A facile total synthesis of (±)-α-cuparenone employing diallylation and RCM as key steps

Article abstract of DOI:10.1016/j.tetlet.2006.12.023

A short and concise total synthesis of α-cuparenone employing one-pot diallylation and RCM as the key steps is described.

Full text of DOI:10.1016/j.tetlet.2006.12.023

Tetrahedron Letters 48 (2007) 965–966
A facile total synthesis of ( )-a-cuparenone employing
diallylation and RCM as key steps
Subhash P. Chavan,* Abasaheb N. Dhawane and Uttam R. Kalkote
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 11 September 2006; revised 29 November 2006; accepted 7 December 2006
Abstract—A short and concise total synthesis of a-cuparenone employing one-pot diallylation and RCM as the key steps is
described.
Ó 2006 Elsevier Ltd. All rights reserved.
The bicyclic sesquiterpenes, cuparenoid and their ana-
logues present an interesting synthetic challenge to
organic chemists owing to the steric congestion and
the presence of two contiguous quaternary centres in the
cyclopentane ring, which has been constructed in a vari-
ety of ways.1 Both a-cuparenone 1a and b-cuparenone
2a were first isolated from the essential oil of Thuja ori-
entallis (Mayurpankhi) by Dev2a and Chetty in 1964.
Benesova2 reported the isolation of a-cuparenone 1b
and b-cuparenone 2b from the liverwort Mannia frag-
rans in 1976.
the utilisation of ring closing metathesis,8 we undertook
the synthesis of a-cuparenone 1 employing RCM as the
key step. RCM plays an important role in the synthesis
of a variety of natural products and terpenes, and is an
important tool for the formation of small, medium and
large ring systems.
Most of the reported syntheses of a-cuparenone have
drawbacks involving lengthy routes or expensive start-
ing materials, tedious reaction conditions and/or overall
low yields. To overcome these problems, there still exists
a need to develop a simple and efficient synthesis of
a-cuparenone.
O
O
O
O
Herein, we report the synthesis of a-cuparenone accord-
ing to the retrosynthetic path described (Scheme 1),
which involves simple diallylation and ring closing
metathesis to construct the cyclopentene ring. Our start-
ing point was the synthesis of intermediate 3 for ring
closing metathesis so as to obtain key intermediate 4.
(+)-α-cuparenone
(+)-β-cuparenone
(-)-α-cuparenone
(-)-β-cuparenone
2b
1a
2a
1b
Many routes have been reported towards the synthesis
of a-cuparenone3 and b-cuparenone,4 either in racemic
or optically active form. The reported syntheses involve
either generation of the quaternary centre starting from
a framework which contains the aromatic ring, or addi-
tion of the p-tolyl moiety to a cyclopentane ring5 deriv-
ative. Also, other methods build up the aromatic ring
starting from a cyclopentane6 ring. Alternatively, differ-
ent methods involve cyclopentannulation of open chain
intermediates having one quaternary centre.4
O
O
O
1
6
5
O
In keeping with our interest in the expedient construc-
tion of the naturally occurring cyclopentane ring7 and
4
3
2
*
Corresponding author. Tel.: +91 20 2590 2289; fax: +91 20 2590
2629; e-mail: sp.chavan@ncl.res.in
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.023

966
S. P. Chavan et al. / Tetrahedron Letters 48 (2007) 965–966
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O
O
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i
ii
iii
2
3
4
5
O
O
PCy3
Ru
Cl
Cl
iv
v
Ph
PCy3
Grubbs 1st. gen. cat.
6
1
Scheme 2. Reagents and conditions: (i) InCl3, Me3SiCl, allyl trimeth-
ylsilane, EDC, 8 h, 30%; (ii) Grubbs’ 1st generation cat., DCM, rt, 5 h,
90%; (iii) PDC, pyridine, 100 °C, 7 h, 65%; (iv) NaH, DMF, CH3I
(excess), rt, 12 h, 70% and (v) H2–Pd/C, EtOH, piperidine, 4 h,
quantitative yield.
4. For a recent synthesis see: Kulkarni, M. G.; Davawala, S.
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Olefin 3 could be realised by one-pot diallylation of 4-
methyl acetophenone 2 on treatment with InCl3,9 allyl
trimethylsilane and TMS–Cl in ethylene dichloride
(EDC) as the solvent at room temperature to furnish
diallyl compound 3 (Scheme 2).
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61, 3873–3879; (e) Chavan, S. P.; Kharul, R. K.; Kale, R.
R.; Khobragade, D. A. Tetrahedron 2003, 59, 2737–2741.
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S. P.; Praveen, Ch. Tetrahedron Lett. 2005, 46, 1939; (c)
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Ring closing metathesis of diallyl compound 3 using
Grubbs’ 1st generation catalyst10 furnished cyclo-
pentene 4. Treatment of 4 with PDC11 in pyridine at
100 °C furnished the rearranged a,b-unsaturated ketone
5. Dimethylation7b of 5 was carried out using sodium
hydride as a base and methyl iodide in DMF as the
solvent to furnish compound 6. Finally hydrogenation
of 6 using 10% Pd/C in ethanol and catalytic piperidine
afforded ( )-a-cuparenone, in quantitative yield.
The analytical and spectral data obtained for a-cupare-
none12,13 were in complete agreement with reported
data. In conclusion, ( )-a-cuparenone was obtained in
an overall yield of 12%, in five steps starting from com-
mercially available 4-methyl acetophenone employing
simple reaction conditions.
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13. All the compounds were characterized by IR, H NMR,
Acknowledgements
1
13C NMR and mass spectral analysis. Spectral data:
Compound 3: 1H NMR (CDCl3, 200 MHz) d: 1.23, (s,
3H), 2.30, (s, 3H), 2.46 (dd, J = 6.6, 13.8 Hz, 2H), 2.25
(dd, J = 6.6, 13.8 Hz, 2H), 4.89–4.99 (m, 4H), 5.40–5.61
(m, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H).
Compound 4: 1H NMR (CDCl3, 200 MHz) d: 1.38 (s, 3H)
2.30 (s, 3H), 2.45 (d, J = 14.2 Hz, 2H), 2.73, (d,
J = 14.2 Hz, 2H), 5.71 (s, 2H), 7.11 (d, J = 8.34 Hz, 2H),
7.20 (d, J = 8.34 Hz, 2H). Compound 5: 1H NMR
(CDCl3, 200 MHz) d: 1.63 (s, 3H) 2.34 (s, 3H) 2.60 (d,
J = 7 Hz, 2H) 6.2 (d, J = 5.5 Hz, 1H), 7.16 (s, 4H), 7.67 (d,
J = 5.6 Hz, 1H). Compound 6: 1H NMR (CDCl3,
200 MHz) d: 0.55 (s, 3H), 1.20 (s, 3H), 1.49 (s, 3H), 1.35
(s, 3H), 6.25 (d, J = 7 Hz, 1H), 7.75 (d, J = 7 Hz, 1H), 7.10
(m, 4H). Compound 1: 1H NMR (CDCl3, 200 MHz) d: 0.6
(s, 3H), 1.20 (s, 3H), 1.30 (s, 3H), 1.90 (m, 1H), 2.30 (s,
3H), 2.50 (m, 2H), 2.60 (m, 1H), 7.20–7.30 (m, 4H).
A.N.D. thanks CSIR, New Delhi, for the award of
fellowship. Funding from DST (CSIR), New Delhi,
India, to S.P.C. is gratefully acknowledged.
References and notes
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3. (a) Chavan, S. P.; Ravindranathan, T.; Patil, S. S.
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therein; (b) Zarraga, A.; Gustavo, J.; Maldonado, Luis A.
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