Synthesis of bisabolane sesquiterpenes: A Johnson-Claisen rearrangement approach

Article abstract of DOI:10.1016/j.cclet.2010.02.024

Several bisabolane sesquiterpenes, (±)-curcumene, (±)-curcuphenol, (±)-curcudiol and (±)-curcuhydroquinone, have been synthesized in racemic form and fully characterized. The salient characteristic of our approach is that a Johnson-Claisen arrangement was

Full text of DOI:10.1016/j.cclet.2010.02.024

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Chinese Chemical Letters 21 (2010) 813–815
www.elsevier.com/locate/cclet
Synthesis of bisabolane sesquiterpenes: A Johnson-Claisen
rearrangement approach
a
a
a
b
Zhen Ting Du a, , Hong Rui Yu , Yan Xu , Yong Li , An Pai Li
*
a Northwest A&F University, College of Science, Yangling 712100, China
b Synthetics Technologica Pte Ltd., 3 Phillip Street, #18-00 Commerce Point 048693, Singapore
Received 25 November 2009
Abstracts
Several bisabolane sesquiterpenes, (Æ)-curcumene, (Æ)-curcuphenol, (Æ)-curcudiol and (Æ)-curcuhydroquinone, have been
synthesized in racemic form and fully characterized. The salient characteristic of our approach is that a Johnson-Claisen
arrangement was involved as a key step.
# 2010 Zhen Ting Du. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Bisabolane sesquiterpenes; Johnson-Claisen rearrangement; Synthesis
The aromatic bisabolane compounds are a small family of sesquiterpenes having the simplest monocarbocyclic
skeleton which have been popular synthetic targets for 30 years [1]. Typified by the parent hydrocarbons
curcumene [2] had been recognized as odor component of many plant essential oils. (+)-Curcuphenol and (+)-
curcudiol were firstly isolated from the water collection of the sponge Didiscus flavus. (+)-Curcuphenol was found
to be an inhibitor of gastric H,K-ATPase and to have antitumor and antifungal activities [3]. (À)-Curcuphenol,
(À)-curcuhydroquinone and (À)-curcuquinone were isolated from the Caribbean gorgonian Pseudopterogorgia
rigida and showed antibacterial activity against Staphylococcus aureus and the marine pathogen Vibro
anguillarum [4]. Curcuhydroquinone and curcuquinone have been used for the synthesis of some heliannuols [5],
one kind of allelochemicals isolated from sunflower Helianthus annuus leaves bearing significant biological
activity. Because of their wide range of biological activities, these compounds and their derivatives are attractive
synthetic targets, and especially to verify the usefulness of newly developed synthetic methodology. Although
several reports of the synthesis this kind of compounds can be found in literatures, the existent routes are either
long or inefficient [6].
Johnson-Claisen rearrangement is a powerful tool in synthesis of naturally occurring products in which a key
intermediate of derivatives of d,e-unsaturated pentanoic acid was involved [7]. As an extension of our continuous
effort to synthesize those kinds of naturally occurring products [8], herein, we wish to report the synthesis of (Æ)-a-
curcumene 1, (Æ)-curcuphenol 2, (Æ)-curcuhydroquinone 3 and (Æ)-curcudiol 4 through a Johnson-Claisen
rearrangement approach.
* Corresponding author.
E-mail address: duzt@nwsuaf.edu.cn (Z.T. Du).
1001-8417/$ – see front matter # 2010 Zhen Ting Du. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.02.024

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Z.T. Du et al. / Chinese Chemical Letters 21 (2010) 813–815
Scheme 1. Reagents and conditions: (a) CH2 CHMgBr, 0 8C–r.t., 85–93%; (b) CH3C(OEt)3, EtCOOH, 165 8C, 1d, 65–86%; (c) H2, 5% Pd/C,
EtOAc, 92–96%; (d) 4 equiv. MeMgI, THF, 0 8C–r.t., 93–97%; (e) I2, THF, reflux, 95–98%; (f) EtSNa, DMF, 130 8C, 93–98%.
As shown in Scheme 1, our synthesis commenced at acetophenones 10a–10c, carbinols 9a–9c will be given after a
Grignard addition in 85–93% yield. The carbinols underwent a Johnson-Claisen rearrangement at the presence of
CH3C(OEt)3, propanoic acid at 165 8C, to give compounds 8a–8c in good yield. The double bonds were reduced after
catalytic hydrogen to furnish 7a–7c in excellent yield. Compounds 7a–7c were subjected to an excess MeMgI addition
to afford the tertiary alcohol. (Æ)-curcudiol 4 was obtained after a demethylation step of compound 6b using NaSEt in
95% yield. (Æ)-a-Curcumene 1 was afforded after dehydration of the 6a by I2, and dehydrated products 5b and 5c
were got in very high yield at same conditions, respectively. Compounds 7b–7d can be converted to (Æ)-curcuphenol
2, (Æ)-curcuhydroquinone 3 and using a NaSEt demethylation protocol in 93–98% yield. The spectrums of target
molecules are identical to the ones in the literature [9]. It is obvious that our synthetic route is terse and effective.
In summary, we have achieved an effective and facile route to synthesis of (Æ)-a-curcumene 1, (Æ)-curcuphenol 2,
(Æ)-curcuhydroquinone 3 and (Æ)-curcudiol 4 in higher yield using cheap starting materials. The Johnson-Claisen
rearrangement was used is our salient characteristic of our approach.
Acknowledgments
Financial support from Program for Excellent Young Talents in Northwest A&F University (No. 2111020712) as
well as the National Natural Science Foundation of China (No. 20802058) is greatly appreciated.
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[9] Select spectrum data: Compound 2, IR (neat): 3537, 2965, 2935, 2866, 1664, 1617, 1421, 808 cmÀ1. 1H NMR: 1.22 (d, 3H, J = 7.0 Hz), 1.54 (s,
3H), 1.55–1.69 (m, 2H), 1.68 (s, 3H), 1.89–1.97 (m, 2H), 2.27 (s, 3H), 2.96 (sextet, 1H, J = 7.0 Hz), 4.67 (s, 1H), 5.13 (br, 1H), 6.59 (br, 1H), 6.72
(d, 1H, J = 8.0 Hz), 7.03 (d, 1H, J = 8.0 Hz). 13C NMR: 17.7, 20.8, 21.1, 25.7, 26.1, 31.4, 37.3, 116.2, 121.7, 124.6, 126.8, 130.0, 132.0, 136.5,
152.8. MS (EI): 218, 203, 161, 148, 138, 119, 91, 77. HRMS: calcd. for C15H22O, 218.1751, found 218.1743. Compound 4, IR (neat): 1070,
1420, 1254, 1619, 1711, 2859, 2924 cmÀ1. 1H NMR: 1.12–1.70 (m, 15H), 2.05 (br, 1H), 2.23 (s, 3H), 3.15–3.18 (m, 1H), 5.02 (br, 1H), 6.61 (s,
1H), 6.78 (d, 1H, J = 7.8 Hz), 7.01 (d, 1H, J = 7.8 Hz). 13C NMR: 21.16, 22.23, 28.99, 29.61, 31.47, 37.96, 43.75, 71.93, 116.60, 121.40, 126.97,
131.07, 136.40, 153.70. MS (EI): 236, 218, 203, 161, 148, 135, 121, 91. HRMS: calcd. for C15H24O2, 236.1856, found 236.1853. Compound 9b,
1H NMR: 1.66 (s, 3H), 2.35 (s, 3H), 3.87 (s, 3H), 4.42 (s, 1H), 5.04, (dd, 1H, J = 10.8 Hz, J = 1.2 Hz), 5.14, (dd, 1H, J = 17.2 Hz, J = 1.2 Hz),
6.18, (dd, 1H, J = 17.6 Hz, J = 10.8 Hz), 6.751 (s, 1H), 6.77 (d, 1H, J = 8 Hz), 7.20 (d, 1H, J = 8 Hz), 13C NMR: 22.3, 27.2, 55.4, 74.7, 111.3,
112.5, 121.4, 126.4, 130.8, 138.5, 145.0, 156.9. HRMS: calcd. for C12H16O2, 192.1150, found 192.1151. Compound 9c, 1.68 (s, 3H), 2.22 (s,
3H), 3.80 (s, 3H), 3.83 (s, 3H), 4.44 (s, 1H), 5.07 (dd, 1H, J = 10.8 Hz, J = 1.2 Hz), 5.16, (dd, 1H, J = 17.2 Hz, J = 1.2 Hz), 6.18, (dd, 1H,
J = 17.2 Hz, J = 10.8 Hz), 6.75 (s, 1H), 6.84 (s, 1H). 13C NMR: 16.0, 27.3, 56.0, 56.1, 74.7, 109.5, 111.5, 114.9, 126.2, 131.8, 144.9, 150.5,
151.6. HRMS: calcd. for C13H18O3 222.1256, found 222.1258.