A facile synthetic approach to the core structure of 6,7-didehydrocarnosoic acid type derivatives

Article abstract of DOI:10.1016/S0040-4020(03)00984-0

In this paper we report on the development of a flexible and efficient synthetic approach towards 6,7-didehydrocarnosoic acid type analogues. The elaboration of the required trans-decalin system, the installation of the carboxylic acid in the angular position as well as the generation of the C₆-C₇ double bond to afford the 6,7-didehydrocarnosoic acid scaffold as it was found in 2 and 3 is described.

Full text of DOI:10.1016/S0040-4020(03)00984-0

Tetrahedron 59 (2003) 6045–6049
A facile synthetic approach to the core structure of
6,7-didehydrocarnosoic acid type derivatives
*
Andreas Luxenburger
¨ ¨ ¨
Institut fur Organische Chemie, Universitat des Saarlandes, Im Stadtwald, P.O. Box 151150, D-66041 Saarbrucken, Germany
Received 29 April 2003; revised 19 June 2003; accepted 20 June 2003
Abstract—In this paper we report on the development of a flexible and efficient synthetic approach towards 6,7-didehydrocarnosoic acid
type analogues. The elaboration of the required trans-decalin system, the installation of the carboxylic acid in the angular position as well as
the generation of the C6–C7 double bond to afford the 6,7-didehydrocarnosoic acid scaffold as it was found in 2 and 3 is described.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
carboxylic acid functionality in the angular position we wish
to describe the synthesis of the simplified carboxylic acid 5
as a model compound in this paper (Fig. 1).
6,7-Didehydrocarnosoic acid 1 is an abietane type diterpe-
noid which is discussed to play a key role in the biosynthesis
of highly oxidized abietane type diterpenes.1,2 In 1965
Wenkert and co-workers1 expected 1 to be an essential
intermediate in the formation of rosmaricine, an alkaloid
which was allegedly isolated from Rosmarinus officinalis L.
in 1962,3 as well as further g-lactone artifacts. To date the
isolation of some 6,7-didehydrocarnosoic acid type natural
compounds is described in the literature. In 1978, Saleh and
2. Results and discussion
According to our previously reported retrosynthetic con-
siderations7 we started our synthesis with the reaction of the
a,b-unsaturated methyl ester 6 with the 3,5-dimethoxy
phenyl acetonitrile 7 in the presence of sodium hydride in
THF (Scheme 1). In a Michael addition combined with a SN-
reaction the nitrile methyl ester 8 was formed in 78% yield.
Additional saponification of the methyl ester function
provided the corresponding carboxylic acid 9 in 89%
yield. To elaborate the ketonitrile 11 with the trans-decalin
structure and the nitrile functionality in the angular position,
two synthetic pathways were to be pursued. Once the amide
10 was synthesized by treating the nitrile carboxylic acid 9
co-workers4 separated the carboxylic acid 2 form Salvia
5
´
lanigera Poir. and Gonzalez et al. reported on the isolation
of the methyl ester 3 form Salvia canariensis L. in 1987.
Due to the evidence for 3 and further research work Luis and
co-workers2 postulated a biosynthetic pathway to highly
oxidized abietane type diterpenoids like rosmanol, isoros-
manol, epirosmanol and rosmadial in which the reaction of
6,7-didehydrocarnosoic acid with singlet oxygen would be
essential. The synthesis of the analogues 4a and 4b was
published by Jones and co-workers6 in 1994 using a Diels–
Alder reaction as the key step. As part of our research
project to study synthetic strategies towards carnosol type
derivatives7 we developed a flexible and efficient synthetic
route to the core structure of 6,7-didehydrocarnosoic acid
type derivatives. This strategy is supposed to give us access
to a wide range of analogues to 1 as well as to further
abietane type compounds with interesting biological proper-
ties. Applying a synthetic route to amide 10 derivatives
reported by Yardley and Rees8 in 1985 as a key strategic
element to install the required trans-decalin scaffold with a
Keywords: 6,7-didehydrocarnosoic acid; natural product; diterpene;
synthesis; analogues.
*
¨
Address: Institut fu¨r Pharmazie, Johannes Gutenberg-Universitat,
Staudinger Weg 5, D-55099 Mainz, Germany. Tel.: þ49-613-
13925728; fax: þ49-613-13923062; e-mail: luxenburger@freenet.de
Figure 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00984-0

6046
A. Luxenburger / Tetrahedron 59 (2003) 6045–6049
Scheme 1.
with concentrated sulfuric acid first. The installation of the
required trans-decalin structure in 10 was confirmed by X-
ray crystallographic analysis (Scheme 1). Subsequent
dehydration of the amide group with TFAA9 gave the
desired ketonitrile 11 in 64% yield in two steps. Alter-
natively, we employed a method described by Effenberger
et al.10 Thus, the carboxylic acid function in 9 was
transformed into the corresponding acid chloride first and
subsequently refluxed in acetonitrile in the presence of
silver trifluoromethanesulphonic acid, so that the ketonitrile
11 was obtained in 92% yield in only one step. Reduction of
the carbonyl functionality in 11 with NaBH4 in methanol11
led to the hydroxy nitrile 12 in 92% yield (Scheme 2). As the
b-oriented nitrile function prevents a reduction from the
upper side of the molecule, the b-directed benzylic alcohol
was formed only. The resulting three-dimensional structure
of 12 was determined from the NOESY correlation between
the benzylic proton at C9 and the bridgehead proton at C10a
as well as by X-ray crystallographic analysis (Fig. 2).
Elimination of water by refluxing 12 in acetone in the
presence of p-TosOH12 provided the nitrile 13 with the
required C6–C7 double bond in 95% yield. The generation
of the corresponding aldehyde 14 was achieved in 75%
yield by the treatment of the nitrile function in 13 with
DIBAL13 in dichloromethane at low temperatures. We tried
to oxidize the aldehyde 14 to the desired carboxylic acid 16
using the Jones oxidation14 or the PDC method.15 Despite
several attempts the acid 16 could not be isolated. Either the
starting material was recovered unchanged or decarboxyla-
tion to 15 occurred. In the case of the Jones oxidation 15 was
Scheme 2.

A. Luxenburger / Tetrahedron 59 (2003) 6045–6049
6047
4.1.1. Methyl [2-cyano-2-(3,4-dimethoxyphenyl)cyclo-
hexyl]-acetate (8). A solution of the 3,4-dimethoxy phenyl
acetonitrile 7 (9.12 g, 51.4 mmol) in dry THF (110 ml) was
added dropwise to a suspension of sodium hydride (60% in
mineral oil; 2.21 g, 55.3 mmol) in dry THF (120 ml) at rt.
The reaction mixture was stirred at rt for further 1.5 h.
Subsequently, a solution of the a,b-unsaturated methyl ester
6 (15.0 g, 48.1 mmol) in dry THF (110 ml) was added
dropwise at rt and the reaction mixture was refluxed for
additional 48 h. After being cooled to rt, acetic acid
(7.60 ml) was added. The solvent was evaporated to small
volume, the residue was diluted with water (300 ml) and
extracted with diethyl ether (4£100 ml). The organic layers
were combined, washed with saturated NaHCO3 solution
and brine, dried over MgSO4 and concentrated. The crude
product was purified by column chromatography (silica gel,
diethyl ether/petroleum ether 7:3) to yield 11.9 g (78%) of 8
as a colourless oil. IR (film) 2985, 2930, 2845, 2220, 1770,
1625, 1545 cm21; 1H NMR (400 MHz, CDCl3) d 7.06 (dd,
J1¼8.4 Hz, J2¼2.2 Hz, 1H), 6.99 (d, J¼1.8 Hz, 1H), 6.87
(d, J¼8.8 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.57 (s, 3H),
2.46–2.37 (m, 1H), 2.22–2.15 (m, 2H), 2.13–2.04 (m, 1H),
2.01–1.92 (m, 1H), 1.91–1.75 (m, 4H), 1.60–1.39 (m, 2H);
13C NMR (100 MHz, CDCl3) d 172.57, 149.30, 148.77,
131.65, 120.60, 118.34, 111.53, 109.35, 56.06, 55.97, 51.59,
49.86, 41.87, 39.95, 37.06, 29.81, 25.26, 23.70; MS (EI) m/z
(%) 318 (Mþþ1, 15), 317 (Mþ, 65), 286 (16), 285 (39), 214
(14), 190 (17), 189 (100), 177 (27), 176 (18), 41 (25).
Figure 2. X-Ray crystal structure of the hydroxy nitrile 12 (ORTEP
drawing, ellipsoids at 30% probability).
separated in 52% yield. Applying the PDC method 23% of 15
were afforded. Finally, the oxidation of the aldehyde 14 to the
desired carboxylic acid 16 was performed using the Lindgren
protocol.16 Thus 14 was treated with NaClO2 in the presence
of 2-methyl-2-butene so that 16 was accomplished in 63%
yield and from 7 in 29% overall-yield in seven steps.
3. Conclusions
In summary, we developed an appropriate and concise
synthetic route to the model compound 5. The synthesis of 5
was accomplished in 29% overall-yield in seven steps and
features the construction of the required trans-decalin system,
the installation of the carboxylic acid functionality in the
angular position as well as the formation of the C6–C7 double
bond. Our strategy is efficient, flexible and should enable us to
synthesize various 6,7-didehydrocarnosoic acid type
derivatives.
4.1.2. [2-Cyano-2-(3,4-dimethoxyphenyl)cyclohexyl]ace-
tic acid (9). A solution of the nitrile methyl ester 8 (11.8 g,
37.2 mmol) in methanol (135 ml) was refluxed with a 20%
aqueous NaOH solution (37 ml) for 3 h. The reaction mixture
was cooled to rt and the methanol was distilled off to small
volume. The residue was diluted with water (250 ml) and
extracted with diethyl ether (2£90 ml). The ethereal extracts
were discarded. Subsequently, the aqueous solution was
acidified to pH 1 by the dropwise addition of 37% HCl and the
resulting acidic suspension was extracted with diethyl ether
(4£100 ml). The combined organic extracts were washed with
brine and dried over MgSO4. Finally, the solvent was
evaporated to give 10.1 g (89%) of 9 as a colourless solid.
An analytical sample was obtained by recrystallization from
water/ethanol. Mp 131–1338C. IR (KBr) 3070, 2940, 2860,
2235, 1710, 1590, 1525 cm21; 1H NMR (400 MHz, CDCl3) d
7.05 (dd, J1¼8.4 Hz, J2¼2.2 Hz, 1H), 6.97 (d, J¼1.8 Hz, 1H),
6.86 (d, J¼8.4 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 2.41–2.34
(m, 1H), 2.30–2.17 (m, 2H), 2.13–1.97 (m, 2H), 1.92–1.76
(m, 4H), 1.61–1.39 (m, 2H); 13C NMR (100 MHz, CDCl3) d
178.03, 149.36, 148.87, 131.48, 120.47, 118.37, 111.63,
109.38, 56.06, 55.95, 49.77, 41.76, 39.89, 37.03, 29.73, 25.25,
23.66; MS (EI) m/z (%) 304 (Mþþ1, 36), 303 (Mþ, 100), 285
(25), 214 (17), 202 (16), 196 (25), 189 (57), 176 (23), 166 (16),
151 (41), 149 (15), 83 (15), 81 (18), 73 (19), 71 (21), 69 (32),
60 (18), 59 (15), 57 (31), 55 (27). Anal. calcd for C17H21NO4:
C, 67.31; H, 6.98; N, 4.62. Found C, 67.24; H, 6.95; N, 4.56.
4. Experimental
4.1. General information
Melting points were obtained on a Bu¨chi apparatus (Dr
Tottoli) and are uncorrected. Infrared spectra were measured
on a Beckmann Acculab 8 and a Bio-Rad Excalibur FTS 3000
spectrometer (FT-IR). 1H NMR and 13C NMR spectra were
recorded on a Bruker AM 400 spectrometer. Chemical shifts
are reported in ppm from tetramethylsilane as the internal
standard. Mass spectra and accurate mass data were obtained
on either a Finnigan MAT 90 (CI, 120 eV, methane) or a
Varian MAT 311 (EI, 70 eV) instrument. X-Ray diffraction
analyses were carried out by Dr Volker Huch at the
Department of Inorganic Chemistry at Saarland University
with a STOE (Image Plate (IPDS)) Area Detector Diffract-
ometer apparatus. Elemental microanalyses were performed
with a Leco CHNS-932. All reactions were monitored by thin
layer chromatography (TLC) using 0.2 mm silica gel (Merck
Kieselgel 60 F254) precoated aluminium roll. Column
chromatography was performed on J. T. Baker silica gel
(particle size 63–260 mm). All solvents were purified and
dried by standard techniques or used as supplied from
commercial sources as appropriate. Reactions in dry solvents
were carried out under an atmosphere of nitrogen.
4.1.3. 6,7-Dimethoxy-9-oxo-trans-1,3,4,9,10,10a-hexahy-
dro-4a(2H)-phenanthrene-carboxylic acid amide (10).
The nitrile carboxylic acid 9 (5.00 g, 16.5 mmol) was stirred
with concentrated sulfuric acid (160 ml) at rt for 24 h. The
reaction mixture was poured onto ice and the resulting
crystalline solid was filtered off, dried in vacuo over CaCl2
The a,b-unsaturated methyl ester 6 was prepared according
to the procedure described in Ref. 7.

6048
A. Luxenburger / Tetrahedron 59 (2003) 6045–6049
and purified by column chromatography (silica gel, ethyl
acetate) to give 3.69 g (74%) of 10 as a colourless solid. Mp
232–2338C. IR (KBr) 3430, 3300, 3195, 3015, 2935, 2915,
2860, 1655, 1590 cm21; 1H NMR (400 MHz, CDCl3) d 7.59
(s, 1H), 6.94 (s, 1H), 5.62 (sb, 1H, NH2), 5.14 (sb, 1H, NH2),
3.98 (s, 3H), 3.93 (s, 3H), 2.96 (dd, J1¼18.6 Hz,
J2¼13.7 Hz, 1H), 2.67–2.62 (m, 1H), 2.52 (dd,
J1¼18.6 Hz, J2¼4.0 Hz, 1H), 2.26–1.98 (m, 3H), 1.93–
1.76 (m, 2H), 1.72–1.63 (m, 1H), 1.55–1.48 (m, 1H), 1.43–
1.28 (m, 1H); 13C NMR (100 MHz, CDCl3) d 196.84,
175.52, 153.80, 148.74, 142.11, 126.38, 109.96, 106.95,
56.24, 56.11, 48.59, 43.63, 42.68, 35.49, 28.56, 25.58,
22.65; MS (EI) m/z (%) 304 (Mþþ1, 14), 303 (Mþ, 64), 260
(60), 259 (100), 231 (30), 217 (42), 191 (70), 189 (18), 151
(18), 115 (17), 77 (14), 44 (24). Anal. calcd for C17H21NO4:
C, 67.31; H, 6.98; N, 4.62. Found C, 67.43; H, 6.92; N, 4.66.
another 3 h. Subsequently, water (30 ml) was added, most of
the methanol was evaporated and the residue was extracted
with diethyl ether (3£15 ml). The ethereal extracts were
combined, washed with brine and dried over MgSO4. The
solvent was evaporated and the obtained colourless solid was
purified by column chromatography (silica gel, ethyl acetate/
cyclohexane 1:1) to yield 2.58 g (92%) of 12 as a colourless
solid. Mp 155–1568C. IR (KBr) 3520, 3020, 2940, 2865,
1
2225, 1605, cm21; H NMR (400 MHz, CDCl3) d 7.14 (s,
1H), 6.82 (s, 1H), 4.73 (dd, J1¼10.6 Hz, J2¼6.2 Hz, 1H), 3.87
(s, 6H), 2.67–2.60 (m, 1H), 2.21 (sb, 1H, OH), 2.11 (dd,
J1¼12.8 Hz, J2¼6.6 Hz, 1H), 1.96–1.86 (m, 4H), 1.74–1.58
(m, 3H), 1.51–1.28 (m, 2H); 13C NMR (100 MHz, CDCl3) d
149.36, 148.86, 132.69, 127.77, 121.79, 110.36, 107.88,
68.84, 56.06, 55.94, 43.35, 41.77, 38.39, 35.63, 30.01, 25.19,
23.41; MS (EI) m/z (%) 288 (Mþþ1, 20), 287 (Mþ, 100), 286
(20), 180 (84). Anal. calcd for C17H21NO3: C, 71.06; H, 7.37;
N, 4.87. Found C, 71.23; H, 7.29; N, 4.93.
4.1.4. 6,7-Dimethoxy-9-oxo-trans-1,3,4,9,10,10a-hexahy-
dro-4a(2H)-phenanthrene-carbonitrile (11). Method A.
To a suspension of the amide 10 (3.50 g, 11.5 mmol) and
dry Et3N (3.22 ml, 23.1 mmol) in dry CH2Cl2 (70 ml) were
added dropwise TFAA (1.93 ml, 13.9 mmol) at 08C. The
reaction mixture was stirred at 08C for 1.5 h and at rt for
further 4 h. Subsequently, a 10% Na2CO3 solution (85 ml)
was added. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3£30 ml). The organic
extracts were combined and dried over MgSO4. Finally, the
solvent was removed and the residue was purified by
column chromatography (silica gel, ethyl acetate/cyclohex-
ane 1:1) to afford 2.86 g (87%) of 11 as a colourless solid.
4.1.6. 6,7-Dimethoxy-trans-1,3,4,10a-tetrahydro-4a(2H)-
phenanthrenecarbonitrile (13). A solution of the hydroxy
nitrile 12 (1.00 g, 3.48 mmol) and a catalytic amount of p-
TosOH (20 mg) in acetone (95 ml) were refluxed for 24 h.
After being cooled to rt, most of the solvent was evaporated
and the residue was taken up in water (50 ml). Sub-
sequently, the aqueous layer was extracted with ethyl
acetate (3£20 ml). The organic extracts were combined,
washed with saturated NaHCO3 solution, brine and dried
over MgSO4. Finally, the solvent was evaporated and the
residue was purified by column chromatography (silica gel,
ethyl acetate/cyclohexane 1:2) to give 891 mg (95%) of 13
as a colourless solid. Mp 146–1478C. IR (KBr) 3020, 2930,
2855, 2225, 1605, 1570 cm21; 1H NMR (400 MHz, CDCl3)
d 6.87 (s, 1H), 6.71 (s, 1H), 6.53 (dd, J1¼9.5 Hz, J2¼2.5 Hz,
1H), 5.71 (dd, J1¼9.5 Hz, J2¼2.0 Hz, 1H), 3.90 (s, 3H),
3.89 (s, 3H), 2.70–2.62 (m, 1H), 2.31–2.22 (m, 1H), 2.01–
1.66 (m, 6H), 1.45–1.31 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 149.12, 148.65, 130.21, 127.59, 127.35, 126.83,
121.21, 110.80, 107.56, 56.26, 56.06, 42.28, 41.70, 32.72,
28.84, 25.35, 23.12; MS (EI) m/z (%) 270 (Mþþ1, 24), 269
(Mþ, 100), 227 (21), 226 (72), 86 (22), 84 (34), 43 (18);
Anal. calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20.
Found C, 75.97; H, 6.99; N, 5.11.
Method B. The nitrile carboxylic acid 9 (2.00 g, 6.59 mmol)
was stirred with oxalyl chloride (11.5 ml, 132 mmol) at rt
for 24 h. The excessive oxalyl chloride was removed in
vacuo. The formed acid chloride was dissolved in dry
acetonitrile (72 ml), silver trifluoromethanesulfonic acid
(1.17 g, 5.30 mmol) was added and the reaction mixture was
heated to reflux for 24 h. Subsequently, the solvent was
distilled off to small volume, the residue was taken up in
water (140 ml) and extracted with CH2Cl2 (3£50 ml). The
combined organic extracts were dried over MgSO4,
concentrated and the residue was purified by column
chromatography (silica gel, ethyl acetate/cyclohexane 1:1)
to give 1.73 g (92%) of 11 as a colourless solid. Mp 154–
1568C. IR (KBr) 3095, 3000, 2935, 2865, 2835, 2225, 1665,
4.1.7. 6,7-Dimethoxy-trans-1,3,4,10a-tetrahydro-4a(2H)-
phenanthrenecarbaldehyde (14). To a solution of the
nitrile 13 (850 mg, 3.16 mmol) in dry toluene (42 ml) was
added dropwise DIBAL (1.5 M in toluene; 2.31 ml,
3.47 mmol) at 2788C. It was stirred at this temperature
for one additional hour. The reaction mixture was allowed to
warm to 2108C. After being stirred at 2108C for 1 h, the
mixture was cooled to 2788C again, ethyl acetate (1 ml)
was added and the mixture was allowed to warm to rt.
Subsequently, the mixture was poured into water (80 ml)
and a saturated K–Na tartrate solution was added until the
formed precipitate was completely dissolved. The organic
layer was separated and the aqueous layer was extracted
with diethyl ether (3£40 ml). The organic extracts were
combined, washed with brine, dried over Na2SO4 and the
solvent was evaporated. The residue was purified by column
chromatography (silica gel, ethyl acetate/cyclohexane 1:2)
to yield 643 mg (75%) of 14 as a colourless solid. Mp 102–
1038C. IR (KBr) 2990, 2905, 2830, 2705, 1740, 1600,
1
1595 cm21; H NMR (400 MHz, CDCl3) d 7.58 (s, 1H),
6.94 (s, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 2.83–2.71 (m, 2H),
2.63 (dd, J1¼17.7 Hz, J2¼3.5 Hz, 1H), 2.17–2.06 (m, 1H),
2.05–1.83 (m, 3H), 1.82–1.58 (m, 3H), 1.46–1.32 (m, 1H);
13C NMR (100 MHz, CDCl3) d 194.19, 154.16, 149.45,
136.17, 125.63, 119.87, 109.51, 106.88, 56.24, 56.14, 42.80,
42.13, 34.66, 29.86, 24.83, 23.21; MS (EI) m/z (%) 286
(Mþþ1, 22), 285 (Mþ, 100), 242 (18), 216 (46), 189 (17),
137 (31), 91 (21), 79 (15), 55 (14), 45 (20), 43 (20). Anal.
calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found C,
71.68; H, 7.00; N, 4.84.
4.1.5. 9-Hydroxy-6,7-dimethoxy-trans-1,3,4,9,10,10a-
hexahydro-4a(2H)-phenanthrene-carbonitrile (12).
A
solution of the nitrile 11 (2.80 g, 9.81 mmol) in methanol
(75 ml) was cooled to 08C and NaBH4 (1.48 g, 39.3 mmol)
was added portionwise at this temperature. The reaction
mixture was stirred at 08C for further 15 min and at rt for

A. Luxenburger / Tetrahedron 59 (2003) 6045–6049
6049
1
1540 cm21; H NMR (400 MHz, CDCl3) d 9.51 (s, 1H),
The spectroscopic data of 6,7-dimethoxy-1,2,3,4-tetrahy-
drophenanthrene 15 were completely identical with those
described for compound 15 in Section 4.1.8.
6.78 (s, 1H), 6.64 (s, 1H), 6.32 (dd, J1¼9.7 Hz, J2¼3.1 Hz,
1H), 5.76 (dd, J1¼9.7 Hz, J2¼2.2 Hz, 1H), 3.87 (s, 3H),
3.86 (s, 3H), 2.70–2.56 (m, 2H), 1.88–1.63 (m, 4H), 1.51–
1.27 (m, 3H); 13C NMR (100 MHz, CDCl3) d 200.71,
148.87, 148.75, 131.32, 128.78, 127.52, 126.60, 110.49,
108.83, 56.16, 55.98, 52.66, 41.03, 29.52, 28.77, 26.13,
22.97; MS (EI) m/z (%) 272 (Mþ, 23), 244 (54), 243 (100),
228 (25), 212 (27), 201 (67), 171 (15), 157 (23), 141 (22),
139 (14), 129 (17), 128 (34), 127 (17), 115 (33). Anal. calcd
for C17H20O3: C, 74.97; H, 7.40. Found C, 74.89; H, 7.31.
Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 209214
for 10 and CCDC 209215 for 12. Copies of the data can be
obtained free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 IEZ, UK (fax: þ44-(0)-1223336033
or e-mail: deposit@ccdc.cam.ac.uk).
4.1.8. 6,7-Dimethoxy-1,2,3,4-tetrahydrophenanthrene
(15). To
a solution of the aldehyde 14 (130 mg,
Acknowledgements
0.48 mmol) in acetone (3 ml) were added dropwise a
solution of CrO3 (71.7 mg, 0.72 mmol) and concentrated
sulfuric acid (0.11 ml) in water (2.15 ml) at 08C. After being
stirred at this temperature for 1 h, the mixture was stirred at
rt for one additional hour. Water (20 ml) and 2-propanol
(3 ml) were added. After extraction with diethyl ether
(3£10 ml) the combined organic layers were washed with
brine and dried over MgSO4. The solvent was distilled off
and the residue was chromatographed on silica gel (ethyl
acetate/cyclohexane 1:2) to afford 60.1 mg (52%) of 15 as a
colourless solid. Mp 146–1478C. IR (KBr) 3000, 2920,
A. L. thanks Professor Dr Dr h. c. T. Eicher for generous
support.
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2835, 1610 cm21; H NMR (400 MHz, CDCl3) d 7.44 (d,
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J¼8.3 Hz, 1H), 7.17 (s, 1H), 7.07–7.03 (m, 2H), 3.98 (s,
3H), 3.96 (s, 3H), 3.04–2.98 (m, 2H), 2.90–2.84 (m, 2H),
1.99–1.90 (m, 2H), 1.89–1.80 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 149.29, 148.48, 132.72, 130.17,
128.04, 127.61, 126.55, 124.16, 107.19, 102.19, 55.75,
30.35, 26.01, 23.41, 23.08; MS (EI) m/z (%) 243 (Mþþ1,
16), 242 (Mþ, 100), 214 (21), 211 (19), 65 (27).
3. (a) Yakhontova, L. D.; Anisimova, M. I. Zh. Obshch. Khim.
1962, 32, 1337. (b) Yakhontova, L. D.; Kuzovkow, A. D. Zh.
Obshch. Khim. 1963, 33, 308.
4. Saleh, M. R. I.; Sabri, N. N.; El-Masry, S. Egypt. J. Pharm.
Sci. 1978, 19, 313–318.
´ ´
5. Gonzalez, A. G.; Rodrıguez, C. M.; Luis, J. G. Phytochemistry
4.1.9. 6,7-Dimethoxy-trans-1,3,4,10a-tetrahydro-4a(2H)-
phenanthrenecarboxylic acid (16). To a mixture of the
aldehyde 14 (600 mg, 2.20 mmol), NaH2PO4·H2O (304 mg,
2.20 mmol), 2-methyl-2-butene (4.66 ml, 44.1 mmol),
1987, 26, 1471–1474.
6. (a) Bush, E. J.; Jones, D. W.; Ryder, T. C. L. M. J. Chem. Soc.,
Perkin Trans. 1 1997, 1929–1938. (b) Bush, E. J.; Jones,
D. W.; Nongrum, F. M. J. Chem. Soc., Chem. Commun. 1994,
2145–2146.
t
water (7 ml) and BuOH (23 ml) was added portionwise
NaClO2 (678 mg, 7.49 mmol) at 08C. After being stirred at
08C for further 2 h, water (50 ml) was added and it was
extracted with diethyl ether (3£30 ml). The combined
organic layers were washed with brine, dried over Na2SO4
and concentrated. The residue was purified by column
chromatography (silica gel, ethyl acetate/cyclohexane 1:1)
to give 399 mg (63%) of 16 as a colourless solid. 114 mg
(18%) of 6,7-Dimethoxy-1,2,3,4-tetrahydrophenanthrene
15 were isolated as by-product (colourless solid). Mp 94–
968C. IR (KBr) 2910, 2845, 2635, 2585, 1720, 1635,
7. Luxenburger, A. Tetrahedron 2003, 59, 3297–3305.
8. Yardley, J. P.; Rees, R. W. Can. J. Chem. 1985, 63,
1013–1017.
9. Kuehne, M. E.; Xu, F. J. Org. Chem. 1997, 62, 7950–7960.
10. (a) Effenberger, F.; Epple, G. Angew. Chem. 1972, 84,
294–295. (b) Effenberger, F.; Epple, G. Angew. Chem.
1972, 84, 295–296.
11. Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117,
8106–8125.
1
1595 cm21; H NMR (400 MHz, CDCl3) d 6.93 (s, 1H),
12. Kametani, T.; Kondoh, H.; Tsubuki, M.; Honda, T. J. Chem.
Soc., Perkin Trans. 1 1990, 5–10.
13. Winterfeldt, E. Synthesis 1975, 617–630.
6.58 (s, 1H), 6.27 (dd, J1¼9.3 Hz, J2¼3.1 Hz, 1H), 5.75 (dd,
J1¼9.3 Hz, J2¼2.2 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H),
2.81–2.73 (m, 1H), 2.50–2.42 (m, 1H), 2.13–2.00 (m, 1H),
1.87–1.71 (m, 3H), 1.64–1.53 (m, 1H), 1.51–1.30 (m, 2H);
13C NMR (100 MHz, CDCl3) d 178.68, 148.42, 148.22,
133.03, 130.11, 127.87, 125.15, 110.05, 109.50, 56.19,
55.94, 49.33, 42.05, 34.51, 28.22, 26.03, 23.64; MS (CI) m/z
(%) 289 (Mþþ1, 15), 288 (Mþ, 42), 276 (18), 258 (34), 244
(19), 243 (59), 242 (100), 211 (15). Anal. calcd for
C17H20O4: C, 70.81; H, 6.99. Found C, 70.96; H, 7.06.
14. (a) Chappuis, G.; Tamm, C. Helv. Chim. Acta 1982, 65,
521–537. (b) Fitzgerald, J. J.; Pagano, A. R.; Sakoda, V. M.;
Olofson, R. A. J. Org. Chem. 1994, 59, 4117–4121.
15. Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 5, 399–402.
16. (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888–890. (b) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem.
Soc. 2000, 122, 4583–4592. (c) Dalcanale, E.; Montanari, F.
J. Org. Chem. 1986, 51, 567–569.