Stereocontrolled total syntheses of (±)-pisiferic acid and (±)-O-methylpisiferic acid

Article abstract of DOI:10.1016/S0040-4020(02)00062-5

A stereocontrolled approach to the construction of the angularly ester substituted trans-octahydrophenanthrene ring system related to diterpenes involving an aryl participated diazoketone cyclisation strategy is delineated. The tetrahydrophenanthrenone 7 was prepared from the tetralone 6 through the intermediates 13, 14, 16 and 17. The formyl derivative of 7 was treated with alkaline H₂O₂ to give the diacid 18 which was converted into the diazomethyl ketone 9. Aryl participated cyclisation of 9 afforded the enedione 10 which was stereoselectively converted into the keto-ester 11. The transformation of 11 into the diterpenes 1 and 4 has been efficiently accomplished.

Full text of DOI:10.1016/S0040-4020(02)00062-5

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1765±1771
Stereocontrolled total syntheses of (^)-pisiferic acid
and (^)-O-methylpisiferic acid
Subrata Kumar Pal, Pranab Dutta Gupta and Debabrata Mukherjeep
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Calcutta 700032, India
Received 26 September 2001; revised 12 December 2001; accepted 10 January 2002
AbstractÐA stereocontrolled approach to the construction of the angularly ester substituted trans-octahydrophenanthrene ring system
related to diterpenes involving an aryl participated diazoketone cyclisation strategy is delineated. The tetrahydrophenanthrenone 7 was
prepared from the tetralone 6 through the intermediates 13, 14, 16 and 17. The formyl derivative of 7 was treated with alkaline H2O2 to give
the diacid 18 which was converted into the diazomethyl ketone 9. Aryl participated cyclisation of 9 afforded the enedione 10 which was
stereoselectively converted into the keto-ester 11. The transformation of 11 into the diterpenes 1 and 4 has been ef®ciently accomplished.
q 2002 Elsevier Science Ltd. All rights reserved.
(1)-Pisiferic acid (1) and a few closely related tricyclic
diterpenes, e.g. methyl (1)-pisiferate (2), (1)-pisiferol
(3), (1)-O-methylpisiferic acid (4), and (1)-pisiferal (5)
were isolated from the leaves of Chamaecyparis pisifera
by Yatagai and co-workers.1,2 The diterpenes 1±5 incorpo-
rate trans-fused octahydrophenanthrene ring system as the
basic carbocyclic framework and possess oxygenated
methyl groups as angular substituents. The abietane-type
diterpene 1 bearing an angular carboxyl group has attracted
attention as a synthetic target because of its antimicrobial
activity3 against all gram positive bacteria tested. Earlier
methodologies for the synthesis of (^)-pisiferic acid (1)
Scheme 1.
Keywords: terpenes; diazo compound; cyclisation; hydrogenation; dealkylation.
Corresponding author. Fax: 191-33-4732805; e-mail: ocdm@mahendra.iacs.res.in
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00062-5

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S. K. Pal et al. / Tetrahedron 58 (2002) 1765±1771
Figure 1.
most commonly employed4,5 transannular oxidation of the
angular methyl group as a key reaction. We describe herein
a stereocontrolled total synthesis of (^)-pisiferic acid (1)
using a conceptually different approach. Our basic strategy
for the construction of an angularly ester substitued trans-
octahydrophenanthrene ring system related to the diterpene
1 is shown in Scheme 1 and Fig. 1. The tetrahydrophenan-
threnone 7, easily prepared from 6-isopropyl-7-methoxy-1-
tetralone (6), was smoothly converted into the half acid-
ester 8 involving an oxidative cleavage of ring A. Aryl
participated intramolecular cyclisation of the corresponding
diazomethyl ketone 9 in the presence of acid afforded the
tricyclic enedione 10 in good yield and this was stereo-
selectively converted into (^)-pisiferic acid (1) through
the intermediates 11 and 12. Aryl participated cyclisation
of diazocarbonyl compounds to generate speci®cally
functionalised hydrophenanthrene ring system related to
naturally occurring ring C-aromatic tricyclic diterpenes
has been relatively unexplored.
The bioactivity of O-methylpisiferic acid (4) as a mite
growth regulator was reported by Ahn et al.6 The diterpene
4 inhibits both the hatching and the feeding of the two-
spotted spider mite, Tetranychus urticae Koch, which is a
serious pest to many crops. During the present studies, the
transformation of the ester 12 into (^)-O-methylpisiferic
Scheme 2. Reagents and conditions: (i) BrCH2CHvCHCO2Me, Zn, Et2O, C6H6, re¯ux, 4.5 h; (ii) H2, 10% Pd±C, AcOH, 71%; (iii) CrO3, AcOH, H2O, 08C to
rt, 4 h, 75%; (iv) Br2, Et2O, 108C to rt, 16 h, 95%; (v) LiBr, Li2CO3, DMF, 120±1258C, 4 h; (vi) MeI, K2CO3, (CH3)2CO, re¯ux, 12 h, 78%; (vii) MeMgI, Et2O,
re¯ux, 4 h; (viii) P2O5, H3PO4, 90±958C, 45 min, 82%; (ix) PCC, CH2Cl2, rt, 24 h, 87%; (x) NaH, HCO2Et, C6H6, 08C to rt, 20 h; (xi) aq. NaOH, H2O2, 08C to
rt, 18 h, H3O1, 87%; (xii) CH2N2, Et2O, 08C, 97%; (xiii) KOH, H2O, THF, rt 24 h, 608C 1 h, H3O1, 90%; (xiv) ClCO2Et, Et3N, Et2O, THF, 2108C, 1 h; (xv)
CH2N2, Et2O, 08C to rt, 14 h, 92%; (xvi) TFA, CH2Cl2, 2208C, 3 min, 62%; (xvii) H2, 10% Pd±C, EtOAc, 94%; (xviii) HSCH2CH2SH, BF3´Et2O, MeOH, rt,
20 h, 91%; (xix) Raney nickel, EtOH, re¯ux, 4 h, 88%; (xx) AlBr3, EtSH, rt, 15 h, 92%; (xxi) t-BuOK, DMSO, 958C, 70 min, 72%.

S. K. Pal et al. / Tetrahedron 58 (2002) 1765±1771
1767
acid (4) has also been achieved. Both the enantiomers of
the diterpene 4 were synthesised by Mori et al.7 from
(S)-3-hydroxy-2,2-dimethylcyclohexanone.
with ethereal CH2N2 afforded the diazoketone 9 in excellent
yield. For synthetic entry into the tricyclic ring system of
methyl O-methylpisiferate (12), aryl participated cycli-
sation14 of the diazoketone 9 was investigated. A brief treat-
ment of 9 with tri¯uoroacetic acid in CH2Cl2 at 2208C
furnished the crystalline enedione 10 in 62% yield. The
1. Results and discussion
1
IR, H- and 13C NMR spectra of this compound were in
full accord with structure 10. Catalytic hydrogenation of
the enedione 10 proceeded stereoselectively with uptake
of three moles of hydrogen to provide the trans-fused
keto-ester 11 as the sole product. The construction of the
basic tricarbocyclic framework of methyl O-methylpi-
siferate (12) was thus accomplished in a stereocontrolled
manner. The stereostructure of the keto-ester 11 was conclu-
sively established by single crystal X-ray crystallography.15
The keto-ester 11 was subsequently transformed into several
known compounds possessing trans-stereochemistry at the
A/B ring juncture. It may be mentioned in this connec-
tion that catalytic hydrogenation by Matsumoto and co-
workers16,17 of closely related enones had generated
exclusively trans-stereochemistry at A/B ring junctures.
Our synthesis of the diterpene acids 1 and 4 from the tetra-
lone 6 is outlined in Scheme 2. Reformatsky reaction of the
tetralone 68 with methyl 4-bromocrotonate was carried out
following essentially a procedure reported by Stork.9 Cata-
lytic hydrogenation of the crude product in acetic acid
containing a few drops of perchloric acid provided the
ester 13 in 71% overall yield. The spectral characteristics
of 13 as revealed through its 1H and 13C NMR spectra were
fully in accord with its structure. Oxidation of 13 with
chromic acid in acetic acid gave the keto-ester 14 in high
yield. Bromination of 14 in ether, according to a procedure
reported by Johnson and co-workers,10 furnished the bromo-
ketone 15 in near quantitative yield. Dehydrobromination of
15 with LiBr and Li2CO3 in DMF followed by methylation
of the crude product 16a with MeI in acetone in the presence
of K2CO3 afforded the ester 16 as a crystalline compound in
high overall yield. The spectral and analytical data of the
ester 16 were fully in agreement with the assigned structure.
Undoubtedly, dehydrobromination of the bromoketone 15
proceeded with concomitant aromatisation yielding the
phenol 16a which underwent methylation to provide the
ether 16. A similar conversion of 6-methoxy-1-tetralone
into 1-hydroxy-6-methoxynaphthalene through bromination
and subsequent dehydrobromination was reported earlier by
Kasturi et al.11 The methyl ester 16 was treated with an
excess of MeMgI in re¯uxing ether and the resulting
crude carbinol was cyclised with polyphosphoric acid to
give the tetrahydrophenanthrene derivative 17 as a crystal-
line compound in high yield. Oxidation of 17 with pyri-
dinium chlorochromate in dichloromethane at room
temperature yielded the tricyclic ketone 7 in excellent
yield. Oxidation at the benzylic position was facilitated
In order to complete the synthesis of the diterpene acids 1
and 4, the compound 11 was converted into the correspond-
ing thioacetal 20 in 91% yield. Desulfurisation of 20 with
Raney nickel furnished the ester 1218 in high yield.
Demethylation of 12 with anhydrous AlBr3 and EtSH19 at
room temperature afforded (^)-pisiferic acid (1) in excel-
lent yield. Treatment of 12 with t-BuOK in DMSO20 at room
temperature furnished (^)-O-methylpisiferic acid (4) in high
yield. The spectral data of the present compounds 12, 1 and 4
agreed very well with those reported in the literature.
In conclusion, in the present work a stereocontrolled route
has been developed for the synthesis of (^)-pisiferic acid
and (^)-O-methylpisiferic acid involving aryl participated
intramolecular cyclisation of an appropriately substitued
diazometyl ketone as the key step.
1
due to the presence of the p-methoxy group and the H
and 13C NMR spectra of the ketone were in full accord
with structure 7. Due to deshielding effect of the carbonyl
group, the aromatic proton at C-5 appeared in the 1H NMR
spectrum of 7 at a very low ®eld (d 9.01 ppm).
2. Experimental
2.1. General
The compounds described and having asymmetric centres
are all racemates. Melting points and boiling points are
uncorrected. IR spectra were recorded on Perkin±Elmer
model PE 298 and Shimadzu FTIR-8300 spectrophoto-
meters. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded in CDCl3 on a Bruker DPX-300 spec-
trometer with SiMe4 as internal standard. The chemical
shifts (d ppm) are reported relative to SiMe4 (dH 0.00) for
1H and the central line of residual CHCl3 (dC 77.0) for 13C.
Moisture sensitive reactions were carried out using standard
syringe±septum technique. Anhydrous solvents were
obtained by standard procedures. All solvent extracts
were dried over anhydrous Na2SO4. Product purities were
routinely checked by TLC. Ether refers to diethyl ether and
light petroleum refers to the fraction of petroleum ether in
the boiling point range 40±608C.
Having an ef®cient route to 7, we turned our attention to
convert 7 into the half acid-ester 8. The ketone 7 was
condensed with ethyl formate in the presence of NaH and
the resulting crude hydroxymethelene derivative was treated
with alkaline H2O2 to give the diacid 18 which on treatment
with an excess of ethereal CH2N2 furnished the dimethyl
ester 19 in high overall yield. Similar oxidative cleavage
of the hydroxymethelene derivative of an octahydrophenan-
threnone to give a seco diacid was reported by Arapakos et
al.12 Partial hydrolysis of the diester 19 under controlled
conditions furnished the crystalline half acid-ester 8 in
90% yield. The spectral and analytical data of the
compounds 18, 19, and 8 agree with the assigned structures.
The conversion of 8 into the corresponding diazomethyl
ketone 9 was successfully accomplished following a pro-
cedure reported by Tarbell and Price.13 Reaction of 8 with
ethyl chloroformate at 2108C in the presence of Et3N
followed by treatment of the resulting mixed anhydride
2.1.1. Methyl 4-(1,2,3,4-tetrahydro-6-isopropyl-7-meth-
oxy-1-naphthyl) butanoate (13). To a solution of methyl

1768
S. K. Pal et al. / Tetrahedron 58 (2002) 1765±1771
4-bromocrotonate (7.6 g, 0.042 mol) and 6-isopropyl-7-
methoxy-1-tetralone (6) (9.2 g, 0.042 mol) in a mixture of
dry ether (50 mL) and dry benzene (15 mL) were added zinc
wool9 (5.5 g, 0.084 g-at.) and a crystal of iodine, and
the mixture was re¯uxed with occasional shaking. Two
additional lots of zinc wool (2£2.8 g) and methyl 4-bromo-
crotonate (2£3.8 g) were introduced at 45 min intervals and
re¯uxing was continued for 3 h after the last addition. The
reaction mixture was cooled, poured into crushed ice,
acidi®ed with glacial AcOH, and allowed to stand at room
temperature for 16 h. The product was extracted repeatedly
with ether. The combined ether extracts were washed with
aqueous ammonia and water, dried and concentrated.
Evaporative distillation of the residue at 175±1788C (bath
temperature)/0.1 mmHg afforded a viscous oily product
(10.3 g). This was dissolved in AcOH (40 mL) and hydro-
genated over Pd±C (10%, 1.5 g) at room temperature and
atmospheric pressure in the presence of a few drops of
perchloric acid. Uptake of hydrogen ceased after 4 h. The
mixture was ®ltered. The ®ltrate was diluted with water
(50 mL) and extracted with CHCl3 (3£70 mL). The organic
extract was washed with aqueous NaHCO3 and water, dried,
and evaporated. The residue was evaporatively distilled to
afford the methyl ester 13 (9.24 g, 72%) as a colourless oil,
bp 164±1668C (bath temperature)/0.1 mmHg; (Found: C,
74.79; H, 9.16. C19H28O3 requires C, 74.96; H, 9.27%);
nmax (®lm) 1735, 1600 cm21; dH (300 MHz, CDCl3) 6.87
(1H, s, ArH), 6.62 (1H, s, ArH), 3.80 (3H, s, ArOMe), 3.67
(3H, s, CO2Me), 3.23 (1H, sept, Jˆ6.9 Hz, CHMe2), 2.74±
2.63 (3H, m), 2.38±2.32 (2H, m), 1.85±1.57 (8H, m), 1.18
(6H, d, Jˆ6.9 Hz, CHMe2); dC (75 MHz, CDCl3) 174.1,
154.8, 138.7, 134.5, 128.6, 126.5, 110.3, 55.5, 51.5, 37.4,
36.3, 34.2, 29.0, 27.3, 26.4, 22.9, 22.6, 20.0.
and left at room temperature for 14 h. It was then washed
successively with water (2£70 mL), saturated aqueous
NaHCO3 (40 mL) and water (2£50 mL), and dried.
Evaporation of the solvent and puri®cation of the product
on a silica gel column using ether±light petroleum (1:19) as
eluent furnished the bromotetralone 15 (3.8 g, 95%) as a
viscous oil; (Found: C, 57.18; H, 6.51. C19H25BrO4 requires
C, 57.44; H, 6.34%); nmax (®lm) 1738, 1675, 1603 cm21; dH
(300 MHz, CDCl3) 7.97 (1H, s, 8-ArH), 6.76 (1H, s, 5-ArH),
4.81 (1H, t, Jˆ4.0 Hz, COCHBr), 3.94 (3H, s, ArOMe), 3.69
(3H, s, CO2Me), 3.50±3.00 (2H, m), 2.67±2.33 (4H, m),
2.03±1.67 (4H, m), 1.21 (6H, d, Jˆ6.9 Hz, CHMe2).
2.1.4. Methyl 4-(6-isopropyl-4,7-dimethoxy-1-naphthyl)
butanoate (16). A mixture of 15 (3.7 g, 9.31 mmol), LiBr
(2 g, 23 mmol), and Li2CO3 (1.6 g, 21.6 mmol) in dry DMF
(30 mL) was stirred at 120±1258C for 4 h under nitrogen.
The reaction mixture was cooled, poured into dilute HCl
(3N, 30 mL) and extracted with ether (3£50 mL). The
ether extract was washed with water (2£30 mL) and dried.
Evaporation of the solvent furnished the crude phenol 16a
as a gummy material (2.8 g) which was dissolved in acetone
(25 mL). Anhydrous K2CO3 (1.5 g, 10.8 mmol) and MeI
(3 mL, 48 mmol) were added and the mixture was re¯uxed
with stirring under nitrogen for 12 h. It was then cooled,
diluted with water (30 mL) and extracted with ether
(3£50 mL). The ether extract was washed with water
(2£30 mL), dried, and concentrated. Evaporative distil-
lation of the crude product followed by crystallisation
from MeOH furnished the ester 16 (2.4 g, 78%) as colour-
less plates, mp 66±678C; (Found: C, 72.83; H, 8.11.
C20H26O4 requires C, 72.70; H, 7.93%); nmax (KBr) 1731,
1625, 1590 cm21; dH (300 MHz, CDCl3) 8.09 (1H, s,
5-ArH), 7.24 (1H, s, 8-ArH), 7.10 (1H, d, Jˆ9.0 Hz,
2-ArH), 6.58 (1H, d, Jˆ9.0 Hz, 3-ArH), 3.98 (3H, s,
ArOMe), 3.94 (3H, s, ArOMe), 3.67 (3H, s, CO2Me), 3.43
(1H, sept, Jˆ7.0 Hz, CHMe2), 2.96 (2H, t, Jˆ7.0 Hz,
ArCH2), 2.42±2.00 (4H, m), 1.32 (6H, d, Jˆ7.0 Hz,
CHMe2); dC (75 MHz, CDCl3) 174.1, 156.5, 154.1, 137.3,
132.3, 127.8, 125.6, 120.7, 119.3, 101.4, 101.3, 55.3, 55.2,
51.4, 33.5, 32.1, 27.3, 25.4, 22.8.
2.1.2. 4-(3-Methoxycarbonylpropyl)-6-methoxy-7-iso-
propyl-1-tetralone (14). A solution of CrO3 (7.2 g,
0.072 mol) in 80% aqueous AcOH (35 mL) was added
slowly to a stirred solution of the ester 13 (9 g, 0.03 mol)
in glacial AcOH (70 mL) at 08C. After the addition, the
mixture was stirred at room temperature for 4 h and then
diluted with water (100 mL). Solid Na2CO3 was added in
portions to neutralise most of the acetic acid and the product
was extracted with ether (3£100 mL). The combined ether
extract was washed with aqueous NaHCO3 and water, dried
and evaporated. The residue was evaporatively distilled to
furnish the tetralone 14 (7 g, 75%) as a colourless oil, bp
178±1808C/0.1 mmHg; (Found: C, 71.60; H, 8.47.
C19H26O4 requires C, 71.67; H, 8.23%); nmax (®lm) 1737,
1672, 1599 cm21; dH (300 MHz, CDCl3) 7.90 (1H, s, 8-
ArH), 6.65 (1H, s, 5-ArH), 3.90 (3H, s, ArOMe), 3.68
(3H, s, CO2Me), 3.25 (1H, sept, Jˆ6.9 Hz, CHMe2),
2.92±2.50 (3H, m), 2.42±2.03 (4H, m), 1.90±1.71 (4H,
m), 1.20 (6H, d, Jˆ6.9 Hz, CHMe2); dC (75 MHz, CDCl3)
197.3, 173.8, 161.1, 148.0, 136.0, 125.6, 125.0, 108.7, 55.5,
51.6, 38.1, 34.5, 33.9, 26.7, 26.5, 23.0, 22.5, 22.4.
2.1.5. 1,2,3,4-Tetrahydro-1,1-dimethyl-6,9-dimethoxy-7-
isopropylphenanthrene (17). To a stirred solution of
MeMgI (prepared from magnesium turnings (1.7 g,
0.07 g-at.) and MeI (9 g, 0.063 mol)) in anhydrous ether
(40 mL) was added slowly under nitrogen a solution of
the ester 16 (4.6 g, 0.014 mol) in ether (15 mL). The mixture
was stirred at room temperature for 30 min and then
re¯uxed for 4 h. It was then cooled in an ice-bath and
decomposed carefully with saturated aqueous NH4Cl
(25 mL). The product was extracted with ether (3£
30 mL). The ether extract was washed with water (2£
25 mL) and dried. Evaporation of the solvent furnished
the crude tertiary alcohol as an oil (4.6 g) (1H NMR
(300 MHz, CDCl3) dH 8.09 (1H, s, 5-ArH), 7.16 (1H, s,
8-ArH), 7.12 (1H, d, Jˆ7.8 Hz, 2-ArH), 6.58 (1H, d, Jˆ
7.8 Hz, 3-ArH), 3.96 (3H, s, ArOMe), 3.94 (3H, s,
ArOMe), 3.43 (1H, sept, Jˆ6.9 Hz, CHMe2), 2.93 (2H, t,
Jˆ7.2 Hz, ArCH2), 1.83±1.55 (5H, m), 1.32 (6H, d, Jˆ
6.9 Hz, CHMe2), 1.19 (6H, s, CMe2)) which was cyclised
by heating with polyphosphoric acid (prepared by heating at
95±1008C for 2 h a mixture of P2O5 (40 g) and H3PO4 (85%,
2.1.3. 2-Bromo-4-(3-methoxycarbonylpropyl)-6-methoxy-
7-isopropyl-1-tetralone (15). A solution of bromine (1.7 g,
10.6 mmol) in AcOH (3 mL) was added dropwise during
15 min to a stirred solution of the tetralone 14 (3.2 g,
10 mmol) in anhydrous ether (280 mL) at 108C, allowing
each drop of bromine to decolourise before more was added.
After the addition, the mixture was stirred at 108C for 2 h

S. K. Pal et al. / Tetrahedron 58 (2002) 1765±1771
1769
20 mL)) at 90±958C for 45 min. The reaction mixture was
cooled, decomposed with crushed ice, and extracted with
ether (3£50 mL). The ether extract was washed with satu-
rated aqueous NaHCO3 (30 mL) and water (2£30 mL), and
dried. Evaporation of the solvent followed by puri®cation of
the residue on a silica gel column using ethyl acetate±light
petroleum (1:49) as eluent furnished a crystalline compound
which was recrystallised from MeOH to give colourless
plates of 17 (3.57 g, 82%), mp 153±1548C; (Found: C,
80.55; H, 9.14. C21H28O2 requires C, 80.73; H, 9.03%);
nmax (KBr) 1628, 1599, 1458, 1236, 1042 cm21; dH (300
MHz, CDCl3) 8.02 (1H, s, 8-ArH), 7.13 (1H, s, 5-ArH),
6.67 (1H, s, 10-ArH), 3.97 (3H, s, ArOMe), 3.93 (3H, s,
ArOMe), 3.41 (1H, sept, Jˆ6.9 Hz, CHMe2), 2.95 (2H, t,
Jˆ6.3 Hz, ArCH2), 1.95±1.86 (2H, m), 1.74±1.70 (2H, m),
1.39 (6H, s, CMe2), 1.30 (6H, d, Jˆ6.9 Hz, CHMe2); 13C
NMR (75 MHz, CDCl3) dC 156.5, 153.4, 142.4, 136.5,
132.8, 121.5, 118.9, 118.9, 101.2, 100.9, 55.3, 55.1, 39.1,
34.5, 31.4, 27.2, 26.5, 22.8, 19.6.
7.00%); dH (300 MHz, CDCl3) 7.98 (1H, s, ArH), 7.04 (1H,
s, ArH), 6.71 (1H, s, ArH), 3.98 (3H, s, ArOMe), 3.87 (3H, s,
ArOMe), 3.40 (1H, sept, Jˆ7.0 Hz, CHMe2), 2.89 (2H, s,
CH2), 1.63 (6H, s, CMe2), 1.28 (6H, d, Jˆ7.0 Hz, CHMe2).
2.1.8. Preparation of the diester 19. A solution of the
diacid 18 (1.4 g, 3.74 mmol) in ether (30 mL) was esteri®ed
with an ice-cold ethereal solution of diazomethane (excess).
Usual work-up furnished a crystalline material which was
recrystallised from light petroleum to afford the diester 19
(1.46 g, 97%) as colourless plates, mp 85±868C; (Found: C,
68.78; H, 7.70. C23H30O6 requires C, 68.64; H, 7.51%); nmax
(KBr) 1732, 1720, 1628, 1600 cm21; dH (300 MHz, CDCl3)
7.98 (1H, s, ArH), 6.77 (2H, s, ArH), 4.00 and 3.98 (3H£2,
s£2, ArOMe and ArCO2Me), 3.88 (3H, s, ArOMe), 3.55
(3H, s, CO2Me), 3.38 (1H, sept, Jˆ6.9 Hz, CHMe2), 2.82
(2H, s, CH2), 1.58 (6H, s, CMe2), 1.28 (6H, d, Jˆ6.9 Hz,
CHMe2); dC (75 MHz, CDCl3) 172.7, 171.9, 157.2, 155.4,
142.3, 138.1, 131.3, 120.9, 118.8, 118.5, 101.8, 101.2, 55.3,
55.0, 52.0, 51.2, 47.8, 38.7, 29.2, 27.2, 22.7.
2.1.6. 1,2,3,4-Tetrahydro-1,1-dimethyl-6,9-dimethoxy-7-
isopropylphenanthren-4-one (7). To a solution of the
compound 17 (2.5 g, 8 mmol) in dry CH2Cl2 (60 mL) was
added a ®nely powdered and homogenised mixture of
pyridinium chlorochromate (8.6 g, 40 mmol) and celite
(6 g). The reaction mixture was stirred at room temperature
for 24 h, diluted with ether (60 mL) and ®ltered through a
column of silica gel (60 g). The column was washed with
two 50 mL portions of ether and the combined ®ltrate was
evaporated under reduced pressure. The solid residue was
crystallised from methanol to afford the ketone 7 (2.27 g,
87%) as white needles, mp 163±1648C; (Found: C, 77.38;
H, 8.24. C21H26O3 requires C, 77.27; H, 8.03%); nmax (KBr)
1660, 1627, 1588 cm21; dH (300 MHz, CDCl3) 9.01 (1H, s,
5-ArH), 8.03 (1H, s, 8-ArH), 6.70 (1H, s, 10-ArH), 4.06
(3H, s, ArOMe), 3.99 (3H, s, ArOMe), 3.41 (1H, sept, Jˆ
6.9 Hz, CHMe2), 2.79 (2H, t, Jˆ7.2 Hz, COCH2CH2), 2.04
(2H, t, Jˆ7.2 Hz, COCH2CH2), 1.44 (6H, s, CMe2), 1.29
(6H, d, Jˆ6.9 Hz, CHMe2); dC (75 MHz, CDCl3) 199.4,
159.7, 159.0, 156.4, 137.5, 133.0, 119.3, 118.6, 118.3,
105.1, 99.6, 55.5, 55.3, 37.0, 36.8, 35.5, 30.0, 27.2, 22.6.
2.1.9. Preparation of the half acid-ester 8. A solution of
KOH (0.4 g) in water (2 mL) was added under nitrogen to a
solution of the diester 19 (1.4 g, 3.48 mmol) in THF (3 mL).
The reaction mixture was stirred at room temperature for
24 h and at 608C for 1 h. It was then cooled, diluted with
water (20 mL) and extracted with ether (15 mL) to remove
any unhydrolysed diester. The aqueous alkaline layer was
acidi®ed with cold dilute HCl and extracted with ether
(3£30 mL). The ether extract was washed with water
(20 mL), dried, and evaporated. The solid residue was
crystallised from a mixture of benzene and light petroleum
to afford the half acid-ester 8 (1.22 g, 90%) as white plates,
mp 158±1598C; (Found: C, 67.91; H, 7.21. C22H28O6
requires C, 68.02; H, 7.27%); nmax (KBr) 1720, 1709,
1628, 1595 cm21; dH (300 MHz, CDCl3) 7.99 (1H, s,
ArH), 6.77 (1H, s, ArH), 6.75 (1H, s, ArH), 3.96 (6H, s,
ArOMe and ArCO2Me), 3.88 (3H, s, ArOMe), 3.38 (1H,
sept, Jˆ6.9 Hz, CHMe2), 2.82 (2H, s, CH2), 1.57 (6H, s,
CMe2), 1.28 (6H, d, Jˆ6.9 Hz, CHMe2); dC (75 MHz,
CDCl3) 176.9, 172.9, 157.2, 155.5, 142.0, 138.2, 131.3,
120.8, 118.8, 118.5, 101.8, 101.2, 55.3, 55.0, 52.1, 47.7,
38.5, 29.3, 27.2, 22.7.
2.1.7. 3-Methyl-3-(1-carboxy-6-isopropyl-4,7-dimethoxy-
2-naphthyl) butanoic acid (18). Ethyl formate (2.22 g,
30 mmol) was added dropwise under nitrogen to a stirred
suspension of NaH (0.55 g, 23 mmol) in benzene (16 mL).
A solution of the ketone 7 (1.5 g, 4.6 mmol) in benzene
(5 mL) containing MeOH (2 drops) was then added at 08C
during 25 min. After stirring at 08C for 2 h and at room
temperature for 18 h, cold water (30 mL) was added with
stirring and the aqueous layer was separated. The benzene
layer was extracted with cold 5% aqueous NaOH (2£
15 mL). The combined aqueous extract containing the
hydroxymethelene derivative of the ketone 7 was cooled
to 08C and H2O2 (30%, 20 mL) was added dropwise with
stirring. After stirring at 08C for 6 h, and at room tempera-
ture for 12 h, the reaction mixture was acidi®ed with cold
dilute HCl and extracted with ethyl acetate (3£70 mL). The
organic extract was washed with water (2£40 mL), dried,
and concentrated. The solid residue was crystallised from a
mixture of ethyl acetate and light petroleum to furnish the
diacid 18 (1.5 g, 87.5%) as white needles, mp 160±1618C;
(Found: C, 67.21; H, 7.20. C21H26O6 requires C, 67.36; H,
2.1.10. Preparation of the diazoketone 9. The diazoketone
9 was prepared from the half acid-ester 8 following the
method of Tarbell and Price.13 A solution of freshly distilled
ethyl chloroformate (330 mg, 3.04 mmol) in anhydrous
ether (4 mL) was added dropwise under nitrogen to a stirred
solution of 8 (1.17 g, 3 mmol) and Et3N (0.31 g, 3.07 mmol)
in dry THF (4 mL) at 2108C. After the addition, the reac-
tion mixture was stirred at 2108C for 1 h. The precipitated
Et3N. HCl was ®ltered off and washed with two 3 mL
portions of dry ether without exposure to moisture. The
®ltrate containing the mixed anhydride was added to an
ice-cold ethereal solution of diazomethane (prepared from
3 g of nitrosomethyl urea). After standing at 08C for 1 h, the
mixture was allowed to reach room temperature overnight.
Evaporation of the solvent under reduced pressure afforded
the diazoketone 9 as a pale yellow viscous liquid (1.14 g,
92%) (nmax (®lm) 2105, 1723, 1628, 1595 cm21; dH (300
MHz, CDCl3) 7.90 (1H, s, ArH), 6.69 (2H, s, ArH), 4.82
(1H, s, COCHN2), 4.00, 3.96 and 3.93 (3H£3, s£3,

1770
S. K. Pal et al. / Tetrahedron 58 (2002) 1765±1771
ArOMe£2 and ArCO2Me), 3.50 (1H, sept, Jˆ7.0 Hz,
CHMe2), 2.66 (2H, s, CH2), 1.53 (6H, s, CMe2), 1.30 (6H,
d, Jˆ7.0 Hz, CHMe2)) which was used for the subsequent
intramolecular cyclisation without further puri®cation.
3.17 (6H, m), 3.58 (3H, s, CO2Me), 2.92±2.52 (3H, m),
2.24±1.51 (5H, m), 1.17 (6H, d, Jˆ7.0 Hz, CHMe2), 1.10
(3H, s, Me), 1.06 (3H, s, Me); dC (75 MHz, CDCl3) 174.2,
154.8, 137.9, 136.0, 128.9, 126.7, 108.5, 65.9, 55.8, 54.2,
51.3, 51.3, 50.1, 49.1, 39.1, 37.6, 35.5, 33.0, 29.0, 26.4,
22.8, 22.8, 22.5, 18.7.
2.1.11. Methyl 12-methoxy-2,7-dioxoabieta-5,8,11,13-
tetraen-20-oate (10). A solution of the diazoketone 9
(1.1 g, 2.67 mmol) in dry CH2Cl2 (15 mL) was added during
2 min under nitrogen to a stirred solution of tri¯uoroacetic
acid (20 mL) in CH2Cl2 (25 mL) at 2208C. The mixture was
stirred at 2208C for another 3 min and then diluted with
CH2Cl2 (40 mL). The dichloromethane solution was washed
with water (3£20 mL), dried and concentrated. The crude
product was chromatographed on silica gel (30 g). Elution
of the column with ether±light petroleum (1:3) furnished
the crystalline enedione 10 which was recrystallised from
light petroleum to afford colourless plates (0.61 g, 62%), mp
208±2098C; (Found: C, 71.25; H, 7.26. C22H26O5 requires
C, 71.33; H, 7.07%); nmax (KBr) 1728, 1715, 1656, 1598
cm21; dH (300 MHz, CDCl3) 8.05 (1H, s, 14-ArH), 6.83
(1H, s, 11-ArH), 6.71 (1H, s, CHvC), 3.89 (3H, s,
ArOMe), 3.64 (3H, s, CO2Me), 3.30 (1H, sept, Jˆ
6.9 Hz, CHMe2), 3.82, 2.39 (2H, ABq, Jˆ18.0 Hz,
CH2COCH2CMe2), 2.53, 2.34 (2H, ABq, Jˆ16.0 Hz,
CH2COCH2CMe2), 1.37 (3H, s, Me), 1.28 (3H, s, Me),
1.26 and 1.23 (3H£2, d£2, Jˆ6.9 Hz each, CHMe2); dC
(75 MHz, CDCl3) 206.5, 183.8, 172.1, 162.1, 160.9,
140.5, 138.4, 127.7, 124.8, 123.4, 106.1, 55.7, 53.5, 51.8,
51.5, 46.6, 38.0, 32.2, 30.5, 26.7, 22.4, 22.1.
2.1.14. Methyl 12-methoxyabieta-8,11,13-trien-20-oate
(12). The thioacetal 20 (0.48 g, 1.1 mmol) was re¯uxed
with freshly prepared Raney nickel (ca. 3 g) in EtOH
(10 mL) for 4 h. The reaction mixture was ®ltered and the
®ltrate was diluted with water (20 mL). Extraction of the
product with ether (3£25 mL) furnished the ester 12 as a
crystalline compound which was recrystallised from metha-
nol to afford 12 (335 mg, 88%) as colourless plates, mp
111±1128C; (Found: C, 76.59; H, 9.43. C22H32O3 requires
C, 76.70; H, 9.36%); nmax (KBr) 1720, 1610 cm21; dH
(300 MHz, CDCl3) 6.89 (1H, s, ArH), 6.74 (1H, s, ArH),
3.76 (3H, s, ArOMe), 3.56 (3H, s, CO2Me), 3.21 (1H, sept,
Jˆ6.9 Hz, CHMe2), 2.97±2.37 (4H, m), 2.01±1.85 (2H, m),
1.65±1.22 (5H, m), 1.18 and 1.17 (3H£2, d£2, Jˆ6.9 Hz
each, CHMe2), 0.97 (3H, s, Me), 0.77 (3H, s, Me); dC
(75 MHz, CDCl3) 176.2, 154.8, 138.2, 135.5, 128.7,
127.0, 107.5, 55.5, 52.3, 51.5, 47.9, 41.8, 37.1, 33.9, 32.1,
29.4, 26.5, 22.8, 22.5, 20.4, 20.1, 18.7.
2.1.15. 12-Hydroxyabieta-8,11,13-trien-20-oic acid [(6)-
pisiferic acid] (1). A mixture of the ester 12 (120 mg,
0.348 mmol) and anhydrous AlBr3 (0.8 g) in ethanethiol
(3.8 mL) was stirred at room temperature for 15 h. The
mixture was poured into cold dilute HCl and extracted
with ether (3£20 mL). The ether extract was washed with
brine, dried, and evaporated. The residue was chromato-
graphed on silica gel (4 g). The solid fractions eluted with
ether±light petroleum (1:3) were crystallised from a mixture
of ether and light petroleum to give pisiferic acid (1)
(102 mg, 92%) as colourless crystals, mp 226±2278C
(sublimed) (lit.,4 mp 226±2278C (sublimed)); (Found: C,
76.01; H, 9.14. C20H28O3 requires C, 75.91; H, 8.92%);
nmax (KBr) 3490, 3400, 3370, 2961, 2900, 1694, 1615,
1593 cm21; dH (300 MHz, CDCl3) 6.89 (1H, s, 14-ArH),
6.69 (1H, s, 11-ArH), 3.12 (1H, sept, Jˆ6.9 Hz, CHMe2),
2.93±2.74 (3H, m), 2.53±1.84 (3H, m), 1.66±1.56 (1H,m),
1.50 (1H, dd, Jˆ12.9, 2.6 Hz, CHCH2), 1.45±1.22 (3H, m),
1.21 (6H, d, Jˆ6.9 Hz, CHMe2), 0.96 (3H, s, Me), 0.84 (3H,
s, Me); dC (75 MHz, CDCl3) 180.2, 150.7, 138.2, 133.5,
129.1, 127.4, 112.3, 52.2, 47.5, 41.8, 36.7, 34.1, 32.1,
29.3, 26.9, 22.6, 22.4, 20.3, 20.2, 18.6. (Lit.,4 IR (CHCl3):
3600, 3500±2400, 1690 cm21; lit.,4 1H NMR (CDCl3,
90 MHz): 0.84 and 0.97 (each 3H and s, CMe2), 1.21 (6H,
d, Jˆ7 Hz, CHMe2), 6.68 and 6.89 (each 1H and s, C-11 H
and C-14 H); lit.,21 13C NMR (CDCl3, 22.5 MHz): 18.6 (t,
2), 20.1 (q, 19), 20.4 (t, 6), 22.4 (q, 16 or 17), 22.6 (q, 16 or
17), 26.9 (d, 15), 29.3 (t, 7), 32.4 (q, 18), 34.1 (s, 4), 36.7 (t,
1), 41.8 (t, 3), 47.5 (s, 10), 52.3 (d, 5), 112.3 (d, 11), 127.3
(d, 14), 129.2 (s, 8), 133.6 (s, 13), 138.2 (s, 9), 150.6 (s, 12),
181.1 (s, 20).
2.1.12. Methyl 12-methoxy-2-oxoabieta-8,11,13-trien-20-
oate (11). A solution of the enedione 10 (0.57 g, 1.54 mmol)
in ethyl acetate (15 mL) was hydrogenated over Pd±C
(10%, 0.3 g) at room temperature and atmospheric pressure.
Uptake of hydrogen (125 mL) ceased after 2 h. The mixture
was ®ltered from the catalyst. Evaporation of the solvent
followed by crystallisation of the solid residue from light
petroleum furnished the keto-ester 11 (0.52 g, 94%) as
colourless plates, mp 150±1518C; (Found: C, 73.79; H,
8.61. C22H30O4 requires C, 73.71; H, 8.44%); nmax (KBr)
1724, 1710, 1600 cm21; dH (300 MHz, CDCl3) 6.96 (1H, s,
ArH), 6.52 (1H, s, ArH), 3.73 (3H, s, ArOMe), 3.61 (3H, s,
CO2Me), 3.66±2.81 (4H, m), 2.46±2.23 (4H, m), 2.01±1.94
(2H, m), 1.19 and 1.17 (3H£2, d£2, Jˆ6.9 Hz each,
CHMe2), 1.12 (3H, s, Me), 0.85 (3H, s, Me); dC (75 MHz,
CDCl3) 209.1, 175.2, 155.2, 136.3, 136.2, 128.0, 127.2,
106.8, 55.4, 55.4, 52.3, 51.4, 51.2, 50.5, 36.2, 32.2, 29.4,
26.5, 22.7, 22.4, 22.0, 19.1.
2.1.13. Methyl 2,2-ethylenedithio-12-methoxyabieta-
8,11,13-trien-20-oate (20). Ethanedithiol (0.6 g) and
BF3´Et2O (0.5 mL) were added to a solution of the keto-
ester 11 (470 mg, 1.3 mmol) in MeOH (3 mL) and the
mixture was stirred at room temperature for 20 h. The
reaction mixture was then diluted with ice-cold aqueous
NaOH (5%, 15 mL) and the product was extracted with
ether (3£25 mL). The ether extract was washed with
water (2£20 mL), dried and evaporated. The solid residue
was crystallised from a mixture of ether and light petroleum
to afford the thioacetal 20 (0.52 g, 91%) as white needles,
mp 161±1628C; (Found: C, 66.08; H, 8.02. C24H34O3S2
requires C, 66.32; H, 7.88%); dH (300 MHz, CDCl3) 6.87
(1H, s, ArH), 6.84 (1H, s, ArH), 3.80 (3H, s, ArOMe), 3.73±
2.1.16. 12-Methoxyabieta-8,11,13-trien-20-oic acid [(6)-
O-methylpisiferic acid] (4). To a solution of the ester 12
(120 mg, 0.348 mmol) in dry DMSO (6 mL) was added
t-BuOK (630 mg, 5.62 mmol) and the mixture was stirred
at 958C for 70 min. It was then cooled, diluted with water

S. K. Pal et al. / Tetrahedron 58 (2002) 1765±1771
1771
(15 mL), acidi®ed with HCl, and extracted with ether
References
(3£25 mL). The ether extract was washed with brine,
dried, and concentrated. The residue was chromatographed
on silica gel (4 g). The solid fractions eluted with ether±
light petroleum (1:4) were crystallised from light petroleum
to afford O-methylpisiferic acid (4) (82 mg, 72%) as white
needles, mp 124±1258C; (Found: C, 76.16; H, 9.19.
C21H30O3 requires C, 76.33; H, 9.15%); IR data in chloro-
form (nmax (CHCl3) 2968, 2940, 1690, 1614, 1460 cm21) are
consistent with the literature values;7 dH (300 MHz, CDCl3)
6.90 (1H, s, 14-ArH), 6.76 (1H, s, 11-ArH), 3.74 (3H, s,
ArOMe), 3.20 (1H, sept, Jˆ6.9 Hz, CHMe2), 2.93±2.74
(3H, m), 2.55±1.85 (3H, m), 1.66±1.57 (1H, m), 1.52
(1H, dd, Jˆ13.0, 2.7 Hz, CHCH2), 1.46±1.22 (3H, m),
1.17 (6H, d, Jˆ6.9 Hz, CHMe2), 0.96 (3H, s, Me), 0.84
(3H, s, Me); dC (75 MHz, CDCl3) 180.6, 154.9, 137.8,
135.9, 128.8, 127.1, 107.6, 55.5, 52.3, 47.7, 41.8, 36.7,
34.1, 32.1, 29.3, 26.5, 22.8, 22.5, 20.4, 20.1, 18.6. (Lit.,7
1H NMR d (100 MHz, CDCl3) 0.83 (3H, s), 0.97 (3H, s),
1.17 (6H, d, Jˆ7 Hz), 1.31±2.68 (9H, m), 2.68±3.03 (2H,
m), 3.21 (1H, sep, Jˆ7 Hz), 3.73 (3H, s), 6.75 (1H, s), 6.90
(1H, s), 11.10 (1H, br.s); lit.,7 13C NMR d (25 MHz, CDCl3)
18.54, 20.08, 20.37, 22.49, 22.78, 26.54, 29.32, 32.09,
34.07, 36.67, 41.82, 47.49, 52.37, 55.41, 107.51, 127.08,
128.81, 135.90, 137.88, 154.88, 182.10; lit.7 nmax (CHCl3)
3650±3100 (br.m), 3040 (w.sh), 2970 (s), 2940 (s), 2920 (s),
2880 (s), 2700±2300 (br.m), 1690 (s), 1615 (m), 1575 (w),
1505 (s), 1460 (s), 1450 (m), 1405 (m), 1390 (m), 1370 (m),
1325 (m), 1315 (w), 1295 (w), 1275 (m), 1250 (s), 1230 (m),
1215 (m), 1200 (w), 1180 (w), 1160 (m), 1140 (w), 1120
(w), 1105 (w), 1085 (w), 1080 (w), 1060 (m), 1030 (w),
1000 (w), 990 (w), 980 (w), 955 (w), 940 (w), 920 (w),
900 (w), 890 (w), 850 (w) cm21).
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Acknowledgements
18. Preliminary communication: Pal, S. K.; Mukherjee, D.
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We are grateful to the CSIR, New Delhi, for ®nancial
support (Grant No. 01(1534)/98/EMR-II). One of us (P. D.
G.) thanks the CSIR for a fellowship. We thank Professor
Animesh Chakraborty, Dr Bimal Kumar Dirghangi and
Mr Swarup Kumar Chattopadhyay of the Department of
Inorganic Chemistry, Indian Association for the Cultivation
of Science, Calcutta for the single-crystal X-ray structure of
the compound 11 and the DST, New Delhi, for the X-ray
diffractometer.
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