Convenient route to enantiopure aryl cyclopentanes via Diels-Alder reaction of asymmetric dienes. Total synthesis of (+)-herbertene and (+)-cuparene

Article abstract of DOI:10.1016/S0040-4020(03)00807-X

A general route for the synthesis of highly substituted aryl cyclopentanes has been developed involving Diels-Alder reaction of asymmetric dienes prepared from (+)-camphoric acid followed by aromatization of the resulting cyclohexene derivatives. Employing this protocol enantiospecific synthesis of (+)-herbertene and (+)-cuparene has been accomplished.

Full text of DOI:10.1016/S0040-4020(03)00807-X

Tetrahedron 59 (2003) 5175–5181
Convenient route to enantiopure aryl cyclopentanes via
Diels–Alder reaction of asymmetric dienes. Total synthesis of
(1)-herbertene and (1)-cuparene
Abhijit Nayek,a Michael G. B. Drewb and Subrata Ghosha
,
*
aDepartment of Organic Chemistry, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mallick Road, Jadavpur,
Kolkata 700 032, India
bDepartment of Chemistry, The University, Whitenknights, Reading RG6 6AD, UK
Received 10 March 2003; revised 28 April 2003; accepted 22 May 2003
Abstract—A general route for the synthesis of highly substituted aryl cyclopentanes has been developed involving Diels–Alder reaction of
asymmetric dienes prepared from (þ)-camphoric acid followed by aromatization of the resulting cyclohexene derivatives. Employing this
protocol enantiospecific synthesis of (þ)-herbertene and (þ)-cuparene has been accomplished. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2a or may be modified after aromatization to provide the
more functionalized members such as 1b,c. The cyclo-
hexene derivatives 3 may be obtained through Diels–Alder
reaction of the asymmetric dienes 4 with the dienophiles 6.
The dienes 4 may, in principle, be easily available from the
cyclopentane derivative 5. The results of the investigation
employing this protocol are described here6 leading to the
total synthesis of (þ)-herbertene and (þ)-cuparene.
Aryl cyclopentanes with two adjacent quaternary centers on
the cyclopentane ring constitute two expanding families1 of
sesquiterpenes, herbertanes and cuparanes. Representative
examples include herbertene 1a, herbertenol 1b, herbertene
diol 1c, cuparene 2a, d-cuparenol 2b etc. Several members
of these families possess important biological properties
such as antifungal, antibiotic, neurotrophic and anti-lipid
peroxidation. Because of these biological properties along
with the difficulty associated with the generation of two
adjacent quaternary centers on a cyclopentane ring,
herbertanes and cuparanes have recently become popular
synthetic targets. The basic approaches that have been
widely employed for their synthesis are construction of the
cyclopentane ring at the benzylic carbon of an appropriately
substituted aromatic ring2 and addition of an aryl nucleo-
phile to a cyclopentenone derivative.3 However, only a few
of these approaches deals with synthesis of enantiopure
compounds. In continuation to our interest in cyclopenta-
noids,4 we undertook a program to develop a general
synthetic protocol for entry into both these families of
sesquiterpenes in enantiomerically pure form. The key
concept of the present strategy5 involves construction of the
aromatic ring onto an appropriate substituent on a pre-
constructed cyclopentane ring. We envisaged that the
structures 1, 2 may be obtained by aromatization of the
cyclohexenes 3 (Scheme 1). The substitutents R3 and R4 in 3
may be removed to lead to the parent hydrocarbons 1a and
Keywords: aromatization; asymmetric synthesis; decarboxylation; Diels–
Alder reactions; terpenes and terpenoids.
*
Corresponding author. Tel.: þ91-33-2473-4971; fax: þ91-33-2473-2805;
e-mail: ocsg@mahendra.iacs.res.in
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00807-X

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A. Nayek et al. / Tetrahedron 59 (2003) 5175–5181
2. Results and discussion
ketone 16 at d 6.85 (J¼7.8 Hz) and 6.93 (J¼7.8 Hz)
indicated the presence of two ortho protons establishing the
structure of the aromatic ketone 16. A portion of the major
diastereoisomer of the mixture of adducts slowly crystal-
lized out of a solution of petroleum ether 60–808C after a
few days at rt. Determination of structure by single crystal
X-ray diffraction8 showed that the major diastereoisomer
has the structure 15. When the reaction of the diene 4a was
carried out with a dienophile with more steric requirement
such as maleic anhydride, diastereoselectivity was signifi-
cantly improved to lead to an inseparable mixture of two
adducts in ca. 1:4 ratio (from integration of the Me singlets
The structural similarity of the cyclopentane derivative 5 to
camphoric acid 7 dictates that the latter can be used to make
the ester 5. To this end dimethyl camphorate 8, prepared
from (þ)-camphoric acid 7, was partially hydrolyzed to
afford the monocarboxylic acid 95e (Scheme 2). The free
carboxylic acid group in the compound 9 could be easily
decarboxylated by using the photodecarboxylation pro-
cedure developed by Okada et al.7 to provide the desired
ester 5.
1
The ester 5 was then reduced with LiAlH4 to provide the
alcohol 10. Swern oxidation of the resulting alcohol
followed by Wittig olefination of the resulting aldehyde
11 with the ylide generated from methallyl triphenyl
phosphonium chloride gave the diene 4a as a single
component in 46% yield. The appearance of two doublets
in H NMR). The major isomer was assigned the structure
17 based on analogy to the formation of the major adduct 15
from reaction of the diene 4a with methyl vinyl ketone. On
the other hand reaction of the diene 4a with less sterically
crowded dienophile such as dimethyl acetylene dicarboxyl-
ate gave a mixture of two products in ca. 1:1 ratio. The
formation of the adducts 15 and 17 as the major products
from Diels–Alder reaction of the diene 4a may be
rationalized by preferential approach of the dienophile
from the endo Si-face of the diene (Fig. 1(a)) as approach
from the Re-face (Fig. 1(b)) of the diene is blocked by the
gem-dimethyl group on the cyclopentane ring. This is
supported by the X-ray crystal structure (Fig. 2) of the
compound 15 which clearly shows that the COMe group is
located away from the gem-dimethyl group. As expected
reaction of the diene 4b with maleic anhydride was less
selective producing a mixture of the adduct 19 along with its
other diastereoisomer (ca. 2:1 ratio).
1
in its H NMR at d 5.74 (1H, J¼16 Hz) and 6.07 (1H,
J¼16 Hz) indicated it to be the E-isomer. The diene 4b was
prepared in the following way; Wittig–Horner reaction of
the aldehyde 11 with trimethyl phosphonoacetate produced
the unsaturated ester 12 in 70% yield as a mixture of E- and
Z-isomers with the former predominating. A three-step
sequence involving LiAlH4 reduction, Swern oxidation and
Wittig reaction with the ylide generated from ethyl(tri-
phenyl phosphonium) bromide converted the unsaturated
ester mixture 12 to the diene 4b as a mixture of probably all
the possible geometrical isomers in overall excellent yield.
The Diels–Alder reaction of the diene 4a was initially
investigated keeping in mind that the methyl ketone 16
obtained after aromatization of the adduct 15 would provide
herbertenol 1b (Scheme 3). Heating a solution of the diene
4a with methyl vinyl ketone in a sealed tube at 1408C for
24 h afforded a liquid in 59% yield. The product was found
mainly to be a mixture of two components in ca. 1:2 ratio
from integration of the olefinic proton singlets at d 5.32 and
5.45. That these two components are not the regioisomers
was established by its transformation to the single aromatic
ketone 16 through dehydrogenation by heating with 10%
With the cyclohexene derivatives 17–19 in hand we
Figure 1.
1
Pd/C. The presence of two doublets in H NMR of the
Scheme 2. Reagents: (i) MeOH, H2SO4, 92%; (ii) MeOH, KOH, 89%;
(iii) hn, t-BuSH, quinoline, C6H6, 59%; (iv) H2C¼C(Me)CH2PPhþ3 Cl2,
n-BuLi, Et2O, 46%; (v) LiAlH4, Et2O; (vi) (COCl)2, DMSO, Et3N, CH2Cl2,
84%; (vii) NaH, (MeO)2POCH2CO2Me, THF, 70%; (viii) n-BuLi, EtPPh3þ-
Br2, THF, 83%.
Figure 2. ORTEP plot of the ketone 15.

A. Nayek et al. / Tetrahedron 59 (2003) 5175–5181
5177
Scheme 3. Reagents: (i) CH2¼CHCOMe, C6H5CH3, 1408C, 82% (for 15),
maleic anhydride, C6H5CH3, 808C (for 17), 1408C (for 19), (63–82%);
(ii) Pd–C (10%), Xylene, 1508C, 57%; (iii) dimethyl acetylene dicar-
boxylate, C6H5CH3, 1408C, 83%.
Scheme 4. Reagents: (i) NaOH, H2O, EtOH, 94%; (ii) hn, acridine, C6H6,
(20–40%); (iii) DDQ, C6H6, 608C, 70–73%; (iv) H2SO4 (98%), 86%.
focussed our attention on the synthesis of the natural
products. For the synthesis of herbertene 1a, the mixture of
the anhydride 17 and its diastereoisomer was hydrolyzed to
afford the dicarboxylic acids 20 (Scheme 4), these were
subjected to decarboxylation. A conventional procedure
involving Pb(OAc)4 gave the diene 22 along with a trace of
herbertene 1a in only 25% yield. We reasoned that
decarboxylation procedure (hn, quinoline or acridine,
tBuSH, benzene) developed by Okada et al.7 to make
alkanes may be useful for bisdecarboxylation of vicinal
dicarboxylic acids to provide olefin in improved yield if the
reaction is carried out in the absence of proton source
(tBuSH).
imposed by the gem-dimethyl group on the adjacent
cyclopentane ring.
3. Conclusion
We have developed an asymmetric synthetic route to highly
substituted cyclopentanes, which contain gem-dimethyl
substituents and this has been used to access the natural
products, (þ)-herbertene and (þ)-cuparene, enantio-
selectively. It involves Diels–Alder reaction of asymmetric
dienes followed by aromatization of the resulting cyclo-
hexenes. Since both enantiomer of camphoric acid are
commercially available it provides opportunity for access to
both enantiomers of aryl cyclopentanes.
Indeed, this protocol worked nicely to afford the diene 22 in
40% yield. Similarly decarboxylation of the crude dicar-
boxylic acids 21 obtained from hydrolysis of the anhydride
mixture 19, provided the diene 23 in moderate yield.
Aromatization of the cyclohexadiene derivatives 22 and 23
was then effected by heating their benzene solution at 608C
with DDQ to afford (þ)-herbertene 1a and (þ)-cuparene 2a
in 70 and 67% yields respectively. This accomplishes the
first synthesis of non-natural enantiomer (þ)-herbertene.
4. Experimental
4.1. General
Melting points were measured in open capillary tubes in
sulphuric acid bath and are uncorrected. All reactions were
carried out under an atmosphere of Ar. A usual work up
involved extraction with an organic solvent, washing of the
organic extract with brine, drying over anhydrous Na2SO4
and removal of the solvent under vacuum. Column
chromatography was performed on silica gel (60–120
mesh). IR spectra were recorded as neat for liquids and as
KBr pellet for solids on a FTIR-8300, SHIMADZU
We next focused our attention on the synthesis of the more
functionalized derivatives such as herbertene diol 1c. The
cyclohexadiene derivative 18 was aromatized with DDQ to
provide the aromatic diester 24 in 72% yield (Scheme 4). It
was envisaged that the ester functionalities in the aryl
cyclopentane 24 could be easily transformed by reaction of
the corresponding dicarboxylic acid with MeLi to the
corresponding methyl ketone 25. Baeyer–Villiger oxidation
of the methyl ketone and hydrolysis of the resulting
diacetate would accomplish the synthesis of herbertene
diol 1c. However alkaline hydrolysis of the diester 24 gave
the monocarboxylic acid 26. Attempted hydrolysis of the
diester 24 under acidic conditions gave the anhydride 27. In
an attempt to make herbertenol 1b Baeyer–Villiger reaction
of the methyl ketone 15 using a variety of reagents also
failed. These failures led us to conclude that nucleophilic
addition to the carbonyl group at C-4 position on the
aromatic ring is strongly inhibited due to steric crowding
1
spectrometer. H and 13C NMR spectra were recorded in
CDCl3 solutions with TMS as internal standard at 300 and
75 MHz respectively on Bruker DPX-300 spectrometer. In
case of inseparable mixture of isomers, NMR spectral data
for the major and minor isomers have been reported from
the spectra of the mixture. Elemental analyses were
performed in the microanalytical laboratory of this
department.
4.1.1. Methyl-1,2,2-trimethylcyclopentane carboxylate
(5). The acid 9 was prepared from (1R, 3S)-(þ)-camphoric
acid according to the procedure described by Fuganti et al.5e

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A. Nayek et al. / Tetrahedron 59 (2003) 5175–5181
A solution of this carboxylic acid 9 (1.7 g, 7.94 mmol) in
benzene (110 mL) containing quinoline (1.22 g, 9.53 mmol)
and BuSH (7.14 g, 79.43 mmol) was irradiated with a
1.43 mmol) in diethyl ether (6 mL). The resulting deep
red solution was cooled to 08C and a solution of the
aldehyde 11 (100 mg, 0.72 mmol) in diethyl ether (2 mL)
was added dropwise. The reaction mixture was allowed to
warm to rt and stirring was continued for 14 h. After
quenching with water (1 mL) the reaction mixture was
worked up with diethyl ether to afford a liquid which was
chromatographed (4% diethyl ether–petroleum ether 60–
808C) to afford the diene 4a (40 mg, 45%) as a colorless
liquid; [Found: C, 87.37; H, 11.77. C13H22 requires C,
87.56; H, 12.44%]; [a]3D0¼þ20.16 (c 0.63, CHCl3); nmax
(Neat) 1681, 1606 cm21; dH (300 MHz, CDCl3) 0.55 (3H, s,
–CH3), 0.89 (3H, s, –CH3), 0.97 (3H, s, –CH3), 1.26–1.92
(6H, m), 1.85 (3H, s, –CH3), 4.88 (2H, br s, vCH2), 5.74
(1H, d, J¼16 Hz, vCH), 6.07 (1H, d, J¼16 Hz, vCH); dC
(75 MHz, CDCl3) 19.2 (CH3), 20.2 (CH2), 22.1 (CH3), 24.2
(CH3), 25.8 (CH3), 37.3 (CH2), 39.7 (CH2), 44.7 (C), 48.9
(C), 114.5 (CH2), 129.8 (CH), 138.3 (CH), 142.9 (C).
t
medium 450 W pressure Hanovia lamp through a water
cooled pyrex immersion well for 6 h. The reaction mixture
was then washed successively with HCl (2£15 mL, 6N),
aqueous saturated NaHCO3 solution (3£20 mL) and brine
(3£20 mL). Evaporation of the solvent followed by column
chromatography of the residual mass (4% diethyl ether–
petroleum ether 60–808C) afforded the ester 5 (800 mg,
59%) as a colorless liquid; [Found: C, 70.78; H, 10.25.
C10H18O2 requires C, 70.55; H, 10.66%]; [a]3D0¼þ5.29 (c
0.34, CHCl3); nmax (Neat) 2962, 2873, 1732 cm21; dH
(300 MHz, CDCl3) 0.86 (3H, s, –CH3), 1.03 (3H, s, –CH3),
1.14 (3H, s, –CH3), 1.50–1.73 (5H, m), 2.36–2.45 (1H, m),
3.65 (3H, s, –COOCH3); dC (75 MHz, CDCl3) 20.3 (CH2),
21.2 (CH3), 24.4 (CH3), 26.0 (CH3), 35.3 (CH2), 40.0 (CH2),
44.6 (C), 51.6 (CH3), 55.2 (C), 176.8 (CO).
4.1.2. 1-Hydroxymethyl-1,2,2-trimethylcyclopentane
(10). To a cooled (08C) magnetically stirred suspension of
LiAlH4 (470 mg, 12.42 mmol) in diethyl ether (14 mL) was
added dropwise a solution of the ester 5 (2.0 g, 11.76 mmol)
in diethyl ether (25 mL). The reaction mixture was allowed
to warm to rt and stirred for additional 2 h. It was again
cooled to 08C and quenched by sequential addition of water
(0.5 mL), 15% aqueous NaOH (0.5 mL) and water (1.5 mL)
and stirred for 15 min. The organic phase was separated and
dried. The solvent was evaporated to give the corresponding
alcohol 10 as a white solid (1.4 g, 84%), mp 138–1408C;
[Found: C, 75.96; H, 12.83. C9H18O requires: C, 75.99; H,
12.75%]; [a]D30¼þ8.02 (c 0.57, CHCl3); nmax (KBr)
3323 cm21; dH (300 MHz, CDCl3) 0.89 (3H, s, –CH3),
0.92 (3H, s, –CH3), 0.93 (3H, s, –CH3), 1.21–1.80 (6H, m),
3.47 (2H, q, J¼9 Hz, –CH2OH); dC (75 MHz, CDCl3) 19.2
(CH3), 19.7 (CH2), 23.8 (CH3), 25.3 (CH3), 34.5 (CH2), 40.4
(CH2), 42.8 (C), 47.4 (C), 68.9 (OCH2).
4.1.5. Methyl-3-(10,20,20-trimethylcyclopentyl)prop-2-ene
carboxylate (12). Trimethyl phosphonoacetate (0.69 g,
3.79 mmol) was added dropwise at rt to a magnetically
stirred suspension of sodium hydride (160 mg, 3.26 mmol,
50% suspension in mineral oil) in THF (7 mL). The
resulting solution was stirred for 45 min. A solution of the
aldehyde 11 (380 mg, 2.71 mmol) in THF (4 mL) was added
to it. After stirring for 12 h, the reaction mixture was
quenched by adding saturated aqueous NH4Cl (4 mL) and
worked up with diethyl ether in the usual way. The liquid
obtained was chromatographed (5% diethyl ether–
petroleum ether 60–808C) to afford a mixture of the E-
and Z-isomer of the ester 12 (440 mg, 83%); [Found: C,
73.86; H, 9.67. C12H20O2 requires C, 73.44; H, 10.27%];
The pure E-isomer could be isolated in small amount during
chromatography which has the following physical
characteristics; [a]3D5¼þ12.43 (c 1.36, CHCl3); nmax
(Neat) 1726 cm21; dH (300 MHz, CDCl3) 0.84 (3H, s,
–CH3), 0.92 (3H, s, –CH3), 0.99 (3H, s, –CH3), 1.43–1.90
(6H, m), 3.73 (3H, s, –COOCH3), 5.75 (1H, d, J¼15.9 Hz,
vCH), 7.08 (1H, d, J¼15.9 Hz, vCH); dC (75 MHz,
CDCl3) 20.2 (CH2), 21.2 (CH3), 24.2 (CH3), 25.6 (CH3),
36.8 (CH2), 39.6 (CH2), 45.0 (C), 49.8 (C), 51.7 (OCH3),
118.3 (CH), 156.9 (CH), 167.9 (CO).
4.1.3. 1,2,2-Trimethylcyclopentane-1-carboxaldehyde
(11). To a magnetically stirred cooled (2788C) solution of
oxalyl chloride (0.72 mL, 8.11 mmol) in dichloromethane
(4 mL), a solution of DMSO (1.2 mL, 16.9 mmol) in
dichloromethane (3 mL) was added dropwise. After stirring
the reaction mixture at 2788C for 15 min, a solution of the
alcohol 10 obtained as above (960 mg, 6.76 mmol) in
dichloromethane (4 mL) was added and stirred for 45 min.
Triethylamine (3.8 mL, 27.04 mmol) was added and the
reaction mixture was allowed to attain rt and stirred for 1 h.
The reaction mixture was quenched by addition of water
(4 mL). The organic layer was separated and washed with
water (3£3 mL), dried and concentrated to provide the
extremely volatile aldehyde 11 (850 mg, 89%) as a colorless
liquid; [a]D35¼þ11.73 (c 0.52, CHCl3); nmax (Neat)
1718 cm21; dH (300 MHz, CDCl3) 0.96 (3H, s, –CH3),
0.98 (3H, s, –CH3), 1.02 (3H, s, –CH3), 1.42–1.78 (5H, m),
2.15–2.19 (1H, m), 9.67 (1H, s, –CHO); dC (75 MHz,
CDCl3) 16.8 (CH3), 20.5 (CH2), 24.3 (CH3), 25.0 (CH3),
32.8 (CH2), 40.7 (CH2), 45.1 (C), 58.1 (C), 207.8 (CO).
4.1.6. 3-(10,20,20-Trimethylcyclopentyl)prop-2-ene-1-ol
(13). A suspension of LiAlH4 (0.31 g, 8.16 mmol) in diethyl
ether (8 mL) was stirred for 0.5 h and allowed to settle. The
clear solution (7 mL) was removed via syringe, leaving the
remaining suspension in the reaction flask and was added
dropwise to a cooled (2308C) solution of the ester mixture
12 (800 mg, 4.08 mmol) in diethyl ether (8 mL). After
stirring for 4 h at this temperature, the reaction mixture was
quenched by sequential addition of water (0.3 mL), 15%
NaOH (0.3 mL) and water (0.9 mL). The organic phase was
separated and dried over Na2SO4. The residual oil after
removal of solvent was chromatographed (12% diethyl
ether–petroleum ether 60–808C) to provide the alcohol 13
(0.48 g, 70%) as a mixture of E- and Z-isomers; [Found: C,
78.24; H, 11.89. C11H20O requires C, 78.51; H, 11.98%];
nmax (Neat) 3313 cm21; NMR: for the major isomer, dH
(300 MHz, CDCl3) 0.78 (3H, s, –CH3), 0.84 (3H, s, –CH3),
0.91 (3H, s, –CH3), 1.21–2.06 (6H, m), 4.08 (2H, d,
J¼6 Hz, –CH2OH), 5.53 (1H, dt, J¼6 Hz, J¼12 Hz,
4.1.4. 2-Methyl-4-(10,20,20-trimethylcyclopentyl)-1,3-
butadiene (4a). n-BuLi (0.8 mL, 1.1 mmol, 1.4 M) in
hexane was added dropwise at rt to a stirred suspension of
methallyltriphenylphosphonium
chloride
(0.50 g,

A. Nayek et al. / Tetrahedron 59 (2003) 5175–5181
5179
vCH), 5.73 (1H, d, J¼15.9 Hz, vCH); dC (75 MHz,
CDCl3) 20.1 (CH2), 22.0 (CH3), 24.1 (CH3), 25.6 (CH3),
37.1 (CH2), 39.6 (CH2), 44.2 (C), 48.7 (C), 64.5 (CH2),
126.2 (CH), 140.3 (CH); for the minor isomer, dC (75 MHz,
CDCl3) 19.9 (CH2), 21.4 (CH3), 24.3 (CH3), 25.0 (CH3),
29.2 (CH2), 32.7 (CH2), 45.4 (C), 54.4 (C), 64.4 (CH2),
130.0 (CH), 134.8 (CH).
19.1 (CH3), 19.4 (CH2), 23.9 (CH3), 24.0 (CH3), 25.4 (CH3),
25.4 (CH2), 28.0 (CH2), 30.8 (CH3), 38.3 (CH2), 41.1 (CH2),
44.4 (CH3), 45.4 (C), 49.2 (C), 50.7 (CH3), 122.8 (CH),
133.8 (C), 213.0 (CO); for the minor adduct, dC (75 MHz,
CDCl3) 19.0 (CH2), 19.8 (CH3), 23.8 (CH2), 24.5 (CH3),
24.7 (CH3), 25.8 (CH3), 26.0 (CH3), 26.4 (CH2), 39.6 (CH2),
40.4 (CH), 42.7 (CH2), 43.2 (C), 47.7 (CH), 49.1 (C), 123.5
(CH), 134.2 (CH), 211.7 (CO).
4.1.7. 3-(10,20,20-Trimethylcyclopentyl)prop-2-en-1-al
(14). The alcohol 13 (380 mg, 2.26 mmol) was oxidised
following the procedure described above for preparation of
the aldehyde 11 to provide the aldehyde 14 (300 mg, 80%)
as a mixture of the E- and Z-isomer; [Found: C, 79.38; H,
10.68. C11H18O requires C, 79.46; H, 10.91%]; nmax (Neat)
1685, 1689 cm21; NMR: for the major isomer, dH
(300 MHz, CDCl3) 0.87 (3H, s, –CH3), 0.95 (3H, s, –
CH3), 1.05 (3H, s, –CH3), 1.60–1.99 (6H, m), 6.07 (1H, dd,
J¼7.7, 15.9 Hz, vCH), 6.95 (1H, d, J¼15.9 Hz, vCH),
9.52 (1H, d, J¼7.7 Hz, –CHO); dC (75 MHz, CDCl3) 19.8
(CH2), 20.7 (CH3), 23.8 (CH3), 25.2 (CH3), 36.5 (CH2), 39.3
(CH2), 44.9 (C), 45.4 (C), 130.4 (CH), 156.9 (CH), 194.2
(CO); for the minor isomer, dC (75 MHz, CDCl3) 13.7
(CH3), 15.1 (CH3), 25.5 (CH3), 27.1 (CH2), 30.3 (CH2), 36.4
(CH2), 45.2 (C), 50.2 (C), 133.3 (CH), 160.2 (CH), 193.7
(CO).
Reaction of the diene 4a with maleic anhydride
A mixture of the diene 4a (400 mg, 2.24 mmol), maleic
anhydride (240 mg, 2.47 mmol) and toluene (5 mL) was
heated at 808C for 2 h. The residue, after removal of toluene,
was chromatographed (5% diethyl ether–petroleum ether
60–808C) to afford a mixture of the adduct 17 and its
diastereomer (380 mg, 61%) in 4:1 ratio; [Found: C, 73.46;
H, 8.88. C17H24O3 requires C, 73.88; H, 8.75%];
[a]3D0¼þ38.0 (c 0.60, CHCl3); nmax (Neat) 1841,
1778 cm21; NMR: for the major adduct, dH (300 MHz,
CDCl3) 0.81 (3H, s, –CH3), 0.98 (3H, s, –CH3), 1.07 (3H,
s, –CH3), 1.30–2.18 (10H, m), 2.29 (1H, br s), 2.63 (1H, d,
J¼13.5 Hz), 3.42 (2H, m) and 5.74 (1H, br s, vCH); dC
(75 MHz, CDCl3) 17.5 (CH3), 19.5 (CH2), 23.8 (CH3), 25.2
(CH3), 26.0 (CH3), 29.7 (CH2), 37.1 (CH2), 40.4 (CH2), 42.8
(CH), 43.1 (CH), 44.6 (CH), 45.5 (C), 46.2 (C), 125.0 (CH),
137.2 (C), 173.4 (CO), 174.4 (CO); for the minor adduct, dC
(75 MHz, CDCl3) 20.3 (CH3), 21.8 (CH3), 23.7 (CH3), 24.6
(CH3), 26.7 (CH3), 30.2 (CH2), 36.0 (CH2), 40.6 (CH2), 42.4
(CH), 42.5 (CH), 43.8 (CH), 46.0 (C), 46.9 (C), 127.1 (CH),
135.2 (C), 171.8 (CO), 174.5 (CO).
4.1.8. 5-(10,20,20-Trimethylcyclopentyl)-2,4-pentadiene
(4b). A solution of the aldehyde 14 (0.38 g, 2.29 mmol) in
THF (4 mL) on reaction with the ylide generated from
ethyltriphenylphosphonium bromide (1.19 g, 3.20 mmol)
according to the procedure described for preparation of
diene 4a afforded the diene 4b (0.34 g, 83%) as a mixture of
all the possible geometrical isomers with the E-isomer
predominating; [Found: C, 87.83; H, 12.09. C13H22 requires
C, 87.56; H, 12.44%]; [a]2D8¼þ25.8 (c 1.88, CHCl3); NMR:
for the major isomer, dH (300 MHz, CDCl3) 0.80 (3H, s,
–CH3), 0.88 (3H, s, –CH3), 0.97 (3H, s, –CH3), 1.40–1.92
(6H, m), 5.78 (d, J¼15.6 Hz), and 6.24 (dd, J¼10.8,
15.6 Hz) merged under 5.30–6.28 (4H, m); dC (75 MHz,
CDCl3) 13.5 (CH3), 19.9 (CH2), 21.8 (CH3), 23.9 (CH3),
25.5 (CH3), 36.8 (CH2), 39.4 (CH2), 44.6 (C), 49.3 (C),
122.2 (CH), 123.6 (CH), 130.4 (CH), 141.6 (CH).
Reaction of the diene 4a with dimethylacetylene dicar-
boxylate
The adduct 18 was obtained as a colorless liquid in 83%
yield in ca. 1:1 mixture; nmax (Neat) 1728 cm21; NMR: for
one adduct, dH (300 MHz, CDCl3) 0.73 (3H, s, –CH3), 0.97
(3H, s, –CH3), 1.05 (3H, s, –CH3), 1.34–1.71 (6H, m), 1.78
(3H, s, –CH3), 2.99 (1H, br d), 3.72 (3H, s, –COOCH3),
3.74 (3H, s, –COOCH3), 5.61 (1H, m, vCH); dC (75 MHz,
CDCl3) 17.3 (CH3), 19.1 (CH3), 19.9 (CH2), 22.8 (CH3),
25.5 (CH3), 33.3 (CH2), 37.4 (CH2), 41.7 (CH2), 45.0 (C),
47.2 (CH), 52.3 (OCH3), 52.4 (OCH3), 53.5 (C), 122.8
(CH), 131.4 (C), 135.2 (C), 138.9 (C), 168.9 (CO), 170.7
(CO); for the other adduct, dH 0.79 (s, –CH3), 0.82 (s,
–CH3), 1.05 (s, –CH3), 1.76 (s, –CH3), 3.71 (s,
–COOCH3), 3.75 (s, –COOCH3); dC (75 MHz, CDCl3)
19.1 (CH3), 19.2 (CH2), 22.7 (CH3), 24.4 (CH3), 25.4 (CH3),
34.3 (CH2), 37.6 (CH2), 41.9 (CH2), 43.5 (OCH3), 45.1 (C),
47.1 (CH), 52.4 (OCH3), 53.8 (C), 125.1 (CH), 130.8 (C),
135.7 (C), 138.6 (C), 169.4 (CO), 169.9 (CO). An
analytically pure sample could not be obtained due to its
strong tendency to undergo aromatization.
Diels–Alder reaction of the dienes 4a and 4b
Unless otherwise stated Diels–Alder reactions were carried
out by heating a mixture of the diene and the dienophile in
toluene solution at 1408C for 24 h. The product was isolated
after solvent removal and filtration of the residual mass
through a short column of silica gel.
Reaction of the diene 4a with methyl vinyl ketone
The crude adduct was obtained as a liquid in 82% yield as a
mixture (2:1) of two diastereomers from which the major
diastereomer 15 (40 mg, 14%) crystallized (petroleum ether
60–808C); mp 114–1168C; [Found: C, 82.13; H, 11.11.
C17H28O requires C, 82.20; H, 11.36%]; [a]2D2¼þ111.29 (c
0.21, CHCl3); nmax (KBr) 1712 cm21; NMR: for the major
adduct, dH (300 MHz, CDCl3) 0.83 (3H, s, –CH3), 0.97
(3H, s, –CH3), 1.01 (3H, s, –CH3), 1.69 (3H, s, –CH3),
1.33–2.04 (10H, m), 2.21 (3H, s, –COCH3), 2.70 (1H, br s),
2.81 (1H, m), 5.58 (1H, br s, vCH); dC (75 MHz, CDCl3)
Reaction of the Diene 4b with maleic anhydride
The adduct 19 along with its other diastereoisomer was
obtained as a colorless liquid in 82% yield in ca. 2:1 ratio;
[Found: C, 73.48; H, 8.45. C17H24O3 requires C, 73.88; H,
8.75%]; nmax (Neat) 1847, 1776 cm21; NMR: for the major
isomer, dH (300 MHz, CDCl3) 0.82 (3H, s, –CH3), 0.97
(3H, s, –CH3), 1.12 (3H, s, –CH3), 1.49 (d, J¼7.3 Hz)

5180
A. Nayek et al. / Tetrahedron 59 (2003) 5175–5181
merged with 1.41–2.43 (11H, m), 3.23–3.30 (1H, m),
3.44–3.71 (1H, m), 5.66–5.83 (1H, m, vCH), 6.09–6.18
(1H, m, vCH); dC (75 MHz, CDCl3) 16.8 (CH3), 18.0
(CH3), 19.6 (CH2), 24.4 (CH3), 25.2 (CH3), 31.0 (C), 31.1
(CH), 37.1 (CH2), 40.4 (CH2), 42.2 (CH), 46.6 (C), 46.9
(CH), 47.8 (CH), 132.1 (CH), 134.5 (CH), 171.9 (CO),
173.0 (CO); for the minor isomer, dH 0.81 (s, CH3), 0.95 (s,
CH3), 1.15 (s, CH3), 1.42 (d, J¼7.3 Hz); dC (75 MHz,
CDCl3) 16.6 (CH3), 20.5 (CH2), 22.7 (CH3), 24.4 (CH3),
26.9 (CH3), 31.0 (CH), 35.2 (CH2), 40.2 (CH2), 41.3 (CH),
45.5 (CH), 46.2 (C), 46.4 (C), 46.9 (CH), 132.3 (CH), 134.5
(CH), 166.7 (CO), 170.1 (CO).
afford the dicarboxylic acid mixture 21 as a white solid
(200 mg, 94%); mp 68–708C; [Found: C, 69.16; H, 9.11.
C17H26O4 requires C, 69.36; H, 8.90%]; nmax (KBr) 2960,
2873, 1710, 1469, 1425, 1375, 1284, 1226, 1180, 1109,
1095, 1041, 933 cm21
.
4.1.12. Herbertene (1a). A solution of the diacid 20
(100 mg, 0.34 mmol) in benzene (12 mL) containing
acridine (0.15 g, 0.82 mmol) was irradiated with a medium
pressure 450W Hanovia Hg vapor lamp through a water
cooled pyrex immersion well for 2 h. The reaction mixture
was then washed successively with HCl (3£3 mL, 6N),
saturated NaHCO3 solution (3£2 mL) and brine (3 mL).
Evaporation of the solvent followed by column chromato-
graphy of the residual mass (3% diethyl ether–petroleum
ether 60–808C) afforded an oil (28 mg, 40%) containing the
diene 22 as the major component, dH (300 MHz, CDCl3)
0.72 (3H, s, –CH3), 1.02 (3H, s, –CH3), 1.25 (3H, s, –CH3),
1.57 (3H, s, –CH3), 2.34–2.84 (3H, m), 2.84 (1H, br s),
5.31–5.81 (3H, m, vCH); dC (75 MHz, CDCl3) 18.4 (CH3),
19.8 (CH2), 23.9 (CH3), 25.4 (CH3), 25.9 (CH3), 30.1 (CH2),
31.5 (CH2), 39.0 (CH2), 39.6 (C), 44.4 (CH), 50.4 (C), 122.3
(CH), 125.7 (CH), 129.2 (CH), 132.7 (C); and possibly a
trace of the corresponding conjugated diene as indicated by
the presence of two olefinic CH units and two olefinic
quaternary carbons in 13C NMR; dC (75 MHz, CDCl3) 18.5
(CH3), 19.7 (CH2), 24.0 (CH3), 25.4 (CH3), 26.0 (CH3), 30.1
(CH2), 31.5 (CH2), 39.0 (CH2), 39.5 (C), 44.3 (CH), 50.5
(C), 123.5 (CH), 124.5 (C), 127.7 (CH), 130.8 (C). Without
further purification a solution of this diene mixture 22
(40 mg, 0.196 mmol) in benzene (3 mL) was heated with
DDQ (80 mg, 0.36 mmol) at 608C for 24 h. Diethyl ether
(5 mL) was added to the reaction mixture. The organic layer
was washed with aqueous NaOH (3£1 mL, 1 M), brine
(2£1 mL) and dried over Na2SO4. Evaporation of the
solvent followed by column chromatography (4% diethyl
ehter–petroleum ether 60–808C) afforded herbertene 1a
(28 mg, 70%); [a]3D0¼þ56.85 (c 0.54, CHCl3); [the natural
enantiomer (2)-herbertene exhibits [a]3D0¼256 (c 1.4,
CHCl3)];5c dH (300 MHz, CDCl3) 0.56 (3H, s, –CH3),
1.07 (3H, s, –CH3), 1.26 (3H, s, –CH3), 1.64–1.81 (6H, m),
2.35 (3H, s, –CH3), 6.99 (1H, m), 7.16 (2H, m), 7.26 (1H,
m); dC (75 MHz, CDCl3) 20.1 (CH2), 22.2 (CH3), 24.7
(CH3), 24.8 (CH3), 26.9 (CH3), 37.2 (CH2), 40.2 (CH2),
44.6 (C), 50.9 (C), 124.5 (CH), 126.5 (CH), 127.7 (CH),
128.2 (CH), 137.1 (C), 148.0 (C). 1H and 13C NMR spectra
data were found identical with those reported in the
literature.5b
4.1.9. 6-(10,20,20-Trimethyl cyclopentyl)-p-tolyl aceto-
phenone (16). A mixture of the methyl ketone 15 (50 mg,
0.2 mmol) and 10% Pd–C (50 mg) in xylene (1 mL) was
heated at 1508C for 3 h. The mass obtained after removal of
the solvent was chromatographed (8% diethyl ether–
petroleum ether 60–808C) to afford the aromatic ketone
16 (30 mg, 57%); [Found: C, 83.32; H, 9.87. C17H24O
requires C, 83.55; H, 9.90%]; nmax (Neat) 1691, 1604 cm21
;
dH (300 MHz, CDCl3) 0.56 (3H, s, –CH3), 1.14 (3H, s,
–CH3), 1.27 (3H, s, –CH3), 2.27 (3H, s, –CH3), 2.48 (3H,
s, –CH3), 6.86 (1H, d, J¼7.8 Hz, C-3), 6.93 (1H, d,
J¼7.7 Hz, C-2), 7.19 (1H, s, C-5); dC (75 MHz, CDCl3)
20.0 (CH2), 21.9 (CH3), 25.2 (CH3), 26.2 (CH3), 26.9 (CH3),
33.2 (CH3), 39.0 (CH2), 40.5 (CH2), 46.1 (C), 52.2 (C),
125.8 (CH), 126.2 (CH), 130.2 (CH), 138.0 (C), 140.9 (C),
144.8 (C), 208.8 (CO).
4.1.10. 6-(10,20,20-Trimethyl cyclopentyl-4-methyl-cyclo-
hex-4-ene-1,2-dicarboxylic acid (20). A solution of the
anhydride 17 (300 mg, 1.09 mmol) in ethanol (5 mL), was
refluxed with a solution of sodium hydroxide (110 mg,
2.72 mmol) in water (1.5 mL) for 1 h. The reaction mixture
was concentrated under reduced pressure and worked-up
with diethyl ether to remove unhydrolysed material. The
basic aqueous part left after ether work-up was acidified by
aqueous HCl (5 mL, 6N). Usual work-up with diethyl ether
afforded the dicarboxylic acid 20 as a white solid (300 mg,
94%); mp 117–1198C; [a]3D0¼þ28.53 (c 0.34, CHCl3);
[Found: C, 69.76; H, 8.80. C17H26O4 requires C, 69.36; H,
8.90%]; nmax (KBr) 1710 cm21; NMR: for the major
isomer, dH (300 MHz, CDCl3) (dimethyl ester) d 0.72
(3H, s, –CH3), 0.91 (3H, s, –CH3), 1.08 (3H, s, –CH3),
1.26–2.26 (5H, m), 1.74 (3H, br s), 2.14–2.21 (2H, m),
2.60–2.64 (2H, m), 2.90–2.97 (1H, m), 3.08 (1H, t,
J¼3.8 Hz), 3.62 (3H, s, –COOCH3), 3.68 (3H, s,
–COOCH3), 5.45 (1H, br s, vCH); dC (75 MHz, CDCl3)
17.1 (CH3), 19.0 (CH2), 23.5 (CH3), 25.8 (CH3), 25.9 (CH3),
30.2 (CH2), 37.3 (CH2), 41.3 (CH2), 41.7 (CH), 44.4 (CH),
45.3 (C), 46.1 (CH), 47.2 (C), 51.2 (CH3), 51.9 (CH3), 120.2
(CH), 134.0 (C), 173.7 (CO), 174.4 (CO); for the minor
isomer, dC (75 MHz, CDCl3) 18.2 (CH3), 18.9 (CH2), 23.7
(CH3), 24.6 (CH3), 24.8 (CH3), 29.7 (CH2), 37.1 (CH2), 42.2
(CH2), 42.3 (CH), 44.4 (C), 44.5 (CH), 46.0 (C), 47.2 (CH),
51.1 (CH3), 51.8 (CH3), 121.7 (CH), 133.4 (C), 173.8 (CO),
174.2 (CO).
4.1.13. Cuparene (2a). Following the above procedure the
diacid 21 (0.16 mg, 0.54 mmol) was bisdecarboxylated to
afford the diene 23 (22 mg, 20%). Without further
purification the crude product (40 mg, 0.2 mmol) was
immediately aromatised with DDQ (80 mg, 0.36 mmol)
according to the procedure used for the synthesis of
herbertene to afford cuparene 2a (18 mg, 67%);
[a]D32¼þ54.05 (c 0.42, CHCl3) [lit.9 [a]2D0¼þ65, c 5.9,
CHCl3]; dH (300 MHz, CDCl3) 0.56 (3H, s, –CH3), 1.06
(3H, s, –CH3), 1.26 (3H, s, –CH3), 1.54–1.81 (5H, m), 2.50
(1H, m), 2.31 (3H, s, –CH3), 7.08 (2H, d, J¼8.07 Hz), 7.24
(2H, d, J¼8.25 Hz); dC (75 MHz, CDCl3) 20.2 (CH2), 21.2
(CH3), 24.7 (CH3), 24.8 (CH3), 26.9 (CH2), 44.6 (C), 50.7
(C), 127.3 (CH), 128.6 (CH), 135.1 (C), 144.9 (C).
4.1.11. 6-(10,20,20-Trimethylcyclopentyl)-3-methylcyclo-
hex-4-ene-1,2-dicarboxylic acid (21). Following the
above procedure the mixture of the anhydride 19 and its
diastereoisomer (200 mg, 0.725 mmol) was hydrolysed to

A. Nayek et al. / Tetrahedron 59 (2003) 5175–5181
5181
4.1.14. 6-(10,20,20-Trimethyl)-4-methylphenyl-1,2-di-
References
methylcarboxylate (24). The diene 18 (300 mg,
0.94 mmol) on aromatization with DDQ (0.43 g,
1.88 mmol) afforded the diester 24 (210 mg, 72%).
[Found: C, 71.28; H, 8.22. C19H26O4 requires C, 71.67; H,
8.23]; nmax (Neat) 1739, 1732, 1606 cm21; dH (300 MHz,
CDCl3) 0.69 (3H, s, –CH3), 1.23 (3H, s, –CH3), 1.31 (3H,
s, –CH3), 1.50–1.84 (6H, m), 2.38 (3H, s, –CH3), 3.85 (3H,
s, –COOCH3), 3.88 (3H, s. –COOCH3), 7.58 (1H, s, C-5),
7.65 (1H, s, C-3); dC (75 MHz, CDCl3) 19.9 (CH2), 21.7
(CH3), 25.5 (CH3), 26.0 (CH3), 27.1 (CH3), 35.8 (CH2),
40.4 (CH2), 46.2 (C), 52.7 (C), 128.9 (CH), 129.0 (C), 131.9
(C), 134.6 (CH), 137.9 (C), 146.1 (C), 167.4 (CO), 172.0
(CO).
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4.1.15. Hydrolysis of the diester 24. Synthesis of the
monocarboxylic acid 26. A solution of the aromatic diester
24 (50 mg, 0.157 mmol) in aqueous (0.3 mL) ethanolic
(2 mL) sodium hydroxide (30 mg, 0.8 mmol) was heated
under reflux for 4 h. The reaction mixture was concentrated
under reduced pressure and worked up with diethyl ether.
The basic aqueous part left after work up was acidified by
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C18H24O4 requires: C, 71.04; H, 7.95.]; nmax (KBr) 1704,
1699, 1606 cm21; dH (300 MHz, CDCl3) 0.69 (3H, s,
–CH3), 1.21 (3H, s, –CH3), 1.32 (3H, s, –CH3), 1.49–1.82
(6H, m), 2.39 (3H, s, –CH3), 3.85 (3H, s, –COOCH3), 7.62
(1H, s, C-5), 7.75 (1H, s, C-3); dC (75 MHz, CDCl3) 19.9
(CH2), 21.7 (CH3), 25.5 (CH3), 26.0 (CH3), 27.0 (CH3), 30.1
(C), 35.8 (CH2), 40.4 (CH2), 46.2 (C), 52.9 (OCH3), 127.9
(C), 129.7 (CH), 132.3 (C), 133.7 (C), 135.4 (CH), 138.1
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4.1.16. Attempted hydrolysis of the methylester 26.
Synthesis of the anhydride 27. A solution of the methyl
ester 26 (40 mg, 0.13 mmol) was added dropwise to a
magnetically stirred ice-cold H2SO4 (0.8 mL, 96%) and
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1.60 (3H, s, –CH3), 1.51–2.19 (6H, m), 2.54 (3H, s, –CH3),
7.68 (1H, s, C-5), 7.70 (1H, s, C-3); dC (75 MHz, CDCl3)
20.6 (CH2), 22.6 (CH3), 23.7 (CH3), 25.5 (CH3), 26.1 (CH3),
39.8 (CH2), 41.2 (CH2), 46.5 (C), 52.7 (C), 124.1 (CH),
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Acknowledgements
8. Crystallographic data for compound 15 has been deposited with
the cambridge crystallographic data centre as supplementary
publication number CCDC 204294. Copies of the data can be
obtained, free of charge, on application to the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK. Fax: þ44-1233-336033,
e-mail: deposit@ccdc.cam.ac.uk.
Financial support from The Department of
Science and Technology, Govt. of India is gratefully
acknowledged. A. N. thanks CSIR, New Delhi for a
Research Fellowship. M. G. B. D. thanks the EPSRC and
the University of Reading for Funds for the Image Plate
System.
9. Enzell, C.; Erdtman, H. Tetrahedron 1958, 4, 361–368.