Synthesis of totarane diterpenes: Totarol, maytenoquinone, 6-deoxymaytenoquinone and 8,11,13-totaratriene-12,13-diol

Article abstract of DOI:10.1248/cpb.56.287

The syntheses of four totarane diterpenes - totarol, 8,11,13-totaratriene- 12,13-diol, 6-deoxymaytenoquinone and maytenoquinone - are described. Totarol was synthesized via cyclization of a modified polyene. 8,11,13-Totaratriene-12, 13-diol was prepared from natural totarol by ortho-oxidation with mCBPO (m-chlorobenzoyl peroxide). Maytenoquinone and 6-deoxymaytenoquinone were synthesized from 8,11,13-totaratriene-12,13-diol. ¹H-NMR analysis showed that tautomeric isomerization between 6-deoxymaytenoquinone (2-hydroxy-4-quinone methide) and the ortho-quinone was very slow.

Full text of DOI:10.1248/cpb.56.287

March 2008
Chem. Pharm. Bull. 56(3) 287—291 (2008)
287
Synthesis of Totarane Diterpenes: Totarol, Maytenoquinone,
-Deoxymaytenoquinone and 8,11,13-Totaratriene-12,13-diol
6
Masahiro TADA,* Jun KURABE, Hiroaki YASUE, and Tomohisa IKUTA
Laboratory of Bioorganic Chemistry, Tokyo University of Agriculture and Technology; Fuchu, Tokyo 183–8509, Japan.
Received October 17, 2007; accepted November 24, 2007; published online January 8, 2008
The syntheses of four totarane diterpenes—totarol, 8,11,13-totaratriene-12,13-diol, 6-deoxymaytenoquinone
and maytenoquinone—are described. Totarol was synthesized via cyclization of a modified polyene. 8,11,13-
Totaratriene-12,13-diol was prepared from natural totarol by ortho-oxidation with mCBPO (m-chlorobenzoyl
peroxide). Maytenoquinone and 6-deoxymaytenoquinone were synthesized from 8,11,13-totaratriene-12,13-diol.
1
H-NMR analysis showed that tautomeric isomerization between 6-deoxymaytenoquinone (2-hydroxy-4-quinone
methide) and the ortho-quinone was very slow.
Key words synthesis; totarol; maytenoquinone; polyene cyclization; quinone methide; tautomeric isomerization
27)
Infections caused by drug-resistant organisms, such as and 6-deoxymaytenoquinone (6) (Fig. 1).
methicillin-resistant Staphylococcus aureus (MRSA), vanco-
mycin-resistant Enterococcus (VRE), and chloroquine-resist- Results and Discussion
ant malaria, are undergoing significant increases worldwide.
Totarol We previously reported syntheses of 12 natural
In previous studies, we reported the syntheses of abietane diterpenes via stereoselective cyclization of a modi-
1)
anti-MRSA and anti-VRE active diterpenes and details of fied polyene. Totarol 3 has a migrated abietane carbon
1)
their structure–activity relationships. Activity was found to skeleton (totarane skeleton) which contains an isopropyl
vary significantly depending on structure, and two quinone group at C-14. Thus, we planned to synthesize totarol 3 via
2,3)
methides, abietaquinone methide
(11-hydroxy-12-oxo- cyclization of another modified polyene (10).
7
,9(11),13-abietatriene) (1) (0.5—1 mg/ml minimum in-
Polyene 10 was synthesized by alkylation of 2-methoxy-6-
(2) (4— methylbenzoic acid (8) with lithium diisopropylamide (LDA)
4—7)
hibitory concentration (MIC)) and taxodione
1
0 mg/ml MIC) showed potent activity against both MRSA and geranyl chloride, followed by esterification with
1) 8—10)
and VRE. In addition, Kubo
reported that a migrated iodomethane and K CO in CH CN. Polyene 10 was treated
2 3 3
abietane (totarane) derivative, totarol (3), which was isolated with boron trifluoride-diethyl ether (BF ·Et O) in ni-
3
2
from the bark of Podocarpus nagi (Podocarpaceae), showed tromethane to give a mixture of the A/B trans-compound 11
potent antibacterial activity against MRSA, and Evans re- and unknown compound 12 in a 3 : 1 ratio (50%). During
1
1—18)
ported anti-MRSA activity in totarol (3), ferruginol (4),
synthesis of abietanes, we were able to control stereoselectiv-
19)
and their abietane derivatives. Totarol was synthesized by ity in the cyclization of the modified polyene by varying the
20—22)
28)
three groups.
W. E. Campbell reported the isolation of 4 size of the ester alkyl group on the polyene (Chart 1).
and 8,11,13-totaratriene-12,13-diol (5) from Harpagophytum
The mechanism of cyclization of 10 is not clear. When we
procumbens as anti-plasmodial compounds which were ac- consider the stepwise mechanism, there are two possible in-
tive against both chloroquine-resistant and chloroquine-sen- termediates, M and N (Chart 2). Intermediate M gives the
23)
sitive strains. Both 4 and 5 showed low cytotoxicity. A/B trans-compound 11, while intermediate N gives the A/B
1
1,24—27)
Maytenoquinone (7)
is an isomeric quinone methide cis-isomer. As the energy difference between the two inter-
of taxodione 2. These results suggested to us that phenolic mediates was estimated to be quite small, further experi-
and quinone methide diterpenes show potential as novel ments varying the alkyl group of ester to improve stereose-
treatments for these drug-resistant organisms. We report here lectivity in the cyclization reaction were not attempted. The
syntheses of 3 and 5 and their quinone methide derivatives 7 crude cyclized product 11 was methylated using methyl-
lithium in tetrahydrofuran (THF) to give acetyl derivative 13
(82%), which was further methylated with methyl magne-
sium bromide in THF to afford tertiary alcohol 14 (63%).
The unknown compound 12 and its derivative were removed
during the purification of tertiary alcohol 14 with column
chromatography. Dehydration of 14 by heating under reflux
in toluene with p-toluenesulfonic acid gave isopropenyl com-
pound 15 (83%). After deprotection of the methyl group of
1
5 with boron tribromide in CH Cl , the product (16) was
2 2
hydrogenated with H -PtO in ethanol for 8 d to give totarol
2
2
(3) (74% from 15). The A/B cis-isomer of totarol, which may
be derived from 12, was not observed in the NMR spectrum
of totarol. As natural totarol has recently been offered for
sale, the NMR spectrum of synthesized crude totarol was
compared with that of natural totarol to confirm that the
Fig. 1. Phenols and Quinone Methides with Abietane and Totarane Skele-
tons
∗
To whom correspondence should be addressed. e-mail: tada@cc.tuat.ac.jp
© 2008 Pharmaceutical Society of Japan

2
88
Vol. 56, No. 3
Chart 1. Synthesis of Totarol via Polyene Cyclization
When the tautomeric equilibrium between ortho-quinone
1
9 and 2-hydroxy-1,4-quinone methide 6 was investigated
1
using H-NMR spectroscopy with acetone as solvent, 19 was
found to undergo slow conversion to 6. The mixture of ortho-
quinone 19 and quinone methide 6 (14 : 1) was dissolved in
acetone and stirred without a catalyst at ambient temperature.
After 2 d, the ratio of 19 to 6 was 2.6 : 1; after 7 d, the ratio
was 0.9 : 1. This shows that the isomerization reaction of 19
to form 6 is slower than in the case of abietaquinone methide
1
, and that quinone methide 6 is a more stable isomer than
quinone 19. The isomerization of 19 to 6 was also observed
on silica gel.
Burnell reported that 6 was prepared by oxidation of cate-
chol 5 with Ag O, and maytenoquinone 7 was obtained from
2
quinone methide 6 by auto-oxidation during silica gel col-
27)
umn chromatography with slow elution by benzene. In our
experiment, both 19 and 6 were obtained by Ag O oxidation
2
Chart 2. Two Transition States (M and N) in the Cyclization of Polyene 12 of 5, and the equilibrium between the two species was very
slow in solution without a catalyst. The isolated quinone me-
structure was correct.
thide 6 was oxidized on a short column of silica gel for
Maytenoquinone Efficient ortho-oxidation of phenol 45 min under a stream of air from a small air pump, giving
was reported in our synthesis of abietaquinone methide from maytenoquinone 7. The spectral properties of 7 were identi-
2
4,25)
dehydroabietic acid using a stable diacyl peroxide, meta- cal to those in the literature.
The structure–activity rela-
3)
chlorobenzoyl peroxide (mCBPO). Totarol 3 was thus tionships and anti-MRSA activities of the synthesized to-
oxidized with mCBPO in CH Cl for 19 h to afford a mixture tarane diterpenes and related compounds will be reported
2
2
of the ortho-oxidation product 17 and its isomer 18, which is elsewhere.
thought to be formed by ester exchange reaction of 17. The
In conclusion, we synthesized four totarane diterpenes. To-
mixture was reduced with LiAlH in THF for 3 h to give a tarol (3) was prepared via polyene cyclization; ortho-oxida-
4
stable catechol (8,11,13-totaratriene-12,13-diol, 5) in 60% tion of totarol with mCBPO followed by deprotection gave
yield. The spectral features of 5 were identical to those of the 8,11,13-totaratriene-12,13-diol (5), which was identical to
plasmodial-active compound which was isolated from the anti-plasmodial compound isolated from Harpagophytum
Harpagophytum procumbens (Devil’s claw) by Campbell et procumbens (Devil’s claw). Oxidation of catechol 5 gave two
23)
al. In the synthesis of abietaquinone methide 1, the inter- isomers, ortho-quinone 19 and quinone methide 6; isomer-
mediate catechol was not isolated because it was easily oxi- ization of 19 to 6 took place slowly. Finally, 6 was oxidized
1,3)
dized to abietaquinone methide 1 with oxygen. As cate- to maytenoquinone 7 on silica gel by oxygen.
chol 5 is stable under air, it was oxidized with Ag O in
2
Experimental
CHCl under reflux for 16 h to give a mixture of two isomers,
3
General Procedures NMR spectra were measured on a JEOL alpha-
ortho-quinone 19 and quinone methide 6 (14 : 1), in 99%
1
13
1
13
6
00 ( H: 600 MHz, C: 150.8 MHz) or JEOL AL-400 ( H: 400 MHz, C:
27)
yield. The isomer ratio varied with reaction conditions and 100.5 MHz) spectrometer in CDCl using tetramethylsilane as an inter-
3
reaction time (Chart 3).
nal standard (J-values in Hz). IR spectra were measured on a JEOL JIR-

March 2008
289
Chart 3. Synthesis of Maytenoquinone
WINSPEC 50 infrared spectrometer. Mass spectra were recorded on a JEOL (316.2038 Calcd for C H O ).
2
0
28
3
JMS-SX102A spectrometer. mp were measured on a MEL-TEMP (Labora-
tory Device) and were uncorrected. TLC was carried out on Silica gel 60
Methyl 1,2,3,4,4a,9,10,10a-Octahydro-7-methoxy-1,1,4a-trimethyl-
phenanthrene-8-carboxylate (11), (12) A solution of 2-(4,8-dimethyl-
(0.25 mm thickness) with fluorescent indicator (Macherey-Nagel). Silica gel nona-3,7-dienyl)-6-methoxy-benzoate (10) (203 mg) in nitromethane (3 ml)
(
6 nm, BW-127ZH, Fuji Silysia Chemical Ltd.) was used for column chro- was added to nitromethane (7 ml) solution of BF ·OEt (0.32 ml, 2.38 mmol)
3
2
matography.
at ambient temperature and the solution was stirred for 15 h at ambient tem-
perature. The reaction was stopped by addition of aqueous saturated
NaHCO3 and the mixture was extracted with EtOAc. The solution was
2-(4,8-Dimethylnona-3,7-dienyl)-6-methoxybenzoic Acid (9) To THF
(20 ml) solution of diisopropylamine (0.6 ml, 3.89 mmol) and n-butyl
lithium in hexane (2.7 ml, 3.89 mmol), 2-methoxy-6-methylbenzoic acid 8
washed with brine, dried over MgSO and evaporated. The residue was chro-
4
(308 mg, 1.85 mmol) in THF (5 ml) was added at ꢀ78 °C. The solution was matographed on a silica gel column with EtOAc–hexane (1 : 7) to give white
stirred for 30 min and then geranyl chloride (480 mg, 2.80 mmol) in THF solid of a mixture (3 : 1) of 11 and 12 (115 mg, 0.32 mmol, 50%), 11
1
(
5 ml) was added. The solution was stirred for further 1 h and was allowed to (major): H-NMR (600 MHz, CDCl ) d: 7.25 (1H, d, Jꢁ8.4 Hz), 6.72 (1H,
3
warm up to ambient temperature, and the reaction was stopped with 1 M-
d, Jꢁ8.4 Hz), 3.89 (3H, s), 3.78 (3H, s), 2.84—2.75 (2H, m), 2.24 (1H, d,
HCl. The mixture was extracted with EtOAc. The organic layer was washed Jꢁ11 Hz), 1.84 (1H, m), 1.15 (3H, s), 0.93 (3H, s), 0.91 (3H, s); C-NMR
13
with brine, dried over MgSO4 and evaporated. The residue was chro- (150 MHz, CDC1 ) d: 169.3, 153.7, 143.1, 133.3, 126.5, 125.8, 108.8, 55.9,
3
matographed on silica gel column with EtOAc–hexane (1 : 4) to give white 52.1, 49.9, 41.6, 39.1, 37.5, 33.3, 33.2, 27.4, 24.9, 21.5, 19.3, 18.5; IR (KBr
ꢀ1
crystals of 9 (321 mg: 57% yield): 2-(4,8-Dimethylnona-3,7-dienyl)-6- cm ) 2944, 2846, 1729, 1591, 1486, 1436, 1383, 1207, 1070, 971, 811; MS
1
ꢂ
methoxybenzoic acid (9): mp 54—55 °C; H-NMR (600 MHz CDC1 ) d: (EI) (rel. int. %) 332 (M 60), 301 (100), 269 (39), 231 (24), 201 (39), 173
3
7
.32 (1H, t, Jꢁ8.0 Hz), 6.89 (1H, d, Jꢁ8.0 Hz), 6.82 (1H, d, Jꢁ8.0 Hz), 5.19
1H, t, Jꢁ7.2 Hz), 5.09 (1H, t, Jꢁ7.2 Hz), 3.90 (3H, s), 2.79 (2H, t,
(16), 115 (12), 91 (4), 69 (12); HR-MS (EI) m/z 316.2011 (316.2038 Calcd
for C H O ); 12 (minor): H-NMR (600 MHz, CDCl ) d: 7.25 (1H, d,
1
(
2
0
28
3
3
Jꢁ8.0 Hz), 2.31 (2H, q, Jꢁ7.3 Hz), 2.08—2.02 (2H, m), 1.99—1.95 (2H, Jꢁ8.7 Hz), 6.73 (1H, d, Jꢁ8.7 Hz), 3.90 (3H, s), 3.79 (3H, s), 1.21 (3H, s),
1
3
13
m), 1.68 (3H, s), 1.59 (3H, s), 1.56 (3H, s); C-NMR (150 MHz; CDC1 ) d: 0.92 (3H, s), 0.90 (3H, s); C-NMR (150 MHz, CDC1 ) d: 168.4, 153.6,
3
3
1
5
2
69.6, 156.8, 143.2, 136.1, 131.3, 131.1, 124.3, 123.3, 122.9, 121.1, 108.8,
136.3, 135.4, 122.9, 108.3, 55.7, 52.1, 49.7, 43.1, 38.1, 36.8, 34.5, 32.6,
ꢀ1
6.2, 39.7, 34.2, 29.8, 26.7, 25.7, 17.6, 15.9; IR (KBr, cm ) 3077, 2917, 23.3, 22.7, 19.1, 17.6, 14.2.
854, 1697, 1587, 1417, 1402, 1267, 1091, 914, 761, 732, 646; MS (EI) (rel. 8-Acetyl-1,2,3,4,4a,9,10,10a-octahydro-7-methoxy-1,1,4a-trimeth-
int. %) 302 (Mꢂ8), 259 (77), 215 (82), 166 (78), 148 (94), 109 (25), 81 ylphenanthrene (13) To THF (10 ml) solution of CH Li (1.8 ml in hexane:
3
(
34), 69 (100); HR-MS (EI) m/z: 302.1845 (Calcd for C H O 302.1882).
2.05 mmol), THF (5 ml) solution of esters 11 and 12 (121 mg, 0.38 mmol)
1
9
26
3
Methy1 2-(4,8-Dimethylnona-3,7-dienyl)-6-methoxy-benzoate (10) was added and the mixture was stirred for 15 h at 0 °C. The reaction was
To CH CN solution (10 ml) of 2-(4,8-dimethylnona-3,7-dienyl)-6-methoxy- stopped by addition of aqueous saturated NH Cl and the mixture was ex-
3
4
benzoic acid 9, K CO (431 mg, 3.11 mmol) and CH I (0.3 ml, 5.13 mmol)
tracted with EtOAc. The solution was washed with brine, dried over MgSO4
2
3
3
were added and the mixture was heated under reflux for 16 h. The reaction
and evaporated. The residue was chromatographed on a silica gel column
was stopped by addition of water and the mixture was extracted with ethyl with EtOAc–hexane (1 : 7) to give white solid of 13 (94 mg, 0.31 mmol,
1
acetate. The organic layer was washed with brine, dried over MgSO and
82%): H-NMR (600 MHz CDC1 ) d: 7.22 (1H, d, Jꢁ8.7 Hz), 6.72 (1H, d,
4
3
evaporated. The product was chromatographed on a silica gel column with Jꢁ8.7 Hz), 3.77 (3H, s), 2.80—2.65 (3H, m), 2.46 (3H, s), 2.24 (1H, d,
EtOAc–hexane (1 : 7) to give a colorless oil of methy1 2-(4,8-dimethylnona- Jꢁ13 Hz), 1.85 (1H, m), 1.16 (3H, s), 0.91 (3H, s), 0.90 (3H, s); C-NMR
13
1
3
,7-dienyl)-6-methoxy-benzoate (10) (268 mg, 0.84 mmol, 82%): H-NMR (150 MHz CDCl ) d: 206.8, 153.2, 143.4, 130.6, 126.0, 125.2, 108.6, 55.6,
3
(
(
600 MHz: CDCl ) d: 7.26 (1H, t, Jꢁ8.0 Hz), 6.82 (1H, d, Jꢁ8.0 Hz), 6.76
49.9, 41.6, 39.2, 37.6, 33.3, 33.2, 32.1, 27.3, 25.0, 21.6, 19.3, 18.8; IR (KBr
ꢀ
3
1
1H, d, Jꢁ8.0 Hz), 5.17—5.131 (1H, m), 5.10—5.06 (1H, m), 3.90 (3H, s), cm ) 2940, 2854, 1693, 1589, 1479, 1373, 1270, 1070, 1018, 809, 570; MS
ꢂ
3
(
.81 (3H, s), 2.56 (2H, t, Jꢁ8.0 Hz), 2.26 (2H, q, Jꢁ7.6 Hz), 2.08—2.03 (EI) (rel. int. %) 300 (M 90), 285 (100), 273 (28), 241 (27), 215 (95), 179
2H, m), 1.99—1.94 (2H, m), 1.68 (3H, s), 1.60 (3H, s), 1.56 (3H, s); C- (39), 148 (57), 109 (22), 91 (16), 69 (76); HR-MS (EI) m/z 300.210
1
3
1
NMR (150 MHz; CDCl ) d: 168.9, 156.2, 140.8, 136.0, 131.3, 130.2, 124.3,
(300.2089 Calcd for C H O ). Minor: H-NMR (600 MHz CDC1 ) d: 6.71
20 28 2 3
13
3
1
1
1
2
23.5, 123.3, 121.6, 108.5, 55.9, 52.1, 39.6, 33.7, 29.6, 26.6, 25.6, 17.6,
(1H, d, Jꢁ8.4 Hz), 3.78 (3H, s), 2.43 (3H, s), 1.12 (3H, s), 0.92 (3H, s); C-
ꢀ1
5.9; IR (NaCl cm ) 2927, 2865, 1735, 1585, 1471, 1375, 1270, 1189, NMR (150 MHz CDCl ) d: 213.0, 146.9, 136.5, 134.1, 132.2, 108.1, 100.6,
3
ꢂ
110, 1072, 954, 833; MS (EI) (rel. int. %) 332 (M 7), 285 (11), 241 (36),
55.4, 49.6, 43.0, 38.2, 34.4, 32.6, 27.1, 23.2, 22.8, 21.9, 21.0, 19.2, 18.7.
1,2,3,4,4a,9,10,10a-Octahydro-8-(1-hydroxy-1-methylethyl)-7-me-
15 (89), 179 (64), 148 (81), 81 (26), 58 (100); HR-MS (EI) m/z 316.2073

2
90
Vol. 56, No. 3
1
3
thoxy-1,1,4a-trimethylphenanthrene (14) To THF solution (10 ml) of
(3H, s), 0.97 (3H, s); C-NMR (CDCl , 150 MHz) d: 142.4, 141.0, 131.7,
3
CH MgBr (1.10 ml in THF: 1.04 mmol), THF (5 ml) solution of 8-acetyl-
125.5, 109.2, 49.6, 41.6, 39.5, 37.6, 33.3, 33.2, 28.2, 27.5, 25.1, 21.6, 20.4,
,2,3,4,4a,9,10,10a-octahydro-7-methoxy-1,1,4a-trimethylphenanthrene 13 20.4, 19.5, 19.4; IR (NaCl cm ) 3502, 2933, 2877, 1711, 1605, 1485, 1466,
3
ꢀ1
1
(
31 mg, 0.10 mmol) was added and the mixture was stirred for 14 h at 0 °C.
1441, 1377, 1275, 1190, 1101, 1043, 1007, 947, 866; LR-EI-MS m/z (%):
302 (88, M ), 287 (100), 217 (47), 191 (54); HR-EI-MS m/z (302.4570 for
ꢂ
The reaction was stopped by addition of 1 M HCl and the mixture was ex-
tracted with EtOAc. The solution was washed with brine, dried over MgSO4 C H O ).
20
30
2
and evaporated. The residue was chromatographed on a silica gel column
o-Quinone (19) and 6-Deoxymaytenoquinone (6) To a solution of the
with EtOAc–hexane (1 : 7) to give white oil of a tertiary alcohol 14 (22 mg,
catechol 5 (82.6 mg, 0.273 mmol) in CHCl3 (10 ml), Ag O (135.0 mg,
0.583 mmol) was added and the mixture was heated under reflux for 16 h.
2
1
0
.070 mmol, 63%): H-NMR (600 MHz CDCl ) d: 7.17 (1H, d, Jꢁ8.7 Hz),
3
6
.80 (1H, d, Jꢁ8.7 Hz), 3.85 (3H, s), 3.09—2.98 (2H, m), 2.20 (1H, d, The mixture was filtered through Celite and the filtrate was evaporated to
give a yellow oil of mixture of o-quinone 19 and 6-deoxymaytenoquinone
Jꢁ13 Hz), 1.87 (1H, m), 1.8—1.5 (3H, m), 1.47 (1H, d, Jꢁ14.4 Hz), 1.4—
.2 (3H, m), 1.70 (3H, s), 1.66 (3H, s), 1.19 (3H, s), 0.94 (3H, s), 0.91 (3H, 6 (81.0 mg, 0.270 mmol, 99%, 19 : 6, 14 : 1 by H-NMR). The products
1
1
13
s); C-NMR (150 MHz CDC1 ) d: 155.0, 144.6, 134.6, 134.3, 124.3, 110.3, (167.0 mg, 0.556 mmol) were dissolved in acetone and absorbed on silica
3
7
1
9
5.5, 55.9, 55.8, 49.7, 41.4, 40.0, 38.5, 33.1, 31.9, 31.5, 31.4, 24.9, 21.6,
gel. The mixture was allowed to stand under air at room temperature for
ꢀ1
9.6, 19.5; IR (KBr cm ) 3502, 2929, 2863, 1585, 1463, 1373, 1249, 1072, 19 h. The product was extracted with EtOAc and the solution was evapo-
44, 804; MS (EI) (rel. int. %) 316 (2), 299 (15), 298 (45), 283 (76); HR-
rated. The residue was chromatographed on a silica gel column with
MS (EI) m/z: 316.2388 (316.2402 Calcd for C H O ).
EtOAc–hexane (1 : 8) to give yellow solid of p-quinone methide 6 (54.6 mg,
2
1
32
2
1
,2,3,4,4a,9,10,10a-Octahydro-8-isopropenyl-7-methoxy-1,1,4a-tri- 0.182 mmol, 33%) and a crude 19 (50.4 mg).
methylphnanthrene (15) Toluene (15 ml) solution of a tertiary alcohol 14
The products (82.6 mg, 0.2.73 mmol) were dissolved in acetone (20 ml)
21 mg, 0.066 mmol) and p-toluenesulfonic acid (5 mg) was heated under re- and stirred for 2 d without catalyst at ambient temperature to give 2.6 : 1
(
flux for 15 h under Ar. The reaction was stopped by addition of aqueous sat- mixture of 19 and 6. The mixture was stirred totally for 7 d and the ratio of
urated NH Cl and the mixture was extracted with EtOAc. The solution was 19 and 6 was changed to 0.9 : 1.
4
1
washed with brine, dried over MgSO and evaporated. The residue was chro-
o-Quinone (19): Reddish oil; H-NMR (CDCl , 600 MHz) d: 6.16 (1H, s),
4
3
matographed on a silica gel column with EtOAc–hexane (1 : 7) to give color- 3.01 (1H, sept, Jꢁ7.2 Hz), 2.94—2.87 (1H, m), 2.74—2.65 (1H, m), 2.00—
less oil of 1,2,3,4,4a,9,10,10a-octahydro-8-isopropenyl-7-methoxy-1,1,4a- 1.92 (1H, m), 1.91—1.84 (1H, m), 1.72—1.59 (3H, m), 1.52—1.30 (3H, m),
1
trimethylphnanthrene 15 (17 mg, 0.05 mmol, 83%): H-NMR (600 MHz
1.27—1.16 (1H, m), 1.24 (3H, d, Jꢁ7.2 Hz), 1.21 (3H, s), 1.20 (3H, d,
1
3
CDC1 ) d: 7.16 (1H, d, Jꢁ8.7 Hz), 6.72 (1H, d, Jꢁ8.7 Hz), 6.71 (1H, d,
Jꢁ8.0 Hz), 5.26 (1H, s), 4.76 (1H, s), 3.77 (3H, s), 2.30—2.26 (1H, m), 181.7, 180.2, 167.094, 145.9, 143.1, 120.8, 46.5, 41.1, 39.5, 38.4, 33.8,
Jꢁ7.2 Hz), 0.95 (3H, s), 0.94 (3H, s); C-NMR (CDCl , 150 MHz) d:
3
3
2
.02—1.9 (4H, m), 1.85 (1H, m), 1.8—1.5 (2H, m), 1.47 (1H, d, 32.7, 27.9, 26.8, 22.4, 21.8, 20.3, 20.0, 18.7, 18.4.
Jꢁ13.2 Hz), 1.4—1.2 (2H, m) 1.28 (3H, s), 1.19 (3H, s), 0.95 (3H, s), 0.93
p-Quinone Methide (6): Yellow solid mp 96 °C; [a]D 27.3° (cꢁ0.011 in
13
1
(
3H, s); C-NMR (150 MHz; CDC1 ) d: 153.6, 135.4, 133.5, 129.0, 128.7, acetone); H-NMR (CDCl , 600 MHz) d: 7.17 (1H, dd, Jꢁ6, 2.4 Hz), 6.96
3
3
1
2
1
1
25.9, 114.7, 108.2, 55.6, 49.7, 41.7, 39.3, 37.0, 33.3, 32.7, 29.6, 25.6, 23.1,
(1H, s), 6.31 (1H, s), 3.12 (1H, sept, Jꢁ7.2 Hz), 2.64—2.59 (1H, m), 2.49—
ꢀ1
1.6, 19.4, 14.0; IR (KBr cm ) 3075, 2927, 2854, 1645, 1585, 1479, 1263,
101, 1076, 892, 802; MS (EI) (rel. int. %) 298 (60), 283 (100), 215 (75),
87 (41), 167 (38), 149 (82), 97 (25), 69 (47); HR-MS (EI) m/z: 298.2301
2.43 (1H, m), 2.02—1.98 (1H, m), 1.72—1.62 (2H, m), 1.56 (1H, dd,
Jꢁ11.4, 4.2 Hz), 1.51—1.42 (2H, m), 1.36 (3H, d, Jꢁ7.2 Hz), 1.32 (3H, d,
Jꢁ7.2 Hz), 1.22 (1H, dt, Jꢁ13.2, 4.2 Hz), 1.09 (3H, s), 1.00 (3H, s), 0.93
1
3
(
298. 2297 Calcd for C H O).
(3H, s); C-NMR (CDCl , 150 MHz) d: 181.6, 162.1, 144.7, 143.4, 130.2,
21
30
3
Totarol (3) To CH Cl (13 ml) solution of 1,2,3,4,4a,9,10,10a-octahy-
127.1, 117.1, 48.7, 41.4, 38.3, 36.9, 33.3, 32.4, 26.5, 26.4, 22.0, 21.6, 20.4,
18.7; IR (cm KBr) 3448, 3327, 3294, 2949, 2929, 2870, 1612, 1549,
2
2
ꢀ1
dro-8-isopropenyl-7-methoxy-1,1,4a-trimethylphnanthrene 15, BBr3 (0.01
ml) was added and the solution was stirred for 3 h at 0 °C. The reaction was 1464, 1431, 1377, 1300, 1277, 1277, 1217, 1196, 1109, 887, 714, 623.
stopped by addition of CH OH and extracted with EtOAc–brine. The or-
Maytenoquinone (7) 6-Deoxymaytenoquinone (18.40 mg, 0.061
6
3
ganic layer was washed with brine, dried over MgSO and evaporated. The mmol) was dissolved in acetone and absorbed on 2 g of silica gel. The silica
4
residue was chromatographed on a silica gel column with EtOAc–hexane gel with 6 was packed in a short column. The silica gel mixture was allowed
(1 : 10) to give white oil. The product was dissolved in EtOH (5 ml) and the to react with air stream through a small air pump at room temperature for
solution was stirred with PtO (1.5 mg) under H for 8 d. The mixture was 45 min. The product was extracted with EtOAc and the solution was evapo-
2
2
filtered through Celite and the solution was evaporated. The residue was rated. The residue was chromatographed on a silica gel column with
chromatographed on a silica gel column with EtOAc–hexane to give color- EtOAc–hexane (1 : 5) to give orange solid of maytenoquinone 7 (3.7 mg,
1
1
less oil of totarol 3 (7 mg, 0.02 mmol, 74%): H-NMR (600 MHz CDCl ) d: 0.012 mmol, 20%): H-NMR (CDCl , 400 MHz) d: 7.14 (1H, s), 6.61 (1H,
3
3
6
.99 (1H, d, Jꢁ8.7 Hz), 6.50 (1H, d, Jꢁ8.7 Hz), 4.42 (1H, s), 3.34—3.23 d, Jꢁ1.2 Hz), 6.40 (1H, d, Jꢁ1.5 Hz), 3.06 (1H, sept, Jꢁ7.1 Hz), 2.49 (1H,
(
2
1H, s), 2.93 (1H, d, Jꢁ16.8, 6.2 Hz), 2.74 (1H, ddd, Jꢁ16.8, 11.7, 7.6 Hz), s), 2.03—1.96 (1H, m), 1.80—1.44 (5H, m), 1.36 (3H, d, Jꢁ7.1 Hz), 1.31
.22 (1H, d, Jꢁ6.6 Hz), 1.91 (1H, dd, Jꢁ12, 7.8 Hz), 1.46 (1H, d, (3H, d, Jꢁ7.1 Hz), 1.26 (3H, s), 1.25 (3H, s), 1.17 (3H, s); C-NMR
13
Jꢁ13.2 Hz), 1.68—1.54 (4H m), 1.28—1.20 (2H, m), 1.35 (3H, d, (CDCl , 100 MHz) d: 199.6, 181.3, 161.5, 146.3, 140.3, 131.0, 126.3, 119.9,
3
Jꢁ7.3 Hz), 1.36 (3H, d, Jꢁ7.3 Hz), 1.17 (3H, s), 0.94 (3H, s), 0.91 (3H, s);
62.1, 43.0, 42.5, 37.2, 33.0, 32.9, 26.8, 26.1, 21.7, 20.2, 18.3; IR (KBr
13
ꢀ1
C-NMR (150 MHz CDCl ) d: 151.9, 143.2, 134.0, 131.0, 23.0, 114.3, cm ) 3417, 3334, 2929, 2872, 2850, 1670, 1620, 1470, 1419, 1290, 1273,
3
4
1
1
2
6
9.6, 41.6, 39.6, 37.7, 33.3, 33.2, 28.7, 27.1, 25.1, 21.6, 20.3, 20.3, 19.5,
1225, 1203, 1144, 995, 872, 706, 623, 586, 525, 478.
ꢀ1
9.3; IR (KBr, cm ) 3420 (br), 2925, 2854, 1704, 1587, 1456, 1365, 1280,
186, 1103, 1076, 971, 902, 809; MS (EI) (rel. int. %) 286 (75), 271 (100),
69 (15), 203 (62), 201 (77), 189 (48), 175 (94), 149 (16), 91 (7), 83 (10),
9 (32), 55 (18); HR-MS (EI) m/z: 286.2315 (286.2297 Calcd for C H O).
References
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2
0
30
(
4aS,10aS)-1,2,3,4,4a,9,10,10a-Octahydro-6,7-dihydroxy-8-isopropyl-
1,1,4a-trimethylphenanthrene: 8,11,13-Totaratriene-12,13-diol (5) To a
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2
2
(546 mg, 1.75 mmol) was added and the solution was stirred for 19 h at am-
bient temperature. The reaction mixture was evaporated and the residue was
dissolved in THF (5 ml). The solution was cooled in an ice bath and LiAlH4
(133 mg, 3.50 mmol) was added to the solution. The mixture was stirred for
3
h at 0 °C to room temperature. The reaction was stopped by addition of
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layer was dried over MgSO4 and evaporated. The residue was chro-
matographed on a silica gel column with EtOAc–hexane (1 : 5) to give
colorless oil of a catechol: 8,11,13-totaratriene-12,13-diol (5) (184.4 mg,
1
0
5
.61 mmol, 60%): H-NMR (CDCl , 600 MHz) d: 6.69 (1H, s), 5.81 (1H, s),
3
.47 (1H, s) , 3.32 (1H, sept, Jꢁ7.0 Hz), 3.03—2.64 (2H, m), 2.16—2.05
(1H, m), 1.96 (1H, dd, Jꢁ 12.9, 7.8 Hz), 1.84—1.48 (4H, m), 1.42 (3H, d,
Jꢁ7.0 Hz), 1.41 (3H, d, Jꢁ7.0 Hz), 1.38—1.23 (3H, m), 1.20 (3H, s), 1.01 10) Haraguti H., Oike S., Muroi H., Kubo I., Planta Med., 62, 122—125

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1
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5