Powerful antioxidative agents based on garcinoic acid from Garcinia kola.

Article abstract of DOI:10.1016/S0968-0896(01)00428-X

Investigation on the structure--antioxidative activity relationships of derivatives based on garcinoic acid from Garcinia kola (Guttiferae) led to discovery of a powerful antioxidative agent.

Full text of DOI:10.1016/S0968-0896(01)00428-X

Bioorganic & Medicinal Chemistry 10 (2002) 1619–1625
Powerful Antioxidative Agents Based on Garcinoic Acid from
Garcinia Kola
Kenji Terashima, Yoshiaki Takaya and Masatake Niwa*
Faculty of Pharmacy, Meijo University, Tempaku, Nagoya 468-8503, Japan
Received 22 October 2001; accepted 4 December 2001
Abstract—Investigation on the structure–antioxidative activity relationships of derivatives based on garcinoic acid from Garcinia
kola (Guttiferae) led to discovery of a powerful antioxidative agent. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
7d was deprotected with concentrated hydrochloric acid
in a mixture of chloroform and methanol as solvent to
give an alkylated hydroquinone (8d), which was oxi-
dized with manganese oxide in benzene to afford the
corresponding quinone (9d). Compound 9d was treated
with pyridine under reflux to give a cyclized compound,
chromen (10d), and then hydrogenated with platinum
oxide in ethyl acetate to afford the chroman (4) having a
saturated side chain. Compound 4 was identical with a
compound derived from the natural product 3. On the
other hand, a hydroquinone with a saturated side chain
(12) was prepared by hydrogenation of 7, followed by
deprotection (Scheme 2).
In the previous paper, we reported two new chroma-
nols, garcinoic acid (1) and garcinal (2), together with d-
tocotrienol (3) from the seed of Garcinia kola (Gutti-
ferae) collected in Nigeria.1 The antioxidant activities of
those natural products (1, 2 and 3) were around 1.5
times that of dl-a-tocopherol by the bleomycin–Fe
method reported by Umezawa et al.1,2 These results
indicated that a functional group, the substituent on the
chroman skeleton, and/or the double bonds on the side
chain, has some influence on the activity. To investigate
which features in those structures are important, we
have synthesized various types of chroman compounds
based on garcinoic acid (1), and found a very powerful
antioxidative compound (10a) showing activity 18.7
times as strong as that of dl-a-tocopherol. In this paper,
we describe the syntheses of the chroman compounds
and the relationships between the structure and anti-
oxidant activity.
Other derivatives with a side chain of different lengths
were also synthesized, using isoprenyl bromide, geranyl
bromide and farnesyl bromide instead of geranylgeranyl
bromide, according to similar methods described above.
Involvement in the functional groups on the side chain
and benzene ring
Since d-tocopherol has a very similar structure to that of
garcinoic acid, at the beginning of this study, we
investigated the participation in the side chain on the
antioxidant activity. As shown in Table 1, the terminal
functional groups on the side chain such as carboxylic
acid (1), aldehyde (2), methyl (3), methoxycarbonyl (1b)
and hydroxymethyl (5) groups had minimal influence on
the activity. However, a phenolic hydroxyl group
appears to be essential to the activity, because the
methyl ether derivatives (1c and 1d) of 1 and 1b did not
show any activity. On the basis of these results, the
activities of the compounds having a methyl group at
the end of the side chain were investigated in this study.
Results
General synthetic methods of compounds for antioxidative
evaluation
As a typical example, a synthesis of the chroman (4) is
shown in Scheme 1. Compound 6, derived easily from o-
cresol,3 was treated with n-butyl lithium, cuprous iodide
and geranylgeranyl bromide to give the 2-alkylated
hydroquinone dimethoxymethyl ether (7d). Compound
*Corresponding author. Tel.:+81-52-832-1781; fax:+81-52-834-8090;
e-mail: masa@meijo-u.ac.jp
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00428-X

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K. Terashima et al. / Bioorg. Med. Chem. 10 (2002) 1619–1625
Scheme 1. Synthesis of hydroquinones, chromens and chromans. Reagents: (a) (1) n-BuLi, CuI, ꢁ78 ꢂC (2), rt:
(b) concd HCl, MeOH/CHCl3,
reflux; (c) MnO2: benzene, rt; (d) pyridine, reflux; (e) PtO2, AcOEt, rt.
Scheme 2. Synthesis of saturated hydroquinones.
Involvement in the length of the side chain
pyran ring and side chain were 1.5–2.0 times as strong
as those of compounds with a dihydropyran ring as well
as a saturated side chain.
Table 2 shows the relationshipbetween the chain length
and antioxidative activity. The results demonstrated
that the length of the side chain had significant influence
on the activity. The decrease of the number of carbons
on the side chain (in the order of R=farnesyl, geranyl,
isoprenyl and H) caused an increase of the activity in all
cases.
Discussion
We synthesized various types of analogues which are
structurally related to garcinoic acid (1) for the
structure–antioxidative activity relationships, and their
Involvement in the pyran ring
Garcinoic acid and vitamin E exhibit high antioxidant
potency, and they all have a pyran ring in their mole-
cule. To ascertain whether the pyran ring is critical for the
antioxidative activity, we compared the activities of
hydroquinones (12a–d), which correspond to the ring-
opening compounds of the pyrans (11a–c and 4), with
those of pyrans. As the result, it was shown that the activ-
ity of the hydroquinones decreased markedly in all cases.
Table 1. Antioxidative activities of garcinoic acid analogues
Entry
R1
R2
Antioxidant activity
d-Tocotrienol (3)
(5)
Garcinal (2)
Garcinoic acid (1)
(1b)
(1c)
(1d)
CH3
CH2OH
CHO
COOH
COOCH3
COOH
COOCH3
H
H
H
H
H
1.47ꢀ0.03
1.52ꢀ0.05
1.52ꢀ0.01
1.53ꢀ0.05
1.51ꢀ0.04
0
Involvement in the unsaturated bond
The remaining points to be investigated were the
unsaturated bonds on the side chain and the pyran ring.
First, the contribution of the unsaturated bonds on the
side chain to the antioxidative activity was investigated
using d-tocotrienol and d-tocopherol (4). This compar-
ison revealed that unsaturation or saturation of the
side-chain did not have any influence practically on the
activity. Moreover, as shown in Table 2, the activities of
compounds which possess unsaturated bonds on the
CH3
CH3
0
d-Tocepherol (4)
(4b)
(4c)
CH3
COOH
COOCH3
H
H
H
1.53ꢀ0.09
1.53ꢀ0.02
1.51ꢀ0.01

K. Terashima et al. / Bioorg. Med. Chem. 10 (2002) 1619–1625
1621
Table 2. Relative antioxidative activities versus dl-a-tocopherol
antioxidative activities were investigated. As the result,
we found a very powerful antioxidative compound (10a)
which is 18.7 times stronger than dl-a-tocopherol. The
activity was consequently found to be affected sig-
nificantly by structural features.
was proved by the evidence that the methylated com-
pound at the 40-position of d-tocotrienol did not show
the activity. However, the participation of the shorter
side chain and the pyran ring was not studied in detail.
On the basis of the results mentioned above, the
mechanism will be revealed, and it will be discussed
elsewhere.
The activity does not depend on the oxidative state of
the terminal of the side chain, but on its length. That is
to say, the shorter the side chain, the higher the potency.
The mono prenylated analogues showed the most
powerful activity. Especially in the case of pyran-type
compounds, the decrease of the isoprenyl unit dramati-
cally strengthened the activities [1.53 (4) to 8.11 (11a),
and 2.58 (10d) to 18.7 (10a)]. Furthermore, chromen-
type compounds showed stronger activity than chro-
man-type compounds, though both of them are sig-
nificantly superior to hydroquinone-type compounds
which were obtained as the synthetic intermediates.
Consequently, to exhibit the strongest antioxidative
activity, as observed in compound 10a, such simple
structural characteristics possessing a phenolic hydroxyl
group, a chromen moiety and a shorter side chain were
revealed to be critical.
The strong antioxidative compounds described in this
paper will be lead compounds of drugs which prevent
oxidative stress diseases such as aging, inflammation,
carcinogenesis, arteriosclerosis and so on.
Experimental
General
IR spectra were recorded on JASCO FT/IR-5000 spec-
trometer. 1H NMR spectra were recorded on JEOL
A-400 spectrometer using chloroform-d as solvent.
1
Chemical shifts for H NMR are given in parts per mil-
lion (d) relative to solvent signal (chloroform-d: dH 7.24)
as internal standards. EI-MS was obtained with Hitachi
M-80 and JEOL MS-700 spectrometers, and FABMS
was obtained with JEOL HX-110 spectrometer using
m-nitrobenzyl alcohol as a matrix. Analytical and pre-
parative TLC were performed on silica gel 60 F254
The mechanism to show antioxidative activity of vita-
min E suggested that a phenoxyl radical, which is
formed via the phenolic hydroxyl group at the 40-posi-
tion, inhibits the autoxidation of lipids.4 This hypothesis

1622
K. Terashima et al. / Bioorg. Med. Chem. 10 (2002) 1619–1625
(Merck) with the thickness 0.25 and 0.5 mm, respec-
tively. Column chromatography was carried out on
silica gel BW-820MH (Fuji Silysia Chemicals, Co.,
Ltd.).
(6H, m), 2.13 (3H, s), 2.23 (2H, dt, J=7.3, 7.6 Hz), 2.71
(2H, br t, J=6.6 Hz), 3.71 (6H, s), 5.11 (2H, br t, J=7.0
Hz), 6.42 (1H, d, J=3.0 Hz), 6.54 (1H, d, J=3.0 Hz),
6.72 (1H, qt, J=1.5, 7.3 Hz); EI-MS m/z 454 [M]+; EI-
HRMS m/z 454.3079 [M+] (C29H42O4 requires
454.3083).
Antioxidant activity assay2
A mixture of 0.2 M Tris–HCl buffer (pH 7.4), 8 mM
sodium arachidonate, a mathanolic solution of an
antioxidant, 1 mM bleomycin and 1.08 mM FeSO4
(each 1 mL) was incubated at 37 ꢂC for 5 min, followed
by addition of 0.2 M HCl (10 mL). After addition of
0.5% thiobarbituric acid (0.2 mL), the solution was
incubated at 37 ꢂC for 30 min. Then, H2O (0.4 mL) and
n-BuOH (1 mL) were added, and the mixture was
vigorously shaken and centrifuged at 3000 rpm for 10
min. The absorbance of the n-BuOH layer at 532 nm
was measured by spectrophotometry. The concentration
of dl-a-tocopherol, used as the positive control, and
samples was controlled to 0.15 mM. The abo-
sorbance of methanol only instead of samples were
served as a blank. The relative antioxidative activity
was defined as a ratio of the value of sample to that of
dl-a-tocopherol.
Preparation of garcinoic acid 40-methyl ether (1c). Com-
pound 1d (40 mg, 0.09 mmol) in 5 mL of 0.35 M potas-
sium hydroxide–methanol solution was refuxed for 3 h.
The reaction mixture was neutralized with concentrated
HCl and extracted with ethyl acetate. The ethyl acetate
layer was washed successively with water and brine, and
dried over anhydrous sodium sulfate. Purification by
column chromatography on SiO2 [hexane–ethyl acetate
(3:1)] afforded 1c (24 mg, 64%) as a yellow oil.
1
Data of 1c: IR nmax (film) 3450 (br), 1688 cmꢁ1; H
NMR d 1.24 (3H, s), 1.57 (2H, m), 1.57 (3H, s), 1.58
(3H, s), 1.73 (2H, m), 1.81 (3H, s), 1.96 (2H, t, J=7.0
Hz), 2.02–2.13 (6H, m), 2.13 (3H, s), 2.26 (2H, dt,
J=7.3, 7.6 Hz), 2.71 (2H, br t, J=7.0 Hz), 3.71 (3H, s),
5.11 (2H, br t, J=7.3 Hz), 6.42 (1H, d, J=3.0 Hz), 6.85
(1H, d, J=3.0 Hz), 6.85 (1H, qt, J=1.5, 7.3 Hz); EI-MS
m/z 440 [M]+; EI-HRMS m/z 440.2940 [M+]
(C28H40O4 requires 440.2927).
Isolation of garcinoic acid (1) and garcinal (2)
Garcinoic acid (1) and garcinal (2) were isolated from
the seed of Garcinia kora described in ref 1.
Hydrogenation of garcinoic acid to form saturated gar-
cinoic acid (4b). Garcinoic acid (1) (17 mg, 0.04 mmol)
and platinum oxide (5 mg) in ethyl acetate (5 mL) were
stirred under hydrogen atmosphere at room tempera-
ture for 2 h. The mixture was filtered through Celite
afforded a saturated garcinoic acid (4b) (17 mg, 100%)
as a yellow oil.
Preparation of methyl garcinoate (1b). Garcinoic acid
(1) (442 mg, 1.04 mmol) in 10 mL of diethylether was
treated with a ethereal solution of diazomethane at
ꢁ78 ꢂC for 5 min. After evaporation of the solvent, the
residue was subjected to column chromatography using
SiO2 [hexane–acetone (4:1)] to give a methyl ester (1b)
(367 mg, 80%) as a colorless oil.
1
Data of 4b: IR nmax (film) 3330 (br) cmꢁ1; H NMR d
0.80–1.80 (32H, m), 2.09 (3H, s), 2.43 (2H, dt, J=7.3,
7.3 Hz), 2.65 (2H, t, J=7.0 Hz), 6.36 (1H, d, J=2.2
Hz), 6.46 (1H, d, J=2.2 Hz); EI-MS m/z 432 [M]+; EI-
HRMS m/z 432.3216 [M+] (C27H44O4 requires
432.3240).
1
Data of 1b: IR nmax (film) 3410, 1696, 1646 cmꢁ1; H
NMR d 1.24 (3H, s), 1.57 (2H, m), 1.57 (3H, s), 1.61
(3H, s), 1.74 (2H, m), 1.81 (3H, d, J=1.5 Hz), 1.95 (2H,
t, J=7.4 Hz), 2.02–2.07 (6H, m), 2.10 (3H, s), 2.21 (2H,
dt, J=7.3, 7.7 Hz), 2.67 (2H, t, J=6.6 Hz), 3.71 (3H, s),
4.53 (1H, s, D2O exchangeable), 5.09 (2H, br t, J=7.6
Hz), 6.36 (1H, d, J=2.9 Hz), 6.46 (1H, d, J=2.9 Hz),
6.72 (1H, dt, J=1.5, 7.3 Hz); EI-MS m/z 440 [M]+; EI-
HRMS m/z 440.2947 [M+] (C28H40O4 requires
440.2927).
Hydrogenation of methyl garcinoate to form saturated
methyl garcinoate (4c). Methyl garcinoate (1b) (11 mg,
0.01 mmol) and platinum oxide (5 mg) in ethyl acetate
(5 mL) were stirred under hydrogen atmosphere at
room temperature for 2 h. The mixture was filtered
through celite afforded a saturated garcinoic acid (4c)
(11 mg, 99%) as a yellow oil.
Preparation of methyl garcinoate 40-methyl ether (1d). A
mixture of methyl garcinoate (1b) (88 mg, 20 mmol),
methyl iodide (57 mg, 40 mmol) and potassium carbon-
ate (55 mg, 40 mmol) in acetone (15 mL) was stirred at
room temperature for 12 h. The reaction mixture was
successively washed with water and brine, and dried
over anhydrous sodium sulfate. Crude product was
purified using SiO2 column and chloroform as eluent to
afford the methyl ether (1d) (66 mg, 72%) as a colorless
oil.
1
Data of 4c: IR nmax (film) 1740 cmꢁ1; H NMR d 0.80–
1.81 (36H, m), 2.10 (3H, s), 2.44 (2H, dt, J=7.3, 7.6
Hz), 2.70 (2H, br t, J=7.0 Hz), 3.71 (3H, s), 6.42 (1H, d,
J=2.7 Hz), 6.54 (1H, d, J=2.7 Hz); EI-MS m/z 446
[M]+; EI-HRMS m/z 446.3390 [M+] (C28H46O4
requires 446.3396).
Reduction of garcinoic acid to form primary alcohol (5).
A mixture of methyl garcinoate (1b) (448 mg, 1.02
mmol), N,N-diisopropylethylamine (526 mg, 4.08 mmol)
and methoxymethyl chloride (328 mg, 4.08 mmol) in
dichloromethane (60 mL) was stirred at room temp-
erature for 12 h. The reaction mixture was extracted
Data of 1d: IR nmax (film) 1717, 1653 cmꢁ1 1H NMR d
1.24 (3H, s), 1.54 (2H, m), 1.54 (3H, s), 1.57 (3H, s), 1.74
(2H, m), 1.80 (3H, s), 1.96 (2H, t, J=7.4 Hz), 2.02–2.13

K. Terashima et al. / Bioorg. Med. Chem. 10 (2002) 1619–1625
1623
with chloroform and the organic layer was washed
successively with water and brine, and dried over anhy-
drous sodium sulfate. Purification by column chroma-
tography on SiO2 (chloroform as eluent) afforded
MOM ether (13) (382 mg, 77%) as a colorless oil.
dropwise, and then the mixture was warmed to room
temperature for 1.5 h. The mixture was extracted with
ethyl acetate and then washed successively with 5%
NaHCO3 aqueous solution, water and brine, and dried
over anhydrous sodium sulfate. Purification by flash
chromatography on SiO2 [hexane–chloroform (1:1)]
afforded a geranylgeranyl protected hydroquinone (7d)
(252 mg, 33%) as a yellow oil. In the same manner, 7a–c
were prepared using isopentenyl bromide, geranyl bro-
mide and farnesyl bromde instead of geranylgeranyl
bromide, respectively.
MOM ether (13) (349 mg, 0.72 mmol) in 40 mL of THF
was treated with lithium aluminum hydride (110 mg,
2.90 mmol) at room temperature for 12 h. After addi-
tion of methanol (35 mL), the mixture was filtered
through celite. The filtrate was extracted with ethyl ace-
tate, and then successively washed with water and brine,
and dried over anhydrous sodium sulfate. By column
chromatography, using SiO2 [hexane–ethyl acetate (5:1)]
afforded a primary alcohol (14) (222 mg, 70%) as a
colorless oil.
To the MOM ether (7d) (120 mg, 0.25 mmol) in a mixed
solvent of chloroform and methanol (1:1) (5 mL) was
added with concentrated hydrochloric acid (30 mL), and
the mixture was refluxed for 1 h. The mixture was
extracted with chloroform (20 mL) and then the resulted
organic layer was washed successively with water and
brine, and dried over anhydrous sodium sulfate. Puri-
fication by column chromatography on SiO2 [chloro-
form–ethyl acetate (20:1)] afforded a hydroquinone (8d)
(96 mg, 98%) as a yellow oil. In the same manner, 8a–c
were prepared.
The alcohol (14) (40 mg, 0.09 mmol) in a mixed solvent
of chloroform and methanol (1:1) (1.5 mL) was treated
with concentrated HCl (50 mL) under reflux for 1 h. The
mixture was extracted with chloroform and then washed
successively with water and brine, and dried over anhy-
drous sodium sulfate. The crude product was purified
by preparative TLC on SiO2 [hexane–ethyl acetate (5:1)]
afforded a reduced garcinoic acid (5) (29 mg, 81%) as a
colorless oil.
Data of 7a: 1H NMR d 1.68 (3H, s), 1.72 (3H, d, J=1.4
Hz), 2.26 (3H, s), 3.32 (2H, d, J=7.3 Hz), 3.45 (3H, s),
3.58 (3H, s), 4.89 (2H, s), 5.09 (2H, s), 5.25 (1H, qt,
J=1.4, 7.3 Hz), 6.66 (1H, d, J=2.9 Hz), 6.70 (1H, d,
J=2.9 Hz); EI-MS m/z 280 [M+], 203 (base); EI-
HRMS m/z 280.1683 [M+] (C16H24O4 requires
280.1675).
1
Data of 13: IR nmax (film) 3372 (br) cmꢁ1; H NMR d
1.24 (3H, s), 1.58 (2H, m), 1.58 (6H, s), 1.74 (2H, m),
1.81 (3H, d, J=1.5 Hz), 1.95 (2H, t, J=7.4 Hz), 2.04–
2.11 (6H, m), 2.13 (3H, s), 2.24 (2H, dt, J=7.3, 7.7 Hz),
2.70 (2H, t, J=6.6 Hz), 3.46 (3H, s), 3.71 (3H, s), 5.05
(2H, s), 5.11 (2H, qt, J=1.5, 7.6 Hz), 6.58 (1H, d,
J=2.9 Hz), 6.66 (1H, d, J=2.9 Hz), 6.72 (1H, qt,
J=1.5, 7.3 Hz); EI-MS m/z 484 [M]+; EI-HRMS m/z
484.3214 [M+] (C30H44O5 requires 484.3189).
1
Data of 7b: H NMR d 1.58 (3H, s), 1.66 (3H, s), 1.68
(3H, s), 2.09 (4H, d, J=7.7 Hz), 2.26 (3H, s), 3.34 (2H,
d, J=7.3 Hz), 3.45 (3H, s), 3.58 (3H, s), 4.89 (2H, s),
5.08 (2H, s), 5.08 (1H, t, J=7.7 Hz), 5.28 (1H, t, J=7.3
Hz), 6.67 (1H, d, J=2.9 Hz), 6.70 (1H, d, J=2.9 Hz);
EI-MS m/z 348 [M+], 69 (base); EI-HRMS m/z
348.2476 [M+] (C21H32O4 requires 348.2301).
1
Data of 14: IR nmax (film) 3372 (br) cmꢁ1; H NMR d
1.24 (3H, s), 1.55 (2H, m), 1.55 (3H, s), 1.56 (3H, s), 1.64
(3H, s), 1.75 (2H, m), 1.93–2.11 (10H, m), 2.12 (3H, s),
2.70 (2H, t, J=7.0 Hz), 3.46 (3H, s), 3.97 (2H, s), 5.05
(2H, s), 5.09 (2H, qt, J=1.5, 7.3 Hz), 5.11 (1H, qt,
J=1.5, 7.3 Hz), 5.36 (1H, dt, J=1.5, 7.3 Hz), 6.58 (1H,
d, J=2.9 Hz), 6.62 (1H, d, J=2.9 Hz); EI-MS m/z 456
[M]+; EI-HRMS m/z 456.3249 [M+] (C29H44O4
requires 456.3240).
1
Data of 7c: H NMR d 1.53 (3H, s), 1.58 (6H, s), 1.66
(3H, s), 1.95–2.15 (8H, m), 2.26 (3H, s), 3.33 (2H, d,
J=7.4 Hz), 3.45 (3H, s), 3.58 (3H, s), 5.08 (2H, s), 5.09
(2H, s), 5.10 (2H, t, J=7.4 Hz), 5.28 (1H, t, J=7.0 Hz),
6.66 (1H, d, J=2.4 Hz), 6.70 (1H, d, J=2.4 Hz); EI-MS
m/z 416 [M+], 149 (base); EI-HRMS m/z 416.2941
[M+] (C26H40O4 requires 416.2927).
1
Data of 5: IR nmax (film) 3330 (br) cmꢁ1; H NMR d
1
1.24 (3H, s), 1.55 (2H, m), 1.55 (3H, s), 1.57 (3H, s), 1.64
(3H, s), 1.75 (2H, m), 1.93–2.11 (10H, m), 2.11 (3H, s),
2.67 (2H, br t, J=7.0 Hz), 3.98 (2H, s), 5.07 (2H, br t,
J=6.8 Hz), 5.36 (1H, dt, J=1.5, 7.3 Hz), 6.35 (1H, d,
J=3.0 Hz), 6.45 (1H, d, J=3.0 Hz); EI-MS m/z 412
[M]+; EI-HRMS m/z 412.2960 [M+] (C27H40O3
requires 412.2977).
Data of 7d: H NMR, d 1.53 (3H, s), 1.66 (6H, s), 1.68
(6H, s), 1.90–2.09 (12H, m), 2.26 (3H, s), 3.33 (2H, d,
J=7.0 Hz), 3.45 (3H, s), 3.58 (3H, s), 4.89 (2H, s), 5.08
(2H, s), 5.09 (3H, t, J=7.3 Hz), 5.26 (1H, t, J=7.3 Hz),
6.66 (1H, d, J=2.9 Hz), 6.70 (1H, d, J=2.9 Hz); EI-MS
m/z 484 [M+], 149 (base); EI-HRMS m/z 484.3560
[M+] (C31H48O4 requires 484.3553).
1
Preparation of hydroquinone (8). To a solution of the
protected hydroquinone (6)3 (462 mg, 1.59 mmol) in
THF (30 mL) was added n-BuLi (152 mg, 2.38 mmol) at
ꢁ78 ꢂC. The mixture was kept at ꢁ78 ꢂC for 30 min
followed by addition of copper iodide(I) (456 mg, 2.38
mmol), and stirred for 2 h. A solution of geranylgeranyl
bromide (731 mg, 2.07 mmol) in THF (5 mL) was added
Data of 8a: IR nmax (film) 3400 (br) cmꢁ1; H NMR, d
1.73 (3H, s), 1.75 (3H, s), 2.17 (3H, s), 3.26 (2H, d,
J=7.3 Hz), 4.34 (1H, s, –OH), 4.72 (1H, s, –OH), 5.26
(1H, t, J=7.3 Hz), 6.43 (1H, d, J=3.2 Hz), 6.48 (1H, t,
J=3.2 Hz); EI-MS m/z 192 [M+], 175 (base); EI-
HRMS m/z 192.1159 [M+] (C12H16O2 requires
192.1150).

1624
K. Terashima et al. / Bioorg. Med. Chem. 10 (2002) 1619–1625
1
Data of 8b: IR nmax (film) 3450 (br) cmꢁ1; H NMR d
1.53 (3H, s), 1.67 (3H, s), 1.75 (3H, s), 2.04 (2H, m), 2.16
(2H, m), 2.16 (3H, s), 3.27 (2H, d, J=7.4 Hz), 4.60 (1H,
s, –OH), 4.77 (1H, s, –OH), 5.03 (1H, t, J=7.4 Hz), 5.25
(1H, t, J=7.4 Hz), 6.44 (1H, d, J=2.7 Hz), 6.48 (1H, d,
J=2.7 Hz); EI-MS m/z 260 [M+], 149 (base); EI-
HRMS m/z 260.1782 [M+] (C17H24O2 requires
260.1776).
326 [M+], 228 (base); EI-HRMS m/z 326.2249 [M+]
(C22H30O2 requires 326.2246).
1
Data of 9d: IR nmax (film) 1650 cmꢁ1; H NMR d 1.55
(3H, s), 1.58 (6H, s), 1.60 (3H, s), 1.65 (3H, s), 1.92–2.03
(8H, m), 2.04 (3H, s), 2.08 (2H, t, J=6.6 Hz), 3.10 (2H,
d, J=7.4 Hz), 5.05 (3H, t, J=7.4 Hz), 5.13 (1H, t,
J=7.4 Hz), 6.44 (1H, d, J=2.5 Hz), 6.53 (1H, d, J=2.5
Hz); EI-MS m/z 394 [M+], 175 (base); EI-HRMS m/z
394.2845 [M+] (C27H38O2 requires 394.2872).
1
Data of 8c: IR nmax (film) 3450 (br) cmꢁ1; H NMR d
1.55 (3H, s), 1.57 (6H, s), 1.75 (3H, s), 1.95–2.16 (8H,
m), 2.03 (3H, s), 3.27 (2H, d, J=7.3 Hz), 5.27 (2H, t,
J=7.3 Hz), 5.28 (1H, t, J=7.3 Hz), 6.43 (1H, d, J=2.7
Hz), 6.48 (1H, d, J=2.7 Hz); EI-MS m/z 328 [M+], 149
(base); EI-HRMS m/z 328.2408 [M+] (C22H32O2
requires 328.2402).
1
Data of 10a: IR nmax (film) 3400 (br) cmꢁ1; H NMR d
1.38 (6H, s), 2.11 (3H, s), 5.60 (1H, d, J=9.5 Hz), 6.20
(1H, d, J=9.5 Hz), 6.31 (1H, d, J=2.9 Hz), 6.46 (1H, d,
J=2.9 Hz); EI-MS m/z 190 [M+], 158 (base); EI-HRMS
m/z 190.1016 [M+] (C12H14O2 requires 190.0994).
1
1
Data of 8d: IR nmax (film) 3450 (br) cmꢁ1; H NMR d
Data of 10b: IR nmax (film) 3350 (br) cmꢁ1; H NMR d
1.53 (3H, s), 1.58 (6H, s), 1.66 (6H, s), 1.91–2.10 (12H,
m), 2.26 (3H, s), 3.33 (2H, d, J=7.4 Hz), 5.09 (3H, t,
J=7.4 Hz), 5.11 (1H, t, J=7.1 Hz), 6.66 (1H, d, J=2.7
Hz), 6.70 (1H, d, J=2.7 Hz); FABMS m/z 397
[M+H]+; FABHRMS m/z 397.3088 [M+H]+
(C27H40O2 requires 397.3107).
1.34 (3H, s), 1.56 (3H, s), 1.64 (3H, s), 1.66 (2H, m), 2.11
(2H, m), 2.12 (3H, s), 4.40 (1H, s, –OH), 5.08 (1H, t,
J=7.0 Hz), 5.56 (1H, d, J=9.8 Hz), 6.23 (1H, d, J=9.8
Hz), 6.30 (1H, d, J=3.0 Hz), 6.45 (1H, d, J=3.0 Hz);
EI-MS m/z 258 [M+], 175 (base); EI-HRMS m/z
258.1649 [M+] (C17H22O2 requires 258.1620).
1
Preparation of chromen-type compounds (10). A solution
of the hydroquinone (8d) (96 mg, 0.24 mmol) in benzene
(8 mL) was treated with manganese dioxide (42 mg, 0.48
mmol) at room temperature for 30 min. The mixture
was filtered through celite. The fitrate was concentrated
in vacuo, and the resulted residue was subjected to flash
chromatography on SiO2 [hexane–ethyl acetate (30:1)]
to afford a quinone (9d) (72 mg, 76%) as a yellow oil.
Data of 10c: IR nmax (film) 3350 (br) cmꢁ1; H NMR d
1.34 (3H, s), 1.56 (3H, s), 1.65 (3H, d, J=1.8 Hz), 1.66
(2H, m), 1.92–2.03 (6H, m), 2.11 (3H, s), 5.06 (1H, qt,
J=1.3, 7.0 Hz), 5.09 (1H, qt, J=1.3, 7.0 Hz), 5.57 (1H,
d, J=9.8 Hz), 6.23 (1H, d, J=9.8 Hz), 6.30 (1H, d,
J=3.0 Hz), 6.45 (1H, d, J=3.0 Hz); EI-MS m/z 326
[M+], 175 (base); EI-HRMS m/z 326.2238 [M+]
(C22H30O2 requires 326.2246).
1
A solution of the quinone (9d) (37 mg, 0.09 mmol) was
refluxed in pyridine (5 mL) under reflux for 4 h. After
removal of pyridine by evaporation, the residue was
purified by preparative TLC on SiO2 [hexane–ethyl
acetate (15:1)] to afford a chromen (10d) (22 mg, 61%)
as a yellow oil. Compound 10a–c were prepared in the
same manner described above.
Data of 10d: IR nmax (film) 3350 (br) cmꢁ1; H NMR d
1.34 (3H, s), 1.56 (3H, s), 1.58 (3H, s), 1.66 (6H, d,
J=1.8 Hz), 1.66 (2H, m), 1.80–2.11 (10H, m), 2.12 (3H,
s), 4.41 (1H, s, –OH), 5.06 (2H, br. t, J=7.0 Hz), 5.08
(1H, t, J=7.0 Hz), 5.56 (1H, d, J=9.8 Hz), 6.23 (1H, d,
J=9.8 Hz), 6.30 (1H, d, J=3.0 Hz), 6.46 (1H, d, J=3.0
Hz); EI-MS m/z 394 [M+], 175 (base); EI-HRMS m/z
394.2841 [M+] (C27H38O2 requires 394.2872).
1
Data of 9a: IR nmax (film) 1655 cmꢁ1; H NMR d 1.61
(3H, s), 1.73 (3H, d, J=1.3 Hz), 2.03 (3H, d, J=1.3
Hz), 3.09 (2H, dd, J=3.0, 7.3 Hz), 5.19 (1H, qt, J=1.3,
7.3 Hz), 6.45 (1H, dt, J=2.4, 3.0 Hz), 6.53 (1H, qd,
J=1.3, 2.4 Hz); EI-MS m/z 190 [M+], 175 (base); EI-
HRMS m/z 190.1005 [M+] (C12H14O2 requires
190.0994).
Hydrogenation of prenylated chromens to form chroman-
type compounds (11). A mixture of the chromen (10d)
(12 mg, 0.03 mmol) and platinum oxide (5 mg) in ethyl
acetate (5 mL) was stirred under hydrogen atmosphere
at room temperature for 2 h. The mixture was filtered
through celite. After evaporation of the filtrate, the
residue was purified by preparative TLC on SiO2
[hexane–acetone (15:1)] afforded a d-tocopherol (4) (9.3
mg, 74%) as a yellow oil. Compounds 11a–c were also
prepared in the same manner from 10a–c.
1
Data of 9b: IR nmax (film) 1650 cmꢁ1; H NMR d 1.55
(3H, s), 1.58 (3H, s), 1.60 (3H, s), 2.03 (2H, m), 2.04
(3H, s), 2.08 (2H, t, J=6.6 Hz), 3.10 (2H, d, J=7.4 Hz),
5.05 (1H, t, J=7.4 Hz), 5.13 (1H, t, J=7.4 Hz), 6.44
(1H, d, J=2.5 Hz), 6.53 (1H, d, J=2.5 Hz); EI-MS m/z
258 [M+], 149 (base); EI-HRMS m/z 258.1634 [M+]
(C17H22O2 requires 258.1620).
1
Data of 11a: IR nmax (film) 3355 (br) cmꢁ1; H NMR d
1.30 (6H, s), 1.76 (2H, t, J=6.8 Hz), 2.12 (3H, s), 2.70
(2H, t, J=6.8 Hz), 6.39 (1H, d, J=2.9 Hz), 6.48 (1H, d,
J=2.9 Hz); EI-MS m/z 192 [M+], 95 (base); EI-HRMS
m/z 192.1141 [M+] (C12H16O2 requires 192.1150).
1
Data of 9c: IR nmax (film) 1650 cmꢁ1; H NMR d 1.55
(3H, s), 1.60 (6H, d, J=1.0 Hz), 1.61 (3H, s), 1.98 - 2.12
(8H, m), 2.03 (3H, s), 3.10 (2H, d, J=7.4 Hz), 5.07 (2H,
t, J=7.4 Hz), 5.14 (1H, qt, J=1.0, 7.0 Hz), 6.44 (1H, d,
J=2.4 Hz), 6.53 (1H, qt, J=1.3, 2.4 Hz); EI-MS m/z
1
Data of 11b: IR nmax (film) 3375 (br) cmꢁ1; H NMR d
0.84 (6H, d, J=8.0 Hz), 0.86 (3H, s), 1.20–1.70 (9H, m),
1.34 (3H, s), 2.10 (3H, s), 2.67 (2H, t, J=7.0 Hz), 6.36

K. Terashima et al. / Bioorg. Med. Chem. 10 (2002) 1619–1625
1625
(1H, d, J=2.8 Hz), 6.46 (1H, d, J=2.8 Hz); EI-MS m/z
262 [M+], 149 (base); EI-HRMS m/z 262.1939 [M+]
(C17H26O2 requires 262.1933).
(2H, s), 6.68 (2H, s); EI-MS m/z 422 [M+] (base); EI-
HRMS m/z 422.3399 [M+] (C26H40O4 requires 422.3396).
1
Data of 15d: H NMR d 0.82 (6H, d, J=8.0 Hz), 0.85
1
Data of 11c: IR nmax (film) 3375 (br) cmꢁ1; H NMR d
(6H, d, J=8.0 Hz), 0.93 (3H, d, J=8.0 Hz), 1.20–1.80
(24H, m), 2.25 (3H, s), 2.45 (1H, td, J=5.4, 11.0 Hz),
2.53 (1H, td, J=5.9, 11.0 Hz), 3.45 (3H, s), 3.58 (3H, s),
4.88 (2H, s), 5.09 (2H, s), 6.67 (2H, s); FABMS m/z 493
[M+H]+; FABHRMS m/z 493.4252 [M+H]+
(C31H56O4 requires 493.4257).
0.84 (6H, d, J=7.4 Hz), 0.86 (3H, d, J=7.4 Hz), 1.20–
1.60 (18H, m), 1.24 (3H, s), 2.18 (3H, s), 2.46 (1H, td,
5.0, 11.0 Hz), 2.56 (1H, td, J=5.8, 11.0 Hz), 6.39 (1H,
d, J=2.8 Hz), 6.45 (1H, d, J=2.8 Hz); EI-MS m/z 332
[M+], 137 (base); EI-HRMS m/z 332.2898 [M+]
(C22H36O2 requires 332.2715).
1
Data of 12a: IR nmax (film) 3400 (br) cmꢁ1; H NMR d
1
Data of 4: IR nmax (film) 3375 (br) cmꢁ1; H NMR d
0.84 (6H, d, J=7.4 Hz), 1.08 (1H, tq, J=5.5, 7.4 Hz),
1.26 (2H, dt, J=5.5, 7.4 Hz), 2.17 (3H, s), 2.67 (2H, t,
J=7.4 Hz), 6.36 (1H, d, J=2.6 Hz), 6.46 (1H, d, J=2.6
Hz); EI-MS m/z 194 [M+], 165 (base); EI-HRMS m/z
194.1329 [M+] (C12H16O2 requires 194.1306).
0.83 (6H, d, J=7.0 Hz), 0.84 (3H, d, J=7.4 Hz), 0.86
(3H, d, J=7.4 Hz), 1.20–1.79 (23H, m), 1.23 (3H, s),
2.11 (3H, s), 2.68 (2H, t, 7.0 Hz), 6.37 (1H, d, J=2.8
Hz), 6.47 (1H, d, J=2.8 Hz); EI-MS m/z 402 [M]+; EI-
HRMS m/z 402.3489 [M+] (C27H46O2 requires
402.3498).
1
Data of 12b: IR nmax (film) 3400 (br) cmꢁ1; H NMR d
0.84 (6H, d, J=7.4 Hz), 0.86 (3H, d, J=7.3 Hz), 1.10–
1.60 (10H, m), 2.18 (3H, s), 2.47 (1H, td, J=5.9, 10.2
Hz), 2.55 (1H, td, J=5.1, 10.2 Hz), 6.45 (2H, s); EI-MS
m/z 264 [M+] (base); EI-HRMS m/z 264.2048 [M+]
(C21H36O4 requires 264.2089).
Preparation of hydroquinone possessing saturated side
chain (12). A mixture of the protected hydroquinone
(7d) (15 mg, 0.03 mmol) and platinum oxide (5 mg) in
ethyl acetate (5 mL) was stirred at room temperature for
2 h. The mixture was filtered through celite. After eva-
poration of the filtrate, the residue was purified by pre-
parative TLC on SiO2 [hexane–acetone (15:1)] afforded
a MOM ether having a saturated side-chain (15d) (14
mg, 89%) as a yellow oil.
1
Data of 12c: IR nmax (film) 3400 (br) cmꢁ1; H NMR d
0.82 (6H, d, J=8.0 Hz), 0.83 (3H, d, J=8.0 Hz), 0.92
(3H, d, J=8.0 Hz), 1.20–1.60 (17H, m), 2.25 (3H, s),
2.47 (1H, td, 5.4, 11.0 Hz), 2.53 (1H, td, J=5.9, 11.0
Hz), 6.69 (2H, s); EI-MS m/z 334 [M+], 175 (base); EI-
HRMS m/z 334.2885 [M+] (C22H38O2 requires
334.2872).
The MOM ether (15d) (11 mg, 0.02 mmol) in a mixed
solvent of chloroform and methanol (1:1) (5 mL) was
refluxed with concentrated hydrochloric acid (30 mL) for
1 h. The mixture was extracted with chloroform (20 mL)
and the organic layer was successively washed with
water and brine, and dried over anhydrous sodium sul-
fate. Purification by column chromatography on SiO2
[chloroform–ethyl acetate (20:1)] afforded compound
12d (6.3 mg, 77%) as a yellow oil. Compounds 12a–c
were also prepared in the same manner.
1
Data of 12d: IR nmax (film) 3400 (br) cmꢁ1; H NMR d
0.82 (6H, d, J=8.0 Hz), 0.84 (6H, d, J=8.0 Hz), 0.93
(3H, d, J=8.0 Hz), 1.20–1.80 (24H, m), 2.25 (3H, s),
2.47 (1H, td, J=5.4, 11.0 Hz), 2.53 (1H, td, J=5.9, 11.0
Hz), 6.46 (2H, s); FABMS m/z 405 [M+H]+;
FABHRMS m/z 405.3726 [M+H]+ (C27H48O2 requires
405.3732).
1
Data of 15a: H NMR, d 0.84 (6H, d, J=7.4 Hz), 1.06
(1H, tq, J=5.5, 7.4 Hz), 1.26 (2H, dt, J=5.5, 7.4 Hz),
2.17 (3H, s), 2.64 (2H, t, J=7.4 Hz), 3.45 (3H, s), 3.58
(3H, s), 4.88 (2H, s), 5.10 (2H, s), 6.36 (1H, d, J=2.6
Hz), 6.46 (1H, d, J=2.6 Hz); EI-MS m/z 282 [M+], 209
(base); EI-HRMS m/z 282.1861 [M+] (C12H16O2
requires 282.1831).
Acknowledgements
This work was partly supported by the Ministry of
Education, Science, Sports and Culture of Japan (High-
Tech Research Center Project). We are also grateful to
the Meijo University Grants Committee and Matsuura
Yakugyo Co., Ltd. for financial supports. We thank
Mr. Tadashi Furukawa for his experimental assistance.
1
Data of 15b: H NMR d 0.83 (6H, d, J=8.0 Hz), 0.85
(3H, d, J=7.3 Hz), 1.10 - 1.60 (10H, m), 2.15 (3H, s),
2.46 (1H, td, J=5.4, 11.0 Hz), 2.52 (1H, td, J=5.9, 11.0
Hz), 3.45 (3H, s), 3.58 (3H, s), 4.88 (2H, s), 5.08 (2H, s),
6.68 (2H, s); EI-MS m/z 352 [M+] (base); EI-HRMS
m/z 352.2568 [M+] (C21H36O4 requires 352.2614).
References and Notes
1. Terashima, K.; Shimamura, T.; Tanabayashi, M.; Aqil, M.;
Akinniyi, J. A.; Niwa, M. Heterocycles 1997, 45, 1559.
2. Ekimoto, H.; Takahashi, K.; Matsuda, A.; Takita, T.;
Umezawa, H. J. Antibiot. 1985, 38, 1077.
3. Mori, K.; Uno, T. Tetrahedron 1989, 45, 1945.
4. Kamal-Eldin, A.; Appelqvist, L. A. Lipids 1996, 31, 671.
1
Data of 15c: H NMR d 0.83 (6H, d, J=8.0), 0.85 (3H,
d, J=8.0), 0.92 (3H, d, J=8.0), 1.20–1.80 (17H, m), 2.25
(3H, s), 2.53 (1H, td, 5.4, 11.0 Hz), 2.63 (1H, td, J=5.9,
11.0 Hz), 3.46 (3H, s), 3.58 (3H, s), 4.88 (2H, s), 5.09