Efficient ortho-oxidation of phenol and synthesis of anti-MRSA and anti-VRE compound abietaquinone methide from dehydroabietic acid

Article abstract of DOI:10.1248/cpb.54.1412

A quinone methide diterpene: abietaquinone methide, which possesses potent anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-vancomycin- resistant Enterococcus (VRE) activities, was synthesized via efficiently ortho-oxidation of ferruginol derived from industrially available dehydroabietic acid. ortho-Oxidation of phenols was developed to give mono esters of catechols using a stable diacyl peroxide, bis(4-chlorobenzoyl) peroxide (m-chlorobenzoyl peroxide: mCBPO) which was synthesized from meta-chlorobenzoic acid. Efficient one pot ortho-oxidation reaction of phenol with an adduct of meta-chloroperbenzoic acid (mCPBA) with dicyclohexylcarbodiimide (DCC) was also reported.

Full text of DOI:10.1248/cpb.54.1412

1412
Chem. Pharm. Bull. 54(10) 1412—1417 (2006)
Vol. 54, No. 10
Efficient ortho-Oxidation of Phenol and Synthesis of Anti-MRSA and
Anti-VRE Compound Abietaquinone Methide from Dehydroabietic Acid
Masahiro TADA* and Kosaku ISHIMARU
Laboratory of Bioorganic Chemistry, Tokyo University of Agriculture and Technology; Fuchu, Tokyo 183–8509, Japan.
Received July 3, 2006; accepted August 2, 2006; published online August 15, 2006
A quinone methide diterpene: abietaquinone methide, which possesses potent anti-methicillin-resistant
Staphylococcus aureus (MRSA) and anti-vancomycin-resistant Enterococcus (VRE) activities, was synthesized via
efficiently ortho-oxidation of ferruginol derived from industrially available dehydroabietic acid. ortho-Oxidation
of phenols was developed to give mono esters of catechols using a stable diacyl peroxide, bis(4-chlorobenzoyl)
peroxide (m-chlorobenzoyl peroxide: mCBPO) which was synthesized from meta-chlorobenzoic acid. Efficient
one pot ortho-oxidation reaction of phenol with an adduct of meta-chloroperbenzoic acid (mCPBA) with dicyclo-
hexylcarbodiimide (DCC) was also reported.
Key words anti-methicillin-resistant bacteria; quinone methide; m-chlorobenzoyl peroxide; ortho-oxidation; anti-methicillin-re-
sistant Staphylococcus aureus (MRSA); anti-vancomycin-resistant Enterococcus (VRE)
Infections caused by methicillin-resistant Staphylococcus polymer synthesis and an effective reagent for ortho-oxida-
aureus (MRSA) and vancomycin-resistant Enterococcus tion of phenols. However, industrial production of dibenzoyl
(VRE) are a significant problem in hospitals worldwide. Our peroxide was ceased in Japan. Although the various reactions
group has worked with natural resources to find antimicro- of diacyl peroxides are well known, its application for or-
bial compounds effective against antibiotic-resistant bacteria. ganic synthesis had been quite limited because of its instabil-
Stable quinone methide compounds have been isolated from ity. R. H. Burnell reported the synthesis of 2 through an oxi-
various plants and have been shown to display interesting bi- dation using benzeneseleninic anhydride.27) In order to allow
ological activities e.g. anti-virus,1,2) antibiotic,2—7) anti-malar- further investigation into the biological activities of quinone
ial,8,9) and anti-tumor10—12) activities. Previously, we have re- methide, e.g. anti-MRSA and anti-VRE activities, we
ported the total synthesis and the anti-MRSA and anti-VRE planned to develop an efficient ortho-oxidation reaction of
activities of 12 variously oxidized natural abietanes13,14): 6,7- phenols using a stable and nontoxic reagent. We attempted
dehydroferruginol methyl ether,15) ferruginol (1),15—17) 11- oxidation of ferruginol with 2-iodoxybenzoic acid (IBX)28,29)
hydroxy-12-oxo-7,9(11),13-abietatriene (2),4) royleanone,16) and iodobenzene diacetate,30,31) obtaining a complex mixture
demethylcryptojaponol,18) salvinolone,19,20) sugiol methyl without the expected 2. Treatment of ferruginol 1 with ceric
ether,21,22) sugiol,15,20,23) 5,6-dehydrosugiol methyl ether,21,22) ammonium nitrate (CAN) was also attempted, but 1 was not
5,6-dehydrosugiol,13,22,24) 6b-hydroxyferruginol,25) and taxo- successfully oxidized to 2.
dione (3)13,17,26) via stereo-selective polyene cyclization. A
Synthesis of mCBPO One of the most popular and sta-
quinone methide 2 (0.5—1 mg/ml of MIC) and taxodione 3 ble commercially available peracids is meta-chloroperben-
(4—10 mg/ml of MIC) showed potent activity against both zoic acid (mCPBA 5). We are therefore interested in the reac-
MRSA and VRE among these series of compounds. As the tivity and the stability of its diacyl peroxide derivative, bis(4-
quinone methide 2 was isolated from an east African medici- chlorobenzoyl) peroxide (m-chlorobenzoyl peroxide: mCBPO
nal plant (Plectranthus elegans) used as a remedy for intes- 6). The synthesis of mCBPO 6 has been reported by several
tinal worms,4) serious human toxicity may be avoidable. We methods, but a practically useful reaction has not been re-
thus planed to synthesize 11-hydroxy-12-oxo-7,9(11),13-abi- ported. Kubota and Takeuchi reported unexpected formation
etatriene 2 via an efficient route from industrially available of mCBPO 6 by heating of mCPBA 5 in dimethyl formamide
dehydroabietic acid (4) in order to provide a larger amount of (DMF) accompanied by explosion.32) In 1963, Greene and
the sample for further investigations into biological activity Kazan reported the synthesis of substituted benzoyl peroxide
and potential application. We propose to adopt the general through the reaction of substituted benzoic acid with dicyclo-
name of abietaquinone methide for 11-hydroxy-12-oxo- hexylcarbodiimide (DCC 7) and hydrogen peroxide.33) They
7,9(11),13-abietatriene 2.
did not, however, report the synthesis of mCBPO 6. We
In the previous total synthesis of abietaquinone methide 2, therefore examined the synthesis of mCBPO 6 using modifi-
we performed ortho-oxidation of ferruginol 1 with dibenzoyl cations of this classical reaction.
peroxide.14) Dibenzoyl peroxide is a well known initiator of
After several attempts, we accomplished the synthesis of
mCBPO 6 by three reactions (Fig. 2). Method A involved the
reaction of two molecules of mCPBA 5 (1.0 eq) with one
molecule of DCC 7 (0.52 eq) in dichloromethane (CH2Cl2) to
give mCBPO 6 (69%). In this reaction, an adduct (A) of
mCPBA 5 could be first formed with DCC 7 and was then
presumed to react with mCPBA 5 again to form mCBPO 6
along with other unknown compounds supposed to be the re-
sult of oxidation of the dicyclohexylurea part of DCC 7 (Fig.
Fig. 1. Abietaquinone Methide and Related Compound
∗ To whom correspondence should be addressed. e-mail: tada@cc.tuat.ac.jp
© 2006 Pharmaceutical Society of Japan

October 2006
1413
Fig. 2. Synthesis of mCBPO
Fig. 3. ortho-Oxidation of Phenols with mCBPO
2-a). Method A needs two molecule of mCPBA 5 to give one of mCBPO 6 in CH2Cl2 at ambient temperature for 16 h. The
mole of mCBPO 6. As the commercial mCPBA contains less products (13, 14) were acetylated with acetic anhydride and
than 30% of meta-chlorobenzoic acid (mCBA 8) as an impu- pyridine. Methoxyphenols 9 and 10 were converted to the
rity, this method gave an impurity of m-chlorobenzoic anhy- ortho-oxidation products 15 (42%) and 16 (39%), respec-
dride together with unknown yellow compounds. In method tively, whereas 11 and 12 gave complex mixtures and no
B, mCBPO 6 was synthesized from adduct B produced from ortho-oxidation products were detected. The lower yields of
reaction of mCBA 8 with DCC 7 (1 : 1) in CH2Cl2. Adduct B the reactions of 9 and 10 may be due to the instability of the
was then treated with mCPBA 5 to give mCBPO 6 (67%) and products, which are catechol derivatives (13, 14).
dicyclohexyl urea (Fig. 2-b). Method C involved the reaction
of adduct A with mCBA 8 (Fig. 2-c). Method B gave the synthetic route of 1 was necessary to provide a larger amount
most pure white crystals among the three methods. of sample for further investigation into biological activity
Synthesis of Ferruginol 1 As stated earlier, an efficient
mCBPO 6 is a diacyl peroxide, but a stable compound and potential application. One of the most popular diterpenes
throughout the duration of our synthetic research. The ob- is dehydroabietic acid (4), which is industrially produced
tained solid of mCBPO 6 melted when heated in a glass tube from the pine resin for the synthesis of various medicines
at over 110 °C and exhibited slow foaming. mCBPO 6 could and additives of plastics and papers. As dehydroabietic acid 4
not be reduced with aqueous Na2S2O3 solution, but was re- has the same carbon skeleton as abietaquinone methide 2, we
duced with NaBH4.
selected dehydroabietic acid 4 as the starting material for the
ortho-Oxidation of Phenols with mCBPO The ortho- synthesis of abietaquinone methide.
oxidation of phenols (4-methoxyphenol 9, 3-methoxyphenol
The carboxyl group at C4 of 4 was converted to a methyl
10, 2-acetylphenol 11 and 4-nitorophenol 12) by mCBPO 6 group according to the procedure of Matsumoto applied in
was then examined (Fig. 3). Phenols were treated with 1.2 eq the synthesis of ferruginol methyl ether from methyl 12-

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Vol. 54, No. 10
Fig. 4. Synthesis of Ferruginol
Fig. 5. Synthesis of Abietaquinone Methide 2
methoxy-8,11,16-abietatriene-18-oate.34) The carboxyl group trifluoroacetic acid and then treated with isopentyl nitrite for
at C4 of 4 was reduced with LiAlH4 in THF to give an alco- 3 h.36) The product (trifluoroacetate: C) was hydrolyzed with
hol (17; 94%),35) which was converted to the tosylate (18) aqueous sodium carbonate without separation to give ferrugi-
with tosyl chloride in pyridine (93%). The tosylate was re- nol (1) in 87% yield. The total yield of ferruginol 1 was 23%
duced with Zn powder-NaI in DMF to give the C4-methyl through 7 steps from dehydroabietic acid 4.
compound: 8,11,13-abietatriene (19) (83%).35) The mesylate
Synthesis of Abietaquinone Methide 2 via Oxidation of
(20) of the alcohol 17 was also synthesized (93%) and re- Ferruginol 1 Oxidation of ferruginol 1 was then examined
duced under similar reaction conditions using Zn powder- using the ortho-oxidation reaction described above. A solu-
NaI in DMF, but the yield of the reduction to give 8,11,13- tion of ferruginol 1 (0.11 mmol) and mCBPO 6 (0.188 mmol)
abietatriene 19 (27%) was lower than that of the tosylate.
in CH2Cl2 was allowed to react at ambient temperature for
The hydroxyl group at C12 was introduced by two meth- 4 h. The oxidation of ferruginol occurred at C11 to give a
ods.
mixture of 11-(3-chlorobenzoyloxy)-12-hydroxy-8,11,13-abi-
1) Friedel-Crafts acylation followed by Baeyer-Villiger re- etatriene (24) and 12-(3-chlorobenzoyloxy)-11-hydroxy-
action; and
8,11,13-abietatriene (25) in 50% yield. 11-(3-Chlorobenzoyl-
2) Nitration-reduction followed by Sandmeyer reaction, oxy)-12-hydroxy-8,11,13-abietatriene 24 could be produced
which is the application of the procedure used in Matsu- via [3.3]sigmatropic shift from the peroxycarboxylate (D) of
shita’s synthesis of tryptoquinones.36)
ferruginol 1 as shown in Fig. 5. 12-(3-Chlorobenzoyloxy)-
Both synthetic routes successfully gave ferruginol, but the 11-hydroxy-8,11,13-abietatriene 25 could be formed via in-
yield of the Baeyer-Villiger reaction of the former route was tramolecular ester exchange reaction from 11-(3-chloroben-
lower in the larger scale experiments. The latter route was zoyloxy)-12-hydroxy-8,11,13-abietatriene 24. The mixture of
thus selected in this synthesis.
catechol monoesters 24 and 25 was then treated with LiAlH4
The 8,11,13-abietatriene was nitrated with nitric acid in in tetrahydrofuran under an oxygen atmosphere for 3 h at am-
acetic anhydride to give a mixture (2 : 1) of 12-nitro-8,11,13- bient temperature to give abietaquinone methide 2 directly in
abietatriene (21) and 14-nitro-8,11,13-abietatriene (22) in 23% yield. The intermediate catechol F could be easily oxi-
70% yield. The products ratio of 21 and 22 was determined dized with oxygen to afford quinone methide 2. The spectral
1
by H-NMR. As the chromatographic properties of the two data of the synthesized quinone methide 2 were identical
nitro-compounds, 21 and 22 were very similar, the mixture with previously synthesized abietaquinone methide 2.4)
was hydrogenated over 10% Pd/C in ethanol without separa-
Although mCBPO is a stable diacylperoxide, one pot
tion to produce a mixture of 12-amino-compound (23) (39% ortho-oxidation reaction of phenol with an adduct of mCPBA
in 2 steps) with unreacted 14-nitro-compound 22. The 12- with DCC was then developed and applied for the synthesis
amino-compound was purified by column chromatography of of abietaquinone methide 2. The adduct A of mCBPA with
the mixture. The amino group of 23 was then converted to a DCC was first synthesized in CH2Cl2 as above (Fig. 6), then
phenol as follows. The amino-compound 23 was dissolved in ferruginol was added directly to the solution and stirred for

October 2006
1415
6.39 mmol) in CH2Cl2 (10 ml) at ambient temperature and the solution was
stirred for 20 min under argon. To the solution, mCPBA (1.12 g, 6.51 mmol)
was added and the mixture was stirred for 4 h at ambient temperature under
argon. The reaction mixture was concentrated to form a precipitate which
was filtered out with Celite. The filtrate was evaporated to give white crys-
tals which were washed with hexane–ethyl acetate to give practically pure 6
(1.33 g, 4.28 mmol, 67%).
m-Chlorobenzoyl Peroxide (mCBPO) (Method C) Powder of DCC
(598.0 mg, 2.90 mmol) was added to a solution of mCBPA (500.0 mg,
2.90 mmol) in CH2Cl2 (5 ml) and the solution was stirred at ambient temper-
ature for 20 min under argon. To the solution, mCBA (454.1 mg, 2.90 mmol)
was added and the mixture was stirred for 145 min under argon. The reac-
tion mixture was concentrated with an evaporator to form a precipitate
which was filtered out with Celite. The filtrate was evaporated to give white
crystals, which were washed with hexane–ethyl acetate to give practically
pure mCBPO 6 (302.3 mg, 0.972 mmol, 67%).
Fig. 6. Synthesis of Abietaquinone Methide 2 Using One Pot ortho-Oxi-
dation
2-Acetoxy-5-methoxyphenyl 3ꢀ-Chlorobenzoate (15) To a solution of
4-methoxyphenol 8 (30.0 mg, 0.242 mmol) in CH2Cl2 (3 ml), was added
mCBPO (90.2 mg, 0.290 mmol) and the solution was stirred for 16 h under
argon. The reaction mixture was evaporated and the residue was dissolved in
a solution of pyridine (1 ml) and Ac2O (0.5 ml). After stirring for 1 h at am-
bient temperature under argon, the reaction was quenched by addition of 1 M
HCl followed by extraction with EtOAc. The organic layer was successively
washed with 1 M HCl, saturated aqueous NaHCO3 and brine, and was dried
over MgSO4 and evaporated. The product was chromatographed on a silica
gel column with EtOAc–hexane (3 : 1) to give a colorless oil of 15 (30.1 mg,
15 h. ortho-Oxidation reaction of ferruginol occurred and a
similar mixture of 24 and 25 was obtained in 58% yield. The
mixture was treated with LiAlH4 in tetrahydrofuran (THF)
under oxygen for 3 h at ambient temperature gave abi-
etaquinone methide directly in 19% yield. The ortho-quinone
26, the tautomeric isomer of abietaquinone methide 2, was
not obtained in this reduction–oxidation step to give quinone
methide 2.
1
0.939 mmol, 39%): H-NMR (CDCl3) d: 8.14 (1H, dd, Jꢀ1.8, 1.8 Hz), 8.05
(1H, ddd, Jꢀ8.1, 1.8, 1.1 Hz), 7.61 (1H, ddd, Jꢀ8.1, 1.8, 1.1 Hz), 7.45 (1H,
dd, Jꢀ8.1, 8.1 Hz), 7.23 (1H, d, Jꢀ8.8 Hz), 6.83 (1H, dd, Jꢀ8.8, 2.9 Hz),
6.78 (1H, d, Jꢀ2.9 Hz), 3.82 (3H, s), 2.17 (3H, s); 13C-NMR (CDCl3) d:
168.20, 163.28, 157.98, 142.65, 135.66, 134.90, 133.77, 130.78, 130.14,
129.99, 128.21, 123.52, 112.00, 109.20, 55.77, 20.55; EI-MS m/z (%): 322
(Mꢂ2, 3), 320 (Mꢂ, 6), 278 (37), 139 (100), 111 (25), 69 (15); HR-EI-MS
m/z: 300.0406 (Calcd for C16H13O5Cl2 300.0452).
Conclusion
We synthesized abietaquinone methide 2 efficiently from
industrially available dehydroabietic acid 4 using novel
ortho-oxidation reaction of phenol (total yield: 2.4%) with
mCBPO. mCBPO is a stable diacyl peroxide which could be
easy synthesized from commercially available mCBA. Fer-
ruginol could be oxidize at ortho-position of the phenol with
mCBPO in a comparable yield with benzoyl peroxide whose
industrial production was ceased in Japan. Efficient one pot
ortho-oxidation reaction of ferruginol with an adduct of
mCPBA with DCC was also described. This synthetic route
is expected to provide large-scale quantities of 2 for further
research aimed towards potential application.
2-Acetoxy-4-methoxyphenyl 3ꢀ-Chlorobenzoate (16) To a solution of
3-methoxyphenol 10 (30.0 mg, 0.242 mmol) in CH2Cl2 (3 ml), mCBPO
(94.2 mg, 0.303 mmol) was added and the solution was stirred at ambient
temperature for 16 h under argon. The reaction mixture was evaporated and
the residue was dissolved in a solution of pyridine (2 ml) and Ac2O (1 ml).
After stirring for 1 h under argon, the reaction was stopped by addition of
1 M HCl followed by extraction with EtOAc. The organic layer was succes-
sively washed with 1 M HCl, saturated aqueous NaHCO3 and brine, and was
dried over MgSO4 and evaporated. The product was chromatographed on a
silica gel column with EtOAc–hexane (5 : 1) to give a colorless oil of 16
(32.4 mg, 0.101 mmol, 42%): 1H-NMR (CDCl3) d: 8.14 (1H, dd, Jꢀ1.8,
1.5 Hz), 8.05 (1H, dd, Jꢀ8.8, 1.2 Hz), 7.62 (1H, br d, Jꢀ8.1 Hz) 7.46 (1H,
dd, Jꢀ8.1, 8.1 Hz), 7.21 (1H, d, Jꢀ8.8 Hz), 6.84 (1H, dd, Jꢀ8.8, 2.4 Hz),
Experimental
General Procedures NMR spectra were measured on a JEOL alpha- 6.78 (1H, d, Jꢀ2.4 Hz), 3.82 (3H, s), 2.17 (3H, s); 13C-NMR (CDCl3) d:
600 (1H: 600 MHz, 13C: 150.8 MHz) spectrometer in CDCl3 using tetra- 168.21, 163.29, 157.98, 142.64, 135.65, 134.89, 133.78, 130.77, 130.14,
methylsilane as an internal standard (J-values in Hz). IR spectra were meas- 129.98, 128.21, 123.53, 112.00, 109.20, 55.78, 20.56; EI-MS m/z (%): 322
ured on a JEOL JIR-WINSPEC 50 infrared spectrometer. Mass spectra were (Mꢂ2, 3), 320 (Mꢂ, 13), 278 (57), 141 (55), 139 (100), 111 (39); HR-EI-
recorded on a JEOL JMS-SX102A spectrometer. Optical rotations were MS m/z: 320.0483 (Calcd for C16H13O5Cl2 320.0452).
measured on a JASCO DIP-360 polarimeter. Melting points (mp) were
measured on a MEL-TEMP (Laboratory Device) and were uncorrected. 79.87 mmol) was added to a dry THF (50 ml) solution of dehydroabietic acid
TLC was carried out on Silica gel 60 (0.25 mm thickness) with fluorescent
4 (21.104 g, 70.24 mmol) under ice cooling. The mixture was stirred at 0 °C
indicator (Macherey-Nagel). Silica gel (6 nm, BW-127ZH, Fuji Silysia for 30 min and then at ambient temperature for further 12 h under argon. The
8,11,13-Abietatriene-18-nol (17) Lithium Aluminum hydride (3.032 g,
Chemical Ltd.) was used for column chromatography.
m-Chlorobenzoyl Peroxide (mCBPO) 6 (Method A) Dicyclohexylcar-
reaction mixture was poured into water and extracted with EtOAc. The or-
ganic layer was successively washed with 1 M HCl, saturated aqueous
bodiimide (621.1 mg, 3.01 mmol) was added to a solution of mCPBA NaHCO3, and brine, and was dried over MgSO4 and evaporated. The residue
(1.000 g, 5.79 mmol) in CH2Cl2 (15 ml) and the mixture was stirred at ambi- was chromatographed on a silica gel column with EtOAc–hexane (3 : 1) to
ent temperature for 105 min under argon. The reaction mixture was concen- give a colorless oil of 17 (18.848 g, 65.80 mmol, 94%).
trated carefully with a rotary evaporator to form a precipitate which was fil-
18-(p-Toluenesulfonyloxy)-8,11,13-abietatriene (18) p-Toluenesul-
tered out with Celite. The filtrate was evaporated to give white crystals fonyl chloride (26.157 g, 137.20 mmol) was added to a solution of the alco-
which were then washed with hexane–ethyl acetate to give practically pure 6
(620.0 mg, 1.99 mmol, 69%) as white crystals (mp 112—113 °C; melted
with slow foaming); 1H-NMR (CDCl3) d: 8.06 (2H, t, Jꢀ1.8 Hz), 7.96 (2H,
ddd, Jꢀ8.1, 1.8, 1.1 Hz), 7.65 (2H, ddd, Jꢀ8.1, 1.8, 1.1 Hz), 7.48 (2H, t,
hol 17 (30.231 g, 105.54 mmol) in pyridine (100 ml) and the solution was
stirred at ambient temperature for 2 h under argon. The mixture was poured
into 1 M HCl–ice. The mixture was extracted with EtOAc and the organic
layer was successively washed with 1 M HCl, saturated aqueous NaHCO3,
Jꢀ8.1 Hz); 13C-NMR (CDCl3) d: 161.80, 135.18, 134.50, 130.25, 129.82, and brine, and was dried over MgSO4 and evaporated. The residue was chro-
127.90, 127.11; IR (KBr) cmꢁ1: 3101, 3075, 1791, 1768, 1220, 1006, 811,
matographed on a silica gel column with EtOAc–hexane (10 : 1) to give a
723; EI-MS m/z (%): 312 (Mꢂ2, 10), 310 (Mꢂ, 17), 158 (14), 156 (44), 141 colorless oil of 18 (43.467 g, 98.64 mmol, 93%): H-NMR (CDCl3) d: 7.77
(30) 139 (100), 111(33); HR-EI-MS m/z: Found, 309.9870 (Calcd for (2H, d, Jꢀ7.8 Hz), 7.34 (2H, d, Jꢀ8.4 Hz), 7.14 (1H, d, Jꢀ7.8 Hz), 6.98
1
C14H8Cl2O4 309.9800).
(1H, dd , Jꢀ8.4, 2.4 Hz), 6.86 (1H, d, Jꢀ2.4 Hz), 3.82 (1H, d, Jꢀ9.2 Hz),
m-Chlorobenzoyl Peroxide (mCBPO) (Method B) Dicyclohexylcar- 3.60 (1H, d, Jꢀ9.2 Hz), 2.85—2.79 (2H, m), 2.78—2.72 (1H, m), 2.46 (3H,
bodiimide (1.34 g, 6.51 mmol) was added to a solution of mCBA (1.000 g, s), 2.24 (1H, br d, Jꢀ12.6 Hz), 1.71 (1H, dt, Jꢀ13.6, 3.7 Hz), 1.39—1.33

1416
Vol. 54, No. 10
(3H, m), 1.22 (6H, d, Jꢀ6.6 Hz), 1.17 (3H, s), 0.88 (3H, s); 13C-NMR
(CDCl3) d: 146.69, 145.68, 144.67, 134.54, 133.03, 129.77, 127.91, 126.77,
124.19, 123.87, 77.73, 43.65, 38.00, 37.33, 37.17, 35.03, 33.42, 29.83,
25.20, 23.96, 21.62, 18.87, 18.34, 17.08; IR (NaCl) cmꢁ1: 3004, 2960, 2927,
22864, 1333, 1194, 1173, 960, 852, 818, 687; EI-MS m/z (%): 440 (Mꢂ,
12), 268 (30), 253 (100), 211 (9); HR-EI-MS m/z: 440.2383 (Calcd for
C27H36O3S 440.2385).
3 h in an argon atmosphere, methanol (4 ml) and aqueous saturated K2CO3
were added and the solution was stirred for further 1 h in argon. The reaction
mixture was poured into 3 M HCl–ice and extracted with EtOAc. The organic
layer was successively washed with 1 M HCl, saturated NaHCO3, and brine,
and was dried over MgSO4 and evaporated. The residue was chro-
matographed on a silica gel column with EtOAc–hexane (5 : 1) to give (ꢂ)-
ferrugonol (1) (612.4 mg, 2.14 mmol, 87%): [a]Dꢀꢂ57.6° (cꢀ0.15 in
EtOH) (lit.,13) ꢂ55.7).
18-Methanesulfonyloxy-8,11,13-abietatriene (20) Methanesulfonyl
chloride (1.10 ml, 14.17 mmol) was added to a solution of alcohol 17
(3.383 g, 11.81 mmol) in pyridine (10 ml), and the solution was stirred for
2 h under argon. The mixture was poured into 1 M HCl–ice. The mixture was
extracted with EtOAc and the organic layer was successively washed with
1 M HCl, saturated aqueous NaHCO3, and brine, and was dried over MgSO4
and evaporated. The residue was chromatographed on a silica gel column
with EtOAc–hexane (10 : 1) to give a colorless oil of 20 (4.004 g,
11-(3-Chlorobenzoyloxy)-12-hydroxy-8,11,13-abietatriene (24) and 12-
(3-Chlorobenzoyloxy)-11-hydroxy-8,11,13-abietatriene (25) To a solu-
tion of ferruginol (31.5 mg, 0.110 mmol) in CH2Cl2 (3 ml), mCBPO
(58.6 mg, 0.188 mmol) was added and the mixture was stirred for 4 h at am-
bient temperature under argon. After addition of aqueous Na2S2O3, the or-
ganic layer was successively washed with Na2S2O3, and brine, and was dried
over MgSO4 and evaporated. The residue was chromatographed on a silica
gel column with EtOAc–hexane (5 : 1) to give a mixture of 24 and 25
(23.3 mg, 0.0548 mmol, 50%): white powder. 1H-NMR (CDCl3) d: 8.24 (1H,
br s), 8.14 (1H, d, Jꢀ8.1 Hz), 7.68—7.65 (1H, m), 7.51 (1H, t, Jꢀ8.1 Hz),
6.64 (1H, s), 5.12 (1H, br), 3.14—3.09 (1H, m), 2.90—2.82 (3H, m), 1.87—
1.84 (1H, m), 1.79—1.70 (2H, m), 1.63—1.52 (4H, m), 1.50—1.46 (2H, m),
1.37 (3H, s), 1.22 (3H, d, Jꢀ7.0 Hz), 1.19 (3H, d, Jꢀ7.0 Hz), 0.991 (3H, s),
0.959 (3H, s); 13C-NMR (CDCl3) d: 163.86, 145.54, 137.39, 135.92, 135.04,
134.95, 134.71, 134.03, 130.48, 130.33, 130.12, 128.42, 118.72, 52.73,
41.41, 39.55, 36.53, 33.74, 32.82, 29.68, 27.59, 23.03, 22.90, 22.12, 20.12,
19.33, 19.06; IR (KBr) cmꢁ1: 3460 (br), 2960, 2924, 2864, 1743, 1652,
1423, 1280, 1254, 1217; EI-MS m/z (%): 442 (Mꢂ2, 5), 440 (Mꢂ, 11), 288
(17), 286 (61), 273 (11), 271 (85); HR-EI-MS m/z: 440.2102 (Calcd for
C27H33ClO3 440.2118).
Abietaquinone Methide (2) Lithium aluminum hydride (6.3 mg,
0.166 mmol) was added to a solution of 25 and 26 (20.9 mg) in THF (5 ml),
and the mixture was stirred for 3 h under oxygen. The reaction was stopped
with EtOAc and water, and the mixture was extracted with EtOAc and 1 M
HCl. The organic layer was successively washed with 1 M HCl, saturated
NaHCO3, and brine, and was dried over MgSO4 and evaporated. The product
was separated by preparative thin layer chromatography using silica gel
(hexane : EtOAcꢀ30 : 1) to give a colorless oil of 2 (3.4 mg, 0.0113 mmol,
23%): [a]Dꢀꢂ28.1° (cꢀ0.08 in EtOH) (lit.,4) ꢂ25.9°).
1
10.98 mmol, 93%): H-NMR (CDCl3) d: 7.17 (1H, d, Jꢀ8.1 Hz), 7.00 (1H,
dd , Jꢀ8.1, 1.8 Hz), 6.89 (1H, d, Jꢀ1.8 Hz), 4.07 (1H, d, Jꢀ9.2 Hz), 3.80
(1H, d, Jꢀ9.2 Hz), 2.99 (3H, s), 2.92—2.85 (2H, m), 2.82 (1H, sept,
Jꢀ6.6 Hz), 2.32—2.27 (1H, m), 1.78—1.47 (8H, m), 1.23 (3H, s), 1.22 (6H,
d, Jꢀ6.6 Hz), 1.22 (3H, s), 0.98 (3H, s); 13C-NMR (CDCl3) d: 146.75,
145.75, 134.49, 126.86, 124.20, 123.94, 76.83, 43.65, 38.07, 37.38, 37.21,
37.16, 35.14, 33.43, 29.93, 25.25, 23.97, 23.94, 18.92, 18.34, 17.09; IR
(NaCl) cmꢁ1: 2954, 2870, 1610, 1500, 1464, 1363, 1171, 960, 844, 752; EI-
MS m/z (%): 364 (Mꢂ, 17), 353 (22), 286 (27), 261 (39), 254 (100), 156
(17), 69 (14); HR-EI-MS m/z: 364.2081: (Calcd for C21H32O3S 364.2072).
8,11,13-Abietatriene (19) A dry DMF (15 ml) solution of the tosylate
17 (1.634 g, 3.71 mmol) was stirred with NaI (total 4.058 g, 27.07 mmol)
and Zn-powder (total 1.891 g, 28.92 mmol), which was added 4 times at in-
tervals of 7 h at 100 °C for 28 h under argon. After cooling, 1 M HCl was
added to the reaction mixture and the resulting precipitate was filtered out.
The filtrate was extracted with hexane and the combined organic layer was
successively washed with 1 M HCl, saturated aqueous NaHCO3, and brine,
and was dried over MgSO4 and evaporated. The residue was chro-
matographed on a silica gel column with EtOAc–hexane (100 : 1) to give a
colorless oil of 19 (832 mg, 3.077 mmol, 83%).
8,11,13-Abietatriene (19) The mesylate 20 (3.232 g, 8.87 mmol) was
dissolved in dry DMF (20 ml) and the solution was stirred at 120 °C with
three times addition of NaI (total 2.658 g, 17.73 mmol) and Zn-powder (total
1.159 g, 17.73 mmol) at intervals of 8 h for 26 h under argon. After cool, the
reaction mixture was quenched with 1 M HCl and the resulting precipitate
was filtered out. The filtrate was extracted with hexane and the organic layer
was successively washed with 1 M HCl, saturated aqueous NaHCO3, and
brine, and was dried over MgSO4 and evaporated. The residue was chro-
matographed on a silica gel column with EtOAc–hexane (100 : 1) to give 19
(645.0 mg, 2.38 mmol, 27%).
12-Nitro8,11,13-abietatriene (21) and 14-Nitro8,11,13-abietatriene
(22) A solution of nitric acid (0.270 ml) in Ac2O (2.73 ml) was added to
the solution of 19 in Ac2O with ice cooling and the mixture was stirred at
ambient temperature for 45 min under argon. The reaction mixture was
poured into water–ice and extracted with EtOAc. The organic layer was suc-
cessively washed with 1 M NaOH, saturated NaHCO3, and brine, and was
dried over MgSO4 and evaporated. The residue was chromatographed on a
silica gel column with EtOAc–hexane (5 : 1) to give a mixture of 21 and 22
(2 : 1, 410.0 mg, 1.30 mmol, 70%).
11-(3-Chlorobenzoyloxy)-12-hydroxy-8,11,13-abietatriene (24) and 12-
(3-Chlorobenzoyloxy)-11-hydroxy-8,11,13-abietatriene (25) Dicyclo-
hexylcarbodiimide (23.9 mg, 0.116 mmol) was added to a solution of
mCPBA (19.9 mg, 0.116 mmol) in CH2Cl2 (5 ml), and the mixture was
stirred for 20 min under argon. Ferruginol 2 (26.0 mg, 0.0908 mmmol) was
added to the mixture and stirred for 15 h under argon. The reaction mixture
was evaporated and the residue was chromatographed on a silica gel column
with EtOAc–hexane (10 : 1) to give a mixture of 24 and 25 (22.3 mg,
0.0525 mmol, 58%).
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