyranose (9b). To a so-
each d, J¼8.3 Hz, eC6H4e), 6.93, 6.87 (4H, each d, J¼9.4 Hz,
eC6H4e), 5.29 (1H, dd, J2,1¼7.8 Hz, J2,3¼9.3 Hz, H-2), 5.18 (1H, dd,
J4,3¼9.5 Hz, J4,5¼9.6 Hz, H-4), 5.02, 4.61 (4H, each s, PhCH2 and
C6H4CH2), 4.87 (1H, d, J1,2¼7.8 Hz, H-1), 4.24 (1H, dd, J6,5¼5.5 Hz,
lution of 7b (500 mg, 0.62 mmol) in CH2Cl2 (1 mL) was added 80% aq
TFA solution (1 mL). After stirring for 5 h at room temperature, the
reaction mixture was carefully poured into saturated aq NaHCO3
(10 mL) solution, and the aqueous layer was extracted with EtOAc
(10 mLꢂ5). The combined organic layers were dried over Na2SO4,
filtered, and concentrated. The residue was then dried in vacuo. The
residue was redissolved in pyridine (5 mL), and acetic anhydride
(5 mL) was added. After stirring for 11 h at room temperature, the
reaction mixture was poured into MeOH at 0 ꢁC and stirred for
10 min. The mixture was evaporated and co-evaporated with
J6,6 ¼12.2 Hz, H-6), 4.15 (1H, dd, J6 ,5¼2.8 Hz, J6 ,6¼12.2 Hz, H-60),
3.77 (1H, dd, J3,2¼9.3 Hz, J3,4¼9.5 Hz, H-3), 3.70 (1H, ddd,
0
0
0
0
J5,4¼9.6 Hz, J5,6¼5.5 Hz, J5,6 ¼2.8 Hz, H-5), 2.70 (2H, t, J¼7.4 Hz,
CH2CH2CH2C6F13), 2.18e1.86 (4H, m, CH2CH2CH2C6F13), 2.05, 2.03,
2.00 (9H, each s, COCH3ꢂ3); 13C NMR (63 MHz, CDCl3):
d 170.6,
169.3, 169.1, 154.8, 151.3, 140.3, 137.0, 135.8, 128.6, 128.4, 128.1,
128.0, 127.4, 118.5, 115.7, 100.5, 80.00, 73.4, 72.4, 72.3, 70.6, 69.6,
62.4, 34.7, 30.3 (t, JCF¼22.3 Hz), 21.8, 20.8, 20.71, 20.69; ESI-HRMS

M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
8285
calcd for C41H39F13O10Na m/z [MþNa]þ: 961.2233. Found:
(13b). To
a
solution of phenyl-
b
-
D
-glucoside 12b (450 mg,
961.2250.
0.42 mmol) in THF/MeOH (45 mL, 1:2 v/v) was added sodium
methoxide (46 mg, 0.84 mmol). After stirring for 12 h at room
temperature, the reaction mixture was neutralized with DOWEXÒ
50WX8-200 ion-exchange resin and then filtered to remove the
resin. The filtrate was concentrated to give 13b. The product was
dried in vacuo at 40 ꢁC for 3 h and used for the next reaction
without further purification. Mp 85.9e91.3 ꢁC (colorless solids,
4.2.10. 4-(2-Benzyloxyethyl)phenyl 2,4,6-tri-O-acetyl-3-O-[4-(4,4,5,
5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl)benzyl]-b-D-
glucopyranoside (12b). To a solution of hemiacetal 9b (340 mg,
0.397 mmol) in dry CH2Cl2 (4 mL) were added trichloroacetonitrile
(478 mL, 4.76 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (17 mL,
0.111 mmol) at 0 ꢁC under argon. After stirring for 10 min, the mix-
ture was directly chromatographed on a silica gel column (hexane/
EtOAc¼5:1 v/v) to give the trichloroacetimidate. A suspension of
H2O-MeOH); Rf¼0.44 (hexane/EtOAc¼1:2 v/v); ½a D24
ꢀ24.30 (c 1.07,
ꢃ
CHCl3); IR (KBr, disk):
n
3368 cmꢀ1 (OH); 1H NMR (250 MHz,
CDCl3):
d
7.35e7.14 (11H, m, PhH), 6.94 (2H, d, J¼8.6 Hz, eC6H4e),
ꢀ
trichloroacetimidate, phenol 11 (181 mg, 0.79 mmol), and MS-4 A
5.01, 4.77 (2H, each d, J¼11.6 Hz, PhCH2), 4.91 (1H, d, J1,2¼7.7 Hz, H-
1), 4.51 (2H, s, PhCH2), 3.92e3.62 (4H, m, H-2, 4, 6, 60), 3.66 (2H, t,
J¼7.0 Hz, CH2CH2OBn), 3.49 (1H, dd, J3,2¼8.8 Hz, J3,4¼9.0 Hz, H-3),
3.52e3.45 (1H, m, H-5), 2.88 (2H, t, J¼7.0 Hz, CH2CH2OBn), 2.71
(2H, t, J¼7.5 Hz, CH2CH2CH2C8F17), 2.51, 2.45 (2H, each br s, OH),
2.19e1.88 (5H, m, CH2CH2CH2C8F17 and OH); 13C NMR (63 MHz,
(400 mg) in dry CH2Cl2 (8 mL) was stirred for 30 min at room tem-
perature under argon. BF3$Et2O complex (25 mL, 0.20 mmol) was
then added at ꢀ20 ꢁC. After stirring for 1 h at the same temperature,
the reaction mixture was quenched with an excess amount of trie-
thylamine and filtered through Celite. The filtrate was washed with
saturated aq NaHCO3 solution (5 mL) and brine (5 mL), dried over
Na2SO4, filtered, and concentrated. The residue was loaded onto
a fluorous reverse-phase silica gel (FluoroFlashÒ) column and the
column was eluted successively with 80% aq MeOH and EtOAc. The
CDCl3):
d 155.4, 140.5, 140.1, 138.9, 138.4, 136.5, 133.8, 130.1, 128.7,
128.5, 128.4, 127.6, 127.5, 127.4, 116.6, 101.0, 83.6, 75.5, 74.6, 74.4,
73.0, 71.2, 70.1, 62.5, 35.5, 34.8, 30.4 (t, JCF¼22.1 Hz), 21.8; ESI-HRMS
calcd for C39H37F17O7Na m/z [MþNa]þ: 963.2166. Found: 963.2187.
EtOAc fraction was concentrated to give phenyl b-D-glucoside 12b
(364 mg, 86% yield) as colorless solids: mp 117.9e119.0 ꢁC (MeOH);
4.2.13. 4-(Benzyloxy)phenyl 4,6-O-benzylidene-3-O-[4-(4,4,5,5,6,6,7,
Rf¼0.41 (hexane/EtOAc¼3:2 v/v); ½a D24
ꢃ
ꢀ8.29 (c 1.05, CHCl3); IR (KBr,
7,8,8,9,9,9-tridecafluorononyl)benzyl]-
(14a). Phenyl -glucoside 13a (1.73 g, 2.13 mmol) and benzal-
dehyde dimethylacetal (623 L, 4.26 mmol) were dissolved in dry
b-D-glucopyranoside
disk):
n
1744 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3):
d
7.36e7.25
b-D
(5H, m, PhH), 7.19, 7.14 (4H, each d, J¼8.3 Hz, eC6H4e), 7.13, 6.90 (4H,
eachd, J¼8.6 Hz, eC6H4e), 5.31 (1H, dd, J2,1¼7.8 Hz, J2,3¼9.3 Hz, H-2),
5.19 (1H, dd, J4,3¼9.4 Hz, J4,5¼9.6 Hz, H-4), 4.95 (1H, d, J1,2¼7.8 Hz, H-
1), 4.61, 4.51 (4H, each s, PhCH2 and C6H4CH2), 4.23 (1H, dd,
m
DMF (40 mL) in a 300 mL round-bottomed flask. After p-TsOH$H2O
(183 mg, 1.07 mmol) was added, the flask was attached to a rotary
evaporator, rotated, evacuated, and lowered into a water bath at
approximately 60 ꢁC to removed the MeOH which was formed
during the reaction. After 2 h, the reaction mixture was quenched
with an excess amount of triethylamine and stirred for 15 min at
room temperature. Water (160 mL) was then added to the reaction
mixture. The solution was directly loaded onto a FluoroFlashÒ col-
umn and the column was eluted successively with 80% aq MeOH
and EtOAc. The EtOAc fraction was concentrated, and the residue
was purified by silica gel column chromatography (hexane/
EtOAc¼5:1 v/v) to give 14a (1.26 g, 66% yield) as colorless solids:
0
0
J6,5¼5.5 Hz, J6,6 ¼12.1 Hz, H-6), 4.15 (1H, dd, J6 ,5¼2.7 Hz,
J6 ,6¼12.1 Hz, H-60), 3.78 (1H, dd, J3,2¼9.3 Hz, J3,4¼9.4 Hz, H-3), 3.73
0
0
(1H, ddd, J5,4¼9.6 Hz, J5,6¼5.5 Hz, J5,6 ¼2.7 Hz, H-5), 3.65 (2H, t,
J¼7.0 Hz, CH2CH2OBn), 2.87 (2H, t, J¼7.0 Hz, CH2CH2OBn), 2.69 (2H,
t, J¼7.5 Hz, CH2CH2CH2C8F17), 2.18e1.86 (4H, m, CH2CH2CH2C8F17),
2.05, 2.02, 2.00 (9H, each s, COCH3ꢂ3); 13C NMR (63 MHz, CDCl3):
d
170.6, 169.3, 169.1, 155.6, 140.3, 138.4, 135.8, 133.9, 129.9, 128.4,
128.3,128.1,127.6,127.5,116.9, 99.6, 80.00, 73.0, 72.4, 72.3, 71.2, 69.6,
62.4, 35.5, 34.7, 30.3 (t, JCF¼22.3 Hz), 21.8, 20.8, 20.71, 20.68; ESI-
HRMS calcd for C45H43F17O10Na m/z [MþNa]þ: 1089.2483. Found:
1089.2495.
mp 162.3e164.4 ꢁC (MeOH); Rf¼0.71 (hexane/EtOAc¼1:1 v/v); ½a 2D3
ꢃ
ꢀ7.45 (c 1.02, CHCl3); IR (KBr, disk):
n
3391 cmꢀ1 (OH); 1H NMR
(250 MHz, CDCl3):
d
7.52e7.31 (12H, m, PhH), 7.14 (2H, d, J¼8.0 Hz,
4.2.11. 4-(Benzyloxy)phenyl 3-O-[4-(4,4,5,5,6,6,7,7,8,8,9,9,9-
eC6H4e), 7.00, 6.90 (4H, each d, J¼9.1 Hz, eC6H4e), 5.59 (1H, s,
PhCH), 5.02 (2H, s, PhCH2), 4.96, 4.79 (2H, each d, J¼11.6 Hz, PhCH2),
4.90 (1H, d, J1,2¼7.3 Hz, H-1), 4.36 (1H, dd, J4,3¼10.4 Hz, J4,5¼4.9 Hz,
H-4), 3.86e3.68 (4H, m, H-2, 3, 6ax, 6eq), 3.57 (1H, ddd, J5,4¼4.9 Hz,
J5,6ax¼9.8 Hz, J5,6eq¼8.6 Hz, H-5), 2.69 (2H, t, J¼7.5 Hz,
CH2CH2CH2C6F13), 2.51 (1H, d, JOH,2¼2.3 Hz, OH), 2.19e1.86 (4H, m,
tridecafluorononyl)benzyl]-
b-D-glucopyranoside (13a). To a solution
of phenyl- -glucoside 12a (2.0 g, 2.13 mmol) in THF/MeOH
b-D
(100 mL, 1:1 v/v) was added sodium methoxide (460 mg,
8.52 mmol). After stirring for 12 h at room temperature, the re-
action mixture was neutralized with DOWEXÒ 50WX8-200 ion-
exchange resin and then filtered to remove the resin. The filtrate
was concentrated to give 13a. The product was dried in vacuo at
40 ꢁC for 3 h and used for the next reaction without further puri-
fication. Mp 99.5e103.4 ꢁC (colorless solids, H2O-MeOH); Rf¼0.34
CH2CH2CH2C6F13); 13C NMR (63 MHz, CDCl3):
d 154.8, 151.1, 140.3,
137.2, 137.0, 136.3, 129.0, 128.6, 128.43, 128.40, 128.3, 127.9, 127.4,
126.0, 118.6, 115.7, 102.4, 101.3, 81.2, 80.2, 74.5, 74.0, 70.5, 68.7, 66.5,
34.7, 30.3 (t, JCF¼22.1 Hz), 21.8; ESI-HRMS calcd for C42H37F13O7Na
m/z [MþNa]þ: 923.2229. Found: 923.2204.
(hexane/EtOAc¼1:1 v/v); ½a D21
ꢃ
ꢀ3.80 (c 1.0, CHCl3); IR (KBr, disk):
n
3355 cmꢀ1 (OH); 1H NMR (250 MHz, CD3OD):
d
7.42e7.25 (7H, m,
PhH), 7.18 (2H, d, J¼8.1 Hz, eC6H4e), 7.04, 6.90 (4H, each d,
J¼9.2 Hz, eC6H4e), 5.02 (2H, s, PhCH2), 4.92, 4.85 (2H, each d,
J¼11.1 Hz, PhCH2), 4.79 (1H, d, J1,2¼7.6 Hz, H-1), 3.88 (1H, dd,
4.2.14. 4-(2-Benzyloxyethyl)phenyl 4,6-O-benzylidene-3-O-[4-(4,4,5,
5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl)benzyl]-
glucopyranoside (14b). Phenyl -glucoside 13a (397 mg,
0.422 mmol) and benzaldehyde dimethylacetal (246 L,1.69 mmol)
b-D-
b-D
0
0
J6,5¼2.3 Hz, J6,6 ¼12.0 Hz, H-6), 3.69 (1H, dd, J6 ,5¼5.4 Hz,
m
J6 ,6¼12.0 Hz, H-60), 3.60e3.36 (4H, m, H-2, 3, 4, 5), 2.72 (2H, t,
were dissolved in dry DMF (8 mL) in a 100 mL round-bottomed
flask. After p-TsOH$H2O (72 mg, 0.211 mmol) was added, the flask
was attached to a rotary evaporator, rotated, evacuated, and low-
ered into a water bath at approximately 60 ꢁC to removed the
MeOH, which was formed during the reaction. After 3 h, the re-
action mixture was quenched with an excess amount of triethyl-
amine and stirred for 15 min at room temperature. Water (40 mL)
was then added to the reaction mixture. The solution was directly
loaded onto a FluoroFlashÒ column and the column was eluted
0
J¼7.4 Hz, CH2CH2CH2C6F13), 2.22e1.85 (4H, m, CH2CH2CH2C6F13);
13C NMR (63 MHz, CDCl3):
d 155.8, 153.5, 141.4, 138.9, 138.4, 129.4,
129.3, 128.8, 128.5, 119.3, 116.9, 103.6, 86.3, 78.1, 75.8, 75.2, 71.7,
71.3, 62.6, 35.5, 31.2 (t, JCF¼22.1 Hz), 23.1; ESI-HRMS calcd for
C35H33F13O7Na m/z [MþNa]þ: 835.1916. Found: 835.1935.
4.2.12. 4-(2-Benzyloxyethyl)phenyl 3-O-[4-(4,4,5,5,6,6,7,7,8,8,9,9,10,
10,11,11,11-heptadecafluoroundecyl)benzyl]-b-D-glucopyranoside

8286
M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
successively with 80% aq MeOH and EtOAc. The EtOAc fraction was
concentrated, and the residue was purified by silica gel column
chromatography (hexane/EtOAc¼5:1 v/v) to give 14b (320 mg, 74%
yield) as colorless solids: mp 104.2e108.9 ꢁC (MeOH); Rf¼0.74
4.68 (1H, d, J3,4¼2.0 Hz, H-3), 4.27 (1H, dt, J4,5¼4.5 Hz, J4,3¼2.0 Hz,
H-4), 3.85 (2H, s, H-6), 3.68 (2H, d, J5,4¼4.5 Hz, H-5); 13C NMR
(63 MHz, CD3OD) b-anomer: d 138.7,130.6,129.2,128.2,107.7,104.2,
96.3, 88.4, 85.8, 64.1, 62.5; a-anomer: d 138.0, 130.8, 129.3, 128.4,
(hexane/EtOAc¼1:1 v/v); ½a D25
ꢃ
ꢀ7.21 (c 0.97, CHCl3); IR (KBr, disk):
n
109.2, 99.3, 92.5, 85.1, 82.8, 63.4, 63.0; ESI-HRMS calcd for
3387 cmꢀ1 (OH); 1H NMR (250 MHz, CDCl3):
d
7.52e712 (16H, m,
C13H16O6Na m/z [MþNa]þ: 291.0845. Found: 291.0840.
PhH), 6.97 (2H, d, J¼8.7 Hz, eC6H4e), 5.59 (1H, s, PhCH), 4.97 (1H, d,
J1,2¼7.3 Hz, H-1), 4.97, 4.80 (2H, each d, J¼11.6 Hz, PhCH2), 4.51 (2H,
s, PhCH2), 4.37 (1H, dd, J4,3¼10.4 Hz, J4,5¼4.9 Hz, H-4), 3.86e3.73
(4H, m, H-2, 3, 6ax, 6eq), 3.66 (2H, t, J¼7.0 Hz, CH2CH2OBn), 3.55
(1H, ddd, J5,4¼4.9 Hz, J5,6ax¼10.0 Hz, J5,6eq¼8.9 Hz, H-5), 2.88 (2H, t,
J¼7.0 Hz, CH2CH2OBn), 2.69 (2H, t, J¼7.5 Hz, CH2CH2CH2C8F17), 2.53
(1H, br s, OH), 2.19e1.86 (4H, m, CH2CH2CH2C8F17); 13C NMR
(63 MHz, CDCl3): 155.4, 140.3, 138.4, 137.2, 136.3, 134.0, 130.0, 129.0,
128.43, 128.39, 128.35, 128.26, 127.58, 127.53, 126.0, 117.1, 101.7,
101.4, 81.2, 80.3, 74.5, 74.1, 73.0, 71.2, 68.7, 66.6, 35.6, 34.8, 30.4 (t,
JCF¼22.2 Hz), 21.8; ESI-HRMS calcd for C46H41F17O7Na m/z
[MþNa]þ: 1051.2479. Found: 1051.2429.
4.3.3. 2,3-O-Benzylidene-a/b-D-apiofuranose (17). To a solution of
16 (197 mg, 0.73 mmol) in MeOH (3.7 mL) was cautiously added
sodium borohydride (83 mg, 2.19 mmol) in small portions. After
stirring for 30 min at room temperature, the reaction mixture was
cooled to 0 ꢁC and then neutralized to pH 7 with 1 M aq HCl so-
lution. To the mixture was then added a solution of sodium peri-
odate (312 mg, 1.46 mmol) in H2O (3.7 mL), and the reaction
mixture was stirred for an additional 1 h at room temperature.
After the solvent was evaporated, the remaining aqueous solution
was extracted with EtOAc (5 mLꢂ3). The combined organic layer
was dried over Na2SO4, filtered, and concentrated. The residue was
purified by silica gel column chromatography (hexane/EtOAc¼3:2
4.3. Preparation of apiofuranosyl donors 19a-d
v/v) to give 17 (152 mg, 87% yield,
a
/
b
¼1:10) as a colorless syrup:
Rf¼0.56 (hexane/acetone¼3:2 v/v); ½a D17
ꢀ42.2 (c 1.0, CHCl3); IR
ꢃ
4.3.1. 2,3-O-Benzylidene-
a
/
b
-
L
-ribofuranose (15). According to the
-ribose
(NaCl, neat): n b-
3420 cmꢀ1 (OH); 1H NMR (250 MHz, CDCl3)
method described by Chan and Just,19 to a suspension of
L
anomer: d 7.53e7.37 (5H, m, PhH), 5.92 (1H, s, PhCH), 5.56 (1H, s, H-
(5.0 g, 33.3 mmol), freshly distilled benzaldehyde (13.5 mL,
133.2 mmol), and CuSO4 (10 g) in dry DMF (15 mL) was added
camphorsulfonic acid (3.9 g, 16.7 mmol). After stirring for 48 h at
room temperature under argon, the reaction mixture was
quenched with triethylamine (15 mL), diluted with CH2Cl2
(30 mL), and then Celite (10 g) was added into the mixture. After
stirring for 15 min, the suspension was filtered through Celite. The
filter cake was washed with CH2Cl2 (10 mLꢂ3), and the filtrate was
concentrated in vacuo. The residue was purified by silica gel col-
umn chromatography (hexane/acetone¼5:1 then 3:2 v/v) to give
1), 4.47 (1H, s, H-2), 4.17, 4.09 (2H, each d, J¼10.2 Hz, H-4), 3.96,
3.89 (2H, each d, J¼11.6 Hz, H-5), 3.18 (1H, br s, OH), 2.42 (1H, br s,
OH);
a
-anomer:
d
6.09 (1H, s, PhCH), 5.13 (1H, dd, J1,2¼3.4 Hz,
J1,OH¼11.5 Hz, H-1), 4.45 (1H, d, J2,1¼10.7 Hz, H-2), 4.15, 4.09 (2H,
each d, J¼7.3 Hz, H-4), 4.10 (1H, d, JOH,1¼11.4 Hz, OH), 2.42 (1H, br s,
OH), 3.99e3.87 (2H, m, H-5, overlapped with H-5 signal of
b-
anomer); 13C NMR (63 MHz, CDCl3)
127.0, 106.0, 101.1, 91.9, 87.2, 73.1, 62.8;
b-anomer:
d
135.9, 129.9, 128.4,
a
-anomer: d 135.7, 130.2,
128.6, 106.9, 97.8, 91.5, 81.0, 68.7, 62.4; ESI-HRMS calcd for
C12H14O5Na m/z [MþNa]þ: 261.0739. Found: 261.0748.
15 (4.55 g, 57% yield,
a/
b¼1:10) as colorless prisms: mp
124.9e126.5 ꢁC (hexane/EtOAc); Rf¼0.26 (hexane/EtOAc¼1:1 v/v);
4.3.4. 5-O-Benzoyl-2,3-O-benzylidene-
a/
b-
D-apiofuranose (18a). To
½
a 1D9
ꢃ
þ26.2 (c 1.01, CHCl3); IR (KBr, disk):
n
3302 cmꢀ1 (OH); 1H
a
solution of 17 (500 mg, 2.10 mmol) and pyridine (864 m
L,
NMR (250 MHz, CDCl3)
b
-anomer:
d
7.52e7.38 (5H, m, PhH), 5.78
10.71 mmol) in dry CH2Cl2 (6 mL) was added dropwise benzoyl
(1H, s, PhCH), 5.57 (1H, br s, H-1), 4.93 (1H, d, J3,2¼6.1 Hz, H-3),
chloride (267
m
L, 2.31 mmol) at ꢀ78 ꢁC. After stirring for 1 h at the
4.69 (1H, d, J2,3¼6.1 Hz, H-2), 4.59 (1H, t, J4,5¼2.2 Hz, H-4), 4.32,
same temperature, the reaction mixture was quenched with satu-
rated aq NaHCO3 solution (10 mL). The aqueous layer was extracted
with CH2Cl2 (10 mLꢂ3), and the combined organic layer was
washed with brine (5 mL), dried over Na2SO4, filtered, and con-
centrated. The residue was purified by silica gel column chroma-
tography, using a gradient eluent (hexane/EtOAc¼5:1/4:1/
3.23 (1H, each br s, OHꢂ2), 3.80 (1H, dd, J5,4¼2.2 Hz, H-5);
a-
anomer:
d
5.99 (1H, s, PhCH), 5.51 (1H, dd, J1,2¼4.2 Hz,
J1,OH¼10.0 Hz, H-1), 4.84 (1H, dd, J3,2¼6.8 Hz, J3,4¼1.9 Hz, H-3), 4.75
(1H, dd, J2,1¼4.2 Hz, J2,3¼6.1 Hz, H-2), 4.41 (1H, dt, J4,3¼1.8 Hz,
J4,5¼3.4 Hz, H-4), 3.91 (1H, d, JOH,1¼10.2 Hz, OH), 3.84e3.74 (2H, m,
H-5, overlapped with H-5 signal of
b
-anomer); 13C NMR (63 MHz,
3:1/2:1 v/v) to give hemiacetal 18a (560 mg, 78% yield,
a
a/b
/
b
¼1:7),
CDCl3)
b-anomer:
d
135.8, 129.9, 128.4, 126.9, 105.8, 102.7, 87.54,
along with 1,5-di-O-benzoylated 18a0 (130 mg, 14% yield,
¼1:3)
87.48, 82.6, 63.7;
a
-anomer:
d
130.2, 128.7, 126.7, 107.4, 97.3, 82.4,
and 1-O-benzoylated 18a00 (37 mg, 4% yield,
a
/b
¼1:4).
80.7, 80.2, 63.5; ESI-HRMS calcd for C12H14O5Na m/z [MþNa]þ:
Compound 18a: Colorless syrup; Rf¼0.27 (hexane/EtOAc¼3:1
261.0739. Found: 261.0761.
v/v); ½a 1D9
ꢃ
ꢀ4.9 (c 1.02, CHCl3); IR (KBr, disk):
n
3447 cmꢀ1 (OH),
-anomer:
1724 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3)
b
4.3.2. 2,3-O-Benzylidene-2-C-(hydroxymethyl)-
a
/
b
-
L
-ribofuranose
d
8.10e8.07 (2H, m, PhH), 7.58e7.37 (8H, m, PhH), 6.00 (1H, s,
PhCH), 5.63 (1H, s, H-1), 4.67 (2H, s, H-5), 4.62 (1H, s, H-2), 4.27,
-anomer: 6.16 (1H, s, PhCH),
(16). To a solution of 15 (310 mg, 1.30 mmol) and potassium car-
bonate (252 mg, 1.82 mmol) in MeOH (4.5 mL) was added 37% aq
formaldehyde solution (2.7 mL). After stirring for 8 h at 85 ꢁC, the
reaction mixture was neutralized with 1 M aq HCl solution and
concentrated. The remaining aqueous solution was extracted with
CH2Cl2 (5 mLꢂ5), and the combined organic layer was dried over
Na2SO4, filtered, and concentrated. The residue was purified by
silica gel column chromatography (hexane/acetone¼1:1 v/v) to
4.22 (2H, each d, J¼10.4 Hz, H-4);
a
d
5.19 (1H, d, J1,2¼3.4 Hz, H-1), 4.64 (2H, s, H-5), 4.55 (1H, d,
J2,1¼3.4 Hz, H-2), 4.30e4.21 (2H, m, H-4, overlapped with H-4
signal of
d
b b-anomer:
-anomer); 13C NMR (63 MHz, CDCl3)
166.1, 135.8, 133.3, 129.9, 129.7, 128.4, 128.3, 127.0, 106.3, 101.6,
90.2, 87.5, 73.2, 64.7; -anomer: 166.0, 135.4, 133.5, 130.2,
a
d
129.6, 129.4, 128.6, 127.0, 107.2, 97.8, 89.6, 81.4, 68.7, 63.9; ESI-
HRMS calcd for C19H18O6Na m/z [MþNa]þ: 365.1001. Found:
365.1010.
give 16 (321 mg, 92% yield,
a
/
b
¼1:4) as colorless prisms: mp
144.1e145.3 ꢁC (EtOH); Rf¼0.26 (hexane/acetone¼1:1 v/v); ½a 1D9
ꢃ
þ2.5 (c 1.1, MeOH); IR (KBr, disk):
n
3367 cmꢀ1 (OH); 1H NMR
(250 MHz, CD3OD)
b
-anomer:
d
7.52e7.35 (5H, m, PhH), 6.06 (1H, s,
4.3.4.1. 1,5-Di-O-benzoyl-2,3-O-benzylidene-b-D-apiofuranose
PhCH), 5.36 (1H, s, H-1), 4.70 (1H, d, J3,4¼0.7 Hz, H-3), 4.31 (1H, dt,
(18a0). Mp 132.2e134.3 ꢁC (colorless prisms, hexane/EtOAc); ½a 2D4
ꢃ
J4,5¼5.1 Hz, J4,3¼0.7 Hz, H-4), 3.93 (2H, s, H-6), 3.68 (2H, d,
ꢀ72.9 (c 1.01, CHCl3); Rf¼0.57 (hexane/EtOAc¼3:1 v/v); IR (KBr,
J5,4¼5.1 Hz, H-5);
a-anomer:
d
6.13 (1H, s, PhCH), 5.22 (1H, s, H-1),
disk): n d 8.08e7.95
1722 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3):

M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
8287
(4H, m, PhH), 7.60e7.35 (11H, m, PhH), 6.63 (1H, s, H-1), 6.09 (1H, s,
PhCH), 4.90 (1H, s, H-2), 4.75 (2H, s, H-5), 4.42, 4.28 (2H, each d,
4.3.6. 2,3-O-Benzylidene-5-O-(4-benzyloxybenzoyl)-
a
/
b
-
D
-apiofur-
anose (18c). To a solution of 17 (439 mg, 1.84 mmol) and pyridine
(760 L, 9.38 mmol) in dry CH2Cl2 (5.3 mL) was added 4-
J¼10.4 Hz, H-4); 13C NMR (63 MHz, CDCl3):
d
166.1, 164.8, 135.5,
m
133.5, 130.1, 129.8, 129.7, 129.3, 129.2, 128.6, 128.49, 128.6, 127.1,
106.8, 101.8, 90.0, 87.1, 74.8, 63.9; ESI-HRMS calcd for C26H22O7Na
m/z [MþNa]þ: 469.1263. Found: 469.1271.
benzyloxybenzoyl chloride (500 mg, 2.03 mmol) at ꢀ78 ꢁC. After
stirring for 1 h at the same temperature, the reaction mixture was
quenched with saturated aq NaHCO3 solution (10 mL). The aqueous
layer was extracted with CH2Cl2 (10 mLꢂ3), and the combined or-
ganic layer was washed with brine (5 mL), dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by silica gel
4.3.4.2. 1-O-Benzoyl-2,3-O-benzylidene-b-D-apiofuranose
(18a00). Mp 143.9e145.6 ꢁC (colorless prisms, hexane/EtOAc); ½a 2D4
ꢃ
ꢀ106.5 (c 1.05, CHCl3); Rf¼0.16 (hexane/EtOAc¼3:1 v/v); IR (KBr,
column chromatography, using a gradient eluent (hexane/
disk):
CDCl3):
n
3518 cmꢀ1 (OH), 1726 cmꢀ1 (C]O); 1H NMR (250 MHz,
8.02e7.99 (2H, m, PhH), 7.56e7.38 (8H, m, PhH), 6.60 (1H,
Et2O¼3:1/1:1 v/v) to give hemiacetal 18c (440 mg, 53% yield,
a
a
/
/
d
b
b
¼1:6), along with 1,5-di-O-acylated 18c0 (27 mg, 2% yield,
s, H-1), 6.00 (1H, s, PhCH), 4.73 (1H, s, H-2), 4.28, 4.11 (2H, each d,
J¼10.4 Hz, H-4), 4.00 (2H, br s, H-5), 2.35 (1H, br s, OH); 13C NMR
¼1:16) and 1-O-acylated 18c00 (57 mg, 7% yield,
b only).
Compound 18c: Mp 118.1e119.8 ꢁC (colorless prisms, hexane/
(63 MHz, CDCl3):
d
164.8, 135.8, 133.5, 130.0, 129.7, 129.4, 128.5,
EtOAc); Rf¼0.32 (hexane/Et2O¼1:1 v/v, TLC developed two times);
a 2D4
ꢀ0.614 (c 1.14, CHCl3); IR (KBr, disk):
3475 cmꢀ1 (OH),
1709 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3)
-anomer: 8.03,
128.4, 127.0, 106.8, 101.3, 92.0, 86.5, 75.1, 63.4; ESI-HRMS calcd for
½
ꢃ
n
C19H18O7Na m/z [MþNa]þ: 365.1001. Found: 365.0993.
b
d
7.00 (4H, each d, J¼8.9 Hz, C6H4OBn), 7.55e7.30 (10H, m, PhH), 5.97
(1H, s, PhCH), 5.60 (1H, d, J1,OH¼1.7 Hz, H-1), 5.10 (2H, s, PhCH2),
4.63 (2H, s, H-5), 4.60 (1H, s, H-2), 4.25, 4.19 (2H, each d, J¼10.1 Hz,
4.3.5. 2,3-O-Benzylidene-5-O-(3-methylbutyryl)-
a/b-D-apiofuranose
(18b). To a solution of 17 (250 mg, 1.05 mmol) and pyridine
(432
m
L, 5.35 mmol) in dry CH2Cl2 (3 mL) was added dropwise 3-
H-4), 2.94 (1H, br d, JOH, 1¼1.7 Hz,);
a-anomer: d 6.14 (1H, s, PhCH),
5.17 (1H, dd, J1,2¼3.4 Hz, J1,OH¼11.8 Hz, H-1), 5.12 (2H, s, PhCH2),
4.60, 4.56 (2H, each d, J¼6.4 Hz, H-5), 4.52 (1H, d, J2,1¼3.4 Hz, H-2),
methylbutyryl chloride (142
m
L, 1.15 mmol) at ꢀ78 ꢁC. After stir-
ring for 2 h at the same temperature, the reaction mixture was
quenched with saturated aq NaHCO3 solution (10 mL). The aqueous
layer was extracted with CH2Cl2 (10 mLꢂ3), and the combined or-
ganic layer was washed with brine (5 mL), dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by silica gel
4.27e4.15 (2H, m, H-4, overlapped with H-4 signal of
3.96 (1H, d, JOH, 1¼11.8 Hz,); 13C NMR (63 MHz, CDCl3)
b
-anomer),
-anomer:
b
d
165.8, 162.8, 136.1, 135.9, 131.8, 129.9, 128.6, 128.4, 128.2, 127.4,
127.1,122.0, 114.6, 106.3, 101.7, 90.3, 87.5, 73.3, 70.1, 64.4; a-anomer:
column chromatography, using
a
gradient eluent (hexane/
d 165.7, 163.0, 136.0, 135.5, 131.8, 130.3, 128.6, 128.2, 127.0, 121.7,
EtOAc¼4:1/3:1/2:1 v/v) to give hemiacetal 18b (262 mg, 78%
114.8, 107.3, 97.9, 89.8, 81.4, 70.2, 68.8, 63.7; ESI-HRMS calcd for
yield,
a
/b
¼1:5), along with 1,5-di-O-acylated 18b0 (46 mg,11% yield,
C26H24O7Na m/z [MþNa]þ: 471.1420. Found: 471.1407.
a
/
b
¼2:3).
Compound 18b: Mp 106.9e107.7 ꢁC (colorless prisms, hexane/
4.3.6.1. 2,3-O-Benzylidene-1,5-di-O-(4-benzyloxybenzoyl)-a/b-D-
EtOAc); Rf¼0.65 (hexane/EtOAc¼1:1 v/v); ½a D19
ꢃ
ꢀ35.6 (c 0.45,
apiofuranose (18c0). Colorless solids; Rf¼0.63 (hexane/Et2O¼1:1 v/
CHCl3); IR (KBr, disk):
NMR (250 MHz, CDCl3)
n
3475 cmꢀ1 (OH), 1739 cmꢀ1 (C]O); 1H
v, TLC developed two times); IR (KBr, disk): n
1716 cmꢀ1 (C]O); 1H
b
-anomer:
d
7.55e7.37 (5H, m, PhH), 5.92
NMR (250 MHz, CDCl3, selected b-anomer signal): d 8.00, 7.92, 6.95,
(1H, s, PhCH), 5.58 (1H, s, H-1), 4.48e4.43 (3H, m, H-2, 5), 4.18, 4.10
(2H, each d, J¼10.1 Hz, H-4), 2.86 (1H, br s, OH), 2.28 (2H, d,
J¼6.6 Hz, COCH2CH(CH3)2), 2.19e2.08 (1H, m, COCH2CH(CH3)2),
6.94 (8H, each d, J¼9.0 Hz, C6H4OBnꢂ2), 7.58e7.32 (15H, m, PhH),
6.59 (1H, s, H-1), 6.06 (1H, s, PhCH), 5.09 (4H, s, PhCH2ꢂ2), 4.87 (1H,
s, H-2), 4.71 (2H, s, H-5), 4.39, 4.24 (2H, each d, J¼10.4 Hz, H-4); 13C
0.98 (6H, d, J¼6.6 Hz, CH3ꢂ2);
a
-anomer:
d
6.08 (1H, s, PhCH), 5.13
NMR (63 MHz, CDCl3, selected b-anomer signal): d 165.7, 164.5,
(1H, dd, J1,2¼3.2 Hz, J1,OH¼11.4 Hz, H-1), 4.48e4.28 (3H, m, H-2, 5,
163.0, 136.02, 136.00, 135.59, 131.94, 131.87, 130.1, 128.7, 128.5,
128.24, 128.23, 127.5, 127.1, 121.9, 121.8, 114.7, 114.6, 106.8, 101.6,
90.1, 87.1, 74.8, 70.2, 63.6; ESI-HRMS calcd for C40H34O9Na m/z
[MþNa]þ: 681.2101. Found: 681.2135.
overlapped with H-2, 5 signals of
overlapped with H-4 signal of
b
b
-anomer), 4.20e4.08 (2H, m,
-anomer), 3.93 (1H, br d,
JOH,1¼12.0 Hz, OH); 13C NMR (63 MHz, CDCl3)
b-anomer: d 172.7,
135.8, 129.9, 128.3, 127.0, 106.2, 101.5, 90.1, 87.4, 73.2, 64.3, 43.1,
25.6, 22.3;
a
-anomer:
d
172.6, 135.4, 130.2, 128.6, 127.0, 107.1, 97.8,
4.3.6.2. 2,3-O-Benzylidene-1-O-(4-benzyloxybenzoyl)-b-D-apio-
89.5, 81.3, 68.7, 63.3, 43.1, 25.6; ESI-HRMS calcd for C17H22O6Na m/z
furanose (18c00). Mp 153.9e157.1 ꢁC (colorless needles, hexane/
EtOAc); Rf¼0.21 (hexane/Et2O¼1:1 v/v, TLC developed two times);
[MþNa]þ: 345.1314. Found: 345.1310.
½
a 2D4
ꢃ
ꢀ85.8 (c 1.02, CHCl3); IR (KBr, disk):
n
3488 cmꢀ1 (OH),
4.3.5.1. 2,3-O-Benzylidene-1,5-di-O-(3-methylbutyryl)-
a
/
b
-
D
-
1720 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3):
d 7.95, 6.98 (4H, each
apiofuranose (18b0). Colorless syrup; Rf¼0.88 (hexane/EtOAc¼1:1
d, J¼8.9 Hz, C6H4OBn), 7.55e7.32 (10H, m, PhH), 6.58 (1H, s, H-1),
v/v); IR (KBr, disk): n
1743 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3)
5.99 (1H, s, PhCH), 5.10 (2H, s, PhCH2), 4.71 (1H, s, H-2), 4.26, 4.09
0
b
-anomer:
d
7.58e7.36 (5H, m, PhH), 6.38 (1H, s, H-1), 5.96 (1H, s,
(2H, each d, J¼10.4 Hz), 4.01 (1H, dd, J5,OH¼6.0 Hz, J5,5 ¼11.9 Hz, H-
5), 3.96 (1H, dd, J5 ,OH¼5.8 Hz, J5 ,5¼11.9 Hz, H-50), 2.31 (1H, dd,
0
0
PhCH), 4.55 (1H, s, H-2), 4.46, 4.40 (2H, each d, J¼12.0 Hz, H-5),
4.26, 4.00 (2H, each d, J¼10.3 Hz, H-4), 2.29, 2.28 (4H, each d,
COCH2CH(CH3)2ꢂ2), 2.18e1.93 (2H, m, COCH2CH(CH3)2ꢂ2), 0.994,
JOH,5¼6.0 Hz, JOH,5 ¼5.8 Hz, OH); 13C NMR (63 MHz, CDCl3):
d 164.4,
0
163.0, 136.1,135.9, 131.9, 130.0, 128.7,128.4, 128.2, 127.4,127.0,121.9,
114.7, 106.8, 101.1, 92.0, 86.5, 75.0, 70.1, 63.5; ESI-HRMS calcd for
C26H24O7Na m/z [MþNa]þ: 471.1420. Found: 471.1452.
0.987, 0.979 (12H, each d, J¼6.6 Hz, CH3ꢂ4);
a-anomer: d 6.23 (1H,
s, PhCH), 6.14 (1H, d, J1,2¼4.2 Hz, H-1), 4.74 (1H, d, J2,1¼4.2 Hz, H-2),
4.49, 4.35 (2H, each d, J¼11.9 Hz, H-5), 4.24, 3.93 (2H, each d,
J¼10.2 Hz, H-4), 2.30e2.21 (4H, m, COCH2CH(CH3)2ꢂ2), 2.18e1.93
(2H, m, COCH2CH(CH3)2ꢂ2), 1.01e0.81 (12H, each d, J¼6.6 Hz,
4.3.7. 2,3-O-Benzylidene-5-O-(4-nitrobenzoyl)-
(18d). To a solution of 17 (500 mg, 2.10 mmol) and pyridine
(864 L, 10.71 mmol) in dry CH2Cl2 (6 mL) was added 4-nitro-
a/b-D-apiofuranose
CH3ꢂ4); 13C NMR (63 MHz, CDCl3)
b
-anomer:
d
172.5, 171.1, 135.6,
m
130.0, 128.4, 127.0, 106.7, 100.6, 89.8, 86.9, 74.7, 63.6, 43.2, 43.1,
benzoyl chloride (585 mg, 3.15 mmol) at ꢀ78 ꢁC. After stirring for
1 h at the same temperature, the reaction mixture was quenched
with saturated aq NaHCO3 solution (10 mL). The aqueous layer was
extracted with CH2Cl2 (10 mLꢂ3), and the combined organic layer
was washed with brine (5 mL), dried over Na2SO4, filtered, and
25.62, 25.59, 22.35, 22.29, 22.26; a-anomer: d 172.5, 171.5, 135.6,
129.7, 128.2, 126.9, 109.5, 96.3, 89.4, 82.4, 72.5, 63.9, 42.9, 25.2, 22.2,
22.1; ESI-HRMS calcd for C22H30O7Na m/z [MþNa]þ: 429.1889.
Found: 429.1882.

8288
M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
concentrated. The residue was purified by silica gel column chro-
matography, using
gradient eluent (hexane/EtOAc¼4:1/
3:1/2:1 v/v) to give hemiacetal 18d (612 mg, 75% yield, only),
along with 1,5-di-O-acylated 18d0 (124 mg, 11% yield,
¼5:1).
128.4, 127.1, 106.8, 104.6, 91.0, 89.7, 86.5, 75.2, 63.4, 43.1, 25.6,
a
22.3; ESI-HRMS calcd for
488.0411. Found: 488.0456.
C
19H22Cl3NO6Na m/z [MþNa]þ:
b
a/b
Compound 18d: Mp 146.3e146.7 ꢁC (light green plates, hexane/
4.3.10. 2,3-O-Benzylidene-5-O-(4-benzyloxybenzoyl)-b-D-apiofur-
EtOAc); Rf¼0.55 (hexane/EtOAc¼1:1 v/v); ½a D19
ꢃ
ꢀ17.2 (c 1.02,
anosyl trichloroacetimidate (19c). To a solution of hemiacetal 18c
(752 mg, 1.68 mmol) in dry CH2Cl2 (7.5 mL) were added tri-
chloroacetonitrile (2.0 mL, 20.12 mmol) and 1,8-diazabicyclo[5.4.0]
CHCl3); IR (KBr, disk):
n
3399 cmꢀ1 (OH), 1727 cmꢀ1 (C]O),
1527 cmꢀ1 (N]O); 1H NMR (250 MHz, CDCl3):
d 8.32e8.23 (4H, m,
C6H4NO2), 7.54e7.38 (5H, m, PhH), 5.97 (1H, s, PhCH), 5.64 (1H, d,
J1,OH¼2.6 Hz, H-1), 4.76, 4.69 (2H, each d, J¼11.9 Hz, H-5), 4.61 (1H,
s, H-2), 4.29, 4.26 (2H, each d, J¼10.1 Hz, H-4), 2.82 (1H, d,
undec-7-ene (70 m
L, 0.47 mmol) at 0 ꢁC under argon. After stirring
for 10 min, the mixture was directly chromatographed on a silica
gel column (hexane/EtOAc¼6:1 v/v) to give trichloroacetimidate
19c (823 mg, 83% yield) as colorless prisms: mp 131.5e134.0 ꢁC
JOH,1¼2.6 Hz, OH); 13C NMR (63 MHz, CDCl3):
d 164.3, 150.8, 135.5,
134.8, 130.9, 130.1, 128.5, 127.0, 123.6, 106.4, 101.6, 90.0, 87.6, 73.3,
65.2; ESI-HRMS calcd for C19H17NO8Na m/z [MþNa]þ: 410.0852.
Found: 410.0866.
(hexane/EtOAc); Rf¼0.57 (hexane/EtOAc¼3:2 v/v); ½a D23
ꢀ39.9 (c
ꢃ
1.05, CHCl3); IR (KBr, disk): n
3351, 1676 cmꢀ1 (NH), 1719 cmꢀ1 (C]
O); 1H NMR (250 MHz, CDCl3):
d 8.67 (1H, s, NH), 8.03, 7.01 (4H,
each d, J¼9.0 Hz, C6H4OBn), 7.56e7.33 (10H, m, PhH), 6.52 (1H, s, H-
1), 6.06 (1H, s, PhCH), 5.13 (1H, s, PhCH2), 4.88 (1H, s, H-2), 4.66 (2H,
s, H-5), 4.41, 4.25 (2H, each d, J¼10.4 Hz, H-4); 13C NMR (63 MHz,
4.3.7.1. 2,3-O-Benzylidene-1,5-di-O-(4-nitrobenzoyl)-a/b-D-apio-
furanose (18d0). Colorless syrup; Rf¼0.75 (hexane/EtOAc¼1:1 v/v);
IR (KBr, disk):
n
1730 cmꢀ1 (C]O), 1529 cmꢀ1 (N]O); 1H NMR
CDCl3): d 165.7, 162.9, 160.5, 136.1, 135.5, 131.9, 130.1, 128.7, 128.4,
(250 MHz, CDCl3)
a
-anomer:
d
8.35e7.90 (8H, m, C6H4NO2ꢂ2),
128.2, 127.4, 127.1, 121.8, 106.9, 104.8, 90.9, 90.0, 86.5, 75.0, 70.2,
63.6; ESI-HRMS calcd for C28H24Cl3NO7Na m/z [MþNa]þ: 614.0516.
Found: 614.0563.
7.57e7.17 (5H, m, PhH), 6.49 (1H, d, J1,2¼4.3 Hz, H-1), 6.41 (1H, s,
PhCH), 5.04 (1H, d, J2,1¼4.3 Hz, H-2), 4.87, 4.75 (2H, each d,
J¼11.9 Hz, H-5), 4.47, 4.23 (2H, each d, J¼10.3 Hz, H-4);
b-anomer:
d
6.65 (1H, s, H-1), 6.08 (1H, s, PhCH), 4.90, 4.79 (2H, each d,
J¼11.9 Hz, H-5), 4.89 (1H, s, H-2), 4.49, 4.29 (2H, each d, J¼10.4 Hz,
H-4); 13C NMR (63 MHz, CDCl3)
-anomer: 164.2, 163.1, 150.9,
150.5, 136.0, 134.6, 134.5, 130.9, 130.8, 129.6, 128.2, 126.2, 123.8,
123.3, 109.9, 97.5, 89.5, 82.9, 73.4, 65.5; -anomer: 163.0, 135.0,
4.3.11. 2,3-O-Benzylidene-5-O-(4-nitrobenzoyl)-b-D-apiofuranosyl
trichloroacetimidate (19d). To a solution of hemiacetal 18d (570 mg,
1.47 mmol) in dry CH2Cl2 (6 mL) were added trichloroacetonitrile
(1.8 mL, 17.64 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene
a
d
b
d
(61 m
L, 0.41 mmol) at 0 ꢁC under argon. After stirring for 10 min,
134.5, 134.4, 130.3, 128.6, 127.0, 123.70, 123.67, 107.1, 102.5, 89.9,
87.0, 75.3, 65.1; ESI-HRMS calcd for C26H20N2O11Na m/z [MþNa]þ:
559.0965. Found: 559.0935.
the mixture was directly chromatographed on a silica gel column
(hexane/EtOAc¼6:1 v/v) to give trichloroacetimidate 19d (632 mg,
81% yield) as colorless needles: mp 141.8e144.8 ꢁC (hexane/EtOAc);
Rf¼0.60 (hexane/EtOAc¼3:2 v/v); ½a D23
ꢀ47.9 (c 1.01, CHCl3); IR (KBr,
ꢃ
4.3.8. 5-O-Benzoyl-2,3-O-benzylidene-
b
-D
-apiofuranosyl trichloroac-
disk): n
3328, 1669 cmꢀ1 (NH), 1723 cmꢀ1 (C]O), 1529 cmꢀ1 (N]
etimidate (19a). To a solution of hemiacetal 18a (1.1 g, 3.21 mmol)
O); 1H NMR (250 MHz, CDCl3):
d 8.72 (1H, s, NH), 8.31, 8.24 (4H,
in dry CH2Cl2 (11 mL) was added trichloroacetonitrile (3.9 mL,
each d, J¼9.1 Hz, C6H4NO2), 7.56e7.40 (5H, m, PhH), 6.55 (1H, s, H-
1), 6.05 (1H, s, PhCH), 4.87 (1H, s, H-2), 4.80, 4.72 (2H, each d,
J¼12.0 Hz, H-5), 4.44, 4.27 (2H, each d, J¼10.4 Hz, H-4); 13C NMR
(63 MHz, CDCl3): 164.2,160.3, 150.9, 135.2,134.5, 130.9, 130.2, 128.5,
127.1, 123.7, 107.0, 104.6, 90.9, 89.7, 86.6, 75.0, 64.7; ESI-HRMS calcd
for C21H17Cl3N2O8Na m/z [MþNa]þ: 552.9948. Found: 552.9919.
38.56 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (134 mL,
0.90 mmol) at 0 ꢁC under argon. After stirring for 10 min, the
mixture was directly chromatographed on a silica gel column
(hexane/EtOAc¼4:1 v/v) to give trichloroacetimidate 19a (1.51 g,
96% yield) as colorless needles: mp 110.9e112.9 ꢁC (hexane);
Rf¼0.62 (hexane/EtOAc¼3:2 v/v); ½a D23
ꢀ52.70 (c 1.11, CHCl3); IR
ꢃ
(KBr, disk):
n
3331, 1669 cmꢀ1 (NH), 1724 cmꢀ1 (C]O); 1H NMR
4.4. Total synthesis of eight cucurbitoside-like phenolic
(250 MHz, CDCl3):
d
8.68 (1H, s, NH), 8.07 (2H, J¼7.3 Hz, PhH),
glycosides 1aeh
7.61e7.39 (8H, m, PhH), 6.53 (1H, s, H-1), 6.08 (1H, s, PhCH), 4.89
(1H, s, H-2), 4.71 (2H, s, H-5), 4.43, 4.26 (2H, each d, J¼10.4 Hz, H-4);
4.4.1. Mixture of 4-(benzyloxy)phenyl 4,6-O-benzylidene-2-O-(5-O-
13C NMR (63 MHz, CDCl3):
d
166.0, 160.5, 135.5, 133.5, 130.1, 129.8,
benzoyl-2,3-O-benzylidene-
(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)benzyl]-
side (20a), 4-(benzyloxy)phenyl 4,6-O-benzylidene-2-O-[2,3-O-ben-
zylidene-5-O-(3-methylbutyryl)- -apiofuranosyl]-3-O-[4-
(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)benzyl]- -glucopyrano-
side (20b), 4-(benzyloxy)phenyl 4,6-O-benzylidene-2-O-[2,3-O-ben-
zylidene-5-O-(4-benzyloxybenzoyl)- -apiofuranosyl]-3-O-[4-
(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)benzyl]- -glucopyrano-
side (20c), 4-(benzyloxy)phenyl 4,6-O-benzylidene-2-O-[2,3-O-ben-
zylidene-5-O-(4-nitrobenzoyl)- -apiofuranosyl]-3-O-[4-
(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)benzyl]- -glucopyrano-
side (20d), 4-(2-benzyloxyethyl)phenyl 4,6-O-benzylidene-2-O-(5-O-
benzoyl-2,3-O-benzylidene- -apiofuranosyl)-3-O-[4-
(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl)benzyl]-
-glucopyranoside (20e), 4-(2-benzyloxyethyl)phenyl 4,6-O-ben-
zylidene-2-O-[2,3-O-benzylidene-5-O-(3-methylbutyryl)- -apio-
furanosyl]-3-O-[4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
heptadecafluoroundecyl)benzyl]- -glucopyranoside (20f), 4-(2-
benzyloxyethyl)phenyl 4,6-O-benzylidene-2-O-[2,3-O-benzylidene-5-
O - ( 4 - b e n z yl o x y b e n z o yl ) - - a p i o f u ra n o s yl ] - 3 - O - [ 4 -
(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl)benzyl]-
b
-
D
-apiofuranosyl)-3-O-[4-
129.2, 128.6, 128.4, 127.1, 106.9, 104.8, 90.9, 90.0, 86.6, 75.1, 63.9;
ESI-HRMS calcd for C21H13Cl3NO6Na m/z [MþNa]þ: 508.0098.
Found: 508.0141.
b-D
-glucopyrano-
b-D
b-D
4.3.9. 2,3-O-Benzylidene-5-O-(3-methylbutyryl)-
b-D-apiofuranosyl
trichloroacetimidate (19b). To solution of hemiacetal 18b
a
b-D
(1.1 g, 3.41 mmol) in dry CH2Cl2 (11 mL) were added tri-
chloroacetonitrile (4.1 mL, 40.92 mmol) and 1,8-diazabicyclo
b-D
[5.4.0]undec-7-ene (142
m
L, 0.96 mmol) at 0 ꢁC under argon.
b-D
After stirring for 10 min, the mixture was directly chromato-
graphed on a silica gel column (hexane/EtOAc¼10:1 v/v) to give
trichloroacetimidate 19b (1.38 g, 86% yield) as colorless needles:
mp 98.5e101.6 ꢁC (hexane/EtOAc); Rf¼0.55 (hexane/EtOAc¼3:1
b-D
b-D
v/v); ½a 2D3
ꢃ
ꢀ76.7 (c 1.11, CHCl3); IR (KBr, disk):
n
3329, 1670 cmꢀ1
8.67 (1H, s,
b-D
(NH), 1739 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3):
d
b-D
NH), 7.56e7.35 (5H, m, PhH), 6.49 (1H, s, H-1), 5.99 (1H, s, PhCH),
4.74 (1H, s, H-2), 4.45 (2H, s, H-5), 4.33, 4.14 (2H, each d,
J¼10.3 Hz, H-4), 2.29 (2H, d, J¼6.8 Hz, COCH2CH(CH3)2),
2.24e2.04 (1H, m, COCH2CH(CH3)2), 0.98 (6H, d, J¼6.6 Hz,
b-D
b - D
CH3ꢂ2); 13C NMR (63 MHz, CDCl3):
d 172.5, 160.4, 135.5, 130.1,

M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
8289
b
-
D
-glucopyranoside (20g), 4-(2-benzyloxyethyl)phenyl 4,6-O-ben-
zylidene-2-O-[2,3-O-benzylidene-5-O-(4-nitrobenzoyl)- -apiofur-
anosyl]-3-O-[4-(4, 4, 5, 5, 6, 6, 7, 7, 8, 8, 9, 9,10,10,11,11,11-
heptadecafluoroundecyl)benzyl]- -glucopyranoside (20h), M-3. A
suspension of fluorous acceptors M-1 (14a; 26 mg, 29.2 mol and
14b; 30 mg, 29.2 mol), acylated donors M-2 (19a; 11 mg,
23.3 mol, 19b; 11 mg, 23.3 mol, 19c; 12 mg, 23.3 mol, and 19d;
14 mg, 23.3 mol), and MS-4 A (280 mg) in dry CH2Cl2 (12 mL) was
stirred for 30 min at room temperature under argon. Trimethylsilyl
trifluoromethane sulfonate (2 L, 11.7 mol) was then added to the
JCF¼22.2 Hz), 25.6, 22.4, 21.8; ESI-HRMS calcd for C59H57F13O12Na
m/z [MþNa]þ: 1227.3540. Found: 1227.3541.
b-D
Compound 20c: Mp 149.8e151.9 ꢁC (colorless needles, hexane/
b
-D
EtOAc); Rf¼0.60 (hexane/EtOAc¼2:1 v/v); ½a D12
ꢀ26.2 (c 0.97,
ꢃ
m
CHCl3); IR (KBr, disk): n
1659 cmꢀ1 (C]O); 1H NMR (250 MHz,
m
CDCl3):
d
7.92, 6.94 (4H each d, J¼8.9 Hz, eC6H4e), 7.55e7.32 (20H,
m
m
m
m, PhH), 7.28, 7.07 (4H, each d, J¼8.0 Hz, eC6H4e), 6.88, 6.79 (4H,
each d, J¼9.2 Hz, eC6H4e), 5.98, 5.58 (2H, each s, PhCHꢂ2), 5.78
(1H, s, H-1api), 5.09, 4.94 (4H, each s, PhCH2ꢂ2), 4.92, 4.75 (2H, each
d, J¼11.3 Hz, PhCH2), 4.81 (1H, d, J1,2¼7.6 Hz, H-1glc), 4.56, 4.46 (2H,
each d, J¼11.8 Hz, H-5api), 4.54 (1H, s, H-2api), 4.35 (1H, dd,
J4,3¼10.5 Hz, J4,5¼4.9 Hz, H-4glc), 4.24, 4.19 (2H, each d, J¼10.2 Hz,
H-4api), 3.95 (1H, dd, J2,1¼7.6 Hz, J2,3¼8.4 Hz, H-2glc), 3.84e3.73 (3H,
m, H-3glc, H-6glc, H-60glc), 3.44 (1H, ddd, J5,4¼4.9 Hz, J5,6¼9.3 Hz,
ꢀ
m
m
m
suspension at ꢀ20 ꢁC. After stirring for 1 h at the same tempera-
ture, the reaction mixture was quenched with an excess amount of
triethylamine and filtered through Celite and the filtrate was con-
centrated. The residue was loaded onto a fluorous reverse-phase
silica gel (FluoroFlashÒ) column and the column was eluted suc-
cessively with 70% aq MeOH and EtOAc. The EtOAc fraction was
concentrated to give M-3 (80.6 mg).
0
J5,6 ¼9.0 Hz, H-5glc), 2.61 (2H, t, J¼7.6 Hz, CH2CH2CH2C6F13),
2.14e1.80 (4H, m, CH2CH2CH2C6F13); 13C NMR (63 MHz, CDCl3):
d
165.6, 162.8, 154.6, 151.1, 140.3, 137.2, 137.1, 136.1, 135.9, 131.8,
129.9, 129.0, 128.8, 128.7, 128.5, 128.4, 128.3, 127.9, 127.4, 127.2,
126.0, 122.1, 117.8, 115.8, 114.6, 107.3, 106.4, 101.3, 100.9, 90.3, 87.3,
81.6, 81.0, 76.2, 74.6, 73.2, 70.5, 70.2, 68.7, 66.2, 64.4, 34.7, 30.4 (t,
JCF¼22.6 Hz), 21.8; ESI-HRMS calcd for C68H59F13O12Na m/z
[MþNa]þ: 1353.3646. Found: 1353.3600.
4.4.2. Semi-preparative HPLC separation of the mixture of eight di-
saccharides (M-3). M-3 (80.6 mg) was dissolved in 90% aq CH3CN
solution (3.0 mL). This solution (3.0 mL) was injected into a serially
connected FluophaseÒ RP (21.2ꢂ250 mm) and InertsilÒ ODS-3
(21.2ꢂ250 mm) columns. The column was eluted over 120 min
with a liner gradient from 90% CH3CN/H2O to 100% CH3CN. The flow
rate was 19 mL/min. The desired eight disaccharides were obtained.
Compound 20a: 8.4 mg (tR¼55.4 min). Compound 20b: 8.5 mg
(tR¼59.2 min). Compound 20c: 9.5 mg (tR¼65.4 min). Compound
20d: 8.8 mg (tR¼48.9 min). Compound 20e: 10.6 mg (tR¼79.4 min).
Compound 20f: 8.6 mg (tR¼84.2 min). 20g: 8.0 mg (tR¼88.8 min).
Compound 20h: 9.1 mg (tR¼71.5 min).
Compound 20d: Mp 160.5e164.9 ꢁC (light yellow needles, hex-
ane/EtOAc); Rf¼0.6 (hexane/EtOAc¼2:1 v/v); ½a D11
ꢀ29.05 (c 1.0,
ꢃ
CHCl3); IR (KBr, disk):
n
1719 cmꢀ1 (C]O), 1529 cmꢀ1 (N]O); 1H
NMR (250 MHz, CDCl3):
d
8.19, 8.07 (4H each d, J¼8.9 Hz, eC6H4e),
7.54e7.32 (15H, m, PhH), 7.28, 7.07 (4H, each d, J¼8.0 Hz, eC6H4e),
6.87, 6.78 (4H, each d, J¼9.3 Hz, eC6H4e), 5.96, 5.58 (2H, each s,
PhCHꢂ2), 5.82 (1H, s, H-1api), 4.95 (2H, s, PhCH2), 4.93, 4.75 (2H,
each d, J¼11.2 Hz, PhCH2), 4.85 (1H, d, J1,2¼7.6 Hz, H-1glc), 4.66, 4.51
(2H, each d, J¼11.9 Hz, H-5api), 4.53 (1H, s, H-2api), 4.36 (1H, dd,
J4,3¼10.5 Hz, J4,5¼4.9 Hz, H-4glc), 4.27, 4.21 (2H, each d, J¼10.2 Hz,
H-4api), 3.98 (1H, dd, J2,1¼7.6 Hz, J2,3¼8.3 Hz, H-2glc), 3.88e3.75 (3H,
m, H-3glc, H-6glc, H-60glc), 3.48 (1H, ddd, J5,4¼4.9 Hz, J5,6¼9.0 Hz,
Compound 20a: Mp 152.2e156.1 ꢁC (colorless needles, hexane/
EtOAc); Rf¼0.59 (hexane/EtOAc¼2:1 v/v); ½a D25
ꢀ28.3 (c 1.0, CHCl3);
ꢃ
IR (KBr, disk):
n
1723 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3):
d
7.99e7.96 (2H, m, PhH), 7.60e7.27 (20H, m, PhH), 7.07 (2H, d,
0
J¼8.0 Hz, eC6H4e), 6.88, 6.80 (4H, each d, J¼9.2 Hz, eC6H4e), 6.00,
5.58 (2H each s, PhCHꢂ2), 5.78 (1H, s, H-1api), 4.95 (2H, s, PhCH2),
4.92, 4.75 (2H, each d, J¼11.3 Hz, PhCH2), 4.82 (1H, d, J1,2¼7.6 Hz, H-
1glc), 4.59, 4.49 (2H, each d, J¼11.9 Hz, H-5api), 4.55 (1H, s, H-2api),
4.34 (1H, dd, J4,3¼10.5 Hz, J4,5¼4.9 Hz, H-4glc), 4.24, 4.20 (2H, each d,
J¼10.2 Hz, H-4api), 3.95 (1H, dd, J2,1¼7.6 Hz, J2,3¼8.6 Hz, H-2glc),
3.84e3.74 (3H, m, H-3glc, H-6glc, H-60glc), 3.45 (1H, ddd, J5,4¼4.9 Hz,
J5,6 ¼8.8 Hz, H-5glc), 2.63 (2H, t, J¼7.6 Hz, CH2CH2CH2C6F13),
2.15e1.82 (4H, m, CH2CH2CH2C6F13); 13C NMR (63 MHz, CDCl3):
d
165.5, 162.7, 154.5, 150.9, 140.1, 137.1, 137.0, 136.0, 135.7, 131.6,
129.7, 128.9, 128.7, 128.5, 128.4, 128.2, 128.12, 128.10,127.8, 127.3,
127.0, 125.9, 122.0, 117.7, 115.6, 114.4, 107.2, 106.3, 101.1, 100.7, 90.1,
87.1, 81.5, 80.9, 76.1, 74.4, 73.1, 70.4, 70.0, 68.6, 66.0, 64.2, 34.6, 30.2
(t, JCF¼22.7 Hz), 21.6; ESI-HRMS calcd for C61H52F13NO14Na m/z
[MþNa]þ: 1292.3078. Found: 1292.3067.
0
J5,6¼9.2 Hz, J5,6 ¼9.2 Hz, H-5glc), 2.61 (2H, t, J¼7.6 Hz,
CH2CH2CH2C6F13), 2.18e1.86 (4H, m, CH2CH2CH2C6F13); 13C NMR
Compound 20e: Colorless amorphous solids; Rf¼0.56 (hexane/
(63 MHz, CDCl3):
d
165.9, 154.6, 151.0140.3, 137.2, 137.1, 136.1, 135.9,
EtOAc¼2:1 v/v); ½a D18
ꢃ
ꢀ26.2 (c 0.97, CHCl3); IR (KBr, disk):
n
1
133.3,129.9,129.7,129.6,129.0, 128.8,128.55,128.46,128.37,128.28,
127.9, 127.4, 127.2, 126.0, 117.8, 115.8, 107.3, 106.5, 101.3, 100.8, 90.2,
87.2, 81.6, 80.9, 76.2, 74.5, 73.3, 70.5, 68.7, 66.2, 34.8, 30.4 (t,
JCF¼22.2 Hz), 21.8; ESI-HRMS calcd for C61H53F13O12Na m/z
[MþNa]þ: 1247.3227. Found: 1247.3233.
1722 cmꢀ1 (C]O); H NMR (250 MHz, CDCl3):
d 7.98e7.94 (2H, m,
PhH), 7.59e7.27 (20H, m, PhH), 7.07 (2H, d, J¼7.9 Hz, eC6H4e), 7.05,
6.85 (4H, each d, J¼8.7 Hz, eC6H4e), 5.99, 5.58 (2H each s,
PhCHꢂ2), 5.78 (1H, s, H-1api), 4.92, 4.76 (2H, each d, J¼11.2 Hz,
PhCH2), 4.90 (1H, d, J1,2¼7.6 Hz, H-1glc), 4.55, 4.46 (2H, each d,
J¼11.9 Hz, H-5api), 4.54 (1H, s, H-2api), 4.50 (2H, s, PhCH2), 4.35 (1H,
dd, J4,3¼10.5 Hz, J4,5¼4.9 Hz, H-4glc), 4.21 (2H, s, H-4api), 3.97 (1H,
Compound 20b: Colorless amorphous solids; Rf¼0.65 (hexane/
EtOAc¼2:1 v/v); ½a D25
ꢃ
ꢀ41.3 (c 1.0, CHCl3); IR (KBr, disk):
n
1737 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3):
d
7.53e7.26 (17H, m,
dd, J2,1¼7.6 Hz, J2,3¼8.5 Hz, H-2glc), 3.85e3.74 (3H, m, H-3glc, H-6glc
,
PhH), 7.07 (2H, d, J¼8.0 Hz, eC6H4e), 6.94, 6.89 (4H, each d,
J¼8.9 Hz, eC6H4e), 5.92, 5.58 (2H, each s, PhCHꢂ2), 5.76 (1H, s, H-
1api), 5.02 (2H, s, PhCH2), 4.92, 4.75 (2H, each d, J¼11.2 Hz, PhCH2),
4.89 (1H, d, J1,2¼7.5 Hz, H-1glc), 4.41 (1H, s, H-2api), 4.35 (1H, dd,
J4,3¼10.5 Hz, J4,5¼5.0 Hz, H-4glc), 4.33, 4.27 (2H, each d, J¼11.9 Hz,
H-5api), 4.12 (2H, s, H-4api), 3.95 (1H, dd, J2,1¼7.5 Hz, J2,3¼8.4 Hz, H-
2glc), 3.87e3.74 (3H, m, H-3glc, H-6glc, H-60glc), 3.48 (1H, ddd,
H-60glc), 3.61 (2H, t, J¼7.1 Hz, CH2CH2OBn), 3.49 (1H, ddd,
0
J5,4¼4.9 Hz, J5,6¼9.2 Hz, J5,6 ¼8.8 Hz, H-5glc), 2.81 (2H, t, J¼7.1 Hz,
CH2CH2OBn), 2.61 (2H, t, J¼7.6 Hz, CH2CH2CH2C8F17), 2.14e1.80 (4H,
m, CH2CH2CH2C8F17); 13C NMR (63 MHz, CDCl3):
d 165.9, 155.3,
140.3, 138.4, 137.2, 136.1, 135.9, 133.5, 133.3, 130.0, 129.9, 129.7,
129.6, 129.1, 128.8, 128.4, 128.38, 128.36, 128.29, 127.59, 127.54,
127.2, 126.0, 116.3, 107.3, 106.5, 101.3, 100.0, 90.2, 87.2, 81.6, 80.9,
76.1, 74.5, 73.2, 73.0, 71.3, 68.7, 66.2, 64.7, 35.5, 34.8, 30.7 (t,
JCF¼22.4 Hz), 21.8; ESI-HRMS calcd for C65H57F17O12Na m/z
[MþNa]þ: 1375.3476. Found: 1375.3519.
0
J5,4¼5.0 Hz, J5,6¼9.0 Hz, J5,6 ¼9.0 Hz, H-5glc), 2.64 (2H, t, J¼7.6 Hz,
CH2CH2CH2C6F13), 2.15 (2H, d, J¼6.5 Hz, COCH2CH(CH3)2), 2.17e1.82
(5H, m, CH2CH2CH2C6F13 and COCH2CH(CH3)2), 0.92 (6H, d,
J¼6.5 Hz, CH3ꢂ2); 13C NMR (63 MHz, CDCl3):
d
172.5, 154.7, 151.1,
Compound 20f: Colorless amorphous solids; Rf¼0.62 (hexane/
140.3, 137.2, 137.1, 136.2, 135.9, 129.9, 128.8, 128.6, 128.4, 128.3,
128.0, 127.4, 127.1, 126.0, 118.1, 115.8, 107.2, 106.4, 90.2, 87.2, 81.6,
81.1, 75.9, 74.5, 73.3, 70.6, 68.7, 66.2, 64.3, 43.1, 34.8, 30.4 (t,
EtOAc¼2:1 v/v); ½a D19
ꢃ
ꢀ44.51 (c 1.02, CHCl3); IR (KBr, disk):
n
1739 cmꢀ1 (C]O); 1H NMR (250 MHz, CDCl3):
d 7.53e7.26 (17H, m,
PhH), 7.15, 6.90 (4H, each d, J¼8.6 Hz, eC6H4e), 7.07 (2H, d,

8290
M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
J¼8.0 Hz, eC6H4e), 5.92, 5.58 (2H, each s, PhCHꢂ2), 5.76 (1H, s, H-
1api), 4.97 (1H, d, J1,2¼7.6 Hz, H-1glc), 4.92, 4.75 (2H, each d,
J¼11.2 Hz, PhCH2), 4.52 (2H, s, PhCH2), 4.40 (1H, s, H-2api), 4.36 (1H,
dd, J4,3¼10.5 Hz, J4,5¼5.0 Hz, H-4glc), 4.30, 4.25 (2H, each d,
J¼12.0 Hz, H-5api), 4.12 (2H, s, H-4api), 3.98 (1H, dd, J2,1¼7.6 Hz,
J2,3¼8.2 Hz, H-2glc), 3.88e3.75 (3H, m, H-3glc, H-6glc, H-60glc), 3.66
(2H, t, J¼7.1 Hz, CH2CH2OBn), 3.52 (1H, ddd, J5,4¼5.0 Hz, J5,6¼9.4 Hz,
with 20%, and 40% aq MeOH. The 40% aq MeOH fraction was con-
centrated, and the crude product was purified by recrystallization
to give 1a (30.3 mg, 80% yield) as colorless prisms: mp
233.6e237.4 ꢁC (MeOH); Rf¼0.19 (CH3Cl/MeOH¼4:1 v/v); ½a D24
ꢃ
ꢀ87.8 (c 0.59, pyridine); IR (KBr, disk):
n
3444, 3353, 3280 cmꢀ1
(OH), 1710 cmꢀ1 (C]O); 1H NMR (600 MHz, CD3OD):
d 7.95 (2H, dd,
J¼1.2 Hz, J¼8.4 Hz, H-2000 and H-6000), 7.58 (1H, t, J¼7.4 Hz, H-4000),
7.42 (2H, t, J¼8.3 Hz, H-3000 and H-5000), 6.84 (2H, d, J¼8.9 Hz, H-2 and
H-6), 6.53 (2H, d, J¼8.9 Hz, H-3 and H-5), 5.50 (1H, d, J1,2¼1.2 Hz, H-
1api), 4.79 (1H, d, J1,2¼7.7 Hz, H-1glc), 4.39, 4.33 (2H, each d,
J¼11.3 Hz, H-5api), 4.33, 3.91 (2H, each d, J¼9.6 Hz, H-4api), 4.01 (1H,
0
J5,6 ¼8.8 Hz, H-5glc), 2.88 (2H, t, J¼7.1 Hz, CH2CH2OBn), 2.64 (2H, t,
J¼7.6 Hz, CH2CH2CH2C8F17), 2.12 (2H, d, J¼6.5 Hz, COCH2CH(CH3)2),
2.16e1.84 (5H, m, CH2CH2CH2C8F17 and COCH2CH(CH3)2), 0.90 (6H,
d, J¼6.5 Hz, CH3ꢂ2); 13C NMR (63 MHz, CDCl3):
d 172.5,155.4, 140.3,
0
0
138.4, 137.2, 136.2, 135.9, 133.6, 130.1, 129.9, 129.0, 128.8, 128.4,
128.3, 127.6, 127.5, 127.1, 126.0, 116.5, 107.2, 106.4, 101.3, 100.1, 90.2,
87.2, 81.6, 81.1, 75.9, 74.6, 73.2, 73.0, 71.3, 68.7, 66.2, 64.2, 43.1, 35.5,
34.8, 30.4 (t, JCF¼22.9 Hz), 25.5, 22.4, 21.8; ESI-HRMS calcd for
C63H61F17O12Na m/z [MþNa]þ: 1355.3789. Found: 1355.3788.
Compound 20g: Mp 129.8e131.9 ꢁC (colorless needles, hexane/
d, J2,1¼1.2 Hz, H-2api), 3.86 (1H, dd, J6,5¼2.1 Hz, J6,6 ¼11.9 Hz, H-6 glc),
0
0
0
3.66 (1H, dd, J6 ,5¼5.2 Hz, J6 ,6¼11.9 Hz, H-6 glc), 3.62 (1H, dd,
J2,1¼7.7 Hz, J2,3¼9.3 Hz, H-2glc), 3.57 (1H, dd, J3,2¼9.3 Hz,
J3,4¼8.2 Hz, H-3glc), 3.38e3.34 (2H, m, H-4glc and H-5glc); 13C NMR
(151 MHz, CD3OD):
d 167.7, 153.6, 152.1, 134.3, 131.1, 130.7, 129.5,
118.7, 116.7, 110.5, 101.8, 79.2, 78.8, 78.7, 78.4, 78.0, 75.4, 71.6, 68.4,
62.5; ESI-HRMS calcd for C24H28O12Na m/z [MþNa]þ: 531.1478.
Found: 531.1449.
EtOAc); Rf¼0.53 (hexane/EtOAc¼2:1 v/v); ½a D9
ꢀ26.2 (c 0.97,
ꢃ
CHCl3); IR (KBr, disk):
n
1717 cmꢀ1 (C]O); 1H NMR (250 MHz,
CDCl3):
d
7.90, 6.94 (4H each d, J¼9.0 Hz, eC6H4e), 7.54e7.27 (22H,
m, PhH), 7.07 (2H, d, J¼8.1 Hz, eC6H4e), 7.05, 6.85 (4H, each d,
J¼8.6 Hz, eC6H4e), 5.98, 5.58 (2H, each s, PhCHꢂ2), 5.77 (1H, s, H-
1api), 5.11, 4.49 (4H, each s, PhCH2ꢂ2), 4.92, 4.75 (2H, each d,
J¼11.4 Hz, PhCH2), 4.89 (1H, d, J1,2¼7.6 Hz, H-1glc), 4.54 (1H, s, H-
2api), 4.52, 4.43 (2H, each d, J¼11.9 Hz, H-5api), 4.35 (1H, dd,
J4,3¼10.5 Hz, J4,5¼4.9 Hz, H-4glc), 4.20 (2H, s, H-4api), 3.97 (1H, dd,
J2,1¼7.6 Hz, J2,3¼8.5 Hz, H-2glc), 3.86e3.72 (3H, m, H-3glc, H-6glc, H-
60glc), 3.61 (2H, t, J¼7.1 Hz, CH2CH2OBn), 3.50 (1H, ddd, J5,4¼4.9 Hz,
4.4.4. 4-Hydroxyphenyl
anosyl]- -glucopyranoside (1b). To a solution of disaccharide 20b
(95 mg, 78.8 mol) in THF/MeOH (60 mL, 1:3 v/v) was added palla-
2-O-[5-O-(3-methylbutyryl)-b-D-apiofur-
b-D
m
dium hydroxide (5 mg, 20 wt % on carbon). The suspension was
stirred for 12 h at room temperature under hydrogen gas. The
mixture was filtered through Celite. The filtrate was concentrated,
and the residue was loaded onto a reverse-phase silica gel
(CosmosilÒ 75C18-OPN, 3 g) column and the column was eluted
successively with 20%, and 40% aq MeOH. The 40% aq MeOH fraction
was concentrated to give 1b (38.5 mg, quant.) with sufficient purity.
The product 1b was further purified by semi-preparative HPLC with
an InertsilÒ ODS-3 column (20ꢂ250 mm, isocratic elution; 15% aq
CH3CN) to give 1b (26.5 mg, 69% yield) as a colorless syrup: Rf¼0.15
0
J5,6¼9.2 Hz, J5,6 ¼8.7 Hz, H-5glc), 2.82 (2H, t, J¼7.1 Hz, CH2CH2OBn),
2.61 (2H, t, J¼7.6 Hz, CH2CH2CH2C8F17), 2.14e1.80 (4H, m,
CH2CH2CH2C8F17); 13C NMR (63 MHz, CDCl3):
d 165.6, 162.8, 155.3,
140.3, 138.4, 137.2, 136.3, 136.2, 135.9, 133.5, 131.8, 130.0, 129.9,
129.0, 128.8, 128.7, 128.4, 128.3, 127.58, 127.52, 127.4, 127.2, 126.0,
122.1, 118.7, 116.3, 115.8, 114.6, 107.3, 106.5, 101.3, 100.0, 90.3, 87.2,
81.6, 81.0, 76.2, 74.6, 73.2, 72.9, 71.3, 70.2, 68.7, 66.2, 64.3, 35.5, 34.6,
30.4 (t, JCF¼22.2 Hz), 21.8; ESI-HRMS calcd for C72H63F17O13Na m/z
[MþNa]þ: 1481.3895. Found: 1481.3886.
(CH3Cl/MeOH¼4:1 v/v); ½a D24
ꢃ
ꢀ88.7 (c 1.1, MeOH); IR (KBr, disk):
n
3392 cmꢀ1 (OH), 1715 cmꢀ1 (C]O); 1H NMR (600 MHz, CD3OD):
d
6.89 (2H, d, J¼8.9 Hz, H-3 and H-5), 6.68 (2H, d, J¼8.9 Hz, H-2 and
H-6), 5.46 (1H, d, J1,2¼1.4 Hz, H-1api), 4.81 (1H, d, J1,2¼7.4 Hz, H-1glc),
4.16, 3.80 (2H, each d, J¼9.6 Hz, H-4api), 4.14, 4.10 (2H, each d,
J¼11.3 Hz, H-5api), 3.90 (1H, d, J2,1¼1.4 Hz, H-2api), 3.86 (1H, dd,
Compound 20h: Mp 145.1e149.8 ꢁC (colorless needles, hexane/
EtOAc); Rf¼0.53 (hexane/EtOAc¼2:1 v/v); ½a D11
ꢀ32.2 (c 0.99,
ꢃ
1730 cmꢀ1 (C]O), 1531 cmꢀ1 (N]O); 1H
J6,5¼2.1 Hz, J6,6 ¼0 12.4 Hz, H-6glc), 3.67 (1H, dd, J6 ,5¼5.3 Hz,
0
0
CHCl3); IR (KBr, disk):
n
0
NMR (250 MHz, CDCl3):
d
8.19, 8.05 (4H each d, J¼8.9 Hz, eC6H4e),
J6 ,6¼12.4 Hz, H-6 glc), 3.60 (1H, dd, J2,1¼7.4 Hz, J2,3¼9.3 Hz, H-2glc),
7.53e7.27 (17H, m, PhH), 7.07 (2H, d, J¼8.0 Hz, eC6H4e), 7.05, 6.85
(4H, each d, J¼8.6 Hz, eC6H4e), 5.96, 5.59 (2H, each s, PhCHꢂ2),
5.82 (1H, s, H-1api), 4.92, 4.75 (2H, each d, J¼11.2 Hz, PhCH2), 4.92
(1H, d, J1,2¼7.6 Hz, H-1glc), 4.63, 4.50 (2H, each d, J¼11.8 Hz, H-5api),
4.53 (1H, s, H-2api), 4.49 (2H, s, PhCH2), 4.36 (1H, dd, J4,3¼10.4 Hz,
J4,5¼4.9 Hz, H-4glc), 4.27, 4.22 (2H, each d, J¼10.2 Hz, H-4api), 4.01
(1H, dd, J2,1¼7.6 Hz, J2,3¼8.2 Hz, H-2glc), 3.89e3.76 (3H, m, H-3glc, H-
6glc, H-60glc), 3.61 (2H, t, J¼7.0 Hz, CH2CH2OBn), 3.51 (1H, ddd,
3.56 (1H, dd, J3,2¼9.3 Hz, J3,4¼8.2 Hz, H-3glc), 3.38e3.35 (2H, m, H-
4glc and H-5glc), 2.09 (2H, d, J¼6.7 Hz, H-2000),1.97 (1H, m, H-3000), 0.88
(6H, d, J¼6.7 Hz, H-5000); 13C NMR (151 MHz, CD3OD):
d 174.5, 153.7,
152.1,118.9,116.7,110.4,101.8, 79.0, 78.74, 78.67, 78.4, 77.9, 75.3, 71.5,
67.7, 62.5, 43.9, 26.7, 22.70, 22.67; ESI-HRMS calcd for C22H32O12Na
m/z [MþNa]þ: 511.1791. Found: 511.1793.
4.4.5. Seguinoside D (1c). To a solution of disaccharide 20c (111 mg,
83.4 mmol) in THF/MeOH (60 mL, 1:3 v/v) was added palladium
0
J5,4¼4.9 Hz, J5,6¼9.3 Hz, J5,6 ¼8.6 Hz, H-5glc), 2.80 (2H, t, J¼7.0 Hz,
CH2CH2OBn), 2.62 (2H, t, J¼7.6 Hz, CH2CH2CH2C8F17), 2.15e1.80
hydroxide (7 mg, 20 wt % on carbon). The suspension was stirred
for 12 h at room temperature under hydrogen gas. The mixture was
filtered through Celite. The filtrate was concentrated, and the res-
idue was loaded onto a reverse-phase silica gel (CosmosilÒ
75C18eOPN, 3 g) column and the column was eluted successively
with 20%, and 40% aq MeOH. The 40% aq MeOH fraction was con-
centrated to give 1c (43.6 mg, quant.) with sufficient purity. To
compare the optical rotation of the synthetic product with that of
the natural product, the product 1b was further purified by semi-
preparative HPLC with an InertsilÒ ODS-3 column (20ꢂ250 mm,
isocratic elution; 25% aq MeOH) to give 1b (34.5 mg, 79% yield) as
(4H, m, CH2CH2CH2C8F17); 13C NMR (63 MHz, CDCl3):
d 164.0, 155.2,
150.7,140.3,138.4,137.2,137.0,135.9,135.8,134.7,133.6,130.7,130.0,
129.1, 128.8, 128.42, 128.38, 128.34, 128.29, 127.5, 127.1, 126.0, 123.5,
116.2, 107.1, 106.5, 101.3, 99.9, 90.0, 87.2, 81.6, 81.1, 75.7, 74.6, 73.1,
72.9, 71.1, 68.7, 66.3, 65.2, 35.4, 34.8, 30.4 (t, JCF¼22.6 Hz), 21.8; ESI-
HRMS calcd for C65H56F17NO14Na m/z [MþNa]þ: 1420.3327. Found:
1420.3343.
4.4.3. Seguinoside C (1a). To a solution of disaccharide 20a (91 mg,
74.3
mmol) in THF/MeOH (60 mL, 1:3 v/v) was added palladium
hydroxide (5 mg, 20 wt % on carbon). The suspension was stirred
for 12 h at room temperature under hydrogen gas. The mixture was
filtered through Celite. The filtrate was concentrated, and the res-
idue was loaded onto a reverse-phase silica gel (CosmosilÒ
75C18eOPN, 3 g) column and the column was eluted successively
colorless amorphous powder: Rf¼0.13 (CH3Cl/MeOH¼4:1 v/v); ½a D23
ꢃ
ꢀ67.4 (c 0.43, MeOH); IR (KBr, disk):
n
3363 cmꢀ1 (OH), 1699 cmꢀ1
d
(C]O); 1H NMR (600 MHz, CD3OD):
7.82 (2H, d, J¼8.8 Hz, H-2000
and H-6000), 6.85 (2H, d, J¼8.9 Hz, H-2 and H-6), 6.78 (2H, d,
J¼8.9 Hz, H-3 and H-5), 6.56 (2H, d, J¼8.9 Hz, H-3000 and H-5000), 5.50

M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
8291
(1H, d, J1,2¼1.0 Hz, H-1api), 4.79 (1H, d, J1,2¼7.6 Hz, H-1glc), 4.34, 4.27
(2H, each d, J¼11.3 Hz, H-5api), 4.31, 3.90 (2H, each d, J¼9.8 Hz, H-
4api), 4.01 (1H, d, J2,1¼0.9 Hz, H-2api), 3.86 (1H, dd, J6,5¼1.9 Hz,
5
glc), 2.63 (2H, dt, J¼7.2 Hz, J¼3.6 Hz, H-7); 13C NMR (151 MHz,
CD3OD):
d 167.7, 157.3, 134.3, 133.9, 131.1, 130.9, 130.7, 129.5, 117.2,
110.4, 100.7, 79.2, 78.8, 78.6, 78.1, 78.0, 75.4, 71.5, 68.5, 64.3, 62.5,
39.4; ESI-HRMS calcd for C26H32O12Na m/z [MþNa]þ: 559.1791.
Found: 559.1767.
0
0
0
0
J6,6 ¼12.4 Hz, H-6 glc), 3.67 (1H, dd, J6 ,5¼5.2 Hz, J6 ,6¼12.2 Hz, H-
60glc), 3.62 (1H, dd, J2,1¼7.6 Hz, J2,3¼9.1 Hz, H-2glc), 3.57 (1H, dd,
J3,2¼9.1 Hz, J3,4¼8.2 Hz, H-3glc), 3.39e3.34 (2H, m, H-4glc and H-
5glc); 13C NMR (151 MHz, CD3OD):
d
167.8, 163.6, 153.5, 152.1, 133.0,
4.4.8. Cucurbitoside
G (1f). To a solution of disaccharide 20f
121.9, 118.8, 116.7, 116.1, 110.5, 101.8, 79.2, 78.7, 78.6, 78.4, 77.9, 75.4,
71.5, 68.0, 62.5; ESI-HRMS calcd for C24H28O13Na m/z [MþNa]þ:
547.1428. Found: 547.1475.
(87 mg, 65.3 mol) in THF/MeOH (60 mL, 1:3 v/v) was added pal-
m
ladium hydroxide (6 mg, 20 wt % on carbon). The suspension was
stirred for 12 h at room temperature under hydrogen gas. The
mixture was filtered through Celite. The filtrate was concentrated,
and the residue was loaded onto a reverse-phase silica gel
(CosmosilÒ 75C18eOPN, 3 g) column and the column was eluted
successively with 20%, and 40% aq MeOH. The 40% aq MeOH frac-
tion was concentrated to give 1f (31.2 mg, 93% yield) with sufficient
purity. To compare the optical rotation of the synthetic product
with that of the natural product, the product was purified by semi-
preparative HPLC with an InertsilÒ ODS-3 column (20ꢂ250 mm,
isocratic elution; 35% aq MeOH) to give 1f (21.7 mg, 64% yield) as
a colorless amorphous powder: Rf¼0.27 (CH3Cl/MeOH¼4:1 v/v);
4.4.6. 4-Hydroxyphenyl
anosyl]- -glucopyranoside (1d). To a solution of disaccharide 20d
(110 mg, 86.6 mol) in EtOAc/MeOH (27 mL, 1:2 v/v) was added
2-O-[5-O-(4-aminobenzoyl)-b-D-apiofur-
b-D
m
0.1 M aq HCl solution (0.78 mL) and palladium hydroxide (8 mg,
20 wt % on carbon). The suspension was stirred for 19 h at room
temperature under hydrogen gas. The mixture was filtered through
Celite, and the filtrate was concentrated. The residue was diluted
with H2O, and then the solution was loaded onto a reverse-phase
silica gel (CosmosilÒ 75C18eOPN, 3 g) column and the column
was eluted successively with 10%, and 20% aq MeOH. The 20% aq
MeOH fraction was concentrated to give 1d (25.0 mg, 55% yield)
with sufficient purity. The product was further purified by semi-
preparative HPLC with an InertsilÒ ODS-3 column (20ꢂ250 mm,
isocratic elution; 25% aq MeOH) to give 1d (17.8 mg, 39% yield) as
colorless amorphous powder; Rf¼0.58 (CH3Cl/MeOH/H2O¼10:10:3
½
a 2D8
ꢃ
ꢀ83.8 (c 0.29, MeOH); IR (KBr, disk):
n
3378 cmꢀ1 (OH),
7.13 (2H, d,
1732 cmꢀ1 (C]O); 1H NMR (600 MHz, CD3OD):
d
J¼8.6 Hz, H-2 and H-6), 6.96 (2H, d, J¼8.7 Hz, H-3 and H-5), 5.46
(1H, d, J1,2¼1.4 Hz, H-1api), 4.94 (1H, d, J1,2¼7.7 Hz, H-1glc), 4.14, 3.81
(2H, each d, J¼9.8 Hz, H-4api), 4.11, 4.07 (2H, each d, J¼11.3 Hz, H-
5api), 3.88 (1H, d, J2,1¼1.4 Hz, H-2api), 3.86 (1H, dd, J6,5¼1.9 Hz,
v/v/v); ½a 2D4
ꢃ
ꢀ64.7 (c 0.62, MeOH); IR (KBr, disk):
n
3367 cmꢀ1 (OH),
J6,6 ¼12.4 Hz, H-6glc), 3.69 (2H,0 t, J¼7.2 Hz, H-8), 3.67 (1H, dd,
0
1696 cmꢀ1 (C]O), 1603 cmꢀ1 (NH); 1H NMR (600 MHz, CD3OD):
J6 ,5¼5.2 Hz, J6 ,6¼12.2 Hz, H-6 glc), 3.64 (1H, dd, J2,1¼7.7 Hz,
J2,3¼9.1 Hz, H-2glc), 3.58 (1H, dd, J3,2¼9.1 Hz, J3,4¼8.6 Hz, H-3glc),
3.40e3.35 (2H, m, H-4glc and H-5glc), 2.75 (2H, t, J¼7.2 Hz, H-7), 2.07
(2H, d, J¼7.7 Hz, H-2000), 1.86 (1H, m, H-3000), 0.870, 0.867 (6H, each d,
0
0
d
7.70 (2H, d, J¼8.8 Hz, H-2000 and H-6000), 6.86 (2H, d, J¼8.9 Hz, H-3
and H-5), 6.58 (2H, d, J¼8.8 Hz, H-3000 and H-5000), 6.56 (2H, d,
J¼8.9 Hz, H-2 and H-6), 5.49 (1H, d, J1,2¼1.1 Hz, H-1api), 4.78 (1H, d,
J1,2¼7.6 Hz, H-1glc), 4.31, 4.23 (2H, each d, J¼11.3 Hz, H-5api), 4.30,
3.89 (2H, each d, J¼9.8 Hz, H-4api), 4.00 (1H, d0, J2,1¼1.0 Hz, H-2api),
J¼6.7 Hz, H-5000); 13C NMR (151 MHz, CD3OD):
d 174.4, 157.4, 134.1,
130.9, 117.4, 110.4, 100.8, 79.0, 78.8, 78.7, 75.3, 71.5, 67.6, 64.4, 62.5,
43.9, 26.7, 22.71, 22.68; ESI-HRMS calcd for C24H36O12Na m/z
[MþNa]þ: 539.2104. Found: 539.2071.
0
3.86 (1H, dd, J6,5¼1.9 Hz, J6,6 ¼11.9 Hz, H-6 glc), 3.67 (1H, dd,
0
0
0
J6 ,5¼5.2 Hz, J6 ,6¼12.0 Hz, H-6 glc), 3.61 (1H, dd, J2,1¼7.6 Hz,
J2,3¼9.3 Hz, H-2glc), 3.57 (1H, dd, J3,2¼9.1 Hz, J3,4¼8.3 Hz, H-3glc),
3.38e3.33 (2H, m, H-4glc and H-5glc); 13C NMR (151 MHz, CD3OD):
4.4.9. Cucurbitoside B (1g). To a solution of disaccharide 20 g
d
168.4, 154.8, 153.6, 152.2, 132.7, 118.9, 118.2, 116.7, 114.3, 110.5,
(135 mg, 92.9 mmol) in THF/MeOH (60 mL, 1:3 v/v) was added pal-
101.9, 79.3, 78.8, 78.7, 78.5, 77.9, 75.4, 71.5, 67.7, 62.5; ESI-HRMS
ladium hydroxide (10 mg, 20 wt % on carbon). The suspension was
stirred for 12 h at room temperature under hydrogen gas. The
mixture was filtered through Celite. The filtrate was concentrated,
and the residue was loaded onto a reverse-phase silica gel
(CosmosilÒ 75C18-OPN, 3 g) column and the column was eluted
successively with 20%, and 40% aq MeOH. The 40% aq MeOH fraction
was concentrated to give 1g (51.2 mg, quant.) with sufficient purity.
To compare the optical rotation of the synthetic product with that of
the natural product, the product was further purified by semi-
preparative HPLC with an InertsilÒ ODS-3 column (20ꢂ250 mm,
isocratic elution; 30% aq MeOH) to give 1g (42.9 mg, 84% yield) as
a colorless amorphous powder: Rf¼0.16 (CH3Cl/MeOH¼4:1 v/v);
calcd for C24H29NO12Na m/z [MþNa]þ: 546.1587. Found: 546.1602.
4.4.7. Cucurbitoside
A (1e). To a solution of disaccharide 20e
(79 mg, 58.4 mol) in THF/MeOH (60 mL, 1:3 v/v) was added palla-
m
dium hydroxide (5 mg, 20 wt % on carbon). The suspension was
stirred for 20 h at room temperature under hydrogen gas. The
mixture was filtered through Celite. The filtrate was concentrated,
and the residue was loaded onto a reverse-phase silica gel
(CosmosilÒ 75C18-OPN, 3 g) column and the column was eluted
successively with 20%, and 40% aq MeOH. The 40% aq MeOH fraction
was concentrated to give 1e (28.1 mg, 90% yield) with sufficient
purity. To compare the optical rotation of the synthetic product with
thatof the natural product, the product was further purified bysemi-
preparative HPLC with an InertsilÒ ODS-3 column (20ꢂ250 mm,
isocratic elution; 35% aq MeOH) to give 1e (15.7 mg, 50% yield) as
½
a 2D4
ꢃ
ꢀ68.8 (c 0.42, MeOH); IR (KBr, disk):
n
3367 cmꢀ1 (OH),
7.78 (2H, d,
1698 cmꢀ1 (C]O); 1H NMR (600 MHz, CD3OD):
d
J¼8.6 Hz, H-2000 and H-6000), 6.94 (2H, d, J¼8.2 Hz, H-2 and H-6), 6.89
(2H, d, J¼8.3 Hz, H-3 and H-5), 6.74 (2H, d, J¼8.6 Hz, H-3000, and H-
5000), 5.51 (1H, s, H-1api), 4.91 (1H, J1,2¼7.6 Hz, H-1glc), 4.33, 3.91 (2H,
each d, J¼9.8 Hz, H-4api), 4.28, 4.22 (2H, each d, J¼11.3 Hz, H-5api),
colorless amorphous powder: Rf¼0.22 (CH3Cl/MeOH¼4:1 v/v); ½a D28
ꢃ
ꢀ76.2 (c 1.0, MeOH); IR (KBr, disk):
n
3379 cmꢀ1 (OH),1716 cmꢀ1 (C]
O); 1H NMR (600 MHz, CD3OD):
d
7.93 (2H, dd, J¼1.4 Hz, J¼8.4 Hz, H-
3.98 (1H, s, H-2api), 3.86 (1H, br d, J6,6 ¼11.7 Hz, H-6glc), 3.68e3.65
0
2000 and H-6000), 7.58 (1H, tt, J¼1.4 Hz, J¼7.4 Hz, H-4000), 7.41 (2H, dd,
J¼7.5 Hz, J¼8.3 Hz, H-3000, and H-5000), 6.93 (2H, d, J¼8.8 Hz, H-2 and
H-6), 6.89 (2H, d, J¼8.8 Hz, H-3 and H-5), 5.51 (1H, d, J1,2¼1.0 Hz, H-
1api), 4.91 (1H, J1,2¼7.7 Hz, H-1glc), 4.34, 4.28 (2H, each d, J¼11.3 Hz,
H-5api), 4.33, 3.92 (2H, each d, J¼9.8 Hz, H-4api), 3.98 (1H, d,
(2H, m, H-2glc, H-60glc), 3.62 (2H, t, J¼7.0 Hz, H-8), 3.60 (1H, t,
J3,2¼8.9 Hz, H-3glc), 3.41e3.36 (2H, m, H-4glc, H-5glc), 2.65 (2H, dt,
J¼7.0 Hz, J¼2.4 Hz, H-7); 13C NMR (151 MHz, CD3OD):
d 167.7, 163.5,
157.3, 133.9, 132.9, 130.9, 121.9, 117.2, 116.1, 110.3, 100.7, 79.2, 78.8,
78.7, 78.1, 78.0, 75.4, 71.4, 67.9, 64.3, 62.5, 39.3; ESI-HRMS calcd for
C26H32O13Na m/z [MþNa]þ: 575.1741. Found: 575.1770.
0
J2,1¼1.0 Hz, H-2api), 3.87 (1H, dd, J6,5¼1.9 Hz, J6,6 ¼12.2 Hz, H-6glc),
3.66 (1H, dd, J2,1¼7.7 Hz, J02,3¼9.3 Hz, H-2glc), 3.66 (1H, dd,
0
0
J6 ,5¼5.2 Hz, J6 ,6¼12.2 Hz, H-6 glc), 3.60 (2H, t, J¼7.2 Hz, H-8), 3.60
4.4.10. Cucurbitoside I (1h). To a solution of disaccharide 20g
(52 mg, 37.5 mmol) in THF/MeOH (20 mL, 1:3 v/v) were added 0.1 M
(1H, t, J3,2¼9.3 Hz, J3,4¼9.8 Hz, H-3glc), 3.40e3.37 (2H, m, H-4glc, H-

8292
M. Kojima et al. / Tetrahedron 67 (2011) 8276e8292
2. Hase, K.; Kadota, S.; Basnet, P.; Namba, T.; Takahashi, T. Phytother. Res. 1996, 10,
387.
3. Beck, E. In Plant Carbohydartes; Loewus, F. A., Tanner, W., Eds.; Springer: New
York, NY, 1982.
4. (a) Zhong, X.-N.; Otsuka, H.; Ide, T.; Hirata, E.; Takushi, S.; Takeda, Y. Phyto-
chemistry 1998, 49, 2149; (b) Zhong, X.-N.; Otsuka, H.; Ide, T.; Hirata, E.; Takeda,
Y. Phytochemistry 1999, 52, 923; (c) Duynstee, H. I.; de Koning, M. C.; van der
Marel, G. A.; van Boom, J. H. Tetrahedron 1999, 55, 9881; (d) Hettinger, P.;
Schildknecht, H. Liebigs Ann. Chem. 1984, 6, 1230.
aq HCl solution (0.35 mL) and palladium hydroxide (5 mg, 20 wt %
on carbon). The suspension was stirred for 4 h at room temperature
under hydrogen gas. The mixture was filtered through Celite, and
the filtrate was concentrated. The residue was diluted with H2O,
and then the solution was loaded onto a reverse-phase silica gel
(CosmosilÒ 75C18eOPN, 3 g) column and the column was eluted
successively with 15%, and 30% aq MeOH. The 30% aq MeOH frac-
tion was concentrated, and the crude product was further purified
by semi-preparative HPLC with an InertsilÒ ODS-3 column
(20ꢂ250 mm, isocratic elution; 30% aq MeOH) to give 1g (6.8 mg,
33% yield) as colorless amorphous powder: Rf¼0.54 (CH3Cl/MeOH/
5. (a) Warashina, T.; Nagatani, Y.; Noro, T. Chem. Pharm. Bull. 2006, 54, 14; (b)
Warashina, T.; Nagatani, Y.; Noro, T. Phytochemistry 2004, 65, 2003.
6. Luo, Z.; Zhang, Q.; Oderatoshi, Y.; Curran, D. P. Science 2001, 291, 1766.
7. (a) Curran, D. P.; Furukawa, T. Org. Lett. 2002, 4, 2233; (b) Zhang, W.; Luo, Z.;
Chen, CH.-T.; Curran, D. P. J. Am. Chem. Soc. 2002, 124, 10443; (c) Zhang, Q.; Lu,
H.; Richard, C.; Curran, D. P. J. Am. Chem. Soc. 2004, 126, 36; (d) Curran, D. P.;
Moura-Letts, G.; Pohlman, M. Angew. Chem., Int. Ed. 2006, 45, 2423; (e) Fukui, Y.;
H2O¼10:10:3 v/v/v); ½a D24
ꢃ
ꢀ63.7 (c 0.51, MeOH); IR (KBr, disk):
n
3364 cmꢀ1 (OH), 1696 cmꢀ1 (C]O), 1604 cmꢀ1 (NH); 1H NMR
€
Bruckner, A. M.; Shi, Y.; Balachandran, R.; Day, B. W.; Curran, D. P. Org. Lett.
(600 MHz, CD3OD):
d
7.66 (2H, d, J¼8.8 Hz, H-2000 and H-6000), 6.95
2006, 8, 301; (f) Yang, F.; Curran, D. P. J. Am. Chem. Soc. 2006, 128, 14200; (g)
Jung, W.-T.; Guyenne, S.; Riesco-Fagundo, C.; Mancuso, J.; Nakamura, S.; Curran,
D. P. Angew. Chem., Int. Ed. 2008, 47, 1130; (h) Tojino, M.; Mizuno, M. Tetrahedron
Lett. 2008, 49, 5920; (i) Sui, B.; Yeh, EA.-H.; Curran, D. P. J. Org. Chem. 2010, 75,
2942; (j) Zhang, K.; Curran, D. P. Synlett 2010, 667.
8. (a) Wilcox, C. S.; Gudipati, V.; Lu, H.; Turkyilmaz, S.; Curran, D. P. Angew. Chem.,
Int. Ed. 2005, 44, 6938; (b) Curran, D. P.; Zhang, Q.; Richard, C.; Lu, H.; Gudipati,
V.; Wilcox, C. S. J. Am. Chem. Soc. 2006, 128, 9561.
9. (a) Wilcox, C. S.; Turkyilmaz, S. Tetrahedron Lett. 2005, 46, 1827; (b) Gudipati, V.;
Curran, D. P.; Wilcox, C. S. J. Org. Chem. 2006, 71, 3599.
10. Kojima, M.; Nakamura, Y.; Nakamura, A.; Takeuchi, S. Tetrahedron Lett. 2009, 50,
939.
(2H, d, J¼8.6 Hz, H-3 and H-5), 6.89 (2H, d, J¼8.6 Hz, H-2 and H-6),
6.57 (2H, d, J¼8.8 Hz, H-3000, and H-5000), 5.50 (1H, s, H-1api), 4.90 (1H,
J1,2¼7.7 Hz, H-1glc), 4.32, 3.89 (2H, each d, J¼9.6 Hz, H-4api), 4.26,
4.18 (2H, each d, J¼11.2 Hz, H-5api), 3.97 (1H, s, H-2api), 3.86 (1H, dd,
0
0
J6,5¼1.5 Hz, J6,6 ¼012.7 Hz, H-6glc), 3.67 (1H, dd, J6 ,5¼5.2 Hz,
0
J6 ,6¼12.5 Hz, H-6 glc), 3.65 (1H, dd, J2,1¼7.7 Hz, J2,3¼9.1 Hz, H-2glc,),
3.63 (2H, t, J¼7.0 Hz, H-8), 3.59 (1H, dd, J3,2¼8.9 Hz, J3,4¼8.6 Hz, H-
3glc), 3.40e3.34 (2H, m, H-4glc, H-5glc), 2.66 (2H, t, J¼7.0 Hz, H-7);
13C NMR (151 MHz, CD3OD):
d 168.4, 157.3, 154.8, 133.9, 132.7, 130.9,
11. Kojima, M.; Nakamura, Y.; Takeuchi, S. Tetrahedron Lett. 2007, 48, 4431.
12. For reviews on FSPE: (a) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837;
(b) Curran, D. P. In The Handbook of Fluorous Chemistry; Gladysz, J. A., Curran, D.
118.2, 117.3, 114.3, 110.4, 100.9, 79.3, 78.8, 78.7, 78.2, 78.0, 75.5, 71.5,
67.8, 64.3, 62.5, 39.4; ESI-HRMS calcd for C26H32O13Na m/z
[MþNa]þ: 575.1900. Found: 574.1932.
ꢁ
P., Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004; p 101; (c) Curran, D. P.
Synlett 2001, 1488.
13. Usually MeOH is used to elute fluorous compounds from a FluoroFlashÒ col-
umn. When the fluorous compounds were sparingly soluble in MeOH, EtOAc
was used to quickly elute the fluorous compounds from the column.
Acknowledgements
ꢁꢂ
ꢁꢂ
ꢂ
ꢁ
€
14. (a) Koos, M.; Micova, J.; Steiner, B.; Alfoldi, J. Tetrahedron Lett. 2002, 43, 5405;
(b) Koos, M.; Mosher, H. S. Carbohydr. Res. 1986, 146, 335; (c) Nachman, R. J.;
We thank Professor Kazuo Koike and Associate Professor Wei Li,
Toho University, for sending us copies of the 1H and 13C NMR
spectra for natural seguinoside C, cucurbitoside A and G. We also
thank Mr. T. Kuroda, Mr. T. Sekigawa, and Mr. A. Nakamura for
technical assistance.
€
Honel, M.; Williams, T. M.; Halaska, R. C.; Mosher, H. S. J. Org. Chem. 1986, 51,
4802; (d) Ho, P.-T. Can. J. Chem. 1979, 57, 381.
15. (a) Kim, Y.-J.; Wang, P.; Navarro-Villalobos, M.; Rohde, B. D.; Derryberry, J.; Gin,
D. Y. J. Am. Chem. Soc. 2006, 128, 11906; (b) Zhu, X.; Yu, B.; Hui, Y.; Schmidt, R. R.
Eur. J. Org. Chem. 2004, 5, 965.
16. 1,6-O-di-acylated and 1-O-acylated derivatives were obtained as a side prod-
ucts. To recycle these compounds,1,6-O-di-acylated and 1-O-acylated de-
rivatives were removed with NaOMe to give 17 in excellent yields.
17. FluophaseÒ RP column packed with a perfluorohexylpropylsiloxane-bonded
stationary phase is available from Thermo Fisher Scientific Inc.
18. InertsilÒ ODS-3 column is available from GL Sciences Inc.
19. Chan, L.; Just, G. Tetrahedron 1990, 46, 151.
References and notes
1. (a) Koike, K.; Li, W.; Liu, L.; Hata, E.; Nikaido, T. Chem. Pharm. Bull. 2005, 53, 225;
(b) Li, W.; Koike, K.; Tatsuzaki, M.; Koide, A.; Nikaido, T. J. Nat. Prod. 2005, 68,1754.