Enantioselective synthesis of (+)-royleanone from sulfinyl quinones

Article abstract of DOI:10.1002/(SICI)1521-3765(20000117)6:2<288::AID-CHEM288>3.0.CO;2-2

A convergent enantioselective synthesis of (+)-royleanone (1) is described starting from enantiomerically pure (S)-3-hydroxy-2-isopropyl-5-tert-butylsulfinyl-p-benzoquinone, which is readily available from 3-isopropyl-1,2,4-trimethoxybenzene and 1,3,3-tri

Full text of DOI:10.1002/(SICI)1521-3765(20000117)6:2<288::AID-CHEM288>3.0.CO;2-2

FULL PAPER
Enantioselective Synthesis of (‡)-Royleanone from Sulfinyl Quinones
M. Carmen CarrenÄo,* Jose L. García Ruano,* and Miguel A. Toledo[a]
Abstract: A convergent enantioselective synthesis of (‡)-royleanone (1) is descri-
bed starting from enantiomerically pure (S)-3-hydroxy-2-isopropyl-5-tert-butylsul-
finyl-p-benzoquinone, which is readily available from 3-isopropyl-1,2,4-trimethoxy-
benzene and 1,3,3-trimethyl-2-vinylcyclohexene. The key step is a tandem asym-
metric Diels ± Alder reaction/pyrolytic sulfoxide elimination process.
Keywords: asymmetric synthesis ´
cycloadditions ´ natural products ´
quinones ´ royleanone ´ sulfoxides
vinyl chromium carbene complex[9] has also been successfully
used for this goal. More recently, a photochemical aromatic
annulation has been applied to the synthesis of several
diterpenoid quinones.[10] One of the more convergent ap-
proaches reported up to date relies on a Diels ± Alder reaction
between an adequately substituted benzoquinone and 1,3,3-
trimethyl-2-vinylcyclohexene as a key step.[11]
Introduction
Among the components of the abietane diterpenoid family,
tricyclic quinones such as (‡)-royleanone (1) and (‡)-
triptoquinone A are of special interest because of their
biological properties.[1] For instance, royleanone was used in
In connection with our research devoted to asymmetric
Diels ± Alder reactions with enantiomerically pure sulfinyl
quinones,[12] we focused on these diterpenoid quinones bear-
ing the angularly fused tricyclic skeleton with the aim of
finding a general approach to efficiently create the C-10
asymmetric center. The protocol takes advantage of the
tandem Diels ± Alder reaction/pyrolytic sulfoxide elimination
which occurs when such sulfinyl quinones are allowed to react
as dienophiles with acyclic dienes, and has been already
applied to the efficient construction of other polycyclic
quinones.[13] Herein we report an enantioselective and con-
vergent synthesis of the natural isomer of royleanone (1)
using a stereocontrolled Diels ± Alder reaction between an
enantiomerically pure sulfinyl quinone 4 and 1,3,3-trimethyl-
2-vinylcyclohexene (2)[14] as the key step.
the Himalaya region as an insecticide and disinfectant, and
shows modest antitumor activity against several types of
cancer, and triptoquinone A is being used in the treatment of
arthritis.[2] These compounds share the common features of a
tricyclic perhydrophenanthrene skeleton and an isopropyl
substituent at the C ring as well as an angular methyl group at
the A/B ring junction.[3] Some of them have additional
oxygenated functions or olefin moieties at various positions.
Royleanone (1), which was first isolated by Edwards et al.[4]
in 1962 from the root of Inula Royleana D.C., was also found
in other plants.[2, 5] The asymmetric syntheses of 1 reported up
to date rely on the transformation of abietic acid derivatives.[6]
Racemic 1 has been the subject of several total syntheses. The
main strategies used for the construction of the tricyclic
framework are based on Robinson annulation,[7] and Friedel ±
Crafts intramolecular acylation.[5c, 8] The Dötz reaction of a
Results and Discussion
As shown in the retrosynthetic scheme (Scheme 1), the
tricyclic derivative 3, an immediate precursor of the natural
product, can be synthesized through the stereoselective
Diels ± Alder reaction of an enantiomerically pure sulfinyl
quinone 4.
We initially attempted to use (S)-3-methoxy-2-isopropyl-5-
(p-tolylsulfinyl)-1,4-benzoquinone (4a)[15] as the dienophile;
however, cycloaddition of 4a with vinylcyclohexene 2 did not
occur in refluxing toluene nor in other solvents (CH2Cl2,
mixtures THF:H2O, H2O). The presence of Lewis acids
promoted the formation of 3-methoxy-2-isopropyl-5-(p-tolyl-
Ä
[*] Prof. M. C. Carreno, Prof. J. L. García Ruano, Dr. M. A. Toledo
Â
Departamento de Química Organica C-I
Â
Universidad Autonoma
E-28049 Madrid (Spain)
Fax : (‡ 34)913973966
E-mail: carmen.carrenno@uam.es
288
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Chem. Eur. J. 2000, 6, No. 2

288±291
Scheme 1. Retrosynthetic scheme for the synthesis of 1.
sulfinyl)-1,4-hydroquinone (BF3 ´ OEt2) and/or the polymer-
ization of the diene and decomposition to uncharacterized
products [Sc(OTf)3, SnCl4] after long reaction times. The
Diels ± Alder adduct was only detected under high-pressure
conditions (CH2Cl2, 12 kbar, 2 days). Under these conditions,
a mixture of the initial adduct and the tricyclic derivative 3a,
resulting from the pyrolytic elimination of the sulfoxide, were
obtained. Finally, the desired quinone 3a was obtained in pure
form after heating the resulting reaction mixture to complete
the pyrolysis of the initially formed adduct (Scheme 2).
Compound 3a was thus isolated in 80% yield and was
demonstrated to be enantiomerically enriched (90% ee).[16]
We further tried to improve the 90% enantiomeric excess
by effecting the reaction between 4a and 2 in other solvents
(diethyl ether, CH3CN, H2O, 12 kbar), but the resulting
compound 3a showed always a similar 90% ee. With MeOH
(12 kbar) as solvent, 1,4-dihydroxy-2-isopropyl-3,6-dime-
thoxy-5-(p-tolylsulfinyl)benzene (5) was formed, and working
in the presence of ZnBr2 (CH2Cl2, 12 kbar) led to a complex
reaction mixture, which contained, among other products, a
benzofuran derivative 6, which has not been fully character-
ized. A similar structure resulting from an initial Michael-type
addition of the vinyl moiety of 2 to C-6 of a benzoquinone
derivative, followed by enolization of the intermediate and
further cyclicization had been already reported by Engler
et al.[11]
Scheme 2.
bearing the lone pair of electrons at sulfur explains the
formation of (S)-3a as the major product. Based on this
mechanistic assumption, we reasoned that the enantiomeric
excess of the final tricyclic quinone could be improved by
using a new chiral quinone 4b bearing the bulkier tert-butyl
sulfoxide. Compound 4b was synthesized by using 2-isoprop-
yl-1,3,4-trimethoxybenzene (7) according to the sequence
given in Scheme 3. The orthometalation/sulfinylation process
with (S)-diacetone glucose tert-butylsulfinate [(S)-tert-BuSO2-
DAG][17] afforded a 85:15 mixture of 8 and its regioisomer
from which sulfoxide 8 was isolated in 70% yield. Direct
oxidative demethylation was attempted with cerium ammo-
nium nitrate (CAN), AgO, and Pb(OAc)4; however, the
desired 3-methoxy-2-isopropyl-5-tert-butylsulfinyl-p-benzo-
quinone was not formed. We finally synthesized the hy-
droxy-substituted (S)-tert-butyl sulfinyl-p-benzoquinone 4b,
after complete demethylation of 8 with AlCl3 in EtSH
followed by oxidation[18] of the intermediate hydroquinone 9
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Pu-
rification of 4b by chromatography on silica gel produced
different degradation products. Therefore, 4b was employed
in the subsequent Diels ± Alder reaction without further
purification.
In accordance with our previous results,[12, 13] the diaster-
eoselectivity of Diels ± Alder reactions with 2-p-tolylsulfinyl
quinone 4a must be explained on steric grounds under the
assumption that the major reaction involves a conformation of
the sulfinyl quinone in which the sulfinyl oxygen atom is
placed s-cis with respect to the dienophilic double bond (see
Scheme 2). The favored approach of the diene from the face
Reaction of (S)-3-hydroxy-2-isopropyl-5-tert-butylsulfinyl-
1,4-benzoquinone (4b) with diene 2 in CH2Cl2 at 12 kbar gave
the tricyclic derivative 3b in 60% overall yield (from 9) and
>97% ee.[19] The tert-butyl sulfoxide group present in
dienophile 4b proved to be more efficient in the asymmetric
cycloaddition than the analogous p-tolyl sulfoxide group,
corroborating the role of steric effects in the control of the
diene approach occurring from the less hindered face of the
sulfinylquinone, which reacts in its s-cis conformation.[12]
Abstract in Spanish: La síntesis enantioselectiva de la (‡)-
Royleanona 1 se ha logrado de forma convergente a partir de la
(S)-3-hidroxi-2-isopropil-5-terc-butilsulfinil-p-benzoquinona
enantiomØricamente pura (obtenida a partir de 3-isopropil-
1,2,4-trimetoxibenceno) y 1,3,3-trimetil-2-vinilciclohexeno. La
Â
etapa clave corresponde a una reaccion de Diels-Alder
Â
Â
asimØtrica seguida de la eliminacion pirolítica del sulfoxido
Â
que tiene lugar de forma espontanea.
Chem. Eur. J. 2000, 6, No. 2
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289

Ä
M. C. Carreno, J. L. García Ruano, and M. A. Toledo
FULL PAPER
OCH3), 3.79 (s, 3H), 3.46 (sept, 1H,
J ˆ 7.1 Hz), 2.37 (s, 3H), 1.29 (t, 6H,
J ˆ 7.1 Hz); 13C NMR: d ˆ 146.6,
144.1, 142.3, 140.6, 139.7, 138.3, 133.7,
130.1 (2C), 125.2 (2C), 114.1, 61.9,
60.9, 25.8, 21.4, 20.8, 20.5.
(S)-12-Methoxy-11,14-dioxoabieta-
5,8,12-triene (3a): A solution of (S)-2-
isopropyl-3,6-dimethoxy-5-(p-tolylsul-
finyl)-1,4-benzoquinone 4a (475 mg,
1.49 mmol) and 1,3,3-trimethyl-2-
vinylcyclohexene (2) (0.7 mL) in
CH2Cl2 (2 mL) was submitted to a
pressure of 13 kbar for three days. The
crude mixture was refluxed for 3 h to
complete the pyrolytic elimination of
p-toluenesulfenic acid. The resulting
solution was concentrated in vacuo
and purified by chromatography (hex-
ane to separate the excess of diene
followed by hexane:AcOEt 100:1).
Scheme 3. Synthesis of 1 from 7 via the key intermediate 4b.
Compound 3a was obtained as
a
yellow solid (80% yield, 90% ee): m.p.: 81 ± 828C (methanol), ref.[11]
Having the tricyclic quinone 3b in hand, the reduction of
the double bond was the only step to complete the total
synthesis of 1. The formation of the trans-fused natural
compound from tricyclic analogues of 3b in the hydrogena-
tion step was known to be difficult.[7b, 20] Therefore, we carried
out the catalytic hydrogenation by using various catalysts (Pd/
C, PtO2 or [Ir(cod)py(PCy3)]PF6 (Crabtree catalyst[21]); cod ˆ
cyclooctadiene, py ˆ pyridine) and solvents (AcOEt, AcOEt
mixed with EtOH and H2O or amines, AcOH). In all cases, we
obtained mixtures of royleanone (1) and its C-5 epimer; the
best result was achieved working with H2 at atmospheric
pressure in the presence of Pd/C and in a 1:1 mixture of
AcOEt:AcOH. Under these conditions a 60:40 mixture of
royleanone (1) and the cis-fused isomer was formed from
which the former could be isolated in pure form after
crystallization from MeOH. The resulting royleanone (‡)-1
was thus isolated in 35% yield and was shown to have all the
characteristics described in the literature for the natural
product.[1] That the natural enantiomer was obtained con-
firmed the 10S absolute configuration for all the precursors,
including compounds 3a and 3b which resulted from the
asymmetric Diels ± Alder reaction.
78.5 ± 798C [a]2D0
ˆ
274 (c ˆ 0.5, CHCl3); 1H NMR: d ˆ 5.70 (dd, 1H,
J ˆ 5.3 and 2.4 Hz), 3.87 (s, 3H), 3.20 (dd, 1H, J ˆ 24.2 and 5.3 Hz), 3.18
(sept, 1H, J ˆ 7.0 Hz), 2.84 (dd, 1H, J ˆ 24.2 and 2.3 Hz), 2.78 (dtd, 1H, J ˆ
13.1, 3.7, and 1.7 Hz), 1.97 ± 1.76 (m, 1H), 1.62 ± 1.42 and 1.39 ± 1.20 (2m,
4H), 1.49 (s, 3H), 1.20 (s, 3H), 1.20 (d, 3H, J ˆ 7.1 Hz), 1.18 (d, 3H, J ˆ
7.1 Hz), 1.13 (s, 3H); 13C NMR: d ˆ 187.7, 183.8 (2C), 156.9, 148.5, 146.3,
139.9, 135.2, 115.6, 60.7, 40.5, 39.2, 36.4, 36.3, 33.0, 30.7, 26.1, 24.8, 24.3, 20.6,
20.4, 18. 7.
(S)-1-(tert-Butylsulfinyl)-4-isopropyl-2,3,5-trimethoxybenzene (8): A solu-
tion of nBuLi (12.42 mL, 28.57 mmol of 2.3m solution in hexane) in THF
(15 mL) was added by cannula to a solution of 2-isopropyl-1,3,4-trimethoxy
benzene (7) (2.50 g, 11.9 mmol) in THF (25 mL) at room temperature.
After the mixture had been stirred for 1 h, it was cooled at 788C and a
solution of
(
)-(S)-diacetone glucose tert-butyl sulfinate[16] (4.77 g,
13.09 mmol) in THF (40 mL) was then added and the evolution was
monitored by TLC. The hydrolytic treatment (saturated solution of NH4Cl)
was effected at 788C. The mixture was extracted with CH2Cl2, dried
over MgSO4, and the solvent evaporated. The residue was a 85:15 mixture
of 8 and its regioisomer (S)-1-(tert-butylsulfinyl)-3-isopropyl-2,4,5-trime-
thoxybenzene. Both isomers were separated by chromatography
(hexane:isopropyl alcohol 30:1). Compound 8: white solid (70% yield):
m.p. 114 ± 1158C; [a]D20
ˆ
101.7 (c ˆ 1, CHCl3); 1H NMR: d ˆ 6.93 (s, 1H),
3.81 (s, 3H), 3.80 (2s, 6H), 3.51 (sept, 1H, J ˆ 7.0 Hz), 1.30 and 1.28 (2d, 6H,
J ˆ 7.0 Hz), 1.21 (s, 9H); 13C NMR: d ˆ 155.0, 151.4, 145.0, 133.8, 131.0,
103.3, 60.8, 60.5, 57.5, 55.8, 25.3, 22.9, 20.9, 20. 7; elemental analysis
calcd (%) for C16H26O4S: C 61.12, H 8.33, S 10.20; found: C 61.09, H 8.31,
S 10.72.
In summary, we have reported a convergent asymmetric
total synthesis of the terpene quinone royleanone (1) from
readily available 3-isopropyl-1,2,4-trimethoxybenzene and
1,3,3-trimethyl-2-vinylcyclohexene in five steps and 13%
overall yield. The key step is the construction of the tricyclic
framework in a one-pot, tandem asymmetric Diels ± Alder
reaction of enantiomerically pure sulfinyl benzoquinone 4b/
pyrolytic sulfoxide elimination process.
(S)-1-(tert-Butylsulfinyl)-3-isopropyl-2,4,5-trimethoxybenzene: White sol-
id; 13% yield; m.p.: 109.5 ± 110.58C; [a]D20
ˆ
195.4 (c ˆ 0.5, CHCl3);
1H NMR: d ˆ 7.15 (s, 1H), 3.89, 3.88 and 3.74 (3s, 9H), 3.36 (sept, 1H, J ˆ
7.1 Hz), 1.37 and 1.30 (2d, 6H, J ˆ 7.1 Hz), 1.18 (s, 9H); 13C NMR: d ˆ 151.3,
150.2, 149.7, 135.2, 127.7, 107.2, 62.3, 60.8, 57.9, 56.0, 25.7, 22.9, 21.8 and 21. 4;
elemental analysis calcd. (%) for C16H26O4S: C 61.12, H 8.33, S 10.20;
found: C 60.97, H 8.42, S 10.66.
(S)-1-(tert-Butylsulfinyl)-2,3,5-trihydroxy-4-isopropylbenzene (9): A solu-
tion of (S)-1-(tert-butylsulfinyl)-4-isopropyl-2,3,5-trimethoxybenzene (8)
(1.28 g, 4.07 mmol) in EtSH (25 mL) was added to a mixture of AlCl3
(5.43 g, 40.72 mmol) and EtSH (25 mL) at 08C by cannula. After the
mixture had been stirred for 10 min, it was poured into cool water (0 ± 48C),
extracted with CH2Cl2, dried over MgSO4, and the solvent was evaporated.
Compound 9 was obtained as a white solid in 90% yield: m.p.: 166 ± 1678C
Experimental Section
(S)-1,4-Dihydroxy-2-isopropyl-3,6-dimethoxy-5-(p-tolylsulfinyl)benzene
(5):
A solution of (S)-2-isopropyl-3,6-dimethoxy-5-(p-tolylsulfinyl)-1,4-
benzoquinone (4a) (60 mg, 0.19 mmol) and 1,3,3-trimethyl-2-vinylcyclo-
hexene (2) (0.08 mL) in MeOH (2 mL) was submitted to a pressure of
13 kbar for three days. The crude mixture was concentrated in vacuo and
purified by chromatography (hexane:AcOEt 4:1): [a]2D0 ˆ 9.9 (c ˆ 1.7 in
CHCl3); 1H NMR (200 MHz, CDCl3, TMS): d ˆ 10.52 (br. s, 1H; OH), 7.68
and 7.28 (4H, 3J(H,H) ˆ 9 Hz, 2H; p-Tol), 5.06 (br. s, 1H; OH), 3.86 (s, 3H;
(decomp) (CH2Cl2); [a]D20
ˆ
146 (c ˆ 0.5, acetone); 1H NMR: d ˆ 10.52 (s,
1H), 5.94 (s, 1H), 5.89 (s, 1H), 5.47 (s, 1H), 3.46 (sept, 1H, J ˆ 7 Hz), 1.35
(d, 6H, J ˆ 7.0 Hz), 1.31 (s, 9H); 13C NMR: d ˆ 149.0, 145.1, 138.5, 125.2,
120.9, 102.9, 57.1, 24.6, 22.7 (3C), 20.5 (2C, CH(CH3)2); elemental analysis
calcd. (%) for C13H20O4S: C 57.33, H 7.40, S 11.77; found: C 57.01, H 7.33, S
12.14.
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Chem. Eur. J. 2000, 6, No. 2

Enantioselective Synthesis of (‡)-Royleanone
288±291
(S)-5-(tert-Butylsulfinyl)-3-hydroxy-2-isopropyl-1,4-benzoquinone (4b): A
solution of 2,3-diciano-5,6-dichloro-1,4-benzoquinone (DDQ) (0.5 g,
2.22 mmol) in CH2Cl2 (50 mL) was added to (S)-1-(tert-butylsulfinyl)-
2,3,5-trihydroxy-4-isopropylbenzene (9) (0.5 g, 1.84 mmol) dissolved in
CH2Cl2 (100 mL) at room temperature. After 10 min, the mixture was
washed with H2O (5 Â 50 mL) and the organic layer was dried over MgSO4
and the solvent evaporated at reduced pressure. The product 4b (82%
yield) was purified by chromatography (silica gel from SDS was essential to
reach the indicated yield, hexane:AcOEt 3:1) or used in the next step
without further purification. Orange solid: m.p. 102 ± 1048C (decomp);
[a]2D0 ˆ ‡90.2 (c ˆ 0.06, CHCl3); 1H NMR: d ˆ 7.16 (s, 1H), 3.23 (sept, 1H, J
ˆ7.0 Hz), 1.27 (s, 9H), 1.21 (2d, 6H, J ˆ 7.0 Hz); 13C NMR: d ˆ 184.4 and
180.5 (2C), 151.0, 146.6, 139.4, 127.1, 58.5, 24.1, 23.1 (3C), 19.5 (2C).
[4] O. E. Edwards, G. Feniak, M. Los, Can. J. Chem. 1962, 40, 1540 ± 1546.
[5] a) J. H. Gough, M. D. Sutherland, Aust. J. Chem. 1966, 19, 329 ± 330;
b) C. H. Brieskorn, L. Buchberger, Planta Med. 1973, 24, 190 ± 195;
c) F. Yoshizaki, P. Rüedi, C. H. Eugster, Helv. Chim. Acta 1979, 62,
2754 ± 2762; d) A. S. Romanova, A. V. Patudin, A. M. Makmedov,
L. N. Pervykh. Khim. Priv. Soedin. 1980, 564; e) J. A. Hueso-
Rodríguez, M. L. Jimeno, B. Rodríguez, G. Savona, M. Bruno,
Â
Phytochemistry 1983, 22, 2005 ± 2009; f) A. Michavila. F. Fernandez-
Gadea, B. Rodríguez, Phytochemistry 1986, 25, 266 ± 268; g) F. Simoes,
A. Michavila, B. Rodríguez, M. C. García Alvarez, M. Hasan,
Phytochemistry, 1986, 25, 755 ± 756.
[6] a) T. Matsumoto, Y. Oshuga, S. Harada, K. Fukui. Bull. Chem. Soc.
Jpn. 1977, 50, 266 ± 272; b) Y. Ohtsuka, A. Tahara. Chem. Pharm. Bull.
1978, 26, 2007 ± 13.
[7] a) T. Matsumoto, Y. Tachibana, K. Fukui, Chem. Lett. 1972, 321 ± 324;
b) Y. Tachibana, Bull. Chem. Soc. Jpn. 1975, 48, 298 ± 301; c) T. Matsui,
J. Sci. Hirosima Univ. Ser. A 1976, 40, 129 ± 141.
[8] L. S. Liebskind, R. Chidabaram, S. Nimkar, D. Liotta. Tetrahedron
Lett. 1990, 31, 3723 ± 3726.
[9] J. King, P. Quayle, J. F. Malone, Tetrahedron Lett. 1990, 31, 5221 ± 5224.
[10] R. K.Danheeiser, D. S. Casebier, F. Firooznia, J. Org. Chem. 1995, 60,
8341 ± 8350.
(S)-12-Hydroxy-11,14-dioxoabieta-5,8,12-triene (3b): The solid resulting in
the oxidation of (S)-1-(tert-butylsulfinyl)-2,3,5-trihydroxy-4-isopropylben-
zene (9) (25 mg) with DDQ was mixed with 1,3,3-trimethyl-2-vivnylcyclo-
hexene (2) (0.05 mL) and CH2Cl2 (2 mL) and the solution was submitted to
a pressure of 13 kbar for 24 h. The resulting mixture was concentrated in
vacuo and purified by chromatography (hexane to separate the excess of
diene followed by hexane:AcOEt 125:1). Compound 3b was obtained as a
yellow solid (60% overall yield from 9, >97% ee): m.p.: 151 ± 1528C
(hexane); [a]2D0
ˆ
118 (c ˆ 0.5, CHCl3); 1H NMR: d ˆ 7.30 (br, s, 1H), 5.66
[11] T. A.Engler, U. Sampath, S. Naganathan, D. Vander Velde, F.
Takusagawa, D. Yohannes, J. Org. Chem. 1989, 54, 5712 ± 5727 and
references therein.
(dd, 1H, J ˆ 5.1 and 2.5 Hz), 3.29 (dd, 1H, J ˆ 25.2 and 5.0 Hz), 3.15 (sept,
1H, J ˆ 7.0 Hz), 2.88 (dd, 1H, J ˆ 25.2 and 2.4 Hz), 2.82 (dtd, 1H, J ˆ 13.1,
3.7, and 1.5 Hz), 1.84 (tt, 1H, J ˆ 13.0 and 3.6 Hz), 1.62 ± 1.20 (m, 4H), 1.46
(s, 3H), 1.20 (2d, 6H, J ˆ 7.0 Hz), 1.19 (s, 3H), 1.12 (s, 3H); 13C NMR: d ˆ
186.7, 183.4 (2C), 150.7, 147.7, 143.1, 142.6, 123.4, 115.1, 40.6, 39.1, 36.4 (2C),
33.1, 30.4, 26.0, 25.4, 24.0, 19.9, 19.8, 18.8; elemental analysis calcd (%) for
C20H26O3: C 76.40, H 8.33; found: C 76.16, H 8.48.
Ä
[12] For recent references see: a) M. C. Carreno, A. Urbano, C. Di Vitta, J.
Org. Chem. 1998, 63, 8320 ± 8330; b) M. C. CarrenÄo, S. García
Cerrada, A. Urbano, C. Di Vitta, Tetrahedron: Asymmetry 1998, 9,
Ä
2965 ± 2969; c) M. C. Carreno, J. L. García Ruano, A. Urbano, M. I.
Â
Ä
Lopez-Solera, J. Org. Chem. 1997, 62, 976 ± 981; d) M. C. Carreno, J. L.
(‡)-Royleanone (1): A mixture of Pd/C (10%) (100 mg) and a solution of
(S)-12-hydroxy-11,14-dioxoabieta-5,8,12-triene (3b) (150 mg, 0.47 mmol)
in a 1:1 mixture of acetic acid and AcOEt (15 mL) was maintained in an
atmosphere of hydrogen at atmospheric pressure for 24 h. The resulting
mixture was filtered over celite and washed with a saturated solution of
NaHCO3. The organic phase was dried over MgSO4 and the solvent
eliminated at reduced pressure. The crude product (90% yield) contained a
60:40 ratio of trans-fused (‡)-(5S,10S)-Royleanone (1) and its cis-fused
(5R,10S)-epimer. After three successive crystallizations (methanol), the
García Ruano, M. A. Hoyos, A. Urbano, J. Org. Chem. 1996, 61,
Ä
2980 ± 2985; e) M. C. Carreno, J. L. García Ruano, M. A. Toledo, A.
Urbano, C. Z.Remor, V. Stefani, J. Org. Chem. 1996, 61, 503 ± 509.
Ä
[13] a) M. C. Carreno, A. Urbano, J. Fischer, Angew. Chem. 109, 1695 ±
1697; Angew. Chem. Int. Ed. Engl. 1997, 36, 1621 ± 1623; b) M. C.
Ä
Carreno, J. L. García Ruano, C. Z. Remor, A. Urbano, Tetrahedron
Lett. 1997, 38, 9077 ± 9080.
[14] D. M. Hollinshead, S. C. Howell, S. V. Sey, M. Mahon, N. M. Ratcliffe,
P. A. Worthington, J. Chem. Soc. Perkin Trans. 1 1983, 1579 ± 1589.
natural epimer (‡)-1 was isolated in 35% yield as a yellow solid: m.p.:
Ä
[15] M. C. Carreno, J. L. García Ruano, M. A. Toledo, A. Urbano,
[1]
180 ± 1818C (ref.[1]: 179 ± 1818C); [a]D20 ˆ ‡133 (c ˆ 1, CHCl3); ref. [a]D
:
Tetrahedron: Asymmetry 1997, 8, 913 ± 921.
1
134 (c ˆ 1, CHCl3); H NMR: d ˆ 7.23 (s, 1H), 3.15 (sept, 1H, J ˆ 6.5 Hz),
2.71 (m, 2H), 2.30 (ddd, 1H, J ˆ 21, 12 and 7 Hz), 1.90 ± 0.98 (m, 6H), 0.94 ±
0.80 (m, 2H), 1.25 (s, 3H), 1.20 and 1.19 (2d, 6H, J ˆ 6.5 Hz), 0.93 and 0.90
(2s, 6H); 13C NMR: d ˆ 187.5, 183.4, 150.6, 146.5, 146.0, 123.7, 51.7, 41.3,
38.4, 36.2, 33.5, 33.4, 26.7, 24.1, 21.8, 20.1, 20.0, 19.9, 18.9, 17.4.
[16] Optical purity was determined by 1H NMR spectroscopy [Pr(hfc)3]
(hfc ˆ 3-(heptafluoropropylhydroxymethylene)-d-camphorate). Rac-
emic 3a necessary for such determination was obtained from racemic
4a.
Â
[17] a) I. Fernandez. N. Khiar, J. M. Llera, F. Alcudia, J. Org. Chem. 1992,
Â
57, 6789 ± 6796; b) N. Khiar, I. Fernandez, F. Alcudia, Tetrahedron
Lett. 1994, 35, 5719 ± 5722.
[18] Y. Oikawa, T. Yoshida, O. Yonemitsu. Tetrahedron Lett. 1982, 23,
885 ± 888.
[19] Optical purity of 3b was determined by 1H NMR [Pr(hfc)3] after its
transformation into 3a (1. Na2S2O4, diethyl ether; 2. K2CO3, Me2SO4,
acetone, reflux).
Acknowledgment
We thank the DGICYT (Grants PB95 ± 0174 and PB96 ± 0035) for financial
support.
[20] See for instance: a) F. Marletti, F. Delle Monache, G. B. Marini-
Bettolo, M. D. C. M. De Araujo, M. D. S. B. Caralcanti, J. L. DꢁAl-
burquerque, O. G. De Lima, Gazz. Chim. Ital. 1976, 106, 119 ± 126;
b) S. P. Tanis, K. Nakanishi, J. Am. Chem. Soc. 1979, 101, 4398 ± 4400.
[21] J. W. Suggs, S. D. Cox, R. H. Crabtree, J. M. Quirk. Tetrahedron Lett.
1981, 22, 303 ± 306.
[1] a) S. M. Kupchan, A. Karim, C. Marks, J. Am. Chem. Soc. 1968, 90,
5923 ± 5924; b) S, M. Kupchan, A. Karim, C. Marks, J. Org. Chem.
1969, 34, 3912 ± 3918.
[2] K. Shishido, K. Goto, S. Miyoshi, Y. Takaishi, M. J. Shibuya, J. Org.
Chem. 1994, 59, 406 ± 414.
[3] K. Nakanishi, T. Goto, S. Ito, S. Natori, S. Nozol, Natural Products
Chemistry, Vol. 1, Academic Press, London, 1974, Chapter 4.
Received: June 10, 1999 [F1843]
Chem. Eur. J. 2000, 6, No. 2
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