Concise synthesis of flavocommelin, 7-O-methylapigenin 6-C-, 4′-O-bis-β-d-glucoside, a component of the blue supramolecular pigment from Commelina communis

Article abstract of DOI:10.1016/j.carres.2013.03.016

Flavocommelin, 7-O-methylapigenin 6-C-, 4′-O-bis-β-d-glucoside, was synthesized in 9 steps from the C-glycosylation of 6-O-benzy-4-O- methylphloroacetophenone via the introduction of a cinnamoyl residue by aldol condensation and the formation of a C-ring by regioselective and oxidative ring-closure to regio- and stereoselective O-glycosylation for an overall yield of 31%.

Full text of DOI:10.1016/j.carres.2013.03.016

Carbohydrate Research 374 (2013) 8–13
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Concise synthesis of flavocommelin, 7-O-methylapigenin 6-C-, 40-O-
bis-b-D-glucoside, a component of the blue supramolecular pigment
from Commelina communis
⇑
Kazufumi Misawa, Yoshiki Gunji, Shingo Sato
Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, Jonan 4-3-16, Yonezawa-shi, Yamagata 992-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Flavocommelin, 7-O-methylapigenin 6-C-, 40-O-bis-b-
D-glucoside, was synthesized in 9 steps from the C-
glycosylation of 6-O-benzy-4-O-methylphloroacetophenone via the introduction of a cinnamoyl residue
by aldol condensation and the formation of a C-ring by regioselective and oxidative ring-closure to regio-
and stereoselective O-glycosylation for an overall yield of 31%.
Article history:
Received 26 February 2013
Accepted 19 March 2013
Available online 30 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
C,O-diglycosylflavonoid
Phloroacetophenone
C-glycosylation
Regioselective oxidative cyclization
Regioselective deprotection
1. Introduction
1 via 12 steps in a 6.2% overall yield from ( ) naringenin, using
the C-glycosylation of the flavan as a key reaction. This is the only
A variety of C-glycosylflavonoids are widely distributed in
plants, in which sugars are generally linked at C-6 and/or C-8 on
the A-ring. C-glycosides show different various biological activi-
ties1 from the related aglycone and O-glycoside, because they are
not enzymatically hydrolyzed in vivo. We have achieved the syn-
thesis of some naturally occurring mono- and di-C-glycosylflavo-
noids (flavone, isoflavone, flavanone, and chalcone) showing
biological activity based on our development of two different C-
glycosylation methods: C-glycosylation of phloroacetophenone
4,6-bis-ether by O–C glycoside rearrangement,2 and a direct mono-
and di-C-glycosylation of the non-protected phloroacetophenone
with a non-protected sugar in an aqueous solution.3 However,
we have not attempted the synthesis of C,O-diglycosylflavonoid.
More than 100 naturally occurring C,O-diglycosylflavonoids have
been discovered and their structure comfirmed.4 Among them,
some compounds have shown biological activity. For example,
saponarin (6-C-glucosylapigenin 7-O-glucoside) shows potent
anti-inflammatory and antidiabetic activities.5
report of the synthesis of C,O-diglycosylflavonoid.7
Herein we describe the concise synthesis of 1 using the former
of our two C-glycoside synthetic methods, with planning and
examination as shown in Scheme 1: (1) C-glycosylation of 2-O-
benzyl-4-O-methylphloroacetophenone by the O–C glycoside
rearrangement method; (2) introduction of a cinnamoyl residue
by aldol condensation; (3) regioselective deprotection of the 6-
OH group on the A-ring followed by the formation of a flavone
skeleton using oxidative cyclization; and, (4) regioselective depro-
tection of the 40-OH group on the B-ring and its stereoselective
O-glycosylation by the Koenigs–Knorr reaction according to the
conditions stipulated by Oyama.6
2. Results and discussion
C-glycosylation of 2-O-benzyl-4-O-methylphloroacetophenone
(2)2e was carried out by raising the reaction temperature from
ꢀ78 °C to room temperature for 5 h, using 1.0 equiv of per-O-
Flavocommelin (1) (Fig. 1) is one of the components of commel-
inin, a blue supramolecular pigment that is a metalloanthocyanin (a
metal-complex anthocyanin) in Commelina communis, which has
been elucidated by Kondo’s group.6 For the structure analysis of
the supramolecular pigment, Oyama and Kondo first synthesized
benzyl-a-D-glucosyl fluoride as a glycosyl donor to 2.0 equiv of 2
in CH2Cl2 in the presence of 1.5 equiv of BF3ꢁOEt2 and powdered
molecular sieves 4A. The desired C-glycoside 32e was furnished in
85% yield. The advantage of this method is that the reaction pro-
ceeds smoothly in an excellent yield using BF3ꢁOEt2 with neither
the use of a potent and expensive catalyst metallocene (Cp2MCl2:
M = Ti, Zr, Hf) and Ag salt, nor scandium(III) trifluoromethanesulfo-
nate [Sc(OTf)3] to give the desired C-glycoside, owing to formation
⇑
Corresponding author. Tel.: +81 238263120.
E-mail address: shingo-s@yz.yamagata-u.ac.jp (S. Sato).
0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.03.016

K. Misawa et al. / Carbohydrate Research 374 (2013) 8–13
9
conditions using 5% or/and 10% Pd–C as a catalyst, reduction of
the olefin proceeded in preference to O-debenzylation. Next,
hydrogenolysis in a solution containing HCl was examined and
the desired 6 was produced in a maximum yield of 38%. Further,
one-pot formation of the flavanone by deprotection and cyclization
by refluxing in HCl aqueous solution or in the presence of DowexÒ
(H+) resin, and one-pot formation of flavones via deprotection and
oxidative cyclization by heating in DMSO in the presence of a cat-
alytic amount of I2 were attempted. However, they yielded a mix-
ture of many products. Since a 6-O-benzyl group of chalcone 5 can
be more labile by comparison with other benzyl groups, 6-O-
debenzylation using a Lewis acid was next examined. A treatment
of 5 with 4.5 equiv of BF3ꢁOEt2 in an ice-salt bath for 5 h proceeded
smoothly, providing 6 in a 76% yield. In succession, regioselective
oxidative cyclization by the heating of 6 in DMSO at 130 °C for
30 min in the presence of 0.1 equiv of I2 proceeded satisfactorily,
affording the desired flavone 7 in an 88% yield2d (Scheme 2).
Toward the next regioselective O-glycosylation, the regioselec-
tive debenzylation of the 40-phenolic benzylether on the B-ring of 7
by the above hydrogenolysis using 5% Pd–C in AcOEt was carried
out, and the desired 40-OH-free flavone 8 was acquired in a 68%
yield. Since a partial deprotection of the benzyl ether of the glucose
hydroxyls proceeded well under these conditions, the yield was
moderate. In order to improve the yield, first, a protecting element
of the 6-OH group of 7 was changed from a benzyl to an acetyl
group, then the regioselective deprotection of the 40-O-acetyl
group on the B-ring of acetate 10 was examined using Oyama’s
method [2.5 equiv of tetramethylguanidine (TMG) in CH3CN at rt,
for 2 h].9 This regioselective deprotection reaction proceeded
smoothly to give 40-OH-free 10 (11) in an 89% yield.
OH
HO
OH
OH
O
O
B
MeO
O
O
C
A
HO
HO
1
OH
HO
OH
O
Figure 1. Structure of flavocommelin (1).
OH
HO
OH
OH
O
O
MeO
O
O
O
regioselective deprotection
HO
HO
and O-glycosylation
HO
OH
1
OH
OR
MeO
O
O
RO
RO
RO
regioselective cyclyzation
OR
OR' O
MeO
O
OH
OR
BnO
BnO
OBn
BnO
OR
O
aldol condensation
and regioselective protection
Finally, the stereoselective O-glycosylation of 11 was carried
out via a Koenigs–Knorr reaction using the procedure established
by Oyama [per-O-acetylglucosyl bromide (3.0 equiv), Ag2CO3
(1.5 equiv), in quinoline, at 0 °C to rt, for 3 h],9 providing 12 in an
80% yield. The final deprotection of acetyl and benzoyl groups
was conducted via treatment with sodium methoxide in methanol
followed by neutralization using DowexÒ 50Wx8 (H+) resin, then
recrystallization from H2O–CH3CN gave 1 as a white solid in an
84% yield. The 1H NMR data of 1 gave a complex spectrum due
to the mixture of rotamers, but it was identical to that of a natural
compound as well as that of Oyama and Kondo’s synthetic one. The
other physico-chemical data were also identical.7
MeO
O
OBn
C-glycosylation
BnO
BnO
BnO
OBn
OH
O
MeO
OBn
O
OH
Scheme 1. Synthetic plan of flavocommelin (1).
3. Conclusion
of the C-glycoside via O-glycosylation to the chelated phenolic
Flavocommelin (1) was efficiently synthesized via 9 steps from
2 in an overall 31% yield. A concise synthesis of C,O-diglycosylflav-
one using phloroacetophenone bis-ether as a starting material was
achieved. The synthetic route proposed here was shown to be via-
ble for the synthesis of various C,O-diglycosylflavonoids. Synthesis
hydroxyl. Further, Schmidt’s C-glycosylation method8 using 2 and
1.2 equiv of per-O-benzyl-a-D-glucosyl trichloroacetimidate in
place of the fluoride as a donor and 0.2 equiv of trimethylsilyl
trifluoromethanesulfonate (TMSOTf) as a catalyst to 1.0 equiv of
2 also afforded 3 in an 81% yield. Structure analysis of the synthetic
compounds was conducted mainly by means of 1H NMR and 1H–1H
COSY, and FAB-MS. A 1H NMR spectrum gave a complex spectrum
due to a mixture of rotamers, particularly on the A-ring bearing a
C-glycoside. The 1H NMR spectra measured in DMSO-d6 at more
than 120 °C were simple without a mixture of rotamers, which
allowed assignment. However, C-glycosides bearing an O-glycoside
could not be measured at more than 120 °C due to instability. Both
the use of fluoride/BF3ꢁOEt2 and imidate/TMSOTf as a combination
of donor and catalyst gave 3 in good yield. Next, the aldol conden-
sation of 3 with 1.1 equiv of p-benzyloxybenzaldehyde in the
presence of 1.5 equiv of sodium methoxide in 1,4-dioxane at room
temperature for 2 h gave chalcone 4 in a 98% yield. After a 2-OH
group on the A-ring of 4 was benzoylated with benzoyl chloride
and pyridine (5 Y: 95%), selective deprotection of the 6-O-benzyl
group on the A-ring was attempted. Under hydrogenolysis
of the more complex 6-C-7-O-b-D-diglucosylapigenin, saponarin is
in progress.
4. Experimental
4.1. General
The solvents used in these reactions were purified by distilla-
tion. Reactions were monitored by TLC on 0.25-mm silica gel
F254 plates (E. Merck) using UV light, and a 7% ethanolic solution
of phosphomolybdic acid with heat as the coloration agent. Flash
column chromatography was performed on silica-gel (40–50 lm,
Kanto Reagents Co. Ltd, silica-gel 60) to separate and purify the
reaction products. Optical rotations were recorded on a JASCO
DIP-370 polarimeter. Melting points were determined using an

10
K. Misawa et al. / Carbohydrate Research 374 (2013) 8–13
MeO
OBn
Ac
MeO
O
OBn
Ac
a
MeO
O
OBn
O
OBn
b
BnO
BnO
BnO
BnO
OBn
BnO
OH
2
OH
OBn
BnO
OR
3
R
4 H
c
5 Bz
OBn
MeO
OH
OBn
MeO
O
O
O
d
BnO
BnO
e
OBn
BnO
BnO
BnO
OBz O
6
OBn
BnO
OBz O
7
OAc
OAc
OAc
OH
AcO
O
O
MeO
O
O
g
MeO
O
f
BnO
BnO
O
BnO
BnO
OBn
BnO
OBz O
8
OBn
BnO
OBz O
9
Reagents and conditions : a) 2 (2 equiv), per-O-benzylglucosyl fluoride (1 equiv), BF3 OEt2 (2 equiv) in CH2Cl2, at -70 oC _ rt,
5 h, Y:85% b) p-BnO-benzaldehyde (1.2 equiv), NaOMe (1.2 equiv), in dioxane, rt, 1.5 h, Y:98% c) BzCl (1.5 equiv), in
.
pyridine, 0 oC _ rt, 3 h, Y: 95% d) BF3 OEt2 (3.5 equiv), in CH2Cl2, -20 _ -10 oC, 3 h, Y:76% e) I2 (0.1 equiv) in DMSO at 130
.
oC, 30 min, Y:88% f) H2 / 5 and 10% Pd-C, in AcOEt, rt, 6 h. Y:68% g) per-O-acetylglucosyl bromide (3.5 equiv), Ag2CO3 (1.5
equiv), in quinoline, at 0 oC _ rt, 3 h, Y:70%
OAc
OH
MeO
O
O
MeO
O
O
AcO
AcO
h
7
i
AcO
AcO
g
OAc
AcO
OBz O
10
OAc
AcO
OBz O
11
OAc
OAc
OAc
AcO
O
O
MeO
O
O
k
AcO
AcO
1
OAc
AcO
OBz O
12
Reagents and conditions : h) 1. H2 / 10% Pd(OH)2, AcOEt/EtOH (1:1), rt, 3 h, 2. Ac2O/Py, rt, 3 h, Y:98%, i) TMG (2.5
equiv), in CH3CN, rt, 3h, Y:80% g) Y:80% k) NaOMe in MeOH, rt, for 1 h, then Dowex50W (H+), Y: 100%.
Scheme 2. Total synthesis of flavocommelin (1).
ASONE micro-melting point apparatus and uncorrected values
were reported. IR spectra were recorded on a Horiba FT-720 IR
spectrometer using a KBr disk. NMR spectra were recorded on a
JEOL ECX-500 spectrometer using Me4Si as the internal standard.
Mass spectral data were obtained by fast-atom bombardment
(FAB) using 3-nitrobenzyl alcohol (NBA) as a matrix on a JEOL
JMS-AX505HA instrument. High-resolution mass spectra (HRMS)
were obtained under electron spray ionization (ESI) conditions
on a JEOL JMS-T100LP. Elemental analyses were performed on a
Perkin–Elmer PE 2400 II instrument. After drying at 70 °C under
reduced pressure for more than 2 h, each product was subjected
to elemental analysis.
4.1.1. 40,6-Dibenzyloxy-3-C-(200,300,400,600-tetra-O-benzyl-b-
D-
glucopyranosyl)-4-methoxychalcone (4)
To a solution of 3 (1.24 g, 1.56 mmol) and p-benzyloxybenzal-
dehyde (0.330 g, 1.56 mmol) in 1,4-dioxane (10 mL), 28%
a
NaOMe–MeOH solution (8.0 mL) was added and the mixture was
stirred at room temperature for 1.5 h. To the reaction mixture,
ice-cold 2 N-HCl solution (20 mL) was added, then the mixture
was extracted three times with AcOEt. The organic layer was
washed with water and brine, dried over anhydrous Na2SO4, and
evaporated to dryness. The residual solid was purified by silica-
gel column chromatography (n-Hexane–AcOEt = 4:1–3:1) to afford
4 (1.51 g, Y: 98%) as a yellow amorphous powder.

K. Misawa et al. / Carbohydrate Research 374 (2013) 8–13
11
½
a 2D2
ꢂ
ꢀ6.6 (c 0.550, CHCl3). IR (KBr): 3425, 3030, 2920, 2856,
for 0.5 h. After cooling at room temperature, ice-cold water was
added to the resultant mixture, which then was extracted three
times with AcOEt. The organic layer was washed with a saturated
Na2S2O3 solution and brine and dried over anhydrous Na2SO4, and
then evaporated to dryness. The residual solid was purified by
silica-gel column chromatography (n-Hexane–AcOEt = 3:1–2:1) to
afford 7 (371 mg, Y: 88%) as a colorless amorphous powder.
1624, 1558, 1508, 1454, 1423, 1230, 1066, 735, 696 cmꢀ1 1H
.
NMR (DMSO-d6, at 120 °C) d 3.50 (1H, m, H500), 3.59 (1H, t,
J = 9.1 Hz, H400), 3.67 (2H, m, H600a,b), 3.68 (1H, m, H300), 3.86 (3H,
s, OCH3), 4.20 (1H, d, J = 12.1 Hz, CH2Ph), 4.31 (1H, t, J = 9.1 Hz,
H200), 4.46 and 4.49 (each 1H, d, J = 12.1 Hz, CH2Ph), 4.56 (1H, d,
J = 12.1 Hz, CH2Ph), 4.62 (1H, d, J = 11.3 Hz, CH2Ph), 4.76–4.85
(3H, m, CH2Ph), 4.81 (1H, d, J = 9.1 Hz, H100), 5.15 (2H, s, ArOCH2Ph),
5.26 (2H, s, ArOCH2Ph), 6.38 (1H, s, 8-ArH), 7.59 and 7.64 (each 1H,
d, J = 15.9 Hz, trans-vinyl H), 6.90–7.51 (34H, m, ArH), 14.0 (1H, br
s, 5-OH); FAB-MS (m/z) 989 (M+H)+. Anal. Calcd for
½
a 2D3
ꢂ
ꢀ5.3 (c 1.77, CHCl3). IR (KBr): 3483, 3062, 3030, 2912,
2866, 1751, 1643, 1608, 1510, 1452, 1352, 1257, 1097, 833, 737,
698 cmꢀ1 1H NMR (CDCl3) d 3.00 (1H, dd, J = 10.9 and 5.7 Hz,
.
H600a), 3.13 (1H, t, J = 9.5 Hz, H400), 3.41 (1H, dd, J = 1.5 and
10.6 Hz, H600b), 3.46 (1H, ddd, J = 1.5, 6.1 and 7.2 Hz, H500), 3.74
(1H, t, J = 9.5 Hz, H300), 4.21-4.29 (4H, m, H200 and CH2Ph), 3.91
and 3.72 (3H, s, OCH3), 4.67 (1H, d, J = 10.6 Hz, H100), 4.66 (1H, d,
J = 11.4 Hz, CH2Ph), 4.68 (1H, d, J = 10.6 Hz, CH2Ph), 4.87 and 4.94
(each 1H, d, J = 11.3 Hz, CH2Ph), 4.99 (1H, d, J = 9.8 Hz, H100), 5.14
(2H, s, ArOCH2Ph), 6.47 (3H, s, ArOCH2Ph), 6.47 (1H, s, H3), 6.83
(1H, s, 8-ArH), 6.96–8.17 (34H, m, ArH); FAB-MS (m/z) 1001
(M+H)+. Anal. Calcd for C64H56O11: C, 76.78; H, 5.64. Found: C,
76.64; H, 5.46.
C
64H60O10ꢁ0.5H2O: C, 77.01; H, 6.16. Found: C, 76.96; H, 6.12.
4.1.2. 2-Benzoyl-40,6-dibenzyloxy-3-C-(200,300,400,600-tetra-O-
benzyl-b- -glucopyranosyl)-4-methoxychalcone (5)
To a solution of 4 (1.21 g, 1.22 mmol) in pyridine (2.5 mL), benzyl
chloride (556 L, 6.71 mmol) was added at 0 °C. The reaction
mixture was stirred at room temperature for 4 h. To the resul-
tant mixture ice-cold water and 2 N HCl (15 mL) were added, then
the mixture was extracted three times with AcOEt. The organic layer
was washed with water and brine, and dried over anhydrous Na2SO4
and then evaporated to dryness. The residual solid was purified by
silica-gel column chromatography (n-Hexane–AcOEt = 3:1–2:1) to
afford 5 (1.27 g, Y:95%) as a pale-yellow amorphous powder.
D
l
4.1.5. 5-Benzoyl-6-C-(200,300,400,600-tetra-O-benzyl-b-
glucopyranosyl)-40-hydroxy-7-methoxyflavone (8)
D-
To a solution of 7 (100 mg, 0.0999 mmol) in AcOEt, 5% Pd–C
(50 mg) was added, and the mixture was stirred vigorously under
hydrogen atmosphere at room temperature for 4 h. To the reaction
mixture 10% Pd–C (10 mg) was added, and the mixture was again
vigorously stirred under hydrogen atmosphere at room tempera-
ture for 1 h. After monitoring the disappearance of 7 by silica-gel
TLC (n-Hexane:AcOEt = 2:1), the resultant mixture was filtered
with a celite pad, followed by washing with AcOEt, and then it
was allowed to evaporate to dryness. The residual solid was
purified by silica-gel column chromatography (n-Hex-
ane:AcOEt = 3:1–2:1) to afford 8 (61.9 mg, Y:68%) as a colorless
solid.
½
a 2D2
ꢂ
ꢀ40 (c 1.88, CHCl3). IR (KBr): 3446, 3031, 2904, 2864, 1743,
1602, 1508, 1452, 1250, 1099, 1070, 737, 698 cmꢀ1 1H NMR
.
(CDCl3) d 2.95 (2H, t, J = 9.1 Hz, H400), 2.95 (1H, m, H600a), 3.36
(1H, br d, J = 10.6 Hz, H600b), 3.43 (1H, br t, J = 6.8 Hz, 8.4, H500),
3.67 (1H, t, J = 9.1 Hz, H300), 3.77 (3H, s, OCH3), 4.09 (1H, t,
J = 9.1 Hz, H200), 4.16 (1H, d, J = 10.6 Hz, CH2Ph), 4.22 and 4.26 (each
1H, d, J = 9.9 Hz, CH2Ph), 4.32 (each 1H, d, J = 12.1 Hz, CH2Ph), 4.60
(2H, t, J = 12.1 and 11.3 Hz, CH2Ph), 4.80 (1H, d, J = 10.6 Hz, CH2Ph),
4.91 (1H, d, J = 10.6 Hz, CH2Ph), 4.95 (1H, d, J = 9.9 Hz, H100), 5.08
(2H, s, ArOCH2Ph), 5.15 (2H, s, ArOCH2Ph), 6.46 (1H, s, 8-ArH),
6.86–8.04 (36H, m, ArH ꢃ 34, vinyl H ꢃ 2); FAB-MS (m/z) 1093
(M+H)+. Anal. Calcd for C71H64O11: C, 78.00; H, 5.90. Found: C,
78.34; H, 5.90.
½
a 2D3
ꢂ
9.0 (c 0.840, CHCl3). IR (KBr): 3435, 3030, 2923, 2860, 1751,
1629, 1608, 1512, 1452, 1354, 1255, 1095, 837, 737, 698 cmꢀ1 1H
.
NMR (CDCl3) was observed with rotamers, d 2.88 (1H, dd, J = 7.6
and 10.6 Hz, H600a), 2.94 (1H, t, J = 9.8 Hz, H400), 3.36 (1H, d,
J = 9.8 Hz, H600b), 3.51 (1H, m, H500), 3.73 (1H, t, J = 8.3 and 9.1 Hz,
H300), 3.73 and 3.82 [3H (2.6:1), each s, OCH3], 4.18 (1H, d,
J = 11.3 Hz, CH2Ph), 4.24 (1H, t, J = 9.1 and 9.8 Hz, H200), 4.27 (1H,
d, J = 11.3 Hz, CH2Ph), 4.32 and 4.33 (each 1H, d, J = 12.1 Hz, CH2Ph),
4.63 (1H, d, J = 10.6 Hz, CH2Ph), 4.66 (1H, d, J = 11.3 Hz, CH2Ph),
4.86 (1H, d, J = 10.6 Hz, CH2Ph), 4.94 (1H, d, J = 11.3 Hz, CH2Ph),
4.95 (1H, d, J = 9.8 Hz, H100), 6.35 (1H, s, H3), 6.53 (1H, s, H8),
6.70–8.40 (30H, m, ArH ꢃ 29 and 40-OH); FAB-MS (m/z) 911
(M+H)+. Anal. Calcd for C57H50O11ꢁ0.25H2O: C, 74.78; H, 5.56.
Found: C, 74.51; H, 5.41.
4.1.3. 2-Benzoyl-40-benzyloxy-3-C-(200,300,400,600-tetra-O-benzyl-b-
D
-glucopyranosyl)-6-hydroxy-4-methoxychalcone (6)
To a solution of 5 (730 mg, 0.668 mmol) in CH2Cl2 (5.0 mL)
BF3ꢁOEt2 (371 L, 3.01 mmol) was dropwise added at ꢀ15 °C, and
l
the mixture was stirred at ꢀ15 to ꢀ10 °C for 5 h. To the reaction
mixture, ice-cold water was added, then the mixture was extracted
three times with AcOEt. The organic layer was washed with water
and brine, dried over anhydrous Na2SO4, and evaporated to dry-
ness. The residual solid was purified by silica-gel column chroma-
tography (n-Hexane–AcOEt = 4:1–3:1) to afford 6 (509 mg, Y: 76%)
as a yellow amorphous powder.
½
a 2D3
ꢂ
ꢀ34 (c 1.95, CHCl3). IR (KBr): 3435, 3031, 2922, 2860, 1751,
1628, 1554, 1508, 1452, 1350, 1219, 737, 698 cmꢀ1 1H NMR
.
4.1.6. 5-Benzoyl-6-C-(200,300,400,600-tetra-O-benzyl-b-
D-
(CDCl3) d 2.87 (1H, dd, J = 10.6 and 5.3 Hz, H600a), 3.06 (1H, t,
J = 9.0 and 9.1 Hz, H400), 3.27 (1H, d, J = 9.8 Hz, H600b), 3.39 (1H, m,
H500), 3.75 (1H, t, J = 9.1 Hz, H300), 3.87 (3H, s, OCH3), 4.26 (1H, t,
J = 9.1 Hz, H200), 4.06 and 4.12 (each 1H, d, J = 12.1 Hz, CH2Ph),
4.20 and 4.62 (each 1H, d, J = 11.3 Hz, CH2Ph), 4.50 and 4.72 (each
1H, d, J = 11.4 Hz, CH2Ph), 4.92 and 4.99 (each 1H, d, J = 11.3 Hz,
CH2Ph), 4.89 (1H, d, J = 9.8 Hz, H100), 5.02 (2H, s, ArOCH2Ph), 6.46
(1H, s, 8-ArH), 6.86–7.99 (36H, m, ArH ꢃ 34, vinyl H ꢃ 2); FAB-
MS (m/z) 1003 (M+H)+. Anal. Calcd for C76H60O11: C, 76.63; H,
5.83. Found: C, 76.89; H, 6.06.
glucopyranosyl)-40-O-(2000,3000,4000,6000-tetra-O-acetyl-b-
D-
glucopyranosyl)-7-methoxyflavone (9)
To a solution of 8 (20.0 mg, 0.0220 mmol) in quinoline (0.3 mL),
Ag2CO3 (9.1 mg, 0.0330 mmol) and acetobromoglucose per-O-ace-
tylglucosyl bromide (27.1 mg, 0.0660 mmol) were added at 0 °C
and the mixture was stirred at room temperature under a shielded
light for 3 h. The reaction was quenched with MeOH, and the mix-
ture was eluted through a short silica-gel column with AcOEt. The
eluate was evaporated to dryness. To the residue, 1 N HCl (0.5 mL)
was added, then the mixture was extracted three times with
AcOEt. The organic layer was washed with water and brine, then
dried over anhydrous Na2SO4. After evaporation, the residual solid
was purified by silica-gel column chromatography (n-Hex-
ane:AcOEt = 2:1–1:1) to afford 12 (19.1 mg, Y: 70%) as a white
solid.
4.1.4. 5-Benzoyl-40-benzyloxy-6-C-(200,300,400,600-tetra-O-benzyl-b-
D
-glucopyranosyl)-7-methoxyflavone (7)
A solution of 6 (422 mg, 0.421 mmol) and iodide (10.6 mg,
0.0421 mmol) in DMSO (1.4 mL) was stirred at 130 °C (oil bath)

12
K. Misawa et al. / Carbohydrate Research 374 (2013) 8–13
½
a 2D4
ꢂ
ꢀ17 (c 1.14, CHCl3). IR (KBr): 3030, 2929, 2866, 1751, 1647,
[1H (1:2.4), t, J = 9.8 Hz, H200], 7.41 (1H, br s, 40-OH), 6.27 and
1610, 1508, 1452, 1232, 1068, 698 cmꢀ1 1H NMR (DMSO-d6) was
.
6.34 [1H (1:2.4), s, H3], 6.78 (1H, s, H8), 7.58 (2H, m, Ph), 7.69
(1H, m, Ph), 8.25 and 8.33 [2H (1:2.4), d, J = 7.6 Hz, Ph]; FAB-MS
(m/z) 719 (M+H)+. Anal. Calcd for C37H34O15ꢁ1.5H2O: C, 59.59; H,
5.00. Found: C, 59.70; H, 4.60.
observed with a mixture of rotamers, d 1.972, 2.010, 2.015, 2.024
(each 3H ꢃ 4, s ꢃ 4, OAc ꢃ 4), 2.65 (1H, dd, J = 6.9 and 10.6 Hz,
H600a), 2.78 (1H, t, J = 9.1 Hz, H400), 3.18 (1H, br d, J = 10.6 Hz,
H600b), 3.39 (1H, m, H500), 3.68 (1H, t, J = 9.1 Hz, H300), 3.97 (3H, s,
OCH3), 4.08 (1H, dd, J = 2.2 and 12.1 Hz, H6000a), 4.14 (1H, t, J = 9.1
and 9.9 Hz, H200), 4.21 (1H, dd, J = 5.3 and 12.1 Hz, H6000b), 4.31
(1H, m, H5000), 4.87 (1H, d, J = 9.9 Hz, H100), 5.03 (1H, t, J = 9.8 Hz,
H4000), 5.11 (1H, dd, J = 8.3 and 9.8 Hz, H2000), 5.43 (1H, t, J = 9.8 Hz,
H3000), 5.76 (1H, d, J = 7.6 Hz, H1000), 6.71 (1H, s, H3), 6.94–8.21
(30H, m, ArH ꢃ 30); FAB-MS (m/z) 1241 (M+H)+. Anal. Calcd for
4.1.9. 5-Benzoyl-6-C-(200,300,400,600-tetra-O-acetyl-b-
D-
glucopyranosyl)-40-O-(2000,3000,4000,6000-tetra-O-acetyl-b-
D-
glucopyranosyl)-7-methoxyflavone (12)
To
a solution of 11 (47.3 mg, 0.0658 mmol) in quinoline
(0.6 mL), Ag2CO3 (27.2 mg, 0.0987 mmol) and acetobromoglucose
per-O-acetylglucosyl bromide (81.2 mg, 0.197 mmol) were added
at 0 °C and the mixture was stirred at room temperature under a
shielded light for 3 h. The reaction was quenched with MeOH
and the mixture was eluted through a short silica-gel column with
AcOEt. The eluate was evaporated to dryness. To the residue, 1 N
HCl (1 mL) was added, then the mixture was extracted three times
with AcOEt. The organic layer was washed with water and brine,
and dried over anhydrous Na2SO4. After evaporation, the residual
solid was purified by silica-gel column chromatography (n-Hex-
ane:AcOEt = 1:1–1:2) to afford 12 (55.2 mg, Y: 80%) as a white
solid.
C
71H68O20: C, 68.70; H, 5.52. Found: C, 68.60; H, 5.35.
4.1.7. 40-Acetoxy-5-benzoyl-6-C-(200,300,400,600-tetra-O-acetyl-b-
D-
glucopyranosyl)-7-methoxyflavone (10)
To a solution of 9 (322 mg, 0.260 mmol) in AcOEt (2.0 mL) and
EtOH (2.0 mL), 10% Pd–C (120 mg) was added and the mixture was
vigorously stirred at room temperature under H2 atmosphere for
3 h. The resultant mixture was filtered with a celite pad followed
by washing with EtOH and the filtrate was evaporated to dryness.
The residual white powder was dissolved in Ac2O (1.5 mL) and pyr-
idine (1.5 mL), and stirred at room temperature for 3 h. To the reac-
tion mixture ice-cold water was added then the mixture was
extracted three times with AcOEt. The organic layer was washed
with water, brine, and dried over anhydrous Na2SO4, and the or-
ganic solvent was evaporated together with toluene to dryness.
The residual solid was purified by silica-gel column chromatogra-
phy (n-Hexane:AcOEt = 2:1–1:1) to afford 10 (194 mg, Y: 98%, 2
steps) as a white solid.
½
a 2D3
ꢂ
ꢀ23 (c 0.515, CHCl3). IR (KBr): 2941, 1755, 1647, 1612,
1508, 1454, 1367, 1232, 1045, 839, 706 cmꢀ1 1H NMR (CDCl3)
.
was observed with a mixture of rotamers, d 1.822, 1.862, 1.954,
1.993, 2.029, 2.050, 2.061, 2.073, 2.077, 2.093 (24H, OAc ꢃ 8),
3.71, 3.77, and 3.91 (1H, m, H500, H5000), 3.99, 4.05, and 4.08 [3H
(3.3:1.0:1.8), s, OCH3], 5.20 and 5.31 (6H, m, H1000, H2000, H300,3000,
H400,4000), 4.17–4.20 (2H, dd, J = 12.3 and 2.3 Hz, H600a), 4.24–4.33
(2H, dd, J = 12.1 and 5.3 Hz, H600b), 4.85 and 5.32 (1H, d,
J = 9.9 Hz, H100), 5.78 and 5.93 [1H (1:2.4), t, J = 9.1 Hz, H200], 6.47
(1H, s, H3), 6.88 and 6.93 [1H (1:2.4), s, H8], 7.58 (2H, m, Ph),
7.68 (1H, m, Ph), 7.09 and 7.79 (each 2H, d, J = 9.1 Hz, p-substituted
ArH), 8.23 and 8.30 [2H (2.4:1), d, J = 7.6 Hz, Ph]; FAB-MS (m/z)
1049 (M+H)+. Anal. Calcd for C51H52O24: C, 58.40; H, 5.00. Found:
C, 58.54; H, 5.01.
½
a 2D2
ꢂ
ꢀ21 (c 0.910, CHCl3). IR (KBr): 3068, 2943, 1764, 1737,
1656, 1612, 1508, 1452, 1369, 912, 847, 706 cmꢀ1. 1H NMR (CDCl3)
was observed with a mixture of rotamers, d 1.82, 1.87, 1.95, 1.99,
2.02, 2.03, 2.06, 2.09 (12H, OAc ꢃ 4), 2.34 (3H, s, ArOAc), 3.64,
3.70, 3.77 (1H, m, H500), 3.98, 4.05, 4.08 [3H (1.8:1.0:3.3), s,
OCH3], 3.76 and 4.17 [1H (1:2.3), br d, J = 12.1 Hz, H600a], 3.89
and 4.26 [1H (1;2.3), dd, J = 12.1 and 4.5 Hz, H600b], 4.77 and 5.17
[1H (1:2.3), m, H400], 4.86 and 5.15 [1H (1:2.3), d, J = 9.9 Hz, H100],
5.19 and 5.28 [1H (1:2.3), m, H300], 5.78 and 5.93 [1H (1:2.3), t,
H200] 6.51 [1H, s, H3], 6.88 and 6.94 [1H (1:2.4), s, H8], 7.24 and
7.85 (each 2H, d, J = 8.3 and 9.1 Hz, p-substituted ArH), 7.57 (2H,
m, Ph), 7.64–7.70 (1H, m, Ph), 8.23 and 8.31 [1H (2.3:1), d,
J = 7.6 Hz, Ph]; FAB-MS (m/z) 761 (M+H)+. Anal. Calcd for
4.1.10. Flavocommelin (1)
To a solution of 12 (24.0 mg, 0.0229 mmol) in MeOH, 28%
NaOMe methanolic solution (ca. 50 mg) was added and the mix-
ture was stirred at room temperature for 1 h. The reaction mixture
was neutralized with DowexÒ 50Wx8 (H+), filtered and washed
with MeOH, and evaporated to dryness. The residual solid was
recrystallized from H2O and CH3CN to afford 1 (11.7 mg, Y: 84%)
as a white solid.
C
39H36O16: C, 61.58; H, 4.77. Found: C, 61.18; H, 4.64.
4.1.8. 5-Benzoyl-40-hydroxy-6-C-(200,300,400,600-tetra-O-acetyl-b-
glucopyranosyl)-7-methoxyflavone (11)
D-
Mp 209–210 °C (natural: 209–210 °C);7
½
a 2D1
ꢂ
ꢀ69 (c 0.33, H2O)
[natural: ½a 2D4
ꢂ
ꢀ57.7 (c 0.3, H2O)];7 IR (KBr): 3400, 2923, 2889,
To a solution of 5 (55.6 mg, 0.0730 mmol) in CH3CN (1.0 mL),
TMG (23.0 mL, 0.183 mmol) was added dropwise at room temper-
ature and the mixture was stirred for 3 h. To the reaction mixture,
a saturated NH4Cl aqueous solution (2.0 mL) was added, then the
solution was extracted three times with AcOEt. The organic layer
was washed with water and brine, and dried over anhydrous
Na2SO4, and evaporated to dryness. The residual solid was purified
by silica-gel column chromatography (CHCl3:MeOH = 30:1) to
afford 11 (42.0 mg, Y: 80%) as a pale-yellow solid.
1655, 1608, 1508, 1491, 1448, 1350, 1244, 1203, 1074, 841,
659 cmꢀ1 1H NMR (DMSO-d6) was observed with a mixture of
.
rotamers, d 3.15–3.12 (1H, m), 3.13–3.22 (3H, m), 3.27–3.34 (2H,
m), 3.35–3.52 (3H, m), 3.68–3.72 (2H, m), 3.88 and 3.91 (3H, s,
OCH3), 4.00 and 4.18 (each 0.5H, m), 4.48 (1H, m), 4.60 (1H, t,
J = 9.8 and 10.6 Hz), 4.63–4.68 (2H, m), 4.87 (1H, d, J = 4.5 Hz,
OH), 4.90 (1H, m), 5.04 (1H, d, J = 6.8 Hz, H1000), 5.11 (1H, d,
J = 4.6 Hz, OH), 5.16 (1H, d, J = 4.6 Hz, OH), 5.43 (1H, d, J = 4.5 Hz,
OH), 3.88 and 6.90 (each 0.5H, s, H3), 6.97 and 6.99 (each 0.5H,
H8), 7.21 and 8.10 (each 2H, d, J = 9.1 and 8.3 Hz, p-substituted
ArH), 13.41 and 13.43 (each 0.5H, s, OH); FAB-MS (m/z) 609
(M+H)+. HRMS (ESI+) calcd for C28H32NaO15 631.16389, found
631.16364.
½
a 2D3
ꢂ
ꢀ21 (c 0.585, CHCl3). IR (KBr): 3442, 2941, 1751, 1631,
1608, 1452, 1352, 1244, 1047, 837, 704 cmꢀ1 1H NMR (CDCl3)
.
was observed with a mixture of rotamers, d 1.941, 1.958, 2.010,
2.036, 2.077, 2.087, 2.094 (12H, each s, OAc ꢃ 4), 3.73 and 3.79
[1H (1:2.4), m, H500], 3.78 and 4.19 [1H (1:2.4), br d, J = 10.6 Hz,
H600a], 3.99, 4.03, and 4.09 [3H (1.8:1.0:3.3), s, OCH3], 4.00 and
4.25 [1H (1:2.4), dd, J = 4.6 and 12.1 Hz, H600b], 4.74 and 5.18 [1H
(1:2.4), t, J = 9.8 Hz, H400], 4.86 and 5.16 [1H (2.4:1), d, J = 9.9 Hz,
H100], 5.20 and 5.21 [1H (2.4:1), t, J = 9.9 Hz, H300], 5.78 and 5.96
Acknowledgement
The authors are grateful to Professor Bunpei Hatano for his
measurement of HRMS.

K. Misawa et al. / Carbohydrate Research 374 (2013) 8–13
13
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2013.
03.016.
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