RCM-based approach to (±)-cuparene

Article abstract of DOI:10.1080/00397910701229214

An efficient approach to the aromatic sesquiterpene cuparene has been described starting from the readily available β-ionone and employing a combination of epoxide rearrangement-based ring-contraction and ring-closing metathesis reactions as key steps. Copyright Taylor & Francis Group, LLC.

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RCM‐Based Approach to (±)‐Cuparene
A. Srikrishna a , G. Satyanarayana a & K. R. Prasad a
a Department of Organic Chemistry , Indian Institute of Science , Bangalore,
India
Published online: 11 May 2007.
To cite this article: A. Srikrishna , G. Satyanarayana & K. R. Prasad (2007) RCM‐Based Approach to
(±)‐Cuparene, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:9, 1511-1516, DOI: 10.1080/00397910701229214
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Synthetic Communicationsw, 37: 1511–1516, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701229214
RCM-Based Approach to (+)-Cuparene
A. Srikrishna, G. Satyanarayana, and K. R. Prasad
Department of Organic Chemistry, Indian Institute of Science, Bangalore,
India
Abstract: An efficient approach to the aromatic sesquiterpene cuparene has been
described starting from the readily available b-ionone and employing a combination
of epoxide rearrangement-based ring-contraction and ring-closing metathesis
reactions as key steps.
Keywords: cupranes, epoxide rearrangement, metathesis, quaternary carbons, terpene
synthesis
The cuparenes and herbertanes belong to a small class of aromatic sesquiter-
penes.[1] Both cuparenes and herbertenes contain a sterically crowded
1-(aryl)-1,2,2-trimethylcyclopentane carbon framework containing two
vicinal quaternary carbon atoms on a cyclopentane ring, differing only in
the position of the methyl group on the aromatic ring. Isolation of the first
and the simplest member of the cuparene class, cuparene 1, was reported[2]
in 1958 from Chomaecyparis thyoides, Biota orientalis, and Widdringtonia,
whereas the first member of the herbertane class of sesquiterpenes, herbertene
2, was isolated in 1981 from the ethyl acetate extract of the liverwort Herberta
adunca (Dicks.) S. Gray, belonging to the family herbertaceae.[3] Several
members of the cuparene and herbertene sesquiterpenes have been shown to
possess interesting biological properties.
Received in India September 25, 2006
Address correspondence to A. Srikrishna, Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India. E-mail: ask@orgchem.iisc.ernet.in
1511

1512
A. Srikrishna, G. Satyanarayana, and K. R. Prasad
Presence of a sterically crowded carbon framework, 1-aryl-1,2,2-tri-
methylcyclopentane, the difficulty associated with the construction of
vicinal quaternary carbon atoms on a cyclopentane ring, and novel biological
properties associated with cuparenes and herbertenes made them challenging
synthetic targets. As a consequence, a large number of versatile approaches
have been developed.[4,5] Most of the approaches relied on the construction
of the cyclopentane moiety starting from an appropriate aromatic precursor.
Relatively few approaches were reported in the literature on the construction
of the six-membered ring starting from a preformed cyclopentane system.[6]
These are based on the Diels–Alder reaction,[6a,c] 6p-electrocyclisation,[6b]
or Robinson annulation.[6d] Herein, we report a short and very efficient
approach to (+)-cuparene 1 starting from the readily available b-ionone,
employing a ring-closing metathesis (RCM) reaction for the construction of
the six-membered ring as the key step.
It was contemplated that addition of vinylmagnesium bromide to the
dione 3 followed by RCM reaction[7] of the bis-allyl alcohol 4 would
generate cyclohexenediol 5, which on dehydration generates cuparene 1
(Scheme 1). An epoxide rearrangement-based ring contraction of b-ionone
6 readily provides access to the dione 3.
The synthetic sequence is depicted in Schemes 2 and 3. The dione 3 was
prepared from b-ionone 6 as reported earlier.[8] Thus, reaction of b-ionone 6
with m-chloroperbenzoic acid (m-CPBA) generated the epoxide 7, which
on treatment with a catalytic amount of boron trifluoride diethyl etherate
furnished the ene-dione 8, containing the 1,2,2-trimethylcyclopentane moiety
of cuparene. Hydrogenation of the ene-dione 8 with 10% palladium on
charcoal as the catalyst generated the dione 3.
However, conversion of the dione 3 into the bis-allyl alcohol 4 was unsuc-
cessful under a variety of conditions. Hence, the strategy was altered, and the
sequence was carried out via the hydroxydiene 9. Accordingly, Wittig reaction
of the dione 3 in benzene with methylenetriphenylphosphorane furnished the
keto-olefin 10 in 90% yield. Sonochemically accelerated Barbier reaction of
the ketone 10 with lithium and allyl bromide generated the hydroxydiene 9
in 92% yield. RCM reaction of the hydroxydiene 9 in refluxing benzene
Scheme 1.

RCM-Based Approach to (+)-Cuparene
1513
.
Scheme 2. (a) m-CPBA, CH2Cl2; (b) BF3 Et2O, CH2Cl2; (c) H2, 10% Pd-C, EtOH.
with Grubbs’s second-generation catalyst quantitatively furnished the cyclo-
hexenol 11. Finally, concomitant dehydration and aromatization of the
tertiary alcohol 11 with p-toluenesulfonic acid (PTSA) in refluxing benzene
1
for 4 h furnished cuparene 1 in 77% yield, which exhibited the H and 13C
NMR spectral data identical to those reported in the literature.[6a] Carrying
out the reaction either at room temperature or refluxing for a lesser time
resulted in the generation of a mixture of cuparene and dihydrocuparenes.
In conclusion, we have developed an efficient approach to cuparene 1
employing an RCM reaction for the construction of the six-membered ring.
Scheme 3. (a) Ph3P55CH2, C6H6; (b) Li, CH255CHCH2Br, THF; (c) Grubbs’s
second-generation catalyst, C6H6; (d) PTSA, C6H6.

1514
A. Srikrishna, G. Satyanarayana, and K. R. Prasad
In the present sequence, cuparene 1 has been obtained starting from the readily
available b-ionone 6 in seven steps, with an average yield of 91.8% in each
step.
EXPERIMENTAL
IR spectra were recorded on a Jasco FTIR 410 spectrophotometer. 1H
(300 MHz) and 13C (75 MHz) NMR spectra were recorded on JNM l-300
spectrometer. Unless otherwise specified, a 1:1 mixture of CDCl3 and CCl4
was used as solvent for preparing the NMR samples. The chemical shifts (d
ppm) and coupling constants (Hz) are reported in the standard fashion with
reference to either internal tetramethylsilane (for 1H) or the central line
(77.0 ppm) of CDCl3 (for 13C). In the 13C NMR spectra, the nature of the
carbons (C, CH, CH2, or CH3) was determined by recording the DEPT-135
spectra and is given in parentheses. High-resolution mass spectra were
recorded using a Micromass Q-TOF micromass spectrometer with electro-
spray ionization.
4-Methyl-1-(1,2,2-trimethylcyclopentyl)pent-4-en-1-one (10)
To a cold (08C), magnetically stirred suspension of methyltriphenylphospho-
nium iodide (1.2 g, 3 mmol) in dry benzene (7 ml), potassium tert-amyl oxide
(2.8 mmol) [prepared from potassium (110 mg, 2.8 mmol) in 3 ml of tert-amyl
alcohol] in dry benzene (2 ml) was added, and the resultant yellow reaction
mixture was stirred for 10 min at rt. To a cold (08C), magnetically stirred
solution of the diketone 3 (210 mg, 1 mmol) in dry benzene (1 ml), methyle-
netriphenylphosphorane was added and stirred for 30 min at 08C. The reaction
mixture was then quenched with water (5 ml) and extracted with ether
(5 ꢀ 5 ml). The organic layer was washed with brine and dried (Na2SO4).
Evaporation of the solvent and purification of the residue over a silica-gel
column using ethyl acetate–hexane (1:60 to 1:40) as eluent furnished the
1
monoketone 10 (187 mg, 90%) as oil. IR (neat): nmax/cm21 1698, 886; H
NMR (300 MHz, CDCl3 þ CCl4): d 4.69 and 4.64 (2H, 2 ꢀ s, H-5), 2.70–
200 (5H, m), 1.73 (3H, s, olefinic-CH3), 1.70–1.40 (5H, m), 1.13 (3H, s),
1.08 (3H, s), and 0.84 (3H, s) [3 ꢀ tert-CH3]; 13C NMR (75 MHz,
CDCl3 þ CCl4): d 213.9 (C, C55O), 144.8 (C, C-4), 110.2 (CH2, C-5), 59.5
(C, C-10), 44.1 (C, C-20), 40.2 (CH2, C-2), 38.6 (CH2), 34.7 (CH2), 31.5
(CH2), 25.7 (CH3), 24.5 (CH3), 22.8 (CH3), 20.9 (CH3), 19.7 (CH2, C-40);
HRMS: m/z calcd. for C14H24ONa (M þ Na): 231.1725. Found: 231.1712.
7-Methyl-4-(1,2,2-trimethylcyclopentyl)octa-1,7-dien-4-ol (9)
A mixture of the ketone 10 (150 mg, 0.72 mmol) and allyl bromide (0.25 ml,
2.9 mmol) in THF (1 ml) was added to a sonochemically irradiated suspension

RCM-Based Approach to (+)-Cuparene
1515
of lithium (40 mg, 5.7 mmol) in dry THF (2 ml) in a round-bottomed flask,
placed in an ultrasonic cleaning bath, at 15–208C over a period of 10 min
and sonochemically irradiated for 50 min. Then the reaction mixture was
decanted from the excess lithium, quenched with saturated aqueous NH4Cl
solution, and extracted with ether (3 ꢀ 5 ml). The ether extract was washed
with brine and dried (Na2SO4). Evaporation of the solvent and purification of
the residue on a silica-gel column using ethyl acetate–hexane (1:20) as eluent
furnished the tertiary alcohol 9 (166 mg, 92%) as oil. IR (neat): nmax/cm21
1
3567, 910, 886; H NMR (300 MHz, CDCl3 þ CCl4): d 6.05–5.80 (1H, m,
H-2), 5.20–4.95 (2H, m, H-1), 4.66 (2H, s, H-8), 2.60–2.00 (6H, m), 1.95–
1.20 (7H, m), 1.74 (3H, s, olefinic-CH3), 1.14 (3H, s), 1.09 (3H, s), and 0.97
(3H, s) [3 ꢀ tert-CH3]; 13C NMR (75 MHz, CDCl3 þ CCl4): d 146.3 (C,
C-7), 135.9 (CH, C-2), 118.1 (CH2, C-1), 109.9 (CH2, C-8), 78.2 (C, C-OH),
53.9 (C), 45.3 (C), 43.5 (CH2), 43.0 (CH2), 35.6 (CH2), 34.1 (CH2), 33.4
(CH2), 27.9 (CH3), 26.2 (CH3), 22.8 (CH3), 21.9 (CH3), 18.7 (CH2); HRMS:
m/z calcd. for C17H30ONa (M þ Na): 273.2194. Found: 273.2184.
4-Methyl-1-(1,2,2-trimethylcyclopentyl)cyclohex-3-en-1-ol (11)
To a magnetically stirred solution of the diene 9 (58 mg, 0.23 mmol) in
anhydrous benzene (10 ml), a solution of second-generation Grubbs’s
catalyst (6 mg, 3 mol%) in anhydrous benzene (10 ml) was added, and the
reaction mixture was refluxed for 30 min. Evaporation of the solvent under
reduced pressure and purification of the residue on a silica-gel column
using ethyl acetate–hexane (1:30) as eluent furnished the cyclohexenol 11
(53 mg, 100%) as oil. IR (neat): nmax/cm21 3584; 1H NMR (300 MHz,
CDCl3 þ CCl4): d 5.22 (1 H, br s, H-3), 2.55–2.25 (2 H, m), 2.30–2.05 (1
H, m), 2.05–1.45 (8H, m), 1.67 (3H, s, olefinic-CH3), 1.45–1.20 (2H, m),
1.14 (3H, s), 1.07 (3H, s), and 0.94 (3H, s) [3 ꢀ tert-CH3]; 13C NMR
(75 MHz, CDCl3 þ CCl4): d 133.6 (C, C-4), 118.8 (CH, C-3), 75.0 (C,
C-OH), 52.0 (C), 45.2 (C), 43.4 (CH2), 35.7 (CH2), 33.4 (CH2), 28.6 (CH3),
28.3 (CH2), 27.3 (CH2), 26.8 (CH3), 23.4 (CH3), 21.9 (CH3), 19.0 (CH2);
HRMS: m/z calcd. for C15H26ONa (M þ Na): 245.1881. Found: 245.1885.
1-(1,2,2-Trimethylcyclopentyl)-4-methylbenzene (Cuparene 1)
To a magnetically stirred solution of the tertiary alcohol 11 (53 mg,
0.23 mmol) in benzene (5 ml) was added p-TSA (44 mg, 0.23 mmol), and
the resultant reaction mixture was refluxed for 4 h. It was then filtered
through a short silica-gel column using CH2Cl2. Evaporation of the solvent
and purification of the residue over a silica-gel column using hexane as
eluent furnished cuparene 1 (37 mg, 77%) as oil. IR (neat): nmax/cm21
1
1516, 812; H NMR (300 MHz, CDCl3 þ CCl4): d 7.20 (2H, d, J 8.4 Hz)

1516
A. Srikrishna, G. Satyanarayana, and K. R. Prasad
and 7.03 (2H, d, J 8.4 Hz) [Ar-H], 2.55–2.40 (1H, m), 2.30 (3H, s, Ar-CH3),
1.90–1.40 (5H, m), 1.25 (3H, s), 1.05 (3H, s), and 0.55 (3H, s) [3 ꢀ tert-CH3];
13C NMR (75 MHz, CDCl3 þ CCl4): d 144.4 (C), 134.5 (C), 128.3 (2 C, CH),
126.9 (2 C, CH), 50.3 (C), 44.3 (C), 39.9 (CH2), 36.9 (CH2), 26.6 (CH3), 24.5
(2 C, CH3), 21.0 (CH3), 19.9 (CH2).
ACKNOWLEDGMENTS
We thank the Department of Science and Technology for the financial support.
REFERENCES
1. Asakawa, Y. In Progress in the Chemistry of Organic Natural Products; Herz, W.,
Kirby, G. W., Moore, R. E., Steglich, W., Tamm, C., (Eds.); Springer-Verlag:
New York, 1995; Vol. 65, p. 140.
2. Enzell, C.; Erdtman, H. Tetrahedron 1958, 4, 361.
3. Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc. Chem. Commun. 1981, 864.
4. Kulkarni, M. G.; Davawala, S. I.; Shinde, M. P.; Dhondge, A. P.; Borhade, A. S.;
Chavhan, S. W.; Gaikwad, D. D. Tetrahedron Lett. 2006, 47, 3027, and references
cited therein.
5. Srikrishna, A.; Satyanarayana, G. Tetrahedron 2006, 47, 1277, and references
cited therein.
6. (a) Nayek, A.; Drew, M. G. B.; Ghosh, S. Tetrahedron 2003, 59, 5175;
(b) Fuganti, C.; Serra, S. J. Org. Chem. 1999, 64, 8728; (c) Ho, T.-L.;
Chang, M.-H. J. Chem. Soc., Perkin Trans. 1 1999, 2479; (d) Abad, A.;
Agullo, C.; Arno, M.; Cunat, A. C.; Garcia, M. T.; Zaragoza, R. J. J. Org.
Chem. 1996, 61, 5916.
7. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413; (b) Fu¨rstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3013; (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18; (d) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
8. Srikrishna, A.; Nagamani, S. A. J. Chem. Soc., Perkin Trans. 1 1999, 3393.;
Frei, B.; Eichenberger, H.; Wartburg, B. V.; Wolf, H. R.; Jeger, O. Helv. Chim.
Acta 1977, 60, 2968.