Concise synthesis of valerena-4,7(11)-diene, a highly active sedative, from valerenic acid

Article abstract of DOI:10.1271/bbb.100297

A concise synthesis of valerena-4,7(11)-diene with potent sedative activity was achieved in three steps involving, reduction of carboxylic acid, bromination of the resulting alcohol, and reduction of the bromide from valerenic acid in a 63% total yield. This synthetic method makes it possible to provide further materials for biological testing to realize comprehensive SAR studies.

Full text of DOI:10.1271/bbb.100297

Biosci. Biotechnol. Biochem., 74 (9), 1963–1964, 2010
Note
Concise Synthesis of Valerena-4,7(11)-diene, a Highly Active Sedative,
from Valerenic Acid
y
2
Takashi KITAYAMA,1; Genki KAWABATA,1 and Michiho ITO
1Department of Advanced Bioscience, Graduate School of Agriculture, Kinki University, Nara 631-8505, Japan
2Department of Pharmacognosy, Graduate School of Pharmaceutical Science, Kyoto University,
Kyoto 606-8501, Japan
Received April 19, 2010; Accepted May 31, 2010; Online Publication, September 7, 2010
[doi:10.1271/bbb.100297]
A concise synthesis of valerena-4,7(11)-diene with
potent sedative activity was achieved in three steps
involving, reduction of carboxylic acid, bromination of
the resulting alcohol, and reduction of the bromide from
valerenic acid in a 63% total yield. This synthetic
method makes it possible to provide further materials
for biological testing to realize comprehensive SAR
studies.
studies can become a reality.
Valerenic acid 2, which has been isolated as the main
component of Valeriana officinalis and previously
synthesized by Mulzer et al.5) and Altmann et al.,6)
`
was purchased from EXTRASYNTHESE (France) as an
optically active compound (½ꢀꢀD ꢁ115ꢂ (c 0.13, CHCl3).
2 has tranquilizing and/or sedative activity from animal
experiments,7) and the activation of adenosine receptors
has been implicated in the action of valerian ingre-
dients.8) We present here the first concise synthesis of
valerena-4,7(11)-diene 1 from valerenic acid 2 as the
starting material via the reduction of ꢀ,ꢁ-unsaturated
carboxylic acid to allylic alcohol with LiAlH4, bromi-
nation of the resulting primary alcohol with CBr4/PPh3,
and reduction of the bromide with super hydride.
Scheme 1 shows how the concise synthesis of target
compound 1 was achieved in three steps from valerenic
acid 2.
Key words: valerena-4,7(11)-diene; valerenic acid; sed-
ative activity; sesquiterpene
Valerena-4,7(11)-diene ((2S,5R,6R)-5,9-dimethyl-2-
(2-methyl-1-propenyl)bicyclo[4.3.0]non-1(9)-ene, 1) as
shown in Fig. 1, has been isolated in a small quantity
from the roots of Nardostachys chinensis1,2) and Valeri-
ana officinalis L.,3,4) and is a bicyclic sesquiterpene that
has recently been shown to dose-dependently reduce the
locomotor activity of mice with a particularly profound
effect, the strongest sedative activity being observed at a
dose of 0.06%.1)
Treatment of valerenic acid 2 with LiAlH4 (LAH) at
0 ꢂC for 3 h gave valerenol 3 in a 93% yield without
reduction of the conjugated olefin.9) Alcohol 3 was
reacted with triphenylphosphine and then exposed to
tetrabromomethane at ꢁ10 ꢂC for 45 min to afford 4 in
an 83% yield. Bromide 4 was converted to desired
compound 1 as soon as possible since 4 easily decom-
posed. Bromide 4 was reacted with LiBHEt3 at ꢁ20 ꢂC
for 1 h to afford target compound 1 in an 82% yield.
Compound 1 showed a minus sign for its specific
rotation which is consistent with the natural product.3)
1
9
2
6
H
1
1
The H-NMR spectrum of synthetic compound 1 was
also completely consistent with the natural product.3)
Characteristic peaks of one olefin and two allylic
protons at the C2 and C6 positions were clearly
observed. The first concise synthesis of 1 was therefore
achieved in three steps from valerenic acid in a 63%
total yield to provide further material for biological
testing. The synthetic route should be applicable to a
variety of derivatives that would be suitable for SAR
investigation. Various derivatives of valerena-4,7(11)-
diene 1 for SAR could be synthesized by introducing
nucleophilic agents including oxygen, nitrogen, and a
sulfur group, and by extending the carbon chain on the
allylic position by using reactive allyl bromide inter-
mediate 4, in addition to converting to carboxylic acid
derivatives by using valerenic acid. We believe that the
development of novel active sedatives might quickly
become possible from the results of this study.
Fig. 1. Valerena-4,7(11)-diene 1.
The unique aspect for the pharmacological activity of
this compound is that it can be administered via
inhalation; the compound is naturally volatile at room
temperature and bears a pleasant smell.1) It may hope-
fully be developed as a less-harmful remedy for
attention deficit hyperactivity disorder (ADHD) and
for the confused elderly. An efficient total synthesis
of 1 therefore appears to be of importance, as more
extensive and elaborate structural variations are envis-
aged. Structure-activity relationship (SAR) studies of
this natural product would not only be able to elucidate
the intrinsic mechanism of action, but would also open a
new avenue for exploring the possible mode of action of
this compound. However, an efficient method for
synthesizing 1 is required before comprehensive SAR
y
To whom correspondence should be addressed. Tel: +81-742-43-7415; Fax: +81-742-43-8976; E-mail: kitayama@nara.kindai.ac.jp

1964
T. KITAYAMA et al.
HO
Br
CO2H
LAH / dry THF
-0oC, 3h
PPh3, CBr4 / CH2Cl2
-10oC, 45 min
H
H
H
Valerenic acid 2
3 (93%)
4 (83%)
LiEt3BH / dry THF
-0oC, 1h
H
Valerena-4,7(11)-diene 1 (82%)
Scheme 1.
42.5, 47.4, 129.8, 130.3, 132.8, 134.4. HRMS (M-Br) m=z: calcd. for
C15H23, 203.1800; found, 203.1823.
Experimental
Column chromatography was performed on silica gel (70–230
mesh), and TLC was performed on Merck 60 F254 silica gel plates.
NMR spectra were recorded by a Bruker instrument at 400 MHz for
protons, and at 100 MHz for 13C in CDCl3, with tetramethylsilane
(TMS) used as the internal standard. Chemical shifts (ꢂ) are reported in
parts per million (ppm) from TMS. Mass spectra were recorded at
70 eV, and high-resolution mass spectra (HRMS) were obtained by
direct injection. Optical rotations were measured by a Jasco DIP-140
polarimeter. All chemicals were of commercially available reagent
grade and were without further purification.
(2S,5R,6R)-5,9-Dimethyl-2-(2-methyl-1-propenyl)bicyclo[4.3.0]non-
1(9)-ene (valerena-4,7(11)-dinene 1). LiBHEt3 (125 ml, 12:5 ꢃ 10ꢁ2
mmol) was added dropwise to a solution of 4 (174.7 mg, 6:3 ꢃ 10ꢁ2
mmol) in absolute THF (1.0 ml) at 0 ꢂC in an N2 atmosphere, and the
mixture was stirred for 1 h in an ice-salt bath. Water (5 ml) was added
to the solution at ꢁ20 ꢂC and the mixture was extracted with hexane
(3 ꢃ 10 ml). The combined organic solution was washed with brine
(3 ꢃ 20 ml), dried over Na2SO4, and concentrated on
a rotary
evaporator. The resulting residue was subjected to silica gel column
chromatography, using hexane as the eluent, to afford valerena-
(2S,5R,6R)-5,9-Dimethyl-2-(3-hydroxy-2-methyl-1-propenyl)bicy-
clo[4.3.0]non-1(9)-ene (Valerenol) (3). Valerenic acid 2 (36 mg,
0.15 mmol) in absolute THF (2 ml) was added dropwise to a suspension
of LiAlH4 (41 mg, 1.1 mmol) in absolute THF (2 ml) at 0 ꢂC in an N2
atmosphere, and the mixture was stirred for 3 h in an ice-salt bath. Cold
water (10 ml) was added, and the mixture was extracted with AcOEt
(3 ꢃ 30 ml). The combined organic solution was washed with brine
23:5
4,7(11)-diene 1 as a colorless oil in an 82% (10.4 mg) yield. ½ꢀꢀ
D
ꢁ6.2ꢂ (c 0.13, CHCl3); NMR ꢂH (CDCl3): 0.75 (3H, d, J ¼ 7:0 Hz,
CH3 at C5), 1.27–1.37 (2H, m, 2CH at C3 and C4), 1.48–1.57 (2H, m,
CH at C7), 1.63 (3H, s, CH3 at C9), 1.66 (3H, s, CH=C(CH3)2), 1.69
(3H, s, CH=C(CH3)2), 1.69–1.88 (2H, m, 2CH at C3 and C4), 1.92–
1.99 (1H, m, CH at C5), 2.15–2.22 (2H, m, CH at C8), 2.88–2.97 (1H,
m, CH at C6), 3.4 (1H, m, CH at C2), 5.46 (1H, d, J ¼ 9:3 Hz,
CH=C(CH3)2); NMR ꢂC (CDCl3): 12.1, 13.4, 17.8, 24.6, 26.1, 26.6,
28.7, 33.6, 33.6, 37.5, 47.4, 126.2, 128.4, 129.8, 136.0.
(3 ꢃ 30 ml), dried over Na2SO4, and concentrated on
a rotary
evaporator. The resulting residue was subjected to silica gel column
chromatography using AcOEt and hexane (1:8) as the eluent, to afford
valerenol 3 as a colorless oil in a 94% (31.4 mg) yield. NMR ꢂH
(CDCl3): 0.77 (3H, d, J ¼ 7:0 Hz, CH3 at C5), 1.27–1.40 (2H, m, 2CH
at C3 and C4), 1.49-1.58 (1H, m, CH at C7), 1.64 (3H, s, CH3 at C9),
1.72 (3H, s, CH=C(CH3)CH2OH), 1.76–1.89 (3H, m, 3CH at C3, C4,
and C7), 1.94–2.00 (1H, m, CH at C5), 2.19 (2H, t, J ¼ 7:6 Hz, CH2 at
C8), 2.89–2.95 (1H, m, CH at C6), 3.45 (1H, m, CHCH=
C(CH3)CH2OH), 4.00 (2H, s, CH=C(CH3)CH2OH), 5.75 (1H, d,
J ¼ 9:3 Hz, CH=C(CH3)CH2OH); NMR ꢂC (CDCl3): 12.0, 13.4, 13.7,
24.5, 26.2, 28.7, 33.2, 33.4, 37.5, 47.4, 69.3, 127.7, 129.1, 133.1, 135.2.
(2S,5R,6R)-5,9-Dimethyl-2-(3-bromo-2-methyl-1-propenyl)bicy-
clo[4.3.0]non-1(9)-ene (4). Triphenylphosphine (52.3 mg, 0.2 mmol)
was added to a solution of valerenol 3 (31.4 mg, 0.14 mmol) in absolute
CH2Cl2 (0.7 ml) at ꢁ10 ꢂC in an N2 atmosphere, and the mixture was
stirred for 3 min in an ice-salt bath. Carbon tetrabromide (56.7 mg,
0.17 mmol) was added to the mixture at the same temperature, and
stirring was continued for 45 min. CH2Cl2 was removed by a rotary
evaporator, pentane (2 ml) was added to the residue, and the mixture
was stirred at room temperature for 5 min. The mixture was finally
subjected to silica gel column chromatography using pentane as the
eluent, to afford (2S,5R,6R)-5,9-dimethyl-2-(3-bromo-2-methyl-1-
propenyl)bicyclo[4.3.0]non-1(9)-ene 4 as a light yellow oil in an
83% (33 mg) yield. NMR ꢂH (CDCl3): 0.75 (3H, d, J ¼ 7:0 Hz, CH3 at
C5), 1.32–1.42 (2H, m, 2CH at C3 and C4), 1.49–1.58 (1H, m, CH at
C7), 1.62 (3H, s, CH3 at C9), 1.64–1.80 (2H, m, 2CH at C3 and C4),
1.80 (3H, d, J ¼ 1:3 Hz, CH=C(CH3)CH2Br), 1.82–1.85 (1H, m, CH
at C7), 1.94–2.00 (1H, m, CH at C5), 2.19 (2H, t, J ¼ 7:6 Hz, CH at
C8), 2.85–2.90 (1H, m, CH at C6), 3.39 (1H, m, CH at C2), 3.98 (2H,
s, CH=C(CH3)CH2Br), 5.89 (1H, d, J ¼ 9:2 Hz, CH=C(CH3)CH2Br);
NMR ꢂC (CDCl3): 12.0, 13.4, 14.7, 24.6, 25.8, 28.7, 33.3, 33.9, 37.5,
Elemental Analysis. Found: C, 88.27; H, 11.73%. Calcd. for
C15H24: C, 88.16; H, 11.84%.
Acknowledgments
We are grateful to Mr. Ken Kondo for the HRMS
measurements.
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