Total synthesis of macrocyclic glycosides, clemochinenosides A and B, and berchemolide, by fluorous mixture synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.08.068

The total synthesis of clemochinenoside A and the first total syntheses of clemochinenoside B and berchemolide were achieved simultaneously via macrocyclization of 4-O-(4-O-^F13benzyl-β-d-glucopyranosyl)syringic acid with 4-O-(4-O-^F17

Full text of DOI:10.1016/j.tetlet.2009.08.068

Tetrahedron Letters 50 (2009) 6143–6149
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of macrocyclic glycosides, clemochinenosides A and B, and
berchemolide, by fluorous mixture synthesis
*
Masaru Kojima, Yutaka Nakamura, Shun Ito, Seiji Takeuchi
Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of clemochinenoside A and the first total syntheses of clemochinenoside B and ber-
chemolide were achieved simultaneously via macrocyclization of 4-O-(4-O-F13benzyl-b-
D
-glucopyrano-
Received 30 June 2009
Revised 20 August 2009
Accepted 21 August 2009
Available online 26 August 2009
syl)syringic acid with 4-O-(4-O-F17benzyl-b-
D-glucopyranosyl)vanillic acid by a fluorous mixture
synthetic method. The spectroscopic data of the synthetic products were identical with those of the nat-
ural products, although the optical rotation of clemochinenoside A differed from the published values in
sign and magnitude.
Keywords:
Fluorous
Ó 2009 Elsevier Ltd. All rights reserved.
Mixture synthesis
Macrocyclic glycoside
Benzylidene group
Berchemolide (Fig. 1) was isolated from the stems of Berchemia
racemosa1 and Clematis armandii.2 Clemochinenosides A and B
(Fig. 1) were isolated from the roots and rhizomes of C. chinensis,3
C. armandii,2 C. mandshurica,4 C. hexapetala,4 and Capparis tenera.5
The stems of B. racemosa have been used as a folk medicine to treat
gall stones and stomachache in Japan. The roots and rhizomes of
Clematis species have been used as anti-inflammatory, anti-tumor,
and analgesic agents in the Chinese Pharmacopoeia. Despite these
plants possessing beneficial health effects, only a few macrocyclic
glycosides have been scientifically evaluated for biological activity.
The structures of macrocyclic glycosides were initially character-
ized by Sakurai’s1 and Song’s group,3 with the assignment of 1H
and 13C NMR data of clemochinenoside B recently revised by Su’s
group.5 Additionally, Wang and co-workers were the first to report
the total synthesis of clemochinenoside A from levoglucosan in an
eight-step reaction.6 However, the identity of clemochinenoside A
could not be established unambiguously, because the only physical
property of the synthetic product to be reported was the melting
point. Therefore, we decided to undertake the total syntheses of
clemochinenosides A and B and berchemolide for the purpose of
confirming their reported spectroscopic data and for further inves-
tigation of their biological activity.
natural products. The high efficiency and practicality of the meth-
odology have attracted many researchers’ interest. We thought
that fluorous mixture synthesis was suited for the expeditious syn-
thesis of macrocyclic glycosides, because these natural products
have a high degree of structural similarity and are comparatively
small molecules.
Recently, we reported the synthesis of fluorous benzylidene
groups as a new fluorous-protecting group.8 This protecting group
is regioselectively introduced into hydroxyl groups of hexopyrano-
sides and is transformed into the corresponding 4-O-benzyl group
by ring-opening reduction. Hence, the fluorous benzylidene group
is considered to be a valuable tool in fluorous mixture synthesis of
macrocyclic glycosides, because solid-phase extraction with a flu-
orous reverse-phase silica gel column (fluorous solid-phase extrac-
tion; FSPE)9 and the unique chemical properties of the benzylidene
group can be utilized for the synthesis.
D-Glc
OH
HO
O
OH
O
O
O
R1
MeO
R1
R2
Curran and co-workers have recently proposed fluorous mix-
ture synthesis as a new combinatorial technique for simple and
fast synthesis of natural products.7 Fluorous mixture synthesis
has shown power in preparing small molecule libraries and study-
ing structure/activity relationships and structure assignments for
Berchemolide
H
H
R2
OMe
O
O
O
O
Clemochinenoside A
Clemochinenoside B
OMe
OMe
OMe
H
HO
OH
D-Glc
OH
* Corresponding author. Tel.: +81 250 25 5164; fax: +81 250 25 5021.
E-mail address: takeuchi@nupals.ac.jp (S. Takeuchi).
Figure 1. The structures of macrocyclic glycosides.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.068

6144
M. Kojima et al. / Tetrahedron Letters 50 (2009) 6143–6149
MeO
MeO
MeO
O
O
O
a)
b)
c)
MeO
R
MeO
R
MeO
R
O
O
O
HO
O
O
O
FSPE
FSPE
FSPE
O
O
i) 80% aq MeOH
ii) acetone
i) 80% aq MeOH
ii) EtOAc
i) 80% aq MeOH
ii) EtOAc
HO
OH
O
OH
O
OBn
FPh
FPh
OH
OH
OBn
then
Flash column
1
: R = OMe
2: y. 91%
3: y. 90%
chromatograhy
6: R = H
(R = OMe, FPh = 4-C6F13(CH2)3C6H4-)
7: y. 78%
(R = OMe, FPh = 4-C6F13(CH2)3C6H4-)
8: y. 96%
(R = H, FPh = 4-C8F17(CH2)3C6H4-)
(R = H, FPh = 4-C8F17(CH2)3C6H4-)
MeO
HO
O
O
d)
MeO
R
MeO
R
4 steps
O
O
O
O
HO
HO
FBnO
1
flash column chromatography
5
10
Compound
Compound
: overall yield 57% from 1
FBnO
OBn
OBn
:
overall yield 56% from 6
OBn
OBn
4
5
: quant.
: y. 69%
(R = OMe, FBn = 4-C6F13(CH2)3C6H4CH2-)
9: y. 75%
(R = OMe, FBn = 4-C6F13(CH2)3C6H4CH2-)
10: quant.
(R = H, FBn = 4-C8F17(CH2)3C6H4CH2-)
(R = H, FBn = 4-C8F17(CH2)3C6H4CH2-)
Scheme 1. Reagents and conditions: (a) 4-CnFn+1 (CH2)3C6H4–CHO (n = 6 or 8), CH(OMe)3, p-TsOHꢀH20, Na2S04/CH3CN, rt; (b) BnBr, NaH/DMF, 0 °C; (c) PhBCl2, Et3SiH, MS-4 Å/
CH2C12, ꢁ78 °C; (d) KOH/EtOH–H20 (10:1), reflux.
We describe herein the fluorous mixture synthesis of clemo-
chinenosides A and B and berchemolide using fluorous benzylidene
groups from phenyl b-D-glucopyranosides and compare their ana-
BnBr (3.0 equiv) in DMF gave the 2,3-di-O-benzylated derivative 3
in 90% yield. In order to convert the 4,6-O-F13benzylidene group
into a 4-O-F13benzyl group, compound 3 was treated with Et3-
SiH–PhBCl2. The crude product was purified by standard silica gel
column chromatography to provide the 4-O-F13benzyl derivative
4 in 69% yield. Saponification of 4 using KOH (2.0 equiv) in 90%
lytical properties with the previous reports.
As shown in Scheme 1, F13Bn-protected carboxylic acid 5 was
prepared from 4-O-b-D-glucopyranosylsyringic acid methyl ester
(1)10 in a four-step reaction. F13Benzaldehyde (1.0 equiv) was re-
acted with 1 (2.5 equiv) in CH3CN to give the 4,6-O-F13benzylidene
derivative 2 in 91% yield. Benzylation of 2 with NaH (3.0 equiv) and
aq EtOH gave 4-O-(4-O-F13benzyl-b-
D-glucopyranosyl)syringic acid
5 in quantitative yield [1H NMR, J1,2 = 6.6 Hz, H-1 (b-linkage)]. In
these reaction steps, FSPE was utilized for the speedy purification
HO
O
OBn
BnO
O
OR3
MeO
O
OMe
O
R1
O
O
O
HO
MeO
F13BnO
OBn
R2
O
OMe
OBn
O
O
O
5
Mix
a)
R4O
OBn
(
F13Bn = 4-C6F13(CH2)3C6H4CH2-)
OBn
Mixture-1
FSPE
HO
O
R1
R2
R3
F13Bn
R4
OMe
F13Bn
F17Bn
F17Bn
O
HO
O
11
12
13
OMe
OMe
H
OMe
H
F13Bn
F17Bn
F17BnO
OBn
OBn
H
10
(
F17Bn = 4-C8F17(CH2)3C6H4CH2-)
Scheme 2. Reagents and conditions: (a) 2-chloro-1-methylpyridinium iodide, pyridine, DMAP/CH2C12 (1.5 mM), 0 °C.

M. Kojima et al. / Tetrahedron Letters 50 (2009) 6143–6149
6145
fluorous compound was eluted with a fluorophilic solvent.11 Next,
a component of berchemolide, 4-O-(4-O-F17benzyl-b-
D-glucopyr-
anosyl)vanillic acid 10, was prepared using a F17benzylidene group
via a similar synthetic route. As a result, the desired compound 10
[1H NMR, J1,2 = 7.3 Hz, H-1 (b-linkage)] was synthesized in 56%
overall yield from 4-O-b-
D-glucopyranosylvanillic acid methyl es-
ter (6).10,12
Using compounds 5 and 10, successfully prepared thus far, we
attempted a fluorous mixture synthesis of macrocyclic glycosides.
We expected that the three precursors of berchemolide, clemo-
chinenosides A and B would be obtained simultaneously by a
single macrocyclization of C6F13-Bn-syringic acid 5 and C8F17-Bn-
vanillic acid 10. In addition, the three components of the mixture
could be separated easily by column chromatography with a Flu-
oro FlashÒ silica gel, because the total number of fluorine atoms
in the products 11, 12, and 13 was 26, 30, and 34, respectively.
At first, cyclodimerization of carboxylic acids 5 and 10, using 2-
chloro-1-methylpyridinium iodide,13 was carried out while main-
taining high dilution conditions (Scheme 2).14 After purification
of the crude product by FSPE, Mixture-1, including the three struc-
tural isomers, was analyzed by HPLC with a FluoroFlashÒ column
to determine the optimal separation conditions (Fig. 2). When a
THF–H2O (70:30) solvent system was used as a mobile phase,
the three components of the product were cleanly separated with
large differences in the retention times for them.15 Therefore,
these three compounds were separated by flash chromatography
Figure 2. HPLC analysis of Mixture-1. FluoroFlashÒ column (4.6 mm i.d. ꢂ 50 mm
length, 5
254 nm.
lm), solvent THF–H2O (70:30), flow rate 1.0 ml/min, UV detection at
of the fluorous intermediates 2–4. Standard flash column chroma-
tography was carried out only once, but compound 5 was success-
fully prepared in 57% overall yield from 1 with sufficient purity for
subsequent use. In FSPE, the reaction mixture was loaded onto a
FluoroFlashÒ column and the column was eluted with 80% aq
MeOH to remove the non-fluorous compounds. Then the desired
OBn
BnO
O
F13Bn
O
OMe
O
O
O
60% aq THF
Pd(OH)2, H2 gas
MeO
Clemochinenoside A (14)
THF-MeOH (1 : 1)
MeO
O
OMe
y. 88%
(from 80% aq MeOH)
O
O
O
FSPE
F13BnO
OBn
OBn
11: 26 fluorine atom
OBn
BnO
O
O
F17Bn
O
O
O
Demix
70% aq THF
Pd(OH)2, H2 gas
MeO
Clemochinenoside B (15)
Mixture-1
Fluorous flash column
chromatography
MeO
O
OMe
THF-MeOH (1 : 1)
quant.
(from 80% aq MeOH)
O
O
O
FSPE
F13BnO
OBn
OBn
12: 30 fluorine atom
OBn
BnO
O
O
F17Bn
O
O
O
100% aq THF
Pd(OH)2, H2 gas
MeO
Berchemolide (16)
OMe
THF-MeOH (3 : 2)
y. 96%
O
O
O
O
(from 80% aq MeOH)
FSPE
F17BnO
OBn
OBn
13: 34 fluorine atom
Scheme 3.

6146
M. Kojima et al. / Tetrahedron Letters 50 (2009) 6143–6149
with a FluoroFlashÒ silica gel column (Scheme 3).16 As expected,
the structural isomers were eluted in order of increasing fluorine
content. The homodimer 11 and the heterodimer 12 were obtained
from the 60% and 70% aq THF fractions, respectively. The pure
homodimer 13 was obtained from 100% THF fraction.17 The MS
analysis, 1H, and 13C NMR data of the products demonstrated that
compounds 11–13 were the desired dimers.18 In addition, notice-
able formation of high molecular weight congeners such as trimers
was not observed in Mixture-1 using fluorous HPLC and TLC anal-
yses. Both the standard and fluorous benzyl groups of dimers 11–
13 were removed by hydrogenolysis (Scheme 3). After the crude
products were purified by FSPE, clemochinenosides A and B and
berchemolide were obtained in 88%,19a quantitative,19b and 96%
yield,19c respectively.
Synthetic clemochinenoside A (14) was isolated as colorless
needles by recrystallization from DMSO–MeOH. The melting point
of synthetic 14 (275.5–278.6 °C) was in good agreement with the
reported values (276–278 °C). The 1H and 13C NMR data of syn-
thetic 14 agreed well with a previous report. Careful analysis of
the 1H–1H and 13C–1H COSY spectra of 14 resulted in all the pro-
tons and carbons being assigned, as shown in Table 1. Additionally,
the 1H and 13C NMR spectra of synthetic 14 were identical to those
of natural clemochinenoside A, kindly supplied by Professor P.-F.
Tu and Dr. S.-P. Shi. However, when the optical rotation of syn-
thetic 14 was measured just after the preparation of the sample
solution, the values of ½a D26
ꢃ
dramatically decreased from +415.6
to +2.2 (c 0.50, pyridine) within 30 min. After 4 h, the optical rota-
tion reached ½a 2D6
ꢃ
ꢁ2.0 (c 0.50, pyridine) and differed from the
published value ([a] +73.3 (c 0.53, pyridine)) in both magnitude
D
and sign.20 Considering this result, it seems that the conformation
of clemochinenoside A gradually changed from a stable conforma-
tion in its crystalline state into its most stable conformation in
pyridine.
Synthetic clemochinenoside B (15) was isolated as a colorless
solid by recrystallization from MeOH. The 1H and 13C NMR data
of synthetic 15 agreed well with the previous reports, except for
the assignment of H-400, 500, 4000, and 5000 in the pyranosidic ring
(Table 2). All signal assignments of synthetic 15 were confirmed
by the 1H–1H and 13C–1H COSY experiments. The 1H and 13C
NMR spectra of synthetic 15 were also identical to those of
natural clemochinenoside B, kindly supplied by Professor P.-F.
Tu and Dr. S.-P. Shi. However, its optical rotation (½a2D5 +66.9 (c
0.49, pyridine)) and melting point (264.1–265.3 °C) differed
from the published value ([a] +40.6 (pyridine, the concentration
D
was not shown in the literature) and mp 290–293 °C) in
magnitude.21
Synthetic berchemolide (16) was isolated as colorless needles
by recrystallization from DMSO–MeOH. Synthetic 16 (½a D24
ꢃ
+119.1
Table 1
1H and 13C NMR data of clemochinenoside A3 (400 MHz, 25 MHz) and synthetic 14a (600 MHz, 151 MHz) in pyridine-d5
OH
HO
O
OH
O
O 7
O
MeO
OMe
1
6
2
5
MeO
OMe
3
4
O
6'
O
5'
O
O
1'
4'
HO
OH
2'
3'
OH
Clemochinenoside A (14)
[α]D -2.0 (c 0.50, pyridine, 26 oC)d
lit.3a [α]D +77.3 (c 0.53, pyridine)
Position
Clemochinenoside A3
Carbon
Synthetic 14
Carbon
Clemochinenoside A3
Proton
Synthetic 14
Proton
d (ppm)
d (ppm)
[d (multiplicity, J(Hz))]
[d (multiplicity, J (Hz))]
1
2
3
4
5
6
7
125.85
107.60
152.58
138.93
154.52
107.86
165.68
126.00
107.55
152.61
138.86
154.62
107.74
165.76
56.18b
56.25b
103.15
75.38
7.23 (d, J = 1.3)
7.50 (d, J = 1.3)
7.27 (d, J = 1.7)
7.51 (d, J = 1.7)
3-OMe
5-OMe
3.44 (s)
3.55 (s)
3.83 (s)
3.82 (s)
10
20
30
40
50
60
102.99
75.21
78.35
72.78
75.41
65.28
5.92 (d, J = 7.3)
3.97 (m)
4.39 (m)
4.39 (m)
4.39 (m)
5.94 (d, J1,2 = 7.4)
4.42 (dd, J2,1 = 7.4, J2,3 = 9.1)c
4.38 (dd, J3,2 = 9.1, J3,4 = 8.4)
3.98 (dd, J4,3 = 8.8, J4,5 = 9.1)c
0
78.48
72.87
75.54
65.38
4.35 (ddd, J5,4 = 10.0, J5,6 = 2.2, J5,6 = 10.3)
0
5.17 (dd, J = 9.6, 9.6)
5.00 (dd, J = 9.6, 1.5)
5.17 (dd, J6,5 = 10.8, J6,6 = 10.8)
5.00 (dd, J6’,6 = 11.5, J6’,5 = 2.2)
a
b
c
Signal assignments were made based on the 1H–1H and 1H–13C COSY spectra.
These signals were supplements.
Signal assignments differed from the literature.
d
In the case of low concentration, the optical rotation was [
a
]
D
ꢁ2.9 (c 0.103, pyridine, 22 °C).

M. Kojima et al. / Tetrahedron Letters 50 (2009) 6143–6149
6147
Table 2
1H and 13C NMR data of clemochinenoside B5 (500 MHz, 125 MHz) and synthetic 15a (600 MHz, 151 MHz) in pyridine-d5
OH
3'''
2'''
HO
1'''
OH
4'''
O
O
7
O
5'''
O
6'''
4'
3'
MeO
2'
OMe
1
6
2
5'
6'
5
1'
OMe
3
4
6''
O
5''
4''
O
7'
O
O
1''
HO
OH
2''
3''
OH
Clemochinenoside B (15)
[ ]
D +66.9 (c 0.49, pyridine, 25 oC)d
α
lit.3b [α]D +40.6 (pyridine)
Position
Clemochinenoside B5
Carbon
Synthetic 15
Carbon
Clemochinenoside B5
Proton
Synthetic 15
Proton
d (ppm)
d (ppm)
[d (multiplicity, J (Hz))]
[d (multiplicity, J (Hz))]
1
2
3
4
5
6
7
10
20
30
40
50
60
70
123.3
115.3
149.7
151.4
113.0
124.3
166.2
126.1
107.7
153.3
139.5
154.7
108.5
166.0
123.1
113.0b
149.7
151.3
115.2b
123.8
166.1
126.0
107.7
153.2
139.4
154.6
108.4
165.9
7.67 (d, J = 1.5)
7.70 (d, J = 1.9)
7.53 (d, J = 9.0)
7.55 (d, J = 8.6)
7.42 (dd, J = 9.0, 2.0)
7.45 (dd, J = 8.6, 1.9)
7.87 (d, J = 1.5)
7.52 (d, J = 2.0)
7.90 (d, J = 1.9)
7.54 (d, J = 1.9)
3-OMe
30-OMe
50-OMe
100
56.2
55.5
56.6
101.5
74.6
78.7
72.5
75.4
65.5
55.5
56.6
56.1
101.4
74.6
78.6
72.4
75.4
65.5
3.57 (s)
3.91 (s)
3.49 (s)
3.60 (s)
3.94 (s)
3.51 (s)
5.61 (d, J = 7.5)
4.32–4.42 (m)
4.51–4.56 (m)
4.32–4.42 (m)
3.98 (t, J = 9.0)
5.29 (dd, J = 11.5, 2.0)
5.03 (dd, J = 11.5, 2.0)
6.13 (d, J = 7.0)
4.32–4.42 (m)
4.21 (t, J = 9.0)
4.32–4.42 (m)
4.05 (t, J = 9.0)
5.18 (dd, J = 11.5,2.0)
4.55 (dd, J = 11.5, 2.0)
5.66 (d, J1,2 = 7.6)
4.46–4.36 (m)
4.46–4.36 (m)
4.08 (dd, J4,3 = 8.6, J4,5 = 9.6)c
4.57 (m)c
5.30 (dd, J6,6 = 11.3, J6,5 = 2.1)
5.09 (dd, J6 ,6 = 11.2, J6 ,5 = 10.1)
6.17 (d, J1,2 = 7.4)
200
300
400
500
600
0
0
0
1000
2000
3000
4000
5000
6000
103.2
75.2
78.9
72.8
75.7
66.2
103.2
75.6b
78.8
4.46–4.36 (m)
4.46–4.36 (m)
72.8
4.01 (dd, J4,3 = 8.6, J4,5 = 9.4)c
75.1b
66.2
4.23 (ddd, J5,4 = 10.0, J5,6 = 2.4, J5,6 = 10.3)c
0
0
5.20 (dd, J6,6 = 11.2, J6,5 = 2.4)
4.57 (dd, J6 ,6 = 11.2, J6 ,5 = 10.5)
0
0
a
b
c
Signal assignments were made based on the 1H–1H and 1H–13C COSY spectra.
Signals may be exchanged.
Signal assignments differed from the literature.
d
In the case of low concentration, the optical rotation was [a] +66.7 (c 0.063, pyridine, 22 °C).
D
(c 0.11, pyridine)) showed almost identical optical rotation with
synthesis by a single silica gel column chromatographic purifica-
tion step. It was also demonstrated that the three fluorous precur-
sors of the natural products were cleanly separated by fluorous
flash column chromatography, depending upon the total number
of fluorine atoms. The complete synthesis of the proposed chemical
structure for clemochinenoside A was achieved; although there is a
discrepancy in the magnitude and sign of the optical rotation for
synthetic 14 and an authentic sample.23 The investigation of the
interesting physical properties and the conformation of clemochin-
enoside A is now in progress.
that reported for natural berchemolide (½a D32
ꢃ
+116 (c 0.1,
pyridine)).22 In addition, the 1H and 13C NMR data for
synthetic 16 agreed well with the previously reported values
(Table 3).
In conclusion, we have simultaneously synthesized three mac-
rocyclic glycosides, berchemolide, clemochinenoside A, and clemo-
chinenoside B, using the fluorous mixture synthesis technique. The
isolation of fluorous intermediates by FSPE was very easy and
quick, and the desired carboxylic acids were obtained during the

6148
M. Kojima et al. / Tetrahedron Letters 50 (2009) 6143–6149
Table 3
1H and 13C NMR data of berchemolide1 (400 MHz, 100 MHz) and synthetic 16a (600 MHz, 151 MHz) in DMSO-d6
OH
HO
O
OH
O
O
7
O
MeO
1
6
2
5
OMe
3
4
O
6'
O
5'
O
O
1'
4'
HO
OH
2'
3'
OH
Berchemolide (16)
[α]D +119.1 (c 0.11, pyridine, 24 oC)b
lit.1 [α]D +116 (c 0.1, pyridine, 32 oC)
Position
Berchemolide1
Carbon
Synthetic 16
Carbon
Berchemolide1
Proton
Synthetic 16
Proton
d (ppm)
d (ppm)
[d (multiplicity, J (Hz))]
[d (multiplicity, J (Hz))]
1
2
3
4
5
6
7
122.50
112.19
148.43
149.85
114.42
122.91
165.06
122.46
112.09
148.40
149.81
114.44
122.93
165.12
7.42 (d, J = 2.0)
7.40 (d, J = 2.1)
7.37 (d, J = 8.6)
7.75 (dd, J = 8.6, 2.0)
7.37 (d, J = 8.8)
7.74 (d, J = 8.6, 2.1)
3-OMe
55.50
98.33
72.80
76.92
70.59
73.46
64.99
55.49
98.28
72.83
76.94
70.59
73.48
65.08
3.80 (s)
5.24 (d, J = 7.1)
3.39 (dd, J = 7.1, 9.0)
3.39 (t, J = 9.0)
3.18 (t, J = 9.0)
3.97 (ddd, J = 9.6, 9.0, 2.0)
4.09 (dd, J = 11.2, 9.6)
4.41 (dd, J = 11.2, 2.0)
3.79 (s)
5.24 (d, J1,2 = 7.4)
3.37 (m)
3.37 (m)
3.17 (dd, J4,3 = 8.6, J4,5 = 9.8)
3.97 (ddd, J5,4 = 10.0, J5,6’ = 1.9, J5,6 = 10.1)
4.07 (dd, J6,6’ = 11.3, J6,5 = 10.5)
4.40 (dd, J6’,6 = 11.3, J6’,5 = 1.7)
10
20
30
40
50
60
a
Signal assignments were made based on the 1H–1H and 1H–13C COSY spectra.
In the case of low concentration, the optical rotation was [a] +110 (c 0.03, pyridine, 23 °C).
D
b
Brückner, A. M.; Shin, Y.; Balachandran, R.; Day, B. W.; Curran, D. P. Org. Lett.
2006, 8, 301; (g) Yang, F.; Curran, D. P. J. Am. Chem. Soc. 2006, 128, 14200; (h)
Jung, W.-T.; Guyenne, S.; Riesco-Fagundo, C.; Mancuso, J.; Nakamura, S.;
Curran, D. P. Angew. Chem., Int. Ed. 2008, 47, 1130; (i) Tojino, M.; Mizuno, M.
Tetrahedron Lett. 2008, 49, 5920.
Acknowledgments
We wish to thank Professor Kenichi Sato and Dr. Shoji Akai,
Kanagawa University, for helpful discussions and for the measure-
ments of the NMR and MS spectra. We also thank Professor Junichi
Kitajima, Showa Pharmaceutical University, for sending us copies
8. Kojima, M.; Nakamura, Y.; Takeuchi, S. Tetrahedron Lett. 2007, 48, 4431.
9. For reviews on FSPE, see: (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. P., Horváth, I. T., Eds.; Wiley-VCH: Weinheim, 2004; pp 101–127; (c)
Curran, D. P. Synlett 2001, 1488.
of the 1H and 13C NMR spectra for natural 4-O-b-
D-glucopyranosyl-
syringic acid methyl ester (1). Lastly, we would like to thank Pro-
fessor Peng-Fei Tu and Dr. She-Po Shi, Peking University Health
Science Center, for sending us copies of the 1H and 13C NMR spectra
for natural clemochinenosides A and B.
10. Synthetic method for starting materials (1) and (6): 2,3,4,6-Tetra-O-acetyl
D-
glucopyranosyl trichloroacetoimidate was prepared from -glucose
D
according to the traditional procedure. The glycosylation of the
trichloroacetoimidate derivative with syringic acid methyl ester
(1.1 equiv) in the presence of BF3ꢀEt2O (1.7 equiv) in anhydrous CH2Cl2
gave the phenyl b-D
-glucopyranoside 10, which was then treated with
References and notes
NaOMe (0.5 equiv) in MeOH to afford 4-O-b-D-glucopyranosylsyringic acid
methyl ester (1) in 91% overall yield. According to a similar procedure, 6
was synthesized from trichloroacetoimidate derivative in 83% overall yield.
The physical data for 10, 1, 60, and 6 were almost identical to the reported
1. Sakurai, N.; Kobayashi, M.; Shigihara, A.; Inoue, T. Chem. Pharm. Bull. 1992, 40,
851.
2. Yan, L.; Yang, S.; Zou, Z.; Luo, X.; Xu, L. Heterocycles 2006, 68, 1917.
3. (a) Song, C. Q.; Xu, R. S. Chin. Chem. Lett. 1992, 3, 119; (b) Song, C. Q.; Xu, R. S.
Chin. Chem. Lett. 1993, 4, 505.
4. Shi, S.-P.; Jiang, D.; Dong, C.-X.; Tu, P.-F. Biochem. Syst. Ecol. 2007, 35, 57.
5. Su, D.-M.; Wang, Y.-H.; Yu, S.-S.; Yu, D.-Q.; Hu, Y.-C.; Tang, W.-Z.; Liu, G.-T.;
Wang, W.-J. Chem. Biodivers. 2007, 4, 2852.
6. Wang, Y.; Mao, J.; Cai, M. Synth. Commun. 1999, 29, 2093.
7. (a) Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766; (b)
Curran, D. P.; Furukawa, T. Org. Lett. 2002, 4, 2233; (c) Zhang, W.; Luo, Z.; Chen,
C. H.-T.; Curran, D. P. J. Am. Chem. Soc. 2002, 124, 10443; (d) Zhang, Q.; Lu, H.;
Richard, C.; Curran, D. P. J. Am. Chem. Soc. 2004, 126, 36; (e) Curran, D. P.;
Moura-Letts, G.; Pohlman, M. Angew. Chem., Int. Ed. 2006, 45, 2423; (f) Fukui, Y.;
values. The 1H and 13C NMR spectra for synthetic
1 were identical to
those of natural 1, kindly supplied by Professor J. Kitajima. (a) Klick, S.;
Herrmann, K. Z. Lebensm. Unters. Forsch. 1988, 187, 444. (b) Fujimatu, E.;
Ishikawa, T.; Kitajima, J. Phytochemistry 2003, 63, 609. (c) Durkee, A. B.;
Siddiqui, I. R. Carbohydr. Res. 1979, 77, 252. Compound 10:
½
a 2D4
ꢃ
ꢁ9.3 (c
0.3, MeOH); mp 109.2–111.5 °C (EtOAc–Hexane) [lit. mp 105 °C
(MeOH)10a]. Compound 1:
ꢁ17.1 (c 0.48, MeOH); mp 186.1–
–20 (c 0.9, MeOH); mp 91–93 °C (MeOH)10b].
½ ꢃ
a 2D4
188.7 °C (MeOH) [lit.
½
a 2D4
ꢃ
Compound 60:
hexane) [lit.
½
a 2D4
a 2D5
ꢃ
ꢁ33.0 (c 0.5, CHCl3); mp 145.2–147.3 °C (EtOAc–
ꢁ34 (c 1.0, CHCl3); mp 143–144 °C (EtOH)10c].
ꢁ69.9 (c 0.7, MeOH); mp 196.2–198.2 °C (MeOH) [lit.
½
ꢃ
Compound 6: ½a 1D8
ꢃ
½
a 2D5
ꢃ
ꢁ71 (c 0.7, MeOH); mp 170–171 °C (H2O)10c].

M. Kojima et al. / Tetrahedron Letters 50 (2009) 6143–6149
6149
MeO
17. From 94.5 mg Mixture-1, homodimer 11 (18.5 mg), heterodimer 12 (47.8 mg),
and homodimer 13 (14.4 mg) were obtained from 60%, 70%, and 100% aq THF
fractions, respectively.
O
18. 1H, 13C NMR data and other physical data of compounds 11–13.Compound 11:
syringic acid methyl ester
BF3 Et2O / CH2Cl2
MeO
OMe
½ ꢃ
a 1D7 +1.7 (c 0.94, CHCl3); 1H NMR (250 MHz, CDCl3) d 7.67–7.05 (32H, m,
O
RO
O
aromatic protons), 5.21 (2H, d, J1,2 = 7.4 Hz, glc H-1), 5.17, 4.80 (4H, each d,
J = 11.0 Hz, –CH2Ph), 5.03, 4.81 (4H, each d, J = 11.1 Hz, –CH2Ph), 4.86, 4.57 (4H,
RO
OR
0
each d, J = 11.1 Hz, –CH2Ph), 4.43 (2H, dd, J6,5 = 3.1 Hz, J6,6 = 11.3 Hz, glc H-6),
4.36 (2H, dd, J6 ,5 = 10.0 Hz, J6 ,6 = 11.2 Hz, glc H-60), 3.85–3.78 (4H, m, glc H-2,
3), 3.75, 3.62 (12H, each s, –OCH3 ꢂ 2), 3.67 (2H, ddd, J5,4 = 9.5 Hz, J5,6 = 3.2 Hz,
OR
0
0
1'
NaOMe / MeOH
y. 91% (2 steps)
: R = Ac
: R = H
CCl3
NH
0
J5,6 = 9.6 Hz, glc H-5), 3,45 (2H, dd, J4,5 = 9.5 Hz, J4,3 = 8.5 Hz, glc H-4), 2.70 (4H,
1
t, J = 7.4 Hz, –CH2CH2CH2C6F13), 2.18–1.86 (8H, m, –CH2CH2CH2C6F13); 13C NMR
(63 MHz, CDCl3) d 165.25, 153.41, 151.59, 140.44, 138.57, 137.80, 135.75,
128.48, 128.39, 128.30, 128.29, 127.81, 127.61, 125.23, 106.92, 106.28, 102.96,
84.81, 82.14, 78.62, 77.20, 75.69, 74.55, 74.41, 72.82, 63.97, 56.34, 56.04, 34.71,
30.25 (t), 21.76. MS (ESI-pos.) calcd for C90H82F26O18Na (M+Na)+ 1967.4984,
found: 1967.4990.
O
AcO
AcO
O
OAc
MeO
O
OAc
trichloroacetoimidate
MeO
Compound 12: ½a 1D7
ꢃ
ꢁ13.2 (c 0.98, CHCl3); 1H NMR (250 MHz, CDCl3) d 7.50–
O
RO
O
6.84 (33H, m, aromatic protons), 5.27, 4.80 (2H, each d, J = 10.9 Hz, –CH2Ph),
5.21 (1H, d, J = 10.8 Hz, –CH2Ph), 5.08–4.98 (4H, m, –CH2Ph ꢂ 3, glc H-1, 6),
4.92–4.78 (7H, m, –CH2Ph ꢂ 6, glc0 H-1), 4.62 (1H, J = 11.4 Hz, –CH2Ph), 4.58
vanillic acid methyl ester
BF3 Et2O / CH2Cl2
RO
OR
(1H, J = 11.1 Hz, –CH2Ph), 4.45 (1H, dd, J6,5 = 1.6 Hz, J6,6 = 11.0 Hz, glc0 H-6),
OR
0
4.05 (1H, dd, J6 ,5 = 10.3 Hz, J6 ,6 = 10.7 Hz, glc H-60), 4.00 (1H, dd, J6 ,5 = 10.1 Hz,
0
0
0
NaOMe / MeOH
y. 83% (2 steps)
6': R = Ac
6: R = H
J6 ,6 = 10.7 Hz, glc0 H-60), 3.94–3.76 (5H, m, glc H-2, 3, 5, glc0 H-2, 3), 3.88, 3.87,
0
3.55 (9H, each s, –OCH3 ꢂ 3), 3.62–3.43 (3H, m, glc H-4, glc0 H-4, 5), 2.73, 2.70
(4H, each d, J = 7.5, 7.3 Hz, –CH2CH2CH2C8F17, –CH2CH2CH2C6F13), 2.16–1.91
(8H, m, –CH2CH2CH2C8F17, –CH2CH2CH2C6F13); 13C NMR (63 MHz, CDCl3) d
165.73, 165.30, 154.25, 152.84, 150.55, 149.12, 140.56, 140.51, 138.75, 138.67,
138.64, 138.24, 138.07, 135.61, 135.59, 128.55, 128.51, 128.51, 128.45, 128.40,
128.37, 128.28, 128.20, 127.93, 127.85, 127.80, 127.76, 127.60, 127.57, 125.94,
124.18, 123.32, 118.42, 114.61, 112.35, 107.01, 106.59, 104.60, 101.62, 84.98,
84.47, 82.24, 81.06, 78.53, 78.38, 77.20, 75.94, 75.75, 74.76, 74.70, 74.67, 74,47,
73.30, 72.83, 64.71, 63.81, 56.21, 56.11, 55.83, 34.73, 30.28 (t), 21.80. MS (ESI-
pos.) calcd for C91H80F30O17Na (M+Na)+ 2037.4814, found: 2037.4788.
11. Usually MeOH is used to elute fluorous compounds from
a
FluoroFlashÒ
column. When the fluorous compounds were sparingly soluble in MeOH, EtOAc
or acetone was used to quickly elute the fluorous compounds from the column.
12. C6F13
amount of CH3CN. Therefore, a lower yield of product 7 than that of 2 is
considered to be due to lower solubility of 4-O-b- -glucopyranosylvanillic acid
methyl ester (6) in CH3CN compared to that of 1.
– and C8F17-benzaldehydes were dissolved completely in the same
D
13. To identify the optimal reaction conditions for cyclodimerization, we initially
examined the conversion of monomer 5 into the corresponding dimer 11 under
various conditions. (a) DCC, DMAP/CH2Cl2, rt, (y. 11%): Wang, Y.; Mao, J.; Cai,
M. Synth. Commun. 1999, 29, 2093. (b) 2-Methyl-6-nitrobenzoic anhydride,
DMAP/CH2Cl2, rt, (y. 52%): Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J.
Org. Chem. 2004, 69, 1822. (c) 2-Chloro-1,3-dimethylimidazolinium chloride,
DMAP/CH2Cl2, 0 °C then rt, (y. 47%): Isobe, T. J. Org. Chem. 1999, 64, 6984. (d) (i)
2,4,6-Trichlorobenzoyl chloride, Et3N/THF, rt. (ii) DMAP/toluene, rt then reflux,
(y. 47%): Inanaga, J.; Hirata, K. Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989. (e) DEAD, PPh3/THF, ꢁ20 °C then rt, (y. 50%):
Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380. (f) 2-Chloro-1-
methylpyridinium iodide, pyridine, DMAP/CH2Cl2, 0 °C, (y. 59%): Mukaiyama,
T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 5, 49.
Compound 13: ½a 1D7
ꢃ
+12.0 (c 0.75, CHCl3); 1H NMR (250 MHz, CDCl3) d 7.72–
7.15 (34H, m, aromatic protons), 5.21, 4.87 (4H, each d, J = 10.8 Hz, –CH2Ph),
5.11 (2H, d, J1,2 = 7.4 Hz, glc H-1), 5.05, 4.85 (4H, each d, J = 11.0 Hz, –CH2Ph),
4.89, 4.59 (4H, each d, J = 10.9 Hz, –CH2Ph), 4.59 (2H, dd, glc H-6), 4.10 (2H, dd,
J6 ,5 = 10.5 Hz, J6 ,6 = 10.9 Hz, glc H-60), 3.90 (2H, ddd, J5,4 = 9.8 Hz, J5,6 = 1.5 Hz,
0
0
0
J5,6 = 10.1 Hz, glc H-5), 3.87 (6H, s, –OCH3), 3.87–3.78 (4H, m, glc H-2, 3), 3.49
(2H, dd, J4,5 = 9.4 Hz, J4,3 = 8.7 Hz, glc H-4), 2.70 (4H, t, J = 7.4 Hz,
–CH2CH2CH2C6F13), 2.19–1.88 (8H, m, –CH2CH2CH2C6F13); 13C NMR (63 MHz,
CDCl3)
d 165.62, 150.25, 149.49, 140.65, 138.28, 138.11, 135.44, 128.57,
128.51, 128.48, 128.45, 128.42, 127.86, 127.78, 124.19, 123.26, 115.44, 112.70,
101.09, 84.68, 81.21, 78.43, 77.21, 75.92, 75.02, 74.74, 73.31, 64.56, 55.92,
34.75, 30.30 (t), 21.80. MS (ESI-pos.) calcd for C92H78F34O16Na (M+Na)+
2107.4645, found: 2107.4657.
14. Cyclodimerization procedure: To a stirred mixture of the carboxylic acids 5
(46.7 mg, 0.047 mmol), 10 (50 mg, 0.047 mmol), and 2-chloro-1-
methylpyridinium iodide (120 mg, 0.47 mmol) in CH2Cl2 (63 ml), pyridine
19. After purification of the crude products by FSPE, 4-(3-perfluoroalkyl)propyl
toluenes were recovered from the MeOH fraction. (a) 4-(3-Perfluorohexyl)propyl
toluene was obtained in 49% yield. (b) A mixture of 4-(3-perfluorohexyl)propyl
toluene and 4-(3-perfluorooctyl)propyl toluene was obtained in 64% yield. (c) 4-
(3-Perfluorooctyl)propyl toluene was obtained in 65% yield. Conversion of 4-(3-
perfluoroalkyl)propyl toluenes into the corresponding 4-(3-perfluoroalkyl)propyl
benzaldehydes for reuse is now in progress.
(114 ll, 1.41 mmol) was slowly added at 0 °C. The reaction mixture was stirred
for 24 h, and then DMAP (69 mg, 0.57 mmol) was added to the reaction
mixture. After monitoring the disappearance of the starting materials on TLC,
the reaction mixture was diluted with CH2Cl2. The organic layer was washed
with 3% HCl, dried over Na2SO4, and concentrated. The residue was loaded onto
a FluoroFlashÒ silica gel (3 g) column and eluted with 80% aq MeOH (100 ml);
the column was subsequently eluted with EtOAc (200 ml) to give a fraction
containing Mixture-1 (94.5 mg).
20. Physical data of clemochinenoside A (14): colorless needles (DMSO–MeOH),
mp 275.5–278.6 °C; ½a D26
ꢁ2.0 (c 0.5, pyridine) [lit. mp 276–278 °C, [a] +73.3
D
ꢃ
(c 0.53, pyridine)3a]; 1H and 13C NMR (Table 1). MS (ESI-pos.) calcd for
C30H36O18Na (M+Na)+ 707.1799, found: 707.1793.
15. Using a FluoroFlashÒ column, Mixture-1 was analyzed with the following
gradient solvent system. The column was initially eluted with CH3CN–H2O
(80:20), then with increasing CH3CN–H2O to 100:0 over a 10-min period.
Compounds 11, 12, and 13 were eluted individually at 10.2, 13.3, and 16.7 min.
16. The three components of Mixture-1 were separated clearly by fluorous TLC
and the differences in Rf values were large enough to separate the components
by fluorous silica gel column chromatography depending upon their fluorine
atom content. Comparatively, on a standard silica gel TLC, the top two spots
were very close and the second spot overlapped with the tail of the top spot.
Therefore, it was predicted that the three components would be difficult to
separate by standard silica gel column chromatography without the fluorous
tags. In addition, it is impossible to predict the structures of the components,
even if separation was successful.
21. Physical data of clemochinenoside B (15): colorless solid (MeOH), mp 264.1–
265.3 °C;
½
a 2D5
ꢃ
+66.9 (c 0.49, pyridine) [lit. mp 290–293 °C,
[
a
]
+40.6
D
(pyridine)3b]; 1H and 13C NMR (Table 2). MS (ESI-pos.) calcd for C29H34O17Na
(M+Na)+ 677.1694, found: 677.1695.
22. Physical data of berchemolide (16): colorless needles (DMSO–MeOH); ½a D24
ꢃ
+119.1
(c 0.11, pyridine) [lit. ½a D32
ꢃ
+116 (c 0.1, pyridine)1]; 1H and 13C NMR (Table 3). MS
(ESI-pos.) calcd for C28H32O16Na (M+Na)+ 647.1588, found: 647.1612.
23. It was not possible to measure the optical rotation of the natural products. No
samples of natural clemochinenosides and were available (Personal
communication by Professor P.-F. Tu and Dr. S.-P. Shi).
A
B