Total synthesis of apigenin 7,4′-di-O-β-glucopyranoside, a component of blue flower pigment of Salvia patens, and seven chiral analogues

Article abstract of DOI:10.1016/j.tet.2004.01.001

We have succeeded in the first total synthesis of apigenin 7,4′-di-O-β-D-glucopyranoside (1a), a component of blue pigment, protodelphin, from naringenin (2). Glycosylation of 2 according to Koenigs-Knorr reaction provided a monoglucoside 4a in 80% yield, and this was followed by DDQ oxidation to give apigenin 7-O-glucoside (12a). Further glycosylation of 4′-OH of 12a with 2,3,4,6-tetra-O-acetyl-α-D- glucopyranosyl fluoride (5a) was achieved using a Lewis acid-and-base promotion system (BF₃·Et₂O, 2,6-di-tert-butyl-4- methylpyridine, and 1,1,3,3-tetramethylguanidine) in 70% yield, and subsequent deprotection produced 1a. Synthesis of three other chiral isomers of 1a, with replacement of D-glucose at 7 and/or 4′-OH by L-glucose (1b-d), and four chiral isomers of apigenin 7-O-β-glucosides (6a,b) and 4′-O-β- glucosides (7a,b) also proved possible.

Full text of DOI:10.1016/j.tet.2004.01.001

Tetrahedron 60 (2004) 2025–2034
Total synthesis of apigenin 7,40-di-O-b-glucopyranoside,
a component of blue flower pigment of Salvia patens,
and seven chiral analogues
Kin-ichi Oyamaa and Tadao Kondob
,
*
aChemical Instrument Center, Nagoya University, Chikusa, Nagoya 464-8601, Japan
bGraduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Received 8 November 2003; revised 27 December 2003; accepted 6 January 2004
Abstract—We have succeeded in the first total synthesis of apigenin 7,40-di-O-b-D-glucopyranoside (1a), a component of blue pigment,
protodelphin, from naringenin (2). Glycosylation of 2 according to Koenigs–Knorr reaction provided a monoglucoside 4a in 80% yield, and
this was followed by DDQ oxidation to give apigenin 7-O-glucoside (12a). Further glycosylation of 40-OH of 12a with 2,3,4,6-tetra-O-
acetyl-a-D-glucopyranosyl fluoride (5a) was achieved using a Lewis acid-and-base promotion system (BF3·Et2O, 2,6-di-tert-butyl-4-
methylpyridine, and 1,1,3,3-tetramethylguanidine) in 70% yield, and subsequent deprotection produced 1a. Synthesis of three other chiral
isomers of 1a, with replacement of D-glucose at 7 and/or 40-OH by L-glucose (1b–d), and four chiral isomers of apigenin 7-O-b-glucosides
(6a,b) and 40-O-b-glucosides (7a,b) also proved possible.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
delphin, a blue pigment from flower of Salvia patens14
which is a metalloanthocyanin, stoichiometric supra-
molecule, composed of six molecules of malonylawobanin
as the anthocyanin, six molecules of 1a as a copigment and
two atoms of Mg2þ (Fig. 1). The components self-assemble
in aqueous solution and become arranged chirally to
develop a beautiful blue color.14b Formation of the
supramolecule was reflected by chiral fitting on the basis
of molecular recognition due to the chirality of the sugar
linked to the chromophores. To establish the role of chirality
of the sugar on the apigenin as a co-pigment, synthesis of
chiral analogues bearing D- or L-glucose is necessary
(Scheme 1). For this purpose regioselective stepwise
glycosylation of the two hydoxyl groups of the flavonoid
Flavonoid glycosides are widely distributed in the plant
kingdom1 and show a wide range of biological activities,1,2
as antioxidants,3 hepatoprotectants,4 protecting against
UV-light,5 and acting as feeding6 and ovipositional7
stimulants for insects. To generate useful materials, many
attempts of glycosylation of phenolic hydroxyl groups of
flavonoids have been performed since 1938.8–12 However,
most glycosylations were limited to the monoglycoside at
the 7-OH position,10 while only two 0methods of glycosyl-
ation of 40-OH of apigenin to the 4 -O-glycoside, giving
unsatisfactory yields by the Koenigs–Knorr11a and phase-
transfer-catalyzed systems,12 have been reported. It is
thought that the nucleophilicity of the phenolic hydroxyl
group at 7-OH is much higher than that at other positions in
flavonoids. Actually, a glycosylation of flavanone using
excess sugar halide and silver salt gave only flavanone
7-mono-O-glycosides in good yield, and not the poly-
glycoside (vide infra).
Some flavone diglycosides are involved in flower-color
development as co-pigments.13,14 Apigenin 7,40-di-O-b-D-
glucopyranoside (1a), one of the components of proto-
Keywords: Glycosylation of phenol; Apigenin 7,40-di-O-glucoside;
Flavone; Antipode; L-Glucose; 2,6-Di-tert-butyl-4-methylpyridine; Lewis
acid-and-base promotion.
Corresponding author. Tel.: þ81-52-789-4138; fax: þ81-52-789-4141;
Scheme 1. Structure of apigenin 7,40-di-O-D-b-glucopyranoside (1a) and
its analogues.
*
e-mail address: kondot@agr.nagoya-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.001

2026
K. Oyama, T. Kondo / Tetrahedron 60 (2004) 2025–2034
Figure 1. The gross structure and the structure of components of protodelphin.
needs to be performed, requiring a new glycosylation
methodology for0 40-OH. We have achieved efficient
glycosylation of 4 -OH using acetylglucosyl fluoride 5a by
promotion with BF3·Et2O as a Lewis acid and 2,6-di-tert-
butyl-4-methylpyridine (DTBMP) as a Lewis base in the
presence of 1,1,3,3-tetramethylguanidine (TMG), to suc-
ceed in total synthesis of the natural occurring apigenin 7,40-
di-O-b-D-glucoside (1a) and a number of chiral analogues
(1b–d, 6a,b, 7a,b).14b
ation with efficient glycosylation of phenolic hydroxyl
groups by promotion with a Lewis acid-and-base
combination.
We examined glycosylation of (^) naringenin (2) with
acetobromoglucose 3a in the presence of Ag2CO3 in
quinoline under Koenigs–Knorr condition9a,11b directly to
obtain naringenin 7-O-b-D-glucoside (4a), which is a 1:1
diastereo-mixture and has a J1,2¼7.8 Hz. As a result of
optimization, 1.5 equiv. of 3a relative to 2 gave 4a in 80%
yield. However, in spite of using 2.2 equiv. of 3a, only 4a
was detected, but no diglucoside predicted by the previous
report11b (Table 1). This direct glycosylation of 2 is
exclusively regioselective at 7-OH and the effort to
synthesize the diglucoside by a Koenigs–Knorr reaction
was not fruitful.
2. Results and discussion
2.1. Synthesis of apigenin 7,40-di-O-b-D-glucopyranoside
(1a) and three non-naturally occurring apigenin 7,40-di-
O-b-glucopyranosides (1b–d)
Our strategy for synthesis of apigenin of 7,40-di-O-b-
glucoside was high yield with short steps,0 to prepare four
chiral isomers, apigenin 7,40-D,D- (1a), 7,4 -D,L- (1b), 7,40-
L,D- (1c) and 7,40-L,L-di-b-glucopyranoside (1d). The first
key reaction is transformation of naringenin to the apigenin
derivative; the second, regioselective stepwise-glycosyl-
To examine 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) oxidation of naringenin to apigenin,15 2 was
protected with 1 equiv. of t-butyldimethylsilyl chloride
(TBDMSCl) in the presence of imidazole in DMF to give
the 7-O-TBDMS 8 and 7,40-di-O-TBDMS 9 in 53 and 7%
yields, respectively (Scheme 4). Thus, the above results
Table 1. Regioselective glycosylation of naringenin (2) to the 7-O-b-D-glucoside 4a by Koenigs–Knorr method
Entry
3a (equiv.)
Ag2CO3 (equiv.)
Yield (%)
1
2
3
1
1
48
80
80
1.5
2.2
1.5
2.2

K. Oyama, T. Kondo / Tetrahedron 60 (2004) 2025–2034
2027
was then applied, but no diglucoside was produced,
indicating the nucleophilicity of the 40-OH of apigenin to
be very low so that the phenolic OH requires activation with
a promoter for glycosylation.
Recently, we established highly efficient b-glycosylation of
a phenoic hydroxyl group with acetylglucosyl fluoride 5a,
using a combination of BF3·Et2O and a hindered Lewis
base, DTBMP.17 In this reaction, activation of 5a with
BF3·Et2O and generation of a phenolate from a less reactive
phenolic OH by using DTBMP occurs simultaneously, and
consequently the phenolic OH can be efficiently glycosyl-
ated. The reaction is influenced by the solvent polarity, and
CH2Cl2 gave the best results.17 For glycosyation of 12a our
modified methodology was applied because 12a was hardly
soluble in CH2Cl2, toluene, or CH3CN. Surprisingly,
addition of TMG allowed 12a to go into solution in a non-
polar solvent. TMG might play a role as a hydrogen bonding
blocker because the lack of solubility of 12a is conceivably
due to strong hydrogen bonding among flavones.
Glycosylation of 40-OH of 12a by a combination of
BF3·Et2O (4 equiv.) and DTBMP (4 equiv.)/TMG
(1 equiv.) in CH2Cl2 gave the desired di-glucoside 13a in
30% yield, the anomeric configuration being almost b with
only trace amounts of the a-isomer (Table 2, entry 3). On
screening of several solvents, less polar gave the best
results. Though PhCl could not dissolve 12a, a mixed
solvent system of PhCl/CH2Cl2 improved the glycosylation
to give a 41% yield (Table 2, entry 4). When a mole ratio of
the donor sugar 5a to 12a was changed from 1:1 to 2:1, the
yield increased to 70% (Table 2, entry 5), but the higher
ratio became plateau of the yield. Finally, deprotection of
13a with NaOCH3 afforded apigenin 7,40-di-O-b-D-gluco-
side (1a) identical to the natural one18 in 92% yield
(Scheme 2). We thus succeeded in development of the
effective short-step synthesis of apigenin 7,40-di-O-b-D-
glucoside (1a). The new glycosylation using 12a and
2 equiv. of 5a (twice to 12a) in the presence of BF3·Et2O,
DTBMP and TMG in CH2Cl2/PhCl (1/6 v/v) allowed a
route to be opened for synthesis of the following chiral
analogues having D- and/or L-glucose. Three chiral isomers,
three non-natural apigenin 7,40-di-O-b-glucopyranosides
(1b–d) were synthesized by alternative replacement of D-
and/or L-glucose (Scheme 2).
Scheme 2. Synthesis of apigenin 7,40-di-O-D-b-glucopyranosides (1a–d).
indicated the reactivity of phenolic hydroxyl groups of
naringenin to be in the order of 7-OH@40-OH@5-OH. 8 was
treated with DDQ to give the 7-O-T0BDMS 10 in 81% yield,
but from 9 the corresponding 7,4 -di-O-TBDMS 11 was
obtained in a lower 44% yield (Table 3, entries 1 and 2).
40-OH free naringenin 8 was readily dehydrogenated, but the
di-TBDMS 9 was very resistant, suggesting that the
oxidation of the benzyl proton at C-2 with DDQ favors
40-OH against protected one. Thus, transformation of 4a to
the corresponding0 apigenin 7-O-glucoside (12a), before
glycosylation of 4 -OH should be carried out to avoid an
unsatisfaction yield and stereo-complications due to
glycosylated products. When 4a was oxidized with
2 equiv. of DDQ in dioxane at 110 8C, a single compound,
12a was generated in 83% yield (Scheme 2). For
glycosylation of 40-OH of 12a, a Koenigs–Knorr reac-
tion9a,11b or Yamaguchi’s method16 using acetylglucosyl
fluoride 5a, BF3·Et2O and TMG (Table 2, entries 1 and 2)
2.2. Synthesis of apigenin 7-O-b-D-glucopyranoside (6a)
and apigenin 7-O-b-L-glucopyranoside (6b)
Table 2. Glycosylation of 40-OH of 12a under various conditions
Apigenin 7-O-b-D-glucopyranoside (6a) was obtained by
deprotection of 12a by treatment with NaOCH3 quanti-
tatively (Scheme 3). Also, 6b, the antipode of 6a, was
synthesized via the naringenin 7-O-L-glucoside (4b),
derived from 2 and L-acetobromoglucose 3b by Koenigs–
Entry 5a (equiv.)
Base (equiv.)
Solvent (v/v)
Yield (%)
1
2
3
4
5
1
1
1
1
2
TMG (4)
TMG (4)
DTBMP/TMG (4/1) CH2Cl2
DTBMP/TMG (4/1) PhCl/CH2Cl2 (6/1)
DTBMP/TMG (4/1) PhCl/CH2Cl2 (6/1)
CH3CN
CH2Cl2
0
0
30
41
70
Scheme 3. Deprotection of 12a,b.

2028
K. Oyama, T. Kondo / Tetrahedron 60 (2004) 2025–2034
Knorr reaction (Scheme 2), according to the same procedure
as that for 6a (Scheme 3).
(Scheme 2 and Table 3). Thus, it was indicated that DDQ
oxidation reactivity from naringenin to apigenin depends on
the number and the position of the free phenolic OH and the
free 40-OH of the flavanone is optimal for this purpose.
8 was oxidized with DDQ followed by glycosylation using
5a in the presence of BF3·Et2O and DTBMP in PhCl to give
the corresponding b-glucoside 16a and the desilylated 17a
in 44 and 28% yields, respectively. During the glycosyla-
tion, desilylation occurred partially. Also, 16a was depro-
tected with TBAF in THF to give 17a in 90% yield. Finally,
deprotection of 17a with NaOCH3 afforded a desired
apigenin 40-O-b-D-diglucoside (7a) in yiel0d 95%
(Scheme 5). By the same procedure, apigenin 4 -O-b-L-
diglucoside (7b) was synthesized (Scheme 5).
Scheme 4. Synthesis of naringenin 40-O-D-b-glucopyranosides (14, 15).
Table 3. Transformation of naringenin to the corresponding apigenin
3. Conclusions
Total synthesis of apigenin 7,40-O-b-D-diglucoside (1a) is
achievable using a combination of our new glycosylation
method and the Koenigs–Knorr reaction. One naturally and
three non-naturally occurring apigenin 7,40-di-O-b-gluco-
sides (1a–d) bearing D-and/or L-glucose could be prepared
using this approach. Furtherm0ore, based on differences in
reactivity between the 7- and 4 -OH of naringenin, apigenin
O-monoglucosides 6a,b and 7a,b were synthesized. The
finding for total synthesis of 1a suggests that many kinds of
mono- or poly-glycosyl-flavonoids could be synthesized in
the same way.
Entry
R
R0
Substrate
Product
Yield (%)
1
2
3
4
TBDMS
TBDMS
TBDMS
H
H
8
9
14
15
10
11
16a
17a
81
44
9
TBDMS
ADG
ADG
25
4. Experimental
4.1. General
Melting points were taken on a Yanagimoto micro-melting
point apparatus and are uncorrected. Optical rotations were
measured on JASCO P-1010-GT polarimeter. IR spectra
were measured on a Perkin–Elmer PARAGON 1000
1
spectrometer. H and 13C NMR spectra were measured on
JEOL JNM-GX 500 spectrometer at 500 and at 125 Hz,
1
respectively. H and 13C chemical shifts are referenced to
the internal deuterated solvent. Elemental analyses were
performed on Perkin Ellmer CHN 2400-2 or YANACO
MT-6 elemental analyser. EI and FAB mass spectra were
obtained using JEOL JMX 700 mass spectrometer. Flash
column chromatography was performed using Merck silica
gel 60 (230–400 mesh ASTM). Thin layer chromatography
was performed on Merck silica gel 60 F254. Solvents were
dried following standard methods. L-glucose was purchased
from Sigma-Aldrich, D-glucose and naringenin from Tokyo
kaei kogyo co., ltd.
Scheme 5. Synthesis of apigenin 40-O-b-D- and L-glucopyranosides (7a,b).
2.3. Synthesis of apigenin 40-O-b-D-glucopyranoside (7a)
and apigenin 40-O-b-L-glucopyranoside (7b)
On the basis of the difference of the reactivity among
phenolic hydroxyl groups of naringenin (2), synthesis of
apigenin 40-O-b-D-glucopyranoside (7a) was performed as
follows: first, regioselective silylation of 7-OH of 2
(Scheme 4); second, DDQ oxidation to 7-O-TBDMS
apigenin (10) (Table 3, entry 1); and finally our glycosyla-
tion using 5a and then deprotection (Scheme 5).
4.1.1. 2,3,4,6-Tetra-O-acetyl-a-L-glucopyranosyl
bromide (3b). According to Lemieux’s method,19 the
bromide 3b was synthesized from L-glucose: mp 87–
88 8C; [a]2D4¼2197.38 (c 1.0, CHCl3); IR (KBr) 1745, 1384,
1229, 1108, 1042 cm21; 1H NMR (CDCl3, 500 MHz) d 2.01
(3H, s), 2.03 (3H, s), 2.07 (3H, s), 2.08 (3H, s), 4.11 (1H, dd,
J¼12.2, 2.0 Hz), 4.28 (1H, ddd, J¼10.0, 4.2, 2.0 Hz), 4.31
(1H, dd, J¼12.2, 4.2 Hz), 4.82 (1H, dd, J¼10.0, 4.2 Hz),
5.14 (1H, t, J¼10.0 Hz), 5.54 (1H, t, J¼10.0 Hz), 6.59 (1H,
The 7-O-TBDMS naringenin (8) was glycosylated by using
a combination of BF3·Et2O and DTBMP in CH2Cl2 to
produce the b-monoglucoside 14 and its de-TBDMS 15 in
71% and 17% yields, respectively (Scheme 4). Treatment of
4a, 14, and 15 with DDQ gave the corresponding apigenin
products 12a (83%), 16a (9%), and 17a (25%), respectively

K. Oyama, T. Kondo / Tetrahedron 60 (2004) 2025–2034
2029
d, J¼4.2 Hz, 1-H); 13C NMR (CDCl3, 125 MHz) d 20.5,
20.6 (£3), 61.0, 67.2, 70.2, 70.6, 72.1, 86.5, 169.4, 169.8
(£2), 170.5; HRMS (FAB) calcd for C14H19O9BrNa
(MþNaþ) 433.0110. Found 433.0111. Anal. calcd for
C14H19O9Br: C, 40.89; H, 4.66. Found: C, 40.78; H, 4.67.
C29H30O14Na (MþNaþ) 625.1533. Found 625.1555. Anal.
calcd for C29H30O14: C, 57.81; H, 5.02. Found: C, 57.81; H,
5.20.
4.1.4. 2,3,4,6-Tetra-O-acetyl-a-L-glucopyranosyl fluor-
ide (5b).20 According to Noyori’s method,21 5b was
synthesized from L-glucose: mp 106–107 8C; [a]2D5289.18
(c 1.0, CHCl3); IR (KBr) 1747, 1380, 1229, 1041,
4.1.2. 7-O-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-
naringenin (4a). A solution of D-glucosyl bromide 3a
(617 mg, 1.5 mmol), Ag2CO3 (414 mg, 1.5 mmol) and 2
(272 mg, 1.0 mmol) in quinoline (7 ml) was stirred for 3 h at
room temperature. After being poured into CH3OH, the
solution was filtered through a short pad of silica gel and
evaporated in vacuo. The residue was dissolved into AcOEt
and washed successively with 1 N HCl and brine, and dried
over anhydrous MgSO4. After evaporation, the resulting
crude product was purified by flash column chromatography
(hexane–AcOEt 1:1) to afford 4a (483 mg, 80%) as a white
foam. The product was an inseparable mixture of dia-
stereomers (1:1); IR (KBr) 3421, 1756, 1644, 1374,
1
923 cm21; H NMR (CDCl3, 500 MHz) d 2.00, (3H, s),
2.01 (3H, s), 2.07 (3H, s), 2.08 (3H, s), 4.12 (1H, dd,
J¼12.3, 2.2 Hz), 4.16 (1H, ddd, J¼10.0, 4.2, 2.2 Hz), 4.26
(1H, dd, J¼12.3, 4.2 Hz), 4.93 (1H, ddd, J¼24.2, 10.0,
2.9 Hz), 5.12 (1H, t, J¼10.0 Hz), 5.47 (1H, t, J¼10.0 Hz),
5.72 (1H, dd, J¼52.8, 2.9 Hz, 1-H); 13C NMR (CDCl3,
125 MHz) d 20.5 (£2), 20.6, 61.2, 67.4, 69.4, 69.8, (d,
J¼4.6 Hz), 70.2 (d, J¼23.8 Hz), 103.7 (d, J¼227.8 Hz),
169.4, 169.9 (£2), 170.5; HRMS (FAB) calcd for
C14H19O9FNa (MþNaþ) 373.0911. Found 373.0913.
Anal. calcd for C14H19O9F: C, 48.00; H, 5.47. Found: C,
48.14; H, 5.48.
1
1227 cm21; H NMR (DMSO-d6, 500 MHz) d 1.95 (4.5H,
s), 1.97 (1.5H, s), 2.00 (6H, s), 2.74 (1H, dd, J¼17.3,
2.5 Hz), 3.35 (0.5H, dd, J¼17.3, 11.8 Hz), 3.38 (0.5H, dd,
J¼17.3, 11.8 Hz), 4.05 (1H, dd, J¼12.2, 2.0 Hz), 4.15 (1H,
dd, J¼12.2, 6.4 Hz), 4.28 (1H, ddd, J¼9.8, 6.4, 2.0 Hz),
4.97 (1H, t, J¼9.8 Hz), 5.05 (1H, dd, J¼9.8, 7.8 Hz), 5.35
(0.5H, t, J¼9.8 Hz), 5.36 (0.5H, t, J¼9.8 Hz), 5.51 (0.5H,
dd, J¼11.8, 2.5 Hz), 5.52 (0.5H, dd, J¼11.8, 2.5 Hz), 5.64
(0.5H, d, J¼7.8 Hz, 1-H), 5.66 (0.5H, d, J¼7.8 Hz, 1-H),
6.10 (1H, d, J¼2.0 Hz), 6.14 (0.5H, d, J¼2.0 Hz), 6.15
(0.5H, d, J¼2.0 Hz), 6.79 (2H, d, J¼8.8 Hz), 7.31 (2H, d,
J¼8.8 Hz), 9.58 (0.5H, s, OH), 9.59 (0.5H, s, OH), 12.02
(0.5H, s, OH) 12.04 (0.5H, s, OH); 13C NMR (MDSO-d6,
125 MHz) d 20.3, 20.4 (£2), 42.1, 42.2, 61.7, 68.1, 70.5,
71.1, 71.9, 78.9 (£2), 95.4, 95.5, 96.1 (£2), 96.5, 103.9 (£2),
115.2, 128.4, 128.5 (£2), 128.6, 157.9 (£2), 162.9, 163.0,
163.8 (£2), 169.1, 169.4, 169.6, 170.0, 197.5 (£2); HRMS
(FAB) calcd for C29H30O14Na (MþNaþ) 625.1533. Found:
625.1548.
4.1.5. 7-O-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-
apigenin (12a). A solution of 4a (90 mg, 0.15 mmol) and
DDQ (68 mg, 0.3 mmol) in 1,4-dioxane (5 ml) was refluxed
for 15 h at 110 8C. The reaction mixture was purified by
flash column chromatography (hexane–AcOEt 1:2) to
afford 12a (75 mg, 83%) as a white solid: mp 207–
208 8C; [a]2D6228.88 (c 0.3, DMSO); IR (KBr) 3431, 1748,
1654, 1603, 1233 cm21; 1H NMR (DMSO-d6, 500 MHz) d
1.97 (3H, s), 2.01 (6H, 2s), 2.02 (3H, s), 4.11 (1H, dd,
J¼12.2, 2.0 Hz), 4.19 (1H, dd, J¼12.2, 5.9 Hz), 4.33 (1H,
ddd, J¼9.8, 5.9, 2.0 Hz), 5.01 (1H, t, J¼9.8 Hz), 5.10 (1H,
dd, J¼9.8, 8.3 Hz), 5.39 (1H, t, J¼9.8 Hz), 5.74 (1H, d,
J¼8.3 Hz, 1-H), 6.43 (1H, d, J¼2.0 Hz), 6.78 (1H, d,
J¼2.0 Hz), 6.87 (1H, s), 6.92 (2H, d, J¼8.8 Hz), 7.94 (2H,
d, J¼8.8 Hz), 10.39 (1H, s, OH); 13C NMR (MDSO-d6,
125 MHz) d 20.2, 20.3, 20.4, 61.6, 67.9, 70.4, 71.1, 71.8,
95.1, 96.4, 99.2, 103.2, 105.9, 116.0, 120.9, 128.6, 156.8,
161.3, 161.4, 161.5, 164.4, 169.0, 169.3, 169.5, 169.9,
182.0; HRMS (FAB) calcd for C29H28O14Na (MþNaþ)
623.1377. Found 623.1391. Anal. calcd for C29H28O14: C,
58.00; H, 4.70. Found: C, 58.01; H, 4.92.
4.1.3. 7-O-(2,3,4,6-Tetra-O-acetyl-b-L-glucopyranosyl)-
naringenin (4b). According to the procedure described
for 4a, 2 (0.545 g, 2.0 mmol) was glycosylated with
L-glucosyl bromide 3b (1.234 g, 3.0 mmol) to afford 4b
(0.975 g, 81%) as a white foam. The product was an
inseparable mixture of diastereomers (1:1); IR (KBr) 3385,
4.1.6. 7-O-(2,3,4,6-Tetra-O-acetyl-b-L-glucopyranosyl)
apigenin (12b). According to the procedure described for
12a, 4b (1.145 g, 1.9 mmol) was treated with DDQ
(863 mg, 3.8 mmol) to afford 12b as a white solid
(0.919 g, 81%): mp 207–208 8C; [a]2D7þ28.78 (c 0.3,
1757, 1644, 1374, 1224 cm21
;
1H NMR (DMSO-d6,
500 MHz) d 1.95 (4.5H, s), 1.96 (1.5H, s), 2.00 (6H, s),
2.73 (1H, dd, J¼17.1, 2.9 Hz), 3.35 (0.5H, dd, J¼17.1,
11.8 Hz), 3.37 (0.5H, dd, J¼17.1, 11.8 Hz), 4.04 (1H, dd,
J¼12.2, 2.5 Hz), 4.15 (1H, dd, J¼12.2, 6.5 Hz), 4.27 (1H,
ddd, J¼9.8, 6.5, 2.5 Hz), 4.97 (1H, t, J¼9.8 Hz), 5.04 (1H,
dd, J¼9.8, 7.8 Hz), 5.34 (0.5H, t, J¼9.8 Hz), 5.35 (0.5H, t,
J¼9.8 Hz), 5.50 (0.5H, dd, J¼11.8, 2.5 Hz), 5.51 (0.5H, dd,
J¼11.8, 2.5 Hz), 5.64 (0.5H, d, J¼7.8 Hz, 1-H), 5.65 (0.5H,
d, J¼7.8 Hz, 1-H), 6.10 (1H, d, J¼2.0 Hz), 6.14 (0.5H, d,
J¼2.0 Hz), 6.15 (0.5H, d, J¼2.0 Hz), 6.78 (2H, d,
J¼8.8 Hz), 7.31 (2H, d, J¼8.8 Hz), 9.57 (0.5H, s, OH),
9.58 (0.5H, s, OH), 12.01 (0.5H, s, OH), 12.03 (0.5H, s,
OH); 13C NMR (MDSO-d6, 125 MHz) d 20.2, 20.3 (£2),
42.0, 42.1, 61.6, 67.9, 70.4, 71.0, 71.8, 78.7, 78.8, 95.3,
95.4, 96.0 (£2), 96.4, 103.7, 103.8, 115.1, 128.3, 128.4 (£2),
128.5, 157.8 (£2), 162.8, 163.0, 163.6, 163.7, 169.0,
169.3, 169.5, 169.8, 197.4 (£2); HRMS (FAB) calcd for
DMSO); IR (KBr) 3422, 1748, 1659, 1607, 1246 cm21
;
1H NMR (DMSO-d6, 500 MHz) d 1.97 (3H, s), 2.01 (6H,
2s), 2.02 (3H, s), 4.11 (1H, dd, J¼12.2, 2.0 Hz), 4.19 (1H,
dd, J¼12.2, 5.9 Hz), 4.34 (1H, ddd, J¼9.6, 5.9, 2.0 Hz),
5.01 (1H, t, J¼9.6 Hz), 5.10 (1H, dd, J¼9.6, 8.3 Hz), 5.39
(1H, t, J¼9.6 Hz), 5.74 (1H, d, J¼8.3 Hz, 1-H), 6.44 (1H, d,
J¼2.0 Hz), 6.79 (1H, d, J¼2.0 Hz), 6.89 (1H, s), 6.93 (2H,
d, J¼8.8 Hz), 7.95 (2H, d, J¼8.8 Hz), 10.40 (1H, s, OH);
13C NMR (MDSO-d6, 125 MHz) d 20.2, 20.3, 20.4, 61.6,
68.0, 70.4, 71.1, 71.8, 95.1, 96.4, 99.2, 103.2, 105.9, 116.0,
120.9, 128.6, 156.8, 161.3, 161.4, 161.5, 164.4, 169.0,
169.3, 169.5, 169.9, 182.0; HRMS (FAB) calcd for
C29H30O14Na (MþNaþ) 623.1377. Found 623.1400. Anal.
calcd for C29H28O14: C, 58.00; H, 4.70. Found: C, 58.02; H,
4.94.

2030
K. Oyama, T. Kondo / Tetrahedron 60 (2004) 2025–2034
4.1.7. 7,40-Di-O-(2,3,4,6-tetra-O-acetyl-b-D-glucopyrano-
syl)apigenin (13a).12 To a solution of D-glucosyl fluoride
5a (105 mg, 0.3 mmol), 12a (90 mg, 0.15 mmol) and TMG
(17 mg, 0.15 mmol) and DTBMP (123 mg, 0.6 mmol) in
CH2Cl2 (0.5 ml) and chlorobenzene (3 ml) was added
BF3·Et2O (80 ml, 0.6 mmol) at room temperature. The
solution was stirred for 1 h at room temperature. The
reaction mixture was quenched by addition of saturated
aqueous NaHCO3 and extracted with AcOEt. The combined
extracts were dried over anhydrous MgSO4 and evaporated
in vacuo, and purified by thin layer chromatography
(AcOE–CHCl3 1:4 and then hexane–AcOEt 1:1) to afford
13a as a white foam (98 mg, 70%); [a]2D7243.18 (c 0.1,
CHCl3); IR (KBr) 1752, 1656, 1615, 1237, 1042 cm21; 1H
NMR (DMSO-d6, 500 MHz) d 1.97 (6H, s), 2.02 (18H, s),
4.08 (1H, dd, J¼12.7, 2.5 Hz), 4.11 (1H, dd, J¼12.7,
2.5 Hz), 4.18 (1H, dd, J¼12.7, 5.9 Hz), 4.19 (1H, dd,
J¼12.7, 5.9 Hz), 4.32 (2H, m), 5.01 (1H, t, J¼9.8 Hz), 5.02
(1H, t, J¼9.8 Hz), 5.10 (2H, dd, J¼9.8, 7.8 Hz), 5.39 (1H, t,
J¼9.8 Hz), 5.41 (1H, t, J¼9.8 Hz), 5.75 (1H, d, J¼7.8 Hz,
1-H), 5.76 (1H, d, J¼7.8 Hz, 1-H), 6.46 (1H, d, J¼2.2 Hz),
6.82 (1H, d, J¼2.2 Hz), 7.03 (1H, s), 7.17 (2H, d,
J¼8.8 Hz), 8.09 (2H, d, J¼8.8 Hz), 12.90 (1H, s, OH);
13C NMR (MDSO-d6, 125 MHz) d 20.4, 20.5 (£2), 20.6
(£2), 61.7, 61.8, 68.1, 70.7, 70.8, 71.2, 71.4, 72.1 (£2), 95.5,
96.6, 96.7, 99.5, 104.8, 106.2, 116.9, 125.0, 128.7, 157.1,
159.3, 161.5, 161.8, 163.8, 169.4 (£2), 169.6, 169.7, 169.9,
170.3 (£2), 182.3; HRMS (FAB) calcd for C43H47O23
(MþHþ) 931.2508. Found 931.2499. Anal. calcd for
C43H46O23: C, 55.48; H, 4.98. Found: C, 55.47; H, 5.07.
4.11 (1H, dd, J¼12.7, 2.4 Hz), 4.19 (1H, dd, J¼12.2,
6.4 Hz), 4.20 (1H, dd, J¼12.7, 5.9 Hz), 4.33 (2H, m), 5.01
(1H, t, J¼9.8 Hz), 5.02 (1H, t, J¼9.8 Hz), 5.10 (2H, dd,
J¼9.8, 7.8 Hz), 5.39 (1H, t, J¼9.8 Hz), 5.42 (1H, t,
J¼9.8 Hz), 5.75 (1H, d, J¼7.8 Hz), 5.76 (1H, d, J¼
7.8 Hz), 6.47 (1H, d, J¼2.0 Hz), 6.83 (1H, d, J¼2.0 Hz),
7.03 (1H, s), 7.18 (2H, d, J¼8.8 Hz), 8.09 (2H, d,
J¼8.8 Hz), 12.91 (1H, s, OH); 13C NMR (MDSO-d6,
125 MHz) d 20.2, 20.3 (£3), 20.4, 61.6 (£2), 67.9, 70.4,
70.6, 71.0, 71.1, 71.8, 71.9, 95.3, 96.4, 99.3, 104.6, 106.0,
116.6, 124.8, 128.5, 156.9, 159.1, 161.3, 161.6, 163.4, 169.0
(£2), 169.2, 169.3, 169.5 (£2), 169.9 (£2), 182.1; HRMS
(FAB) calcd for C43H47O23 (MþHþ) 931.2508. Found
931.2504. Anal. calcd for C43H46O23: C, 55.48; H, 4.98.
Found: C, 55.48; H, 5.20.
4.1.10. 7,40-Di-O-(2,3,4,6-tetra-O-acetyl-b-L-glucopyra-
nosyl)apigenin (13d). According to the procedure
described for 13a, 12b (90 mg, 0.15 mmol) was glycosyl-
ated with 5b (105 mg, 0.3 mmol) to afford 13d as a white
foam (101 mg, 72%); [a]D26þ43.08 (c 0.1, CHCl3); IR (KBr)
1
1755, 1656, 1611, 1234, 1042 cm21; H NMR (DMSO-d6,
500 MHz) d 1.97 (6H, s), 2.01 (6H, s), 2.02 (12H, s), 4.08
(1H, dd, J¼12.7, 2.5 Hz), 4.12 (1H, dd, J¼12.7, 2.5 Hz),
4.19 (1H, dd, J¼12.7, 5.9 Hz), 4.20 (1H, dd, J¼12.7,
5.9 Hz), 4.32 (2H, m), 5.01 (1H, t, J¼9.8 Hz), 5.02 (1H, t,
J¼9.8 Hz), 5.10 (2H, dd, J¼9.8, 8.3 Hz), 5.39 (1H, t,
J¼9.8 Hz), 5.42 (1H, t, J¼9.8 Hz), 5.75 (1H, d, J¼7.8 Hz),
5.76 (2H, d, J¼7.8 Hz), 6.47 (1H, d, J¼2.0 Hz), 6.83 (1H, d,
J¼2.0 Hz), 7.03 (1H, s), 7.18 (2H, d, J¼8.8 Hz), 8.09 (2H,
d, J¼8.8 Hz), 12.91 (1H, s, OH); 13C NMR (MDSO-d6,
125 MHz) d 20.2, 20.3 (£3), 20.4, 61.5, 61.6, 67.9, 70.4,
70,6, 71.0, 71.1, 71.8 (£2), 95.3, 96.4, 99.3, 104.6, 106.0,
116.6, 124.8, 128.5, 156.9, 159.1, 161.3, 161.6, 163.4, 169.0
(£2), 169.2, 169.3, 169.5 (£2), 169.9 (£2), 182.1; HRMS
(FAB) calcd for C43H47O23 (MþHþ) 931.2508. Found
931.2529. Anal. calcd for C43H46O23: C, 55.48; H, 4.98.
Found: C, 55.49; H, 5.07.
4.1.8. 7-O-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-
40-O-(2,3,4,6-tetra-O-acetyl-b-L-glucopyranosyl)-
apigenin (13b). According to the procedure described
for 13a, 12a (120 mg, 0.2 mmol) was glycosylated with
L-glucosyl fluoride 5b (140 mg, 0.4 mmol) to afford 13b as
a white foam (123 mg, 66%); [a]2D5225.58 (c 0.1, CHCl3);
1
IR (KBr) 1757, 1657, 1619, 1233, 1039 cm21; H NMR
(DMSO-d6, 500 MHz) d 1.97 (6H, s), 2.02 (18H, s), 4.08
(1H, dd, J¼12.2, 2.2 Hz), 4.11 (1H, dd, J¼12.7, 2.4 Hz),
4.18 (1H, dd, J¼12.2, 6.4 Hz), 4.19 (1H, dd, J¼12.7,
5.9 Hz), 4.33 (2H, m), 5.01 (1H, t, J¼9.8 Hz), 5.02 (1H, t,
J¼9.8 Hz), 5.10 (2H, dd, J¼9.8, 7.8 Hz), 5.39 (1H, t,
J¼9.8 Hz), 5.42 (1H, t, J¼9.8 Hz), 5.75 (1H, d, J¼7.8 Hz,
1-H), 5.76 (1H, d, J¼7.8 Hz, 1-H), 6.47 (1H, d, J¼2.0 Hz),
6.83 (1H, d, J¼2.0 Hz), 7.04 (1H, s), 7.17 (2H, d,
J¼8.8 Hz), 8.10 (2H, d, J¼8.8 Hz), 12.91 (1H, s, OH);
13C NMR (MDSO-d6, 125 MHz) d 20.2, 20.3, 20.4 (£2),
20.5, 61.6 (£2), 67.9, 70.4, 70.6, 71.0, 71.1, 71.8, 71.9, 95.3,
96.4, 99.2, 104.6, 106.0, 116.6, 124.8, 128.5, 156.9, 159.1,
161.3, 161.6, 163.5, 169.0, 169.1, 169.3 (£2), 169.5, 169.6,
169.9 (£2), 182.1; HRMS (FAB) calcd for C43H47O23
(MþHþ) 931.2508. Found 931.2501. Anal. calcd for
C43H46O23: C, 55.48; H, 4.98. Found: C, 55.49; H, 5.07.
4.1.11. 7,40-Di-O-(b-D-glucopyranosyl)apigenin (1a). To
a solution of 13a (102 mg, 0.11 mmol) in a mixture of
CH3OH (2 ml) and CHCl3 (1 ml) was added NaOCH3
(30 mg) at room temperature. After stirring for 2 h, the
reaction mixture was neutralized with Dowex 50W-
8X(Hþ), filtered, and evaporated in vacuo. The residue
was recrystallized from EtOH to afford 1a as a white
solid (60 mg, 92%): mp 180–181 8C; [a]2D8255.58 (c 0.1,
DMSO); IR (KBr) 3422, 1656, 1609, 1242, 1075 cm21; 1H
NMR (DMSO-d6, 500 MHz) d 3.17 (2H, m), 3.40 (1H, m),
3.46 (5H, m), 3.70 (4H, m), 5.03 (1H, d, J¼7.3 Hz, 1-H),
5.06 (1H, d, J¼7.8 Hz, 1-H), 6.45 (1H, d, J¼2.0 Hz), 6.86
(1H, d, J¼2.0 Hz), 6.98 (1H, s), 7.20 (2H, d, J¼8.8 Hz),
8.06 (2H, d, J¼8.8 Hz), 12.88 (1H, s, OH). Signals of four
protons were overlapped with the signals of H2O; 13C NMR
(DMSO-d6, 125 MHz) d 60.6 (£2), 69.5, 69.6, 73.0, 73.1,
76.4, 76.5, 77.1, 94.9, 99.6, 99.8 (£2), 104.0, 105.4, 116.6,
123.8, 128.2, 157.0, 160.4, 161.1, 163.0, 163.6, 182.0;
HRMS (FAB) calcd for C27H31O15 (MþHþ) 595.1663.
Found 595.1659.
4.1.9. 7-O-(2,3,4,6-Tetra-O-acetyl-b-L-glucopyranosyl)-
40-O-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-
apigenin (13c). According to the procedure described for
13a, 12a (90 mg, 0.15 mmol) was glycosylated with 5a
(105 mg, 0.3 mmol) to afford 13c as a white foam (95 mg,
68%); [a]2D5þ25.88 (c 0.1, CHCl3); IR (KBr) 1756, 1657,
1618, 1233, 1039 cm21; 1H NMR (DMSO-d6, 500 MHz) d
1.97 (6H, s), 2.02 (18H, s), 4.08 (1H, dd, J¼12.2, 2.2 Hz),
4.1.12. 7-O-(b-L-Glucopyranosyl)-40-O-(b-D-glucopyra-
nosyl)apigenin (1b). According to the procedure described
for 1a, 13b (93 mg, 0.1 mmol) was treated with NaOCH3

K. Oyama, T. Kondo / Tetrahedron 60 (2004) 2025–2034
2031
and recrystallized to afford 1b as a white solid (54 mg,
92%): mp 190–191 8C; [a]2D6211.98 (c 0.3, DMSO); IR
12.95 (1H, s, OH); 13C NMR (MDSO-d6, 125 MHz) d 60.6,
69.5, 73.1, 76.4, 77.1, 94.8, 99.5, 99.9, 102.9, 105.3, 116.0,
120.7, 128.5, 156.9, 161.1, 162.9, 164.3, 181.9; HRMS
(FAB) calcd for C21H21O10 (MþHþ) 433.1135. Found
433.1133.
(KBr) 3393, 1660, 1609, 1242, 1075 cm21 1H NMR
;
(DMSO-d6, 500 MHz) d 3.17 (2H, m), 3.40 (1H, m), 3.46
(5H, m), 3.70 (4H, m), 5.03 (1H, d, J¼7.3 Hz, 1-H), 5.06
(1H, d, J¼7.8 Hz, 1-H), 6.45 (1H, d, J¼2.0 Hz), 6.86 (1H, d,
J¼2.0 Hz), 6.97 (1H, s), 7.20 (2H, d, J¼8.8), 8.06 (2H, d,
J¼8.8 Hz), 12.88 (1H, s, OH). Signals of four protons were
overlapped with the signals of H2O; 13C NMR (MDSO-d6,
125 MHz) d 60.6 (£2), 69.5, 69.6, 73.1 (£2), 76.4, 76.5,
77.1, 94.9, 99.6, 99.8, 99.9, 104.1, 105.4, 116.6, 123.8,
128.2, 157.0, 160.4, 161.1, 163.0, 163.6, 182.0; HRMS
(FAB) calcd for C27H31O15 (MþHþ) 595.1663. Found
595.1664.
4.1.16. 7-O-(b-L-Glucopyranosyl)apigenin (6b). Accord-
ing to the procedure described for 6a, 12b (30 mg,
0.05 mmol) was treated with NaOCH3 and recrystallized
to afford 6b (20 mg, 93%) as a white solid: mp 238–239 8C;
[a]2D5243.68 (c 0.2, DMSO); IR (KBr) 3443, 1655, 1612,
1
1177, 1085 cm21; H NMR (DMSO-d6, 500 MHz) d 3.1–
3.2 (1H, m), 3.4–3.5 (2H, m), 3.6–3.7 (1H, m), 5.05 (1H, d,
J¼7.3 Hz, 1-H), 6.43 (1H, d, J¼2.0 Hz), 6.82 (1H, d,
J¼2.0 Hz), 6.85 (1H, s), 6.93 (2H, d, J¼8.8 Hz), 7.95 (2H,
d, J¼8.8 Hz), 10.37 (1H, s, OH), 12.95 (1H, s, OH); 13C
NMR (MDSO-d6, 125 MHz) d 60.6, 69.5, 73.1, 76.4, 77.1,
94.8, 99.5, 99.9, 103.1, 105.3, 115.9, 121.0, 128.5, 156.9,
161.1, 161.3, 162.9, 164.2, 181.9; HRMS (FAB) calcd for
C21H21O10 (MþNaþ) 433.1135. Found 433.1115.
4.1.13. 7-O-(b-D-Glucopyranosyl)-40-O-(b-L-glucopyra-
nosyl)apigenin (1c). According to the procedure described
for 1a, 13c (56 mg, 0.06 mmol) was treated with NaOCH3
and recrystallized to afford 1c as a white solid (34 mg,
94%): mp 190–191 8C; [a]2D6þ11.98 (c 0.3, DMSO); IR
(KBr) 3490, 1666, 1609, 1241, 1075 cm21 1H NMR
;
(DMSO-d6, 500 MHz) d 3.17 (2H, m), 3.40 (1H, m), 3.46
(5H, m), 3.70 (4H, m), 5.03 (1H, d, J¼7.3 Hz, 1-H), 5.06
(1H, d, J¼7.8 Hz, 1-H), 6.45 (1H, d, J¼2.0 Hz), 6.86 (1H, d,
J¼2.0 Hz), 6.97 (1H, s), 7.20 (2H, d, J¼8.8), 8.06 (2H, d,
J¼8.8 Hz), 12.88 (1H, s, OH). Signals of four protons were
overlapped with the signals of H2O; 13C NMR (MDSO-d6,
125 MHz) d 60.6 (£2), 69.5, 69.6, 73.0, 73.1, 76.4, 76.5,
77.1, 94.9, 99.6, 99.8, 99.9, 104.1, 105.4, 116.6, 123.8,
128.2, 157.0, 160.4, 161.1, 163.0, 163.6, 182.0; HRMS
(FAB) calcd for C27H31O15 (MþHþ) 595.1663. Found
595.1668.
4.1.17. 7-O-tert-Butyldimethylsilylnaringenin (8) and
7,40-di-O-(tert-butyldimethylsilyl) naringenin (9). To a
solution of 2 (1.361 g, 5.0 mmol) and imidazole (0.681 g,
10.0 mmol) in DMF (10 ml) was added tert-butyldimethyl-
silyl chloride (0.754 g, 5.0 mmol) at room temperature.
After stirring for 13 h, the reaction mixture was diluted with
Et2O and washed with brine. After being dried over
anhydrous MgSO4, the solvent was evaporated in vacuo.
The residue was purified by flash column chromatography
(hexane–AcOEt 2:1) to afford 8 (1.033 g, 53%) and 9
(0.185 g, 7%) as a yellow amorphous powder, respectively.
Data for 8: IR (KBr) 3612, 2958, 2935, 1638, 1179 cm21
;
4.1.14. 7,40-Di-O-(b-L-glucopyranosyl)apigenin (1d).
According to the procedure described for 1a, 13d (93 mg,
0.1 mmol) was treated with NaOCH3 and recrystallized to
afford 1d as a white solid (52 mg, 88%): mp 180–181 8C;
[a]2D7þ54.88 (c 0.1, DMSO); IR (KBr) 3420, 1663, 1609,
1H NMR (DMSO-d6, 500 MHz) d 0.22 (6H, s), 0.95 (9H, s),
2.76 (1H, dd, J¼17.1, 3.0 Hz), 3.07 (1H, dd, J¼17.1,
12.8 Hz), 4.96 (1H, s, OH), 5.33 (1H, dd, J¼12.8, 3.0 Hz),
5.96 (1H, d, J¼2.2 Hz), 5.99 (1H, d, J¼2.2 Hz), 6.87 (2H, d,
J¼8.8 Hz), 7.31 (2H, d, J¼8.8 Hz), 11.92 (1H, s, OH); 13C
NMR (MDSO-d6, 125 MHz) d 24.4, 18.2, 25.5, 43.3, 78.9,
99.9, 101.3, 103.6, 115.7, 128.0, 130.7, 156.1, 162.8, 163.9,
165.0, 196.1; HRMS (EI) calcd for C21H26O5Si (Mþ)
386.1550. Found 386.1546. Data for 9: IR (KBr) 2957,
1
1242, 1075 cm21; H NMR (DMSO-d6, 500 MHz) d 3.17
(2H, m), 3.40 (1H, m), 3.46 (5H, m), 3.70 (4H, m), 5.03 (1H,
d, J¼7.3 Hz, 1-H), 5.06 (1H, d, J¼7.8 Hz, 1-H), 6.45 (1H, d,
J¼2.0 Hz), 6.86 (1H, d, J¼2.0 Hz), 6.97 (1H, s), 7.20 (2H,
d, J¼8.8), 8.06 (2H, d, J¼8.8 Hz), 12.87 (1H, s, OH).
Signals of four protons were overlapped with the signals of
H2O; 13C NMR (MDSO-d6, 125 MHz) d 60.6 (£2), 69.5,
69.6, 73.1 (£2), 76.4, 76.5, 77.1, 94.9, 99.6, 99.8 (£2),
104.1, 105.4, 116.6, 123.8, 128.2, 157.0, 160.4, 161.1,
163.0, 163.6, 182.0; HRMS (FAB) calcd for C27H31O15
(MþHþ) 595.1663. Found 595.1673.
2935, 1642, 1166, 839 cm21
;
1H NMR (DMSO-d6,
500 MHz) d 0.19 (6H, s), 0.22 (6H, s), 0.97 (9H, s), 0.94
(9H, s), 2.75 (1H, dd, J¼17.1, 2.9 Hz), 3.07 (1H, dd,
J¼17.1, 13.2 Hz), 5.32 (1H, d, J¼2.2 Hz), 5.96 (1H, d,
J¼2.2 Hz), 5.99 (1H, d, J¼2.2 Hz), 6.86 (1H, d, J¼8.6 Hz),
7.29 (1H, d, J¼8.6 Hz); 13C NMR (DMSO-d6, 125 MHz); d
24.4, 18.2, 25.5, 25.6, 43.4, 79.0, 99.9, 101.2, 103.6, 120.4,
127.6, 131.0, 156.3, 162.9, 163.9, 165.0, 196.2; HRMS (EI)
calcd for C27H40O5Si2 (Mþ) 500.2414. Found 500.2434.
4.1.15. 7-O-(b-D-Glucopyranosyl)apigenin (6a). To a
solution of 12a (30 mg, 0.05 mmol) in a mixture of
CH3OH (3 ml) and THF (3 ml) was added NaOCH3
(15 mg) at room temperature. After stirring for 13 h, the
reaction mixture was neutralized with Dowex 50W-
8X(Hþ), filtered, and evaporated in vacuo. The residue
was recrystallized from EtOH to afford 6a (20 mg, 93%) as
a white solid: mp 238–239 8C; [a]2D8242.18 (c 0.2, DMSO);
4.1.18. 7-O-tert-Butyldimethylsilyl-40-O-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl) naringenin (14) and 40-O-
(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)naringenin
(15). To a solution of 5a (263 mg, 0.75 mmol), 8 (193 mg,
0.5 mmol) and DTBMP (411 mg, 2.0 mmol) in CH2Cl2
(3 ml) was added BF3·Et2O (0.25 ml, 2.0 mmol) at room
temperature. After stirring for 1 h, the reaction mixture was
quenched by addition of saturated aqueous NaHCO3 and
extracted with CH2Cl2. The combined extracts were dried
over anhydrous MgSO4 and evaporated in vacuo. The
crude product was purified by thin layer chromatography
1
IR (KBr) 3452, 1656, 1608, 1178, 1073 cm21; H NMR
(DMSO-d6, 500 MHz); d 3.1–3.2 (1H, m), 3.4–3.5 (2H, m),
3.6–3.7 (1H, m), 5.05 (1H, d, J¼7.3 Hz, 1-H), 6.44 (1H, d,
J¼2.2 Hz), 6.82 (1H, d, J¼2.2 Hz), 6.86 (1H, s), 6.93 (2H,
d, J¼8.8 Hz), 7.95 (2H, d, J¼8.8 Hz), 10.37 (1H, s, OH),

2032
K. Oyama, T. Kondo / Tetrahedron 60 (2004) 2025–2034
(hexane–AcOEt 3:2 (for 14) and hexane–AcOEt 1:1 (for
15)) to give 14 (253 mg, 71%) as a white amorphous powder
and 15 (51 mg, 17%) as a white foam, respectively. Both 14
and 15 were an inseparable mixture of diastereomers (1:1):
NMR (CDCl3, 125 MHz) d 24.4, 18.2, 25.5, 25.6, 98.7,
103.9, 104.3, 106.0, 120.6, 124.1, 128.1, 157.6, 159.3,
162.0, 162.3, 164.2, 182.6; HRMS (EI) calcd for
C27H38O5Si2 (Mþ) 498.2258. Found 498.2239.
Data for 14: IR (KBr) 2958, 1755, 1644, 1370, 1223 cm21
;
1H NMR (DMSO-d6, 500 MHz) d 0.22 (3H, s), 0.94 (6H, s),
2.02 (3H, s), 2.03 (3H, s), 2.04 (3H, s), 2.06 (3H, s), 2.77
(1H, dd, J¼17.1, 3.0 Hz), 3.04 (0.5H, dd, J¼17.1, 12.7 Hz),
3.05 (0.5H, dd, J¼17.1, 12.7 Hz), 3.85 (1H, ddd, J¼9.8, 5.4,
2.0 Hz), 4.15 (0.5H, dd, J¼12.2, 2.0 Hz), 4.16 (0.5H, dd,
J¼12.2, 2.0 Hz), 4.27 (1H, dd, J¼12.2, 5.4 Hz), 5.08 (0.5, d,
J¼7.8 Hz, H-1), 5.09 (0.5H, d, J¼7.8 Hz, H-1), 5.16 (1H, t,
J¼9.8 Hz), 5.26 (1H, dd, J¼9.8, 7.8 Hz), 5.29 (1H, t,
J¼9.8 Hz), 5.36 (1H, dd, J¼12.7, 3.0 Hz), 5.95 (1H, d,
J¼2.2 Hz), 5.99 (1H, d, J¼2.2 Hz), 7.02 (2H, d, J¼8.8 Hz),
7.37 (2H, d, J¼8.8 Hz), 11.88 (1H, s, OH); 13C NMR
(CDCl3, 125 MHz) d 24.4, 18.2, 20.5, 20.6, 20.7, 25.5,
43.3, 61.9, 68.3, 71.2, 72.1, 72.7, 99.0, 99.8, 101.3, 103.6,
117.3, 127.7, 133.4, 157.1, 162.6, 164.0, 165.0, 169.2,
169.4, 170.2, 170.5, 195.7; HRMS (FAB) calcd for
C35H44O14SiNa (MþNaþ) 739.2398. Found 739.2380.
4.1.21. 7-O-tert-Butyldimethylsilyl-40-O-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl) apigenin (16a) from 14. A
solution of 14 (93 mg, 0.13 mmol) and DDQ (59 mg,
0.26 mmol) in 1,4-dioxane (5 ml) was refluxed for 17 h at
110 8C. The reaction mixture was purified by flash column
chromatography (hexane–AcOEt 3:2) to afford 16a (8 mg,
9%) as a white amorphous powder; [a]2D4218.38 (c 0.2,
CHCl3); IR (KBr) 2958, 2936, 1759, 1608, 1234 cm21; 1H
NMR (DMSO-d6, 500 MHz) d 0.28 (6H, s), 0.97 (9H, s),
1.97 (3H, s), 2.01 (3H, s), 2.02 (3H, s), 4.08 (1H, dd,
J¼12.3, 2.0 Hz), 4.20 (1H, dd, J¼12.3, 5.6 Hz), 4.31 (1H,
ddd, J¼10.0, 5.6, 2.0 Hz), 5.02 (1H, t, J¼9.8 Hz), 5.10 (1H,
dd, J¼9.8, 7.8 Hz), 5.43 (1H, t, J¼9.8 Hz), 5.76 (1H, d,
J¼7.8 Hz, 1-H), 6.27 (1H, d, J¼2.5 Hz), 6.68 (1H, d,
J¼2.5 Hz), 7.00 (1H, s), 7.16 (2H, d, J¼9.3 Hz), 8.12 (2H,
d, J¼9.3 Hz), 12.84 (1H, s, OH); 13C NMR (MDSO-d6,
125 MHz) d 23.2, 17.7, 20.3, 20.4, 20.5, 25.8, 61.6, 68.0,
70.6, 71.0, 71.9, 94.1, 96.5, 99.0, 103.8, 104.3, 116.6, 125.2,
128.4, 157.4, 159.0, 161.4, 162.8, 164.4, 169.1, 169.3,
169.6, 170.0, 181.8; HRMS (FAB) calcd for C35H43O14Si
(MþHþ) 715.2422. Found 715.2435.
Data for 15: IR (KBr) 3422, 2961, 1755, 1641, 1231 cm21
;
1H NMR (CDCl3, 500 MHz) d 2.02 (3H, s), 2.03 (3H, s),
2.04 (3H, s), 2.06 (3H, s), 2.78 (1H, dd, J¼17.1, 3.0 Hz),
3.04 (1H, dd, J¼17.1, 12.7 Hz), 4.16 (1H, dd, J¼9.5, 5.3,
2.0 Hz), 4.27 (1H, dd, J¼12.2, 5.3 Hz), 5.09 (1H, d,
J¼7.8 Hz, H-1), 5.16, (1H, t, J¼9.5 Hz), 5.26 (1H, dd,
J¼9.5, 7.8 Hz), 5.29 (1H, t, J¼9.5 Hz), 5.37 (1H, dd,
J¼12.7, 3.0 Hz), 5.85 (1H, br, OH), 5.95 (1H, d, J¼2.2 Hz),
5.98 (1H, d, J¼2.2 Hz), 7.02 (1H, d, J¼8.8 Hz), 7.36 (1H, d,
J¼8.8 Hz), 11.99 (1H, s, OH); 13C NMR (CDCl3, 125 MHz)
d 20.6, 20.7, 43.1, 61.9, 68.3, 71.2, 72.1, 72.7, 78.6, 95.5,
96.8, 98.9, 103.1, 117.2, 117.3, 127.7, 133.3, 157.1, 163.0,
164.3, 165.0, 169.4, 169.5, 170.4, 170.7, 195.6; HRMS
(FAB) calcd for C29H30O14Na (MþNaþ) 625.1533. Found
625.1512.
4.1.22. 40-O-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyrano-
syl)apigenin (17a) from 15. A solution of 15 (271 mg,
0.45 mmol) and DDQ (204 mg, 0.9 mmol) in 1,4-dioxane
(5 ml) was refluxed for 14 h at 110 8C. The reaction mixture
was purified by flash column chromatography (hexane–
AcOEt 1:2) to afford 17a as a white solid (67 mg, 25%): mp
154–155 8C; [a]2D4221.08 (c 0.2, THF); IR (KBr) 3421,
1755, 1656, 1620, 1233 cm21
;
1H NMR (DMSO-d6,
500 MHz) d 1.97 (3H, s), 2.01 (3H, s), 2.02 (6H, s), 4.08
(1H, dd, J¼12.2, 2.0 Hz), 4.20 (1H, dd, J¼12.2, 5.4 Hz),
4.30 (1H, ddd, J¼9.8, 5.4, 2.0 Hz), 5.02 (1H, t, J¼9.8 Hz),
5.10 (1H, dd, J¼7.8, 9.8 Hz), 5.42 (1H, t, J¼9.8 Hz), 5.74
(1H, d, J¼7.8 Hz, 1-H), 6.20 (1H, d, J¼2.0 Hz), 6.51 (1H, d,
J¼2.0 Hz), 6.92 (1H, s), 7.16 (2H, d, J¼8.8 Hz), 8.07 (2H,
d, J¼8.8 Hz), 10.86 (1H, s, OH), 12.85 (1H, s, OH); 13C
NMR (MDSO-d6, 125 MHz) d 20.2, 20.3, 20.4, 61.5, 67.9,
70.6, 71.0, 71.8, 94.0, 96.5, 98.9, 103.8, 104.3, 116.6, 125.1,
128.4, 157.3, 158.9, 161.4, 162.8, 164.3, 169.0, 169.3,
169.5, 169.9, 181.8; HRMS (FAB) calcd for C29H29O14
(MþHþ) 601.1557. Found 601.1554.
4.1.19. 7-O-tert-Butyldimethylsilylapigenin (10). A sol-
ution of 8 (387 mg, 1.0 mmol) and DDQ (454 mg,
2.0 mmol) in 1,4-dioxane (5 ml) was refluxed for 15 h at
110 8C. The reaction mixture was purified by flash column
chromatography (hexane–AcOEt 3:2) to afford 10 (310 mg,
81%) as a white solid: mp 176–177 8C; IR (KBr) 3452,
2957, 2933, 1653, 1602 cm21; 1H NMR (CDCl3, 500 MHz)
d 0.26 (6H, s), 0.98 (9H, s), 5.79 (1H, s, OH), 6.28 (1H, d,
J¼2.2 Hz), 6.41 (1H, d, J¼2.2 Hz), 6.55 (1H, s), 6.94 (2H,
d, J¼8.8 Hz), 7.78 (2H, d, J¼8.8 Hz), 12.69 (1H, s, OH);
13C NMR (CDCl3, 125 MHz) d 24.4, 18.2, 25.5, 98.8,
103.9, 104.0, 105.9, 116.2, 123.3, 128.4, 157.6, 159.6,
161.9, 162.4, 164.5, 182.7; HRMS (EI) calcd For
C21H24O5Si (Mþ) 384.1393. Found 384.1388.
4.1.23. Glycosylation of 10 to 16a and 17a. To a solution of
5a (140 mg, 0.4 mmol), 10 (77 mg, 0.2 mmol), and DTBMP
(164 mg, 0.8 mmol) in PhCl (3 ml) was added BF3·Et2O
(0.1 ml, 0.8 mmol) at room temperature. After stirring for
1 h, the reaction mixture was quenched by addition of
saturated aqueous NaHCO3 and extracted with AcOEt. The
combined extracts were dried over anhydrous MgSO4,
evaporated in vacuo, and purified by thin layer chromato-
graphy (hexane–AcOEt 3:2 (for 16a) and hexane–AcOEt
1:2 (for 17a)) to afford 16a (63 mg, 44%) and 17a (34 mg,
28%), respectively.
4.1.20. 7,40-di-O-(tert-Butyldimethylsilyl)apigenin (11). A
solution of 9 (100 mg, 0.2 mmol) and DDQ (91 mg,
0.4 mmol) in 1,4-dioxane (5 ml) was refluxed for 17 h at
110 8C. The reaction mixture was purified by flash column
chromatography (hexane–AcOEt 6:1) to afford 11 (44 mg,
44%) as a white solid: mp 99–100 8C; IR (KBr) 2932, 1655,
1604, 1272, 1165 cm21; 1H NMR (CDCl3, 500 MHz) d 0.23
(6H, s), 0.26 (6H, s), 0.99 (18H, s), 6.28 (1H, d, J¼2.0 Hz),
6.41 (1H, d, J¼2.0 Hz), 6.55 (1H, s), 6.93 (2H, d,
J¼8.8 Hz), 7.77 (2H, d, J¼8.8 Hz), 12.7 (1H, s, OH); 13C
4.1.24. Glycosylation of 10 to 16b and 17b. According to
the procedure described for 16a and 17a, 10 (77 mg,
0.2 mmol) was glycosylated with L-glucosyl fluoride 5b

K. Oyama, T. Kondo / Tetrahedron 60 (2004) 2025–2034
2033
(140 mg, 0.4 mmol) to afford 16b (40 mg, 28%) as a white
amorphous powder and 17b (47 mg, 39%) as a white solid:
Data for 16b: [a]2D4þ18.38 (c 0.2, CHCl3); IR (KBr) 2960,
160.2, 161.4, 163.1, 164.2, 181.8; HRMS (FAB) calcd for
C21H21O10 (MþHþ) 433.1135. Found 433.1137.
2934, 1753, 1655, 1607, 1235 cm21; H NMR (DMSO-d6,
4.1.28. 40-O-(b-L-Glucopyranosyl)apigenin (7b). Accord-
ing to the procedure described for 7a, 17b (30 mg,
0.05 mmol) was treated with NaOCH3 and recrystallized
to afford 7b as a white solid (20 mg, 91%): mp 173–174 8C;
[a]2D5þ29.18 (c 0.2, DMSO); IR (KBr) 3456, 1656, 1609,
1
500 MHz) d 0.27 (6H, s), 0.96 (9H, s), 1.97 (3H, s), 2.01
(3H, s), 2.02 (3H, s), 4.08 (1H, dd, J¼12.3, 2.2 Hz), 4.20
(1H, dd, J¼12.3, 5.5 Hz), 4.31 (1H, ddd, J¼9.8, 5.5,
2.2 Hz), 5.03 (1H, t, J¼9.8 Hz), 5.10 (1H, dd, J¼9.8, 7.9,
Hz), 5.43 (1H, t, J¼9.8 Hz), 5.75 (1H, d, J¼7.9 Hz, 1-H),
6.26 (1H, d, J¼2.2 Hz), 6.67 (1H, d, J¼2.2 Hz), 6.99 (1H,
s), 7.16 (2H, d, J¼9.2 Hz), 8.11 (2H, d, J¼9.2 Hz), 12.83
(1H, s, OH); 13C NMR (DMSO-d6, 125 MHz) d 24.7, 17.9,
20.2, 20.3, 20.4, 25.3, 61.5, 67.9, 70.6, 71.0, 71.9, 96.4,
98.8, 103.2, 104.4, 105.4, 116.5, 124.9, 128.5, 157.0, 159.1,
161.2, 161.6, 163.2, 169.0, 169.2, 169.5, 169.9, 182.0;
HRMS (FAB) calcd for C35H43O14Si (MþHþ) 715.2422.
Found 715.2420.
1
1168, 1075 cm21; H NMR (DMSO-d6, 500 MHz) d 3.1–
3.2 (1H, m), 3.3–3.4 (1H, m), 3.4–3.5 (1H, m), 3.6–3.7
(1H, m), 5.02 (1H, d, J¼7.6 Hz, 1-H), 6.19 (1H, d,
J¼2.0 Hz), 6.50 (1H, d, J¼2.0 Hz), 6.88 (1H, s), 7.18
(2H, d, J¼8.8 Hz), 8.03 (2H, d, J¼8.8 Hz), 10.91 (1H, s,
OH), 12.89 (1H, s, OH); 13C NMR (MDSO-d6, 125 MHz) d
60.6, 69.6, 73.1, 76.5, 77.1, 94.0, 98.9, 99.8, 103.7, 103.8,
116.5, 123.9, 128.1, 157.3, 160.2, 161.4, 163.0, 164.3,
181.7; HRMS (FAB) calcd for C21H21O10 (Mþ) 433.1135.
Found 433.1138.
Data for 17b: mp 154–155 8C; [a]2D3þ21.28 (c 0.2, CHCl3);
1
IR (KBr) 3397, 1754, 1656, 1619, 1234 cm21; H NMR
(DMSO-d6, 500 MHz); d 1.97 (3H, s), 2.01 (3H, s), 2.02
(6H, s), 4.08 (1H, dd, J¼12.2, 2.2 Hz), 4.20 (1H, dd,
J¼12.2, 5.4 Hz), 4.30 (1H, ddd, J¼9.8, 5.4, 2.2 Hz), 5.02
(1H, t, J¼9.8 Hz), 5.10 (1H, dd, J¼9.8, 8.3 Hz), 5.42 (1H, t,
J¼9.8 Hz), 5.74 (1H, d, J¼8.3 Hz, 1-H), 6.20 1H, (1H, d,
J¼2.0 Hz), 6.51 (1H, d, J¼2.0 Hz), 6.92 (1H, s), 7.16 (2H,
d, J¼8.8 Hz), 8.07 (2H, d, J¼8.8 Hz), 10.85 (1H, s, OH),
12.85 (1H, s, OH); 13C NMR (DMSO-d6, 125 MHz) d 20.2,
20.3, 20.4, 61.5, 67.9, 70.6, 70.9, 71.8, 94.0, 96.5, 98.9,
103.8, 104.3, 116.6, 125.1, 128.3, 157.3, 158.9, 161.4,
162.7, 164.3, 169.0, 169.2, 169.5, 169.9, 181.7; HRMS
(FAB) calcd for C29H29O14 (MþHþ) 601.1557. Found
601.1548.
Acknowledgements
We deeply thank Professor Kumi Yoshida, Nagoya
University, for valuable discussion. We are grateful to
Mr. S. Kitamura of Analytical Laboratory at School of
Bioagricultural Sciences, Ngoya University for performing
the elemental analyses. We gratefully acknowledge the
financial support for this research provided as Grants-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports, Culture and Technology, Japan (Scientific
Research (B) No. 12460052, Research COE 07CE2004 and
Scientific Research on Priority Area N0. 10169224) and the
Ministry of Agriculture, Forestry and Fisheries of Japan (the
Pioneer Research Project).
4.1.25. Desilylation of 16a to 17a. To a solution of 16a
(36 mg, 0.05 mmol) in THF (2 ml) was added TBAF·3H2O
(63 mg, 0.2 mmol) at room temperature. After 20 min, the
reaction mixture was poured into saturated aqueous NH4Cl
and extracted with AcOEt. The combined extracts were
dried over anhydrous MgSO4 and evaporated in vacuo. The
crude product was purified by thin layer chromatography
(hexane–AcOEt 1:1) to afford 17a (27 mg, 90%).
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