Synthesis of (R)-(-)-carvone derivatives

Article abstract of DOI:10.1515/znb-2010-1114

(R)-(-)-Carvone, the main constituent of spearmint oil, has several synthetic applications and is used in cosmetics, food, and pharmaceutical preparations. In a recent study we demonstrated that (R)-(-)-carvone shows significant analgesic activity. In the

Full text of DOI:10.1515/znb-2010-1114

Synthesis of (R)-(–)-Carvone Derivatives
Damia˜o P. de Sousaa, Ellen Raphaelb, and Timothy J. Brocksomb
a Laborato´rio de Qu´ımica de Produtos Naturais e Sinte´ticos Bioativos (LAPROBIO), Departamento
de Fisiologia, Universidade Federal de Sergipe, CEP 49100-000 Sa˜o Cristo´va˜o, Sergipe, Brazil
b Laborato´rio de Qu´ımica Bio-Orgaˆnica, Departamento de Qu´ımica, Universidade Federal de
Sa˜o Carlos, Caixa Postal 676, 13565-905 Sa˜o Carlos, SP, Brazil
Reprint requests to Dr. Damia˜o P. de Sousa. E-mail: damiao desousa@yahoo.com.br
Z. Naturforsch. 2010, 65b, 1381 – 1383; received July 12, 2010
(R)-(–)-Carvone, the main constituent of spearmint oil, has several synthetic applications and is
used in cosmetics, food, and pharmaceutical preparations. In a recent study we demonstrated that
(R)-(–)-carvone shows significant analgesic activity. In the present report, (R)-(–)-carvone derivatives
which have pharmacological potential are described. These compounds can be used in studies of
structure-activity relationship to develop novel drugs.
Key words: Terpenes, Essential Oils, p-Menthanes, Structure-Activity Relationship
Introduction
Carvone (p-mentha-6,8-dien-2-one) is a represen-
Results and Discussion
In this study we synthesized a series of p-menthane
tative monoterpene ketone. The best-known source derivatives using (R)-(–)-carvone as starting material.
of (R)-(–)-carvone is spearmint oil (Mentha spicata), In the first step, the reaction of (R)-(–)-carvone with
which is steam-distilled from the leaves of the plant, potassium cyanide and acetic acid in ethanol under the
whereas the (S)-enantiomer of carvone is a constituent published conditions [12] produced the ketonitrile 2
of dill and caraway oils [1 – 3]. Among terpene chi- (Scheme 1). Reduction of compound 2 with sodium
rogens the carvones ((+)- and (–)-forms) are probably borohydride gave a 96 : 4 mixture of the cyanoalcohols
the most versatile. They have been used in the syn- 3a and 3b in 97 % yield. Dehydration of the secondary
thesis of diverse intermediates and natural compounds, cyanoalcohols 3 using p-toluenesulfonyl chloride af-
principally other terpenoids [3 – 5].
forded the nitrile 4 in 48 % yield. Reduction of com-
pound 4 with LiAlH4 gave the free amine 5 in 91 %
yield.
Developing treatments for pain relief has been the
motivating factor behind many studies carried out by
academic investigators, and in the pharmaceutical in-
The synthesis of terpene derivatives often results in
dustry, in response to the demand for powerful anal- compounds with stereogenic centers and high stereose-
gesics that exhibit pharmacological response through lectivity. The monoterpene starting materials are read-
new mechanisms of action and lower side effects. It ily available, frequently in both enantiomeric forms,
has been shown that monoterpene derivatives exhibit and contain the scaffolds of the desired mono-, sesqui-,
several types of pharmacological properties, such as and diterpene skeletons. The range of pharmacological
antinociceptive [6, 7], sedative [8], and antidepressant activity that has been recorded for terpenes is remark-
[9] activity. The antinociceptive activity of (R)-(–)- ably wide. Terpene derivatives also exhibit several ef-
carvone (1) and monoterpene analogs has also been fects on the central nervous system (CNS), including
demonstrated [10]. Recently, we investigated the anal- analgesic activity [6, 7], apparently due to a variety of
gesic potential of the p-toluenesulfonamide, a syn- action mechanisms. Actually, terpene derivatives have
thetic derivative of (R)-(–)-carvone (1). This sulfon- shown pharmacological activity better than the terpene
amide shows a more potent pharmacological effect starting materials [6, 7, 11]. The best pharmacological
than (R)-(–)-carvone itself [11]. These facts led us profile arises upon addition of functional groups to the
to synthesize structurally related new (R)-(–)-carvone terpene chemical structure. The psychopharmacologi-
derivatives with pharmacological potential.
cal activity of compounds of this group must originate
c
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D. P. de Sousa et al. · Synthesis of (R)-(–)-Carvone Derivatives
Scheme 1. Reagents and con-
ditions: (a) KCN, EtOH, H2O,
acetic acid, 0 ◦C, 16 h, 90 %;
(b) NaBH4, MeOH, r. t., 5 min,
97 %; (c) TsCl, Py, 120 ◦C, 30 h,
48 %; (d) LiAlH4, diethyl ether,
0 ◦C, 10 min, 91 %.
1
from the presence of a highly lipophilic bulky frag- [α]1D8 = −4.0 (c = 1.04 in CHCl3)]. H and 13C NMR data
were in agreement with the literature [12].
ment which is capable of directly interacting with CNS
membranes containing a lipid layer, as well as with hy-
drophobic fragments of proteins. Through appropriate
structural modification of terpenes it should be possi-
ble to develop novel drugs with greater specificity in
the pharmacological action. Therefore, the new com-
pounds synthesized in this study have a high poten-
(1R, 2S, 4R, 6R)-6-Cyano-8-p-menthen-2-ol (3a) and
(1R, 2R, 4R, 6R)-6-cyano-8-p-menthen-2-ol (3b)
A 50 mL flask with a magnetic stirrer was charged with
a solution of 0.50 g (2.82 mmol) of the carbonitrile 2 in
methanol (6 mL). After addition of 0.15 g (3.95 mmol)
tial as psychoactive drugs that may have application in of sodium borohydride the reaction mixture was stirred for
5 min at r. t. After addition of CH2Cl2 (40 mL), followed by a
saturated solution of NaCl (15 mL), the mixture was washed
with water (15 mL). Filtration yielded a clear solution which
was dried over anhydrous sodium sulfate. The cyanoalcohols
3a and 3b, in a 96 : 4 ratio by gas chromatographic analy-
sis, were isolated by removal of the solvent under reduced
pressure (0.49 g, 2.73 mmol, 97 % yield). The 3a/3b mixture
was subjected to column chromatography on silica gel, elut-
ing with hexane – EtOAc (1 : 1) to afford the cyanoalcohol
3a (0.45 g, 89 % yield). Compound 3a: [α]2D7 = +2.4 (c =
2.1, CHCl3). – IR (film): ν = 3479, 2934, 2236, 1644, 993,
896 cm−1. – 1H NMR: δ = 4.80 – 4.77 (1H, m), 4.75 (1H,
s), 2.95 – 2.99 (1H, m), 2.85 (1H, td, J = 4.8 Hz, 2.8 Hz),
2.69 (1H, tt, J = 12.5 Hz, 3.0 Hz), 2.13 – 2.05 (1H, m), 1.75
(3H, s), 1.72 – 1.65 (2H, m), 1.61 (1H, s), 1.53 – 1.42 (2H,
m), 1.26 (3H, d, J = 12.2 Hz). – 13C NMR: δ = 147.8, 121.6,
109.7, 69.9, 38.1, 36.3, 33.8, 33.5, 30.4, 20.9, 16.3. – MS:
m/z = 180 [M+1]+. – Anal. for C11H17NO: calcd. C 73.70,
H 9.56, N 7.81; found C 73.62, H 9.58, N 7.79.
medical practice.
Experimental Section
General
GLC analyses were performed on a Shimadzu GC-17A
instrument equipped with a flame-ionization detector, using
a DB-1 (30 m × 0.25 mm) glass column. Column chro-
matography was performed on silica gel 60 (70 – 230 mesh
ASTM Merck). Radial thin-layer chromatography was car-
ried out on a Chromatotron model 8924 (silica gel 60PF274
Merck). Melting points were determined on a Microquim-
ica MQWAPF-301 apparatus and are uncorrected. Infrared
spectra were recorded with a Bomen Hartman & Braun MB-
Series spectrometer. 1H and 13C NMR spectra were recorded
at 200 and 50 MHz, respectively, on a Bruker ARX-200
spectrometer or at 400 and 100 MHz on a Bruker DRX-400
spectrometer, in CDCl3 with TMS as internal standard. The
mass spectra were recorded on a Micromass mass spectrom-
eter Quattro LC, coupled with a chemical ionization source
(reagent MeOH) under atmospheric pressure (APCI). Micro-
analyses were performed on a Fisons EA 1108 CHNS-O ana-
lyzer at the Chemistry Department, Universidade Federal de
Sa˜o Carlos. Solvents were purified prior to use: ethyl acetate
and hexane were refluxed over P2O5, distilled and stored
over molecular sieves; pyridine was stirred and refluxed over
KOH, distilled and stored over KOH. Tetrahydrofuran (THF)
was distilled from sodium under nitrogen.
(6R, 4S)-6-Cyano-p-mentha-1,8-diene (4)
To a solution of the cyanoalcohols 3a, b (4.00 g,
22.34 mmol) in dry pyridine (6.5 mL, 80.42 mmol) stirred
under a nitrogen atmosphere was added p-toluenesulfonyl
chloride (4.69 g, 24.58 mmol) at r. t. The solution was heated
◦
to 120 C for 30 h, and then cooled to r. t. Hexane (15 mL)
and HCl 1M solution (1.0 M solution, 20 mL) were then
added. The reaction mixture was extracted with hexane,
washed with saturated copper sulfate, water, and sodium bi-
carbonate, dried over anhydrous sodium sulfate, and concen-
trated under reduced pressure. The residue was purified by
radial chromatography (hexane – EtOAc, 90 : 10) on silica
(–)-(1R,2R,5R)-2-Methyl-5-(1ꢀ-methylvinyl)-3-oxocyclo-
hexanecarbonitrile (2)
Reaction of (R)-(–)-carvone (1) (12.50 g) with hydrogen gel to yield the pure product 4 (1.74 g, 10.80 mmol, 48 %
◦
cyanide gave nitrile 2 in 90 % yield; m. p. 91.5 – 92.2 C, yield). Compound 4: [α]2D7 = +233.0 (c = 1.5, CHCl3). –
[α]3D0 = −3.8 (c = 1.20 in CHCl3) [lit. [12]: 93 – 94 ◦C, IR (film): ν = 2922, 2237, 1645, 892 cm−1. – 1H NMR:
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D. P. de Sousa et al. · Synthesis of (R)-(–)-Carvone Derivatives
1383
δ = 5.68 – 5.64 (1H, m), 4.80 (1H, quin, J = 1.4 Hz), 4.74 was formed. Filtration yielded a clear ether solution which
(1H, quin, J = 0.8 Hz), 3.15 – 3.10 (1H, m), 2.54 – 2.35 (1H, was washed with water (20 mL) and dried over anhydrous
m), 2.23 – 2.07 (2H, m), 1.84 – 1.82 (3H, m), 1.79 – 1.72 (2H, sodium sulfate. The free amine was isolated by removal of
m), 1.76 (3H, s). – 13C NMR: δ = 147.5, 126.9, 126.1, the ether under reduced pressure (0.38 g, 2.32 mmol, 91 %
120.9, 109.7, 37.1, 31.6, 30.8, 30.1, 21.7, 20.7. – MS: m/z = yield). Compound 5: [α] = +88.3 (c = 1.2, CHCl3). – IR
162 [M+1]+. – Anal. for C11H15N: calcd. C 81.94, H 9.38, (film): ν = 3376, 2922, 1644, 1037, 887 cm−1. – 1H NMR:
N 8.69; found C 82.01, H 9.40, N 8.66.
δ = 5.48 – 5.44 (1H, m), 4.72 (2H, t, J = 0.9 Hz), 2.88 (1H,
dd, J = 13.0 Hz, 3.4 Hz), 2.61 (1H, dd, J =12.7 Hz, 9.2 Hz),
2.25 – 2.13 (1H, m), 2.24 – 2.13 (1H, m), 2.04 (2H, s), 1.94 –
1.82 (2H, m), 1.74 (3H, s), 1.48 (3H, s), 1.45 – 1.37 (2H,
m). – 13C NMR: δ = 149.7, 134.2, 122.9, 108.5, 43.9, 43.0,
36.0, 30.9, 29.3, 22.0, 20.7. – MS: m/z = 166 [M+1]+. –
Anal. for C11H19N: calcd. C 79.94, H 11.59, N 8.47; found
C 79.88, H 11.62, N 8.49.
(6R, 4S)-6-Aminomethylene-p-mentha-1,8-diene (5)
A dry, nitrogen-purged, 50 mL three-necked flask with a
magnetic stirrer was charged with a suspension of lithium
aluminum hydride (0.19 g, 5.15 mmol) in anhydrous ether
(6.2 mL). A solution of 0.41 g (2.57 mmol) of nitrile 4 in
ether (6.2 mL) was added dropwise over 10 min to this sus-
pension maintained at 0 ◦C, and the stirring was continued for
further 10 min. Destruction of the excess lithium aluminum
hydride was completed by cautious dropwise addition of wa-
ter (6 mL), 15 % NaOH (6 mL) and again water (18 mL).
Stirring was continued until a granular colorless precipitate
Acknowledgements
We thank FAPESP, CNPq and CAPES for financial sup-
port. (R)-(–)-carvone was generously donated by Firmenich
S.A.
[1] Y. M. H. Younis, S. M. Beshir, J. Essent. Oil Res. 2004,
16, 539 – 541.
[2] J. Buckingham (Ed.), Dictionary of Natural Products,
Vol. 4, Chapman & Hall, London, 1994, p. 3824.
[3] T. L. Ho, Enantioselective Synthesis: Natural Products
from Chiral Terpenes, Wiley, New York, 1992, chapter
6, pp. 123 – 125.
[4] X. Liang, W. Fang, Medicinal Chemistry of Bioactive
Natural Products, Wiley Hoboken, NJ, 2006.
[5] T. J. Brocksom, U. Brocksom, D. P. De Sousa, D. Fred-
erico, Tetrahedron: Asymmetry 2005, 16, 3628 – 3632.
[6] D. P. De Sousa, E. Raphael, U. Brocksom, T. J. Brock-
som, Biol. Pharm. Bull. 2004, 27, 910 – 911.
[7] F. S. Oliveira, D. P. De Sousa, R. N. De Almeida, Biol.
Pharm. Bull. 2008, 31, 588 – 591.
[8] D. P. De Sousa, F. S. Oliveira, R. N. De Almeida, Biol.
Pharm. Bull. 2006, 29, 811 – 812.
[9] D. P. De Sousa, R. R. Schefer, U. Brocksom, T. J.
Brocksom, Molecules 2006, 11, 148 – 155.
[10] D. P. De Sousa, E. V. M. Ju´nior, F. S. Oliveira, R. N.
Almeida, X. P. Nunes, J. M. Barbosa-Filho, Z. Natur-
forsch. 2007, 62c, 39 – 42.
[11] D. P. de Sousa, F. F. F. No´brega, R. N. de Almeida, T. J.
Brocksom, Z. Naturforsch. 2009, 64b, 351 – 355.
[12] W. Cocker, D. H. Grayson, P. V. R. Shannon, J. Chem.
Soc., Perkin Trans. 1 1995, 1153 – 1162.
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