Antiparkinsonian activity of some 9-N-, O-, S- and C-derivatives of 3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol

Article abstract of DOI:10.1016/j.bmc.2013.01.003

Earlier it was found, that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex- 3-ene-1,2-diol (1) possess high antiparkinsonian activity. The N-, O-, S- and C-derivatives at the C-9 position of diol 1 were synthesized in this work. The antiparkinsonian activity of these compounds was studied in MPTP mice models. As a rule, the introduction of substituents containing nitrogen atoms at the C-9 position led to a considerable decrease or loss of antiparkinsonian activity. A derivative of 2-aminoadamantane 8 significantly decreased the locomotor activity time, thus enhancing the symptoms of the parkinsonian syndrome. However the introduction of butyl or propylthio substituents at the C-9 position of diol 1 did not diminish the antiparkinsonian activity comparing to parent compound. This information is important when choosing a route for immobilization of compound 1 to find possible targets.

Full text of DOI:10.1016/j.bmc.2013.01.003

Bioorganic & Medicinal Chemistry 21 (2013) 1082–1087
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Antiparkinsonian activity of some 9-N-, O-, S- and C-derivatives
of 3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol
⇑
Oleg V. Ardashov, Alla V. Pavlova, Dina V. Korchagina, Konstantin P. Volcho , Tat’yana G. Tolstikova,
Nariman F. Salakhutdinov
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Earlier it was found, that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (1) possess
high antiparkinsonian activity. The N-, O-, S- and C-derivatives at the C-9 position of diol 1 were synthe-
sized in this work. The antiparkinsonian activity of these compounds was studied in MPTP mice models.
As a rule, the introduction of substituents containing nitrogen atoms at the C-9 position led to a consid-
erable decrease or loss of antiparkinsonian activity. A derivative of 2-aminoadamantane 8 significantly
decreased the locomotor activity time, thus enhancing the symptoms of the parkinsonian syndrome.
However the introduction of butyl or propylthio substituents at the C-9 position of diol 1 did not diminish
the antiparkinsonian activity comparing to parent compound. This information is important when choos-
ing a route for immobilization of compound 1 to find possible targets.
Received 31 October 2012
Revised 24 December 2012
Accepted 3 January 2013
Available online 11 January 2013
Keywords:
(1R,2R,6S)-3-Methyl-6-
(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol
Monoterpenoid
Ó 2013 Elsevier Ltd. All rights reserved.
Derivatives
Antiparkinsonian activity
MPTP model
Mice
1. Introduction
and amantadine, thereby normalizing the patient symptomati-
cally.3,6,9 Nevertheless
L-DOPA (L-3,4-dihydroxyphenylalanine)
Parkinson’s disease (PD) is the second most common progres-
sive, neurodegenerative disorder, affecting approximately four
million people worldwide, and this is expected to double by
2030.1,2 PD is an age-related neurodegenerative disease, being pri-
marily a disease of elderly persons.3–5 Thus, about 2% of people
over 65 years of age and 4–5% of people over 85 are sufferers of
PD.3 This is an incurable disease with extensive involvement of
motor behavior as well as widespread cognitive, emotional and
mood disturbances.6 The major clinical diagnostic criteria for PD
are tremor, rigidity, akinesia, postural instability, and bradyphre-
nia.5,7,8 Currently, the only therapies approved for the treatment
of PD are agents that attenuate the symptoms of the disease. PD
treatment focuses on the replacement of lost dopamine (DA) with
continues to be the most effective pharmacological treatment
strategy, which counteracts most of the major motor symptoms
of PD. L-DOPA therapy often has to be curtailed, because of the
development of debilitating, treatment-limiting adverse effects,
including ‘wearing-off’ phenomena and other motor complica-
tions such as dyskinesia.2
Recently,10,11 we found that (1R,2R,6S)-3-methyl-6-(prop-1-
en-2-yl)cyclohex-3-ene-1,2-diol 1 displayed a potent antiparkin-
sonian activity in animal MPTP and haloperidol models of PD.
The compound possessed low acute toxicity, its LD50 being
4250 mg/kg.10 It was found that a pronounced antiparkinsonian
effect of 1 could be only achieved if it contained all the four func-
tional groups (two hydroxy groups and two double bonds).12
While studying the effect of chemical modification on the anti-
parkinsonian activity, therefore, we decided to leave the hydroxyl
groups and double bonds of molecule 1 intact, using methyl
groups as modification sites. The goal of this work was to synthe-
size and investigate the antiparkinsonian activity of the deriva-
tives of diol 1 modified at the C-9 position. Modification of the
compound at this position can substantially affect its pharmaco-
logical activity and stimulate the development of approaches to
immobilization of 1 without loss of activity for identification of
possible targets.
L-DOPA therapy, DA agonists, treatment with monoamine
oxidase (MAO) B and catechol-O-methyltransferase inhibitors,
Abbreviations: CC, column chromatography; DMF, dimethylformamide; DMSO,
dimethylsulfoxide; L-DOPA, L-3,4-dihydrophenylalanine; MAO, monoamine oxi-
dase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NBS, N-bromosuccin-
imide; PD, Parkinson’s disease; r.t., room temperature.
⇑
Corresponding author. Tel.: +7 3833308870; fax: +7 3833309752.
E-mail address: volcho@nioch.nsc.ru (K.P. Volcho).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.01.003

O. V. Ardashov et al. / Bioorg. Med. Chem. 21 (2013) 1082–1087
1083
obtained by the reaction of bromide 2 with 2-aminoadamantane
hydrochloride in CHCl3 for 4 days. NEt3 was used as a base. The
preparative yield of 8 was 76%. One more N-derivative 9 was ob-
tained by the reaction of 2 with N1,N1-dimethylethane-1,2-diamine
in 27% yield. The yield was less than in the cases of compounds 7
and 8 due to competitive alkylation of tertiary N-atom in the re-
agent and in the product 9.
Further, when n-BuLi was used as a reagent, the reaction in THF
performed for 1 day gave the corresponding butyl derivative 10
with a 18% yield and heterocyclization product 11 with a 15% yield
(Scheme 1).
2. Results and discussion
2.1. Chemistry
Compound 1 has ten allylic protons, which substantially hinder
the choice of selective methods. One of the widely used methods
for modification of natural compounds at the allylic positions is
their oxidation with SeO2.13–15 It appeared, however, that for diol
1 oxidation with SeO2 was not selective; according to GLC data,
the reaction mixture contained four major products in approxi-
mately equal amounts and a set of minor products.
Finally, S-derivative 12 was obtained by the reaction with
n-PrSNa in EtOH in 58% yield.
Allylic bromination of diol 1 was more selective probably for
steric reasons. The reaction of 1 with NBS in CCl4 in the presence
of (t-BuO)2 under reflux for 3 h followed by the application of the
mixture to a SiO2 column (without water treatment) and chroma-
tography gave bromide 2 with a 34% yield (Scheme 1). For compar-
ison, after the standard treatment of the reaction mixture (washing
with a Na2SO3 solution, drying of the organic phase, subsequent
concentration, and separation by column chromatography) the
yield of bromide 2 was only 10%. Note that using 1,2-diacetate in-
stead of diol 1 in allylic bromination led to lower selectivity and to
the formation of a complex mixture of products.
Analogous reaction of bromide 2 with n-PrONa in dioxane led
only to the formation of 11 with the 55% yield. Of course the pro-
tection groups may be used in this case but the use of sequence
‘protection–deprotection’ is not convenient for immobilization
procedure.
Thus a series of N-, O-, C-, and S-derivatives of diol 1 at the C-9
position were synthesized for the first time.
2.2. Pharmacology
The reaction of bromide 2 with NaOAc in aqueous DMSO gave
acetate 3 with a 72% yield. Saponification of acetate 3 with an
aqueous methanol solution of NaOH led to the formation of triol
4 with a 76% yield. The overall yield of triol 4 based on the starting
diol 1 was 19% in three steps (Scheme 1).
In animal studies, neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetra-
hydropyridine (MPTP) is commonly used to create experimental
model of PD, which may be used to model certain aspects of the
disease, such as catalepsy, motor imbalance, and slowing of move-
ment.18 MPTP produces a statistically significant different and
reproducible lesion of the nigrostriatal dopaminergic pathway
after its systemic administration and is the only known dopami-
nergic neurotoxin capable of causing a clinical picture in humans
indistinguishable from PD.19
We studied the antiparkinsonian activity of the compounds 1,
4–12 (Scheme 1) in accordance with MPTP mouse model of Parkin-
son’s disease published in Nature protocols.19 It involves one injec-
tion of MPTP (20 mg/kg per dose) to mice of C57Bl/6 line every 2 h
for a total of 4 doses over a 6 h period in 1 day. The studied agents
were administered per os 24 h after the last injection of MPTP in a
dose of 20 mg/kg. The main markers of the locomotor activity were
measured 2 h after the administration of the agent with the ‘Open
The amino derivative 5 was synthesized by Gabriel’s proce-
dure16 via the corresponding phthalimide 6. The reaction of
bromide 2 with potassium phthalimide in DMF for 1 day gave com-
pound 6 with a 78% yield after column chromatography. Attempts
to convert this product into amino derivative 5 by the standard
procedure17 failed even when using
a large excess of the
commonly used reagent N2H4 ꢀ H2O which gave only the starting
compound 6 in all cases. We showed that ethylenediamine is an
effective reagent for removing the phthalate group. The reflux of
compound 6 with ethylenediamine in a CHCl3/EtOH (2:1) for 4 h
gave the desired product 5 with a 93% yield (Scheme 1).
The reaction of bromide 2 with morpholine in CHCl3 for 2 days
led to compound 7 with a 63% yield (Scheme 1). Compound 8 was
OH
OH
OH
OH
OH
NaOH,
H2N
CHCl3/EtOH (2:1),
,
NH2
MeOH, H2O,
24 h
OH
OH
O
OH
OH
N
12
16
13
11
11
O
NH2
17
18
15
14
reflux, 4 h
4
3
6
5
O
72%
12
76%
78%
O
93%
NaOAc,
O
DMSO/H2O,
DMF,
24 h
HO
2
KN
24 h
OH
,
H
10
10
2
O
O
1
3
4
+
14
3
4
8
7
OH
OH
OH
NBS,
(t-BuO)2,
OH
6
5
12
1OH
11
13
THF,
24 h
H
6
n-BuLi,
5
9
10
18%
11
15%
CCl4,
reflux, 3 h
9
Br
7
8
1
2
34%
H3N
Cl
NEt3, CHCl3,
N
SNa
,
,
H2N
HN
CHCl3, 2 d.
OH
OH
N11
O
,
CHCl3, 20 h
EtOH, 20 h
,
OH
OH
OH
OH
OH
4 d.
17
12
OH
12
16
15
13
N11
12 N 13
11
13
S
17
12
O
HN
12 14
13
7
8
76%
11
13
12
14
H
9
14
63%
27%
58%
Scheme 1. Synthesis of compounds 2–12.

1084
O. V. Ardashov et al. / Bioorg. Med. Chem. 21 (2013) 1082–1087
Table 1
Study of the antiparkinsonian activity of compounds 1, 4–12 in C57Bl/6 mice
Group
Time of locomotor activity (s)
Movement distance (cm)
Movement speed (cm/s)
Immobility time (s)
Saline
MPTP
72.4 2.6
56.2 3.2**
69.2 4.2#
53.5 7.1
58.3 4.4
48.5 6.7
34.8 9.0#
63.2 2.6
46.6 6.5
68.1 2.3
26.1 8.0***
37.2 10.7
66.9 5.1
37.3 6.2**
51.2 3.3
61.4 3.5##
372.1 27.2
241.1 20.7**
302.0 17.4#
248.6 36.8
280.0 32.4
215.3 34.5
149.7 42.8
335.2 29.5#
214.0 38.5
337.5 16.5
106.0 37.0***
182.1 55.2
343.7 43.7
145.0 26.8**
225.0 20.9#
317.6 26.6###
3.1 0.2
2.0 0.2**
2.6 0.1#
2.0 0.3
2.3 0.3
1.7 0.3
1.2 0.4
2.7 0.3#
1.7 0.3
2.8 0.1
0.8 0.3***
1.5 0.5
2.8 0.4
1.2 0.2**
1.8 0.2#
2.6 0.2###
47.6 2.6
63.8 3.2**
50.8 4.2#
66.5 7.1
61.7 4.4
71.5 6.8
85.2 9.0#
56.8 2.7
73.4 6.5
51.9 2.3
93.9 7.9***
80.0 1.2
53.1 5.1
82.7 6.2**
68.8 3.3
58.6 3.5##
MPTP and 1
MPTP and 5
MPTP and 6
MPTP and 7
MPTP and 8
MPTP and 10
MPTP and 11
Saline
MPTP
MPTP and 4
Saline
MPTP
MPTP and 9
MPTP and 12
⁄P <0.05.
**
P <0.01.
***
#
P <0.001 statistically significant different in comparison with saline group.
P <0.05.
P <0.01.
##
###
P <0.001 statistically significant different in comparison with MPTP group.
field’ test for 2 min. The effectiveness of the studied medication
was evaluated according to its ability to reduce the symptoms of
hypokinesia induced by MPTP.
Thus the introduction of a substituent at the C-9 position differ-
ently affected the antiparkinsonian activity of the agents. Almost
all of the nitrogen-containing derivatives synthesized in this study,
namely, the amino derivative (5) and the derivatives of morpholine
(7) and phthalimide (6), did not exhibit statistically significant dif-
ferent results for any of the given activity parameters. An exception
were dinitrogen containing compound 9, which partly restored the
locomotor activity, and the derivative of 2-aminoadamantane 8,
which caused an increase of the neurotoxin action.
The introduction of a hydroxyl group at the C-9 position of diol
1 led to a significant decrease in the antiparkinsonian activity in
comparison with parent compound 1. Moreover, heterocyclization
product 11 worked in the opposite direction, appreciably decreas-
ing the locomotor activity of animals. This confirms the importance
for diol 1 to contain hydroxy group in the 1st position, found
earlier.12
The n-Bu and n-PrS derivatives 10 and 12 were the most active
among the synthesized 9-derivatives of diol 1. According to Table 1,
the compounds substantially increased the distance and the move-
ment rate, restoring all locomotor activity markers at the level
close to that of saline treated animals and showing nearly the same
level of efficiency as diol 1.
From the data obtained it may be supposed that the interaction
of bromide 2 with thiol with long aliphatic chain may be used for
immobilization of diol 1 without lost of the antiparkinsonian
activity.
Four administrations of MPTP led to a considerable effect on the
locomotor activity of animals (Table 1): the locomotor activity
time, the movement distance and the movement speed decreased,
while the immobility time increased. The administration of 1 along
with MPTP neurotoxin injections led to a significant recovery of the
parameters of the locomotor activity of animals. Compounds 4, 9
and 12 were studied in other series of experiments; data for the
saline treated and MPTP groups for these compounds are given
separately in the Table 1.
When amino derivative 5 was administrated, none of the given
locomotor activity parameters deviated from those in the MPTP
group. Similar results were obtained for phthalimide 6. An insignif-
icant difference was an increase in the mean of movement dis-
tance, but differences from the MPTP group were not statistically
significant different. For compound 7, having a morpholine substi-
tuent, all the four markers of the locomotor activity were worse
than those in the MPTP group, but the differences were not statis-
tically significant different again.
Compound 8 (a derivative of 2-aminoadamantane) produced a
more significant effect. This compound considerably decreased
the locomotor activity time, thus enhancing the symptoms of the
parkinsonian syndrome. The distance and the movement speed de-
creased markedly, through not statistically significant different.
Another nitrogen containing derivative, compound 9, markedly
increased movement distance and speed of the animals but the
values were far from the ones in the saline treated group.
Administration of compound 10 statistically significant differ-
ent increased the distance and movement speed of animals almost
to the level exhibited by saline treated animals. The locomotor
activity time was also increased, although changes in this parame-
ter was not statistically significant different.
3. Conclusion
As a result of our studies, we elaborated a procedure for selec-
tive modification of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclo-
hex-3-ene-1,2-diol (1) at the C-9 position, which allowed us to
synthesize a series of N-, O-, S- and C-derivatives of diol 1. Studies
of the antiparkinsonian activity of the resulting compounds on
mice using the MPTP model showed that the introduction of sub-
stituents containing heteroatoms at the C-9 position led to a loss
of the antiparkinsonian activity except triol 4 and containing two
nitrogen atoms compound 9 which partly restored motion markers
of the animals. At the same time, this compound retained its high
antiparkinsonian activity when an aliphatic or thioaliphatic substi-
tuent was introduced at the C-9 position of diol 1. This information
The heterocyclic analog of triol 4, compound 11, produced an
opposite effect, reducing the locomotor activity of animals sub-
stantially, though not statistically significant different.
Finally, the best results were achieved when using compound
12, which is the sulfur containing derivative of diol 1. Administra-
tion of compound 12 led to the restoration of all the four markers
of the locomotor activity of the mice.

O. V. Ardashov et al. / Bioorg. Med. Chem. 21 (2013) 1082–1087
1085
is extremely important for choosing the route for immobilization
of compound 1 to find possible targets.
reaction mixture was stirred for 24 h at rt and then transferred
to a saturated NaCl solution (150 ml). The product was extracted
with ethylacetate (4 ꢀ 30 ml). The combined extracts were dried
over Na2SO4. The solvent was evaporated. The residue was purified
by CC on silica gel (4.5 g) using 0–100% ethylacetate gradient in
4. Experimental section
hexane as eluent. This gave 3 (0.075 g, 0.36 mmol, 72%). ½a D18
ꢂ
4.1. General chemical methods
ꢃ50.6 (c 0.77, CHCl3). 1H NMR (CDCl3 + CCl4 (1:1), dH): 1.74 (3H,
m; all J 6 2.5 Hz, H-10), 1.99 (1H, dddq; 2J 17.5, J5e,6a 5.3, J5e,4 4.5,
J5e,10 1.5 Hz, H-5e), 2.04 (3H, s; H-12), 2.22 (1H, dddqd; 2J 17.5,
J5a,6a 10.0, J5a,4 2.8, J5a,10 2.5, J5a,2e 1.1 Hz, H-5a), 2.50 (1H, dddd;
J6a,5a 10.0, J6a,5e 5.3, J6a,1e 2.1, J6a,8 0.7 Hz, H-6a), 2.53 and 2.85
(2H, br s; 2 OH), 3.76 (1H, br d; J2e,1e 3.3 Hz, H-2e), 3.81 (1H, dd;
J1e,2e 3.3, J1e,6a 2.1 Hz, H-1e), 4.55 (1H, d; 2J 13.6 Hz, H-9) and
Reagents and solvents were purchased from commercial suppli-
ers and used as received. Dry solvents were obtained according to
the standard procedures. GC: 7820A gas chromatograph (Agilent
Tech., USA); flame-ionization detector; HP-5 capillary column
(0.25 mmol Ø ꢀ 30 m ꢀ 0.25
lm), He as carrier gas (flow rate
2 ml/min, flow division 99:1). Optical rotation: polAAr 3005 spec-
trometer; CHCl3 soln. 1H and 13C NMR spectra/Bruker DRX-500
apparatus at 500.13 MHz (1H) and 125.76 MHz (13C) in CCl4/CDCl3
1:1 (v/v), CDCl3 or CDCl3 + CD3OD (ꢁ10:1); chemical shifts d in
ppm rel to residual CHCl3 [d(H) 7.24, d(C) 76.90 ppm], J in Hz.
The structure of the products was determined by analyzing the
1H and 13C NMR spectra, 1H,1H double-resonance spectra and
13C,1H-type 2D-COSY (J(C,H) = 160 Hz). HR-MS: DFS Thermo
Scientific spectrometer in a full scan mode (15–500 m/z, 70 eV
electron impact ionization, direct sample administration). Spectral
and analytical investigations were carried out at Collective Chem-
ical Service center of Siberian Branch of Russian Academy of Sci-
ences. Column chromatography (CC) was performed on silica gel
2
4.60 (1H, d; J 13.6 Hz, H-90)—AB-system, 5.06 (1H, br s; H-8),
5.13 (1H, br s; H-80), 5.55 (1H, ddq; J4,5e 4.5, J4,5a 2.8, J4,10 1.4 Hz,
H-4). 13C NMR, dC:71.95 (d; C-1), 72.03 (d; C-2), 132.11 (s; C-3),
124.43 (d; C-4), 25.21 (t; C-5), 36.95 (d; C-6), 144.42 (s; C-7),
113.27 (t; C-8), 66.33 (t; C-9), 20.59 (q; C-10), 170.67 (s; C-11),
20.79 (q; C-12). HR-MS: 208.1096 (M+, C12H16O3; Calc. 208.1094).
4.4. (1R,2R,6S)-6-(3-Hydroxyprop-1-en-2-yl)-3-methylcyclohex-
3-ene-1,2-diol (4)
A mixture of acetate 3 (0.052 g, 0.25 mmol), NaOH (0.146 g,
3.65 mmol), H2O (0.5 ml), and MeOH (5 ml) was stirred for 1 day
at rt. The reaction mixture was diluted with H2O (10 ml). MeOH
was evaporated under reduce pressure. The residual water phase
was saturated with NaCl. The product was extracted with ethylace-
tate (5 ꢀ 10 ml). The combined extracts were dried over Na2SO4.
The solvent was distilled off. The residue was purified by CC on sil-
ica gel (4.5 g) using 0–100% ethylacetate gradient in hexane as elu-
(60–200 l, Macherey-Nagel). The purity of the target compounds
was determined by gas chromatography methods. All of the target
compounds reported in this paper have a purity of no less then
95%.
(1R,2R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-
diol (1) (½a 3D1
ꢃ49.1 (c 2.6, CHCl3)) was synthesized from (ꢃ)-ver-
ꢂ
benone (Aldrich) (½a D25
ꢃ210.5 (c 0.77, CHCl3)) according to
ꢂ
ent. This gave 4 (0.035 g, 0.19 mmol, 76%). ½a D38
ꢃ38.6 (c 0.43,
ꢂ
previously described procedure.20,21
CHCl3). 1H NMR (CDCl3, dH): 1.76 (3H, m; all J 6 2.5 Hz, H-10),
2.02 (1H, dddq; 2J 17.7, J5e,6a 5.3, J5e,4 4.5, J5e,10 1.5 Hz, H-5e), 2.26
(1H, dddq; 2J 17.7, J5a,6a 9.8, J5a,4 2.8, J5a,10 2.5 Hz, H-5a), 2.64 (1H,
dddd; J6a,5a 9.8, J6a,5e 5.3, J6a,1e 2.1, J6a,8 0.7 Hz, H-6a), 3.32 (1H, br
s; OH) and 3.92 (2H, br s; 2 OH), 3.81 (1H, br d; J2e,1e 3.8 Hz, H-
2e), 3.83 (1H, dd; J1e,2e 3.8, J1e,6a 2.1 Hz, H-1e), 4.04 (1H, d; 2J
4.2. (1R,2R,6S)-6-(3-Bromoprop-1-en-2-yl)-3-methylcyclohex-3-
ene-1,2-diol (2)
Freshly
recrystallized
N-bromosuccinimide
(0.992 g,
2
12.6 Hz, H-9), 4.11 (1H, d; J 12.6 Hz, H-90), 5.04 (1H, br s; H-8),
5.57 mmol) and (t-BuO)2 (80
ll, 0.44 mmol) were added to a solu-
5.13 (1H, br s; H-80), 5.59 (1H, ddq; J4,5e 4.5, J4,5a 2.8, J4,10 1.4 Hz,
H-4). 13C NMR, dC: 72.78 (d; C-1), 72.12 (d; C-2), 132.00 (s; C-3),
124.58 (d; C-4), 25.78 (t; C-5), 38.42 (d; C-6), 148.65 (s; C-7),
114.55 (t; C-8), 65.39 (t; C-9), 20.42 (q; C-10). HR-MS: 166.0986
(M+ꢃH2O, C10H14O2; calcd 166.0988).
tion of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-
1,2-diol (1) (0.757 g, 4.51 mmol) in CCl4 (20 ml) (distilled and
passed through a column with calcinated Al2O3). The reaction mix-
ture was boiled for 2 h, then diluted with CCl4 (15 ml), and applied
without treatment on a column with silica gel (17 g). The mixture
was chromatographed using hexane solutions of ether and chloro-
form as eluent (0–100% gradient). Compound
2 (0.383 g,
4.5. 2-(2-((1S,5R,6R)-5,6-Dihydroxy-4-methylcyclohex-3-
enyl)allyl)isoindoline-1,3-dione (6)
1.55 mmol, 34%) was isolated. ½a D27
ꢂ
ꢃ28.4 (c 2.10, CHCl3). 1H
NMR (CDCl3 + CCl4 (1: 1), dH): 1.77 (3H, m; all J 6 2.5 Hz, H-10),
2.09 (1H, dddq; 2J 17.7, J5e,6a 5.3, J5e,4 4.7, J5e,10 1.5 Hz, H-5e), 2.20
(1H, dddqd; 2J 17.7, J5a,6a 9.8, J5a,4 2.8, J5a,10 2.5, J5a,2e 1.1 Hz, H-
5a), 2.47 (2H, br s; 2 OH), 2.74 (1H, ddddd; J6a,5a 9.8, J6a,5e 5.3,
Potassium phthalimide was obtained from phthalimide and
KOH by the procedure.22 Potassium phthalimide (0.105 g,
0.568 mmol) was added to a solution of 2 (0.118 g, 0.480 mmol)
in DMF (6 ml). The reaction mixture was stirred for 1 day at rt.
Then H2O (10 ml) was added and DMF was distilled off at reduced
pressure with a water azeotrope, for which we added another por-
tion of H2O (3 ꢀ 5 ml). The solid residue was extracted with ethyl-
acetate (3 ꢀ 5 ml) and filtered off through a silica gel layer to
remove phthalimide. The solvent was distilled off. The product
was purified by CC on silica gel (4.5 g) using 0–100% ethylacetate
0
J6a,1e 2.2, J6a,8 1.1, J6a,8 0.7 Hz, H-6a), 3.78 (1H, br d; J2e,1e 3.7 Hz,
H-2e), 3.88 (1H, dd; J1e,2e 3.7, J1e,6a 2.2 Hz, H-1e), 3.99 (1H, d; 2J
2
10.2 Hz, H-9), 4.11 (1H, d; J 10.2 Hz, H-90), 5.13 (1H, br s; H-8),
5.34 (1H, br s; H-80), 5.58 (1H, ddq; J4,5e 4.7, J4,5a 2.8, J4,10 1.4 Hz,
H-4). 13C NMR, dC:71.86 (d; C-1), 72.25 (d; C-2), 132.08 (s; C-3),
124.63 (d; C-4), 25.92 (t; C-5), 36.91 (d; C-6), 145.90 (s; C-7),
116.74 (t; C-8), 36.65 (t; C-9), 20.55 (q; C-10). HR-MS: 229.0211
(M+-OH, C10H14OBr; Calc. 229.0228).
gradient in hexane as eluent. The product was
6 (0.117 g,
0.373 mmol, 78%). ½a D24
ꢂ
ꢃ45.8 (c 1.83, CHCl3). 1H NMR (CDCl3 + CCl4
(1:1), dH): 1.75 (3H, m; all J 6 2.5 Hz, H-10), 2.01 (1H, dddq; 2J 17.7,
J5e,6a 5.3, J5e,4 4.6, J5e,10 1.5 Hz, H-5e), 2.28 (1H, dddqd; 2J 17.7, J5a,6a
9.8, J5a,4 2.6, J5a,10 2.5, J5a,2e 1.1 Hz, H-5a), 2.54 (1H, dddd; J6a,5a 9.8,
4.3. 2-((1S,5R,6R)-5,6-Dihydroxy-4-methylcyclohex-3-enyl)allyl
acetate (3)
A 1 M solution (7.5 ml) of NaOAc (7.5 mmol) was added to a
solution of (1R,2R,6S)-6-(3-bromoprop-1-en-2-yl)-3-methylcyclo-
hex-3-ene-1,2-diol (2) (0.124 g, 0.502 mmol) in DMSO (9 ml). The
0
J6a,5e 5.3, J6a,1e 2.0, J6a,8 0.7 Hz, H-6a), 2.81 (1H, br s; OH), 2.88 (1H,
br s; OH), 3.86 (1H, br d; J2e,1e 3.4 Hz, H-2e), 4.01 (1H, br t; J1e,2e 3.4,
J1e,6a 2.0 Hz, H-1e), 4.25 (1H, d; 2J 16.3 Hz, H-9), 4.34 (1H, br d; 2J

1086
O. V. Ardashov et al. / Bioorg. Med. Chem. 21 (2013) 1082–1087
16.3 Hz, H-90), 4.90 (1H, br s; H-80), 5.01 (1H, br s; H-8), 5.54 (1H,
m; all J < 5.0 Hz, H-4), 7.63–7.68 (2H, m; H-14, H-15) and 7.75–
7.80 (2H, m; H-13, H-16)—A2B2-system. 13C NMR, dC: 71.90 (d; C-
1), 72.16 (d; C-2), 132.27 (s; C-3), 124.28 (d; C-4), 25.34 (t; C-5),
37.97 (d; C-6), 143.90 (s; C-7), 111.96 (t; C-8), 41.63 (t;
C-9), 20.57 (q; C-10), 131.97 (s; C-11, C-12), 123.30 (d; C-13,
C-16), 133.84 (d; C-14, C-15), 167.94 (s; C-17, C-18). HR-MS:
313.1311 (M+, C18H19O4N; calcd 313.1309).
using 0–100% chloroform gradient in hexane and 0–100% ethanol
in chloroform with a 0.5% NEt3 addition as eluent. This gave 8
(0.041 g, 0.13 mmol, 76%). ½a D24
ꢂ
ꢃ3.25 (c 0.80, CHCl3). 1H NMR
(CDCl3, dH): 1.48 (2H, br d; 2J 12.5 Hz, H-13), 1.77 (3H, m; all
J 6 2.5 Hz, H-10), 1.87 (1H, dddq; 2J 17.5, J5e,6a 5.2, J5e,4 4.7, J5e,10
2
1.5 Hz, H-5e), 1.92 (2H, br d; J 12.5 Hz, H-130), 2.29 (1H, dddqd;
2J 17.5, J5a,6a 10.6, J5a,4 2.5, J5a,10 2.5, J5a,2e 1.2 Hz, H-5a), 2.70 (1H,
ddd; J6a,5a 10.6, J6a,5e 5.2, J6a,1e 2.0 Hz, H-6a), 2.72 (1H, br. s; H-
11), 3.13 (1H, d; 2J 12.2 Hz, H-9) and 3.14 (1H, d; 2J 12.2 Hz, H-
90)—AB-system, 3.67 (1H, dd; J1e,2e 3.4, J1e,6a 2.0 Hz, H-1e), 3.83
(1H, br d; J2e,1e 3.4 Hz, H-2e), 4.92 (1H, br d; 2J 2.0 Hz, H-8), 5.02
4.6. (1R,2R,6S)-6-(3-Aminoprop-1-en-2-yl)-3-methylcyclohex-3-
ene-1,2-diol (5)
(1H, dd; 2J 2.0, J8 ,6a 0.7 Hz, H-80), 5.56 (1H, ddq; J4,5e 4.7, J4,5a 2.5,
0
A mixture of 6 (0.045 g, 0.14 mmol), ethylenediamine (0.043 g,
0.72 mmol), CHCl3 (10 ml), and EtOH (5 ml) was boiled for 4 h
(GLC control). The solvent was evaporated. The residue was sepa-
rated by CC on silica gel (4.5 g) using 0–100% chloroform gradient
in hexane with a 0.5% NEt3 addition as eluent. This procedure gave
J4,10 1.4 Hz, H-4), 1.50–1.92 (10 H, m; other protons). 13C NMR,
dC: 73.82 (d; C-1), 72.17 (d; C-2), 132.54 (s; C-3), 124.06 (d; C-4),
26.04 (t; C-5), 42.32 (d; C-6), 149.19 (s; C-7), 116.94 (t; C-8),
49.81 (t; C-9), 20.72 (q; C-10), 61.27 (d; C-11), 31.15 (d) and
31.25 (d; 2C-12), 30.58 (t; 2C-13), 27.12 (d) and 27.45 (d; C-14,
C-16), 37.77 (t; C-15), 37.54 (t; 2C-17). HR-MS: 317.2348 (M+,
C20H31O2N; calcd 317.2349).
5 (0.024 g, 0.13 mmol, 93%). ½a D28
ꢂ
ꢃ35.0 (c 0.60, EtOH). 1H NMR
(CDCl3 + CD3OD (ꢁ10:1), dH): 1.73 (3H, m; all J 6 2.5 Hz, H-10),
1.93 (1H, dddq; 2J 17.7, J5e,6a 5.4, J5e,4 4.5, J5e,10 1.5 Hz, H-5e), 2.22
(1H, dddqd; 2J 17.7, J5a,6a 9.8, J5a,4 2.8, J5a,10 2.5, J5a,2e 1.1 Hz, H-
4.9. (1R,2R,6S)-6-(3-(2-(Dimethylamino)ethylamino)prop-1-en-
0
5a), 2.62 (1H, dddd; J6a,5a 9.8, J6a,5e 5.4, J6a,1e 2.2, J6a,8 0.7 Hz, H-
2-yl)-3-methylcyclohex-3-ene-1,2-diol (9)
6a), 3.29 (1H, dd; 2J 13.2, J9,8 0.8 Hz, H-9), 3.31 (1H, dd; 2J 13.2,
J9 ,8 1.1 Hz, H-90), 3.71 (1H, dd; J1e,2e 3.8, J1e,6a 2.2 Hz, H-1e), 3.77
A mixture of 2 (0.070 g, 0.28 mmol) and N1,N1-dimethylethane-
1,2-diamine (Acros, 0.125 ll, 1.14 mmol) in CHCl3 (20 ml) was al-
0
0
(1H, br d; J2e,1e 3.8 Hz, H-2e), 5.00 (1H, dd; 2J 1.4, J8,9 0.8 Hz, H-
8), 5.03 (1H, ddd; 2J 1.4, J8 ,9 1.1, J8 ,6a 0.7 Hz, H-80), 5.53 (1H,
ddq; J4,5e 4.5, J4,5a 2.8, J4,10 1.4 Hz, H-4). 13C NMR, dC: 72.87 (d; C-
1), 72.01 (d; C-2), 132.48 (s; C-3), 123.86 (d; C-4), 26.09 (t; C-5),
40.80 (d; C-6), 148.10 (s; C-7), 116.04 (t; C-8), 44.55 (t; C-9),
20.35 (q; C-10). HR-MS: 183.1255 (M+, C10H17O2N; calcd
183.1254).
lowed to stay for 20 h at rt. Then the reaction mixture was washed
with the concentrated solution of NaHCO3 (10 ml) and dried over
Na2SO4. The solvent was evaporated. The residue (39.4 mg) was
separated by CC on silica gel (2 g) using as eluent 25–100% chloro-
form gradient in hexane and 0–50% ethanol gradient in chloroform
(both with a 0.5% NEt3 addition). This gave 9 (0.019 g, 0.075 mmol,
0
0
0
27%). ½a 2D4
ꢂ
ꢃ14.6 (c 0.27, CHCl3). 1H NMR (CDCl3, dH): 1.79 (3H, m;
4.7. (1R,2R,6S)-3-Methyl-6-(3-morpholinoprop-1-en-2-
all J 6 2.5 Hz, H-10), 1.93 (1H, dddq; 2J 17.7, J5e,6a 5.3, J5e,44.7, J5e,10
1.5 Hz, H-5e), 2.21 (6H, s; H-13, H-14), 2.29 (1H, ddm; 2J 17.7, J5a,6a
10.6, H-5a), 2.44 (2H, t; J12,11 6.0 Hz, H-12), 2.63 (1H, dt; 2J 12.3,
J11,12 6.0 Hz, H-11), 2.69–2.74 (1H, m; H-6a), 2.71 (1H, dt; 2J 12.3,
yl)cyclohex-3-ene-1,2-diol (7)
A mixture of 2 (0.073 g, 0.30 mmol) and morpholine (0.068 g,
0.78 mmol) in CHCl3 (10 ml) was allowed to stay for 2 days at rt.
Then a solution of NaHCO3 (1 g) and NaCl (1 g) in H2O (20 ml)
was added. The organic layer was separated. The aqueous layer
was extracted with CHCl3 (3 ꢀ 10 ml). The combined organic
phases were dried over Na2SO4. The solvent was evaporated. The
residue was separated by CC on silica gel (4.5 g) using 0–100%
chloroform gradient in hexane with a 0.5% NEt3 addition as eluent.
J11 ,12 6.0 Hz, H-110), 3.14 (1H, d; 2J 12.3 Hz, H-9) and 3.31 (1H, d;
0
2J 12.3 Hz, H-90)—AB-system, 3.71 (1H, dd; J1e,2e 3.7, J1e,6a 2.0 Hz,
H-1e), 3.84 (1H, br d; J2e,1e 3.7 Hz, H-2e), 4.21 (3H, br s; 2OH,
2
NH), 4.99 (1H, br s; H-8), 5.07 (1H, br d; J 1.8 Hz, H-80), 5.53–
5.59 (1H, m; all J 6 4.7 Hz, H-4). 13C NMR, dC: 73.55 (d; C-1),
72.47 (d; C-2), 132.61 (s; C-3), 124.05 (d; C-4), 26.28 (t; C-5),
42.09 (d; C-6), 147.59 (s; C-7), 117.63 (t; C-8), 52.70 (t; C-9),
20.61 (q; C-10), 45.49 (t; C-11), 57.77 (t; C-12), 45.24 (q; C-13, C-
14). HR-MS: 254.1984 (M+, C14H26O2N2; calcd 254.1989).
This gave 7 (0.049 g, 0.19 mmol, 63%). ½a D28
ꢃ18.6 (c 1.55, CHCl3).
ꢂ
1H NMR (CDCl3 + CCl4 (1:1), dH): 1.78 (3H, m; all J 6 2.5 Hz, H-
10), 1.90 (1H, dddq; 2J 17.6, J5e,6a 5.2, J5e,4 4.8, J5e,10 1.5 Hz, H-5e),
2.27 (1H, dddqd; 2J 17.6, J5a,6a 10.6, J5a,4 2.5, J5a,10 2.5, J5a,2e 1.1 Hz,
H-5a), 2.35–2.47 (2H, m) and 2.54–2.66 (2H, m; H-11, H-14),
2.72 (1H, ddd; J6a,5a 10.6, J6a,5e 5.2, J6a,1e 2.0 Hz, H-6a), 2.73 (1H,
4.10. (1R,2R,6S)-6-(Hept-1-en-2-yl)-3-methylcyclohex-3-ene-
1,2-diol (10) and (3aS,7R,7aR)-6-methyl-3-methylene-
2,3,3a,4,7,7a-hexahydrobenzofuran-7-ol (11)
d; 2J 12.4 Hz, H-9), 3.17 (1H, d; J 12.4 Hz, H-90), 3.67 (1H, dd;
2
J1e,2e 3.4, J1e,6a 2.0 Hz, H-1e), 3.68–3.74 (4H, m; H-12, H-13), 3.82
(1H, br d; J2e,1e 3.4 Hz, H-2e), 4.95 (1H, br s; H-8), 5.16 (1H, d; 2J
1.9 Hz, H-80), 5.58 (1H, ddq; J4,5e 4.8, J4,5a 2.5, J4,10 1.4 Hz, H-4).
13C NMR, dC: 73.63 (d; C-1), 72.24 (d; C-2), 132.42 (s; C-3),
124.13 (d; C-4), 25.96 (t; C-5), 42.31 (d; C-6), 145.06 (s; C-7),
119.71 (t; C-8), 62.15 (t; C-9), 20.68 (q; C-10), 52.85 (t; C-11, C-
14), 66.16 (t; C-12, C-13). HR-MS: 253.1684 (M+, C14H23O3N; calcd
253.1672).
A 15% solution of n-BuLi in hexane (0.40 ml, 0.64 mmol) was
added under argon to a solution of 2 (0.063 g, 0.27 mmol) in THF
(dried and distilled over sodium) (12 ml). The reaction mixture
was stirred for 4 h at rt and allowed to stay overnight. EtOH
(0.5 ml) was added dropwise. The solvent was distilled off. Ether
(20 ml) was added to the residue. The precipitate was filtered off.
The filtrate was evaporated and separated by CC on silica gel
(4.5 g) using 0–100% ether gradient in hexane as eluent. This gave
10 (0.011 g, 0.049 mmol, 18%) and 11 (0.007 g, 0.04 mmol, 15%).
4.8. (1R,2R,6S)-6-{1-[(2-Adamantylamino)methyl]vinyl}-3-
methylcyclohex-3-ene-1,2-diol (8)
Compound 10. ½a 2D6
ꢂ
ꢃ29.4 (c 0.37, CHCl3). 1H NMR (CDCl3 + CCl4
(1:1), dH): 0.89 (3H, t; J14,13 7.0 Hz, H-14), 1.23–1.36 (4H, m; H-12,
H-13), 1.38–1.53 (2H, m; H-11), 1.81 (3H, m; all J 6 2.5 Hz, H-10),
1.92 (1H, dddq; 2J 17.7, J5e,6a 5.2, J5e,44.6, J5e,10 1.5 Hz, H-5e), 2.05–
2.11 (2H, m; H-9), 2.23 (1H, dddqd; 2J 17.7, J5a,6a 11.1, J5a,4 2.5, J5a,10
2.5, J5a,2e 1.2 Hz, H-5a), 2.40 (1H, ddd; J6a,5a 11.1, J6a,5e 5.2, J6a,1e
2.2 Hz, H-6a), 3.82 (1H, br t; J1e,2e 3.4, J1e,6a 2.2 Hz, H-1e), 3.85
A
mixture of 2 (0.042 g, 0.17 mmol), 2-aminoadamantane
hydrochloride (0.044 g, 0.24 mmol), NEt3 (0.060 g, 0.60 mmol),
and CHCl3 (7 ml) was stored at rt for 4 days. The solvent was
distilled off. The residue was separated by CC on silica gel (4.5 g)

O. V. Ardashov et al. / Bioorg. Med. Chem. 21 (2013) 1082–1087
1087
(1H, br d; J2e,1e 3.4 Hz, H-2e), 4.88 (1H, br s; H-8), 4.95 (1H, m; all
J 6 2.0 Hz, H-80), 5.51 (1H, ddq; J4,5e 4.6, J4,5a 2.5, J4,10 1.4 Hz, H-4).
13C NMR, dC: 71.13 (d; C-1), 71.82 (d; C-2), 131.77 (s; C-3), 125.35
(d; C-4), 24.84 (t; C-5), 38.44 (d; C-6), 150.03 (s; C-7), 110.37 (t; C-
8), 35.99 (t; C-9), 20.86 (q; C-10), 27.78 (t; C-11), 31.64 (t; C-12),
22.58 (t; C-13), 14.11 (q; C-14). HR-MS: 224.1767 (M+, C14H24O2;
calcd 224.1771).
Scientific Purposes, and the requirements and recommendations of
the Guide for the Care and Use of Laboratory Animals.
4.13. MPTP mouse model of Parkinson’s disease19
MPTP was injected intraperitoneally to 8-weeks male mice of
C57Bl/6 line weighing 22–25 g every 2 h for a total of 4 doses over
a 6 h period in 1 day in a dose of 0.12 mmol/kg (20 mg/kg) for a to-
tal of 4 doses. The studied agent was administrated per os 24 h
after the last injection of MPTP in a dose of 0.12 mmol/kg
(20 mg/kg). The effectiveness of the studied medications was eval-
uated according to their ability to reduce the symptoms of hypoki-
nesia induced by MPTP. Hypokinesia caused by neurotoxin
administration was evaluated with the ‘Open field’ test performed
for 2 min using TruScan (U.S.) 2 h after the administration of the
studied agent, registering the main markers of the locomotor activ-
ity: time of locomotor activity (s), movement distance (cm), move-
ment speed (cm/s) and immobility time (s).
Compound 11. ½a 2D6
ꢂ
ꢃ69.0 (c 0.23, CHCl3). 1H NMR (CDCl3 + CCl4
(1: 1), dH): 1.78 (3H, m; all J 6 2.5 Hz, H-10), 2.03 (1H, dddq; 2J 17.7,
J5e,6 6.3, J5e,4 3.3, J5e,10 2.5 Hz, H-5e), 2.38 (1H, dddqd; 2J 17.7, J5a,6
8.2, J5a,4 5.0, J5a,10 1.5, J5a,2 1.3 Hz, H-5a), 2.79 (1H, dddtdd; J6,5a
0
8.2, J6,1 6.9, J6,5e 6.3, J6,9 2.3, J6,8 2.2, J6,8 1.1 Hz, H-6), 3.95 (1H, br.
d; J2,1 5.2 Hz, H-2), 3.98 (1H, dd; J1,6 6.9, J1,2 5.2 Hz, H-1), 4.33
(1H, dtd; 2J 13.2, J8,9 2.2, J8,6 1.1 Hz, H-8), 4.36 (1H, dtd; 2J 13.2,
J8 ,9 2.2, J8 ,6 2.2 Hz, H-80), 4.87–4.92 (2H, m; H-9), 5.43 (1H, dddq;
J4,5a 5.0, J4,5e 3.3, J4,2 1.8, J4,10 1.5 Hz, H-4). 13C NMR, dC: 84.11 (d;
C-1), 69.76 (d; C-2), 134.70 (s; C-3), 121.33 (d; C-4), 26.38 (t;
C-5), 38.73 (d; C-6), 151.70 (s; C-7), 69.84 (t; C-8), 103.47 (t; C-
9), 19.12 (q; C-10). HR-MS: 151.0755 (M+-CH3, C9H11O2; calcd
151.0759).
0
0
Acknowledgements
4.11. (1R,2R,6S)-3-Methyl-6-(3-(propylthio)prop-1-en-2-
yl)cyclohex-3-ene-1,2-diol (12)
The reported study was supported by RFBR, research project No.
12-03-31257.
1-Propanethiol (0.100 ll, 1.11 mmol) was added to the sus-
Supplementary data
pense of NaOH (0.045 g, 1.13 mmol) in 2 ml EtOH. The reaction
mixture was stirred for 20 min at rt (NaOH was fully dissolved).
Then a solution of 2 (0.181 g, 0.733 mmol) in EtOH (6 ml) was
added. The reaction mixture was stirred for 20 h at rt. The solvent
was distilled off. The residue (0.288 g) was separated by CC on sil-
ica gel (9 g). This procedure gave 12 (0.103 g, 0.426 mmol, 58%).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2013.01.003.
References and notes
½
a 2D6
ꢂ
ꢃ23.0 (c 0.88, CHCl3). 1H NMR (CDCl3, dH): 0.93 (3H, t; J13,12
1. Dorsey, E. R.; Constantinescu, R.; Thompson, J. P.; Biglan, K. M.; Holloway, R. G.;
Kieburtz, K.; Marshall, F. J.; Ravina, B. M.; Schifitto, G.; Siderowf, A.; Tanner, C.
M. Neurology 2007, 68, 384.
2. Buck, K.; Ferger, B. Drug Discovery Today 2010, 15, 867.
3. Outeiro, T. F.; Ferreira, J. Curr. Pharm. Des. 2009, 15, 3968.
4. Obeso, J. A.; Rodriguez-Oroz, M. C.; Goetz, C. G.; Marin, C.; Kordower, J. H.;
Rodriguez, M.; Hirsch, E. C.; Farrer, M.; Schapira, A. H. V.; Halliday, G. Nat. Med.
2010, 16, 653.
7.3 Hz, H-13), 1.49–1.61 (2H, m; H-12), 1.78 (3H, ddd; J10,5a 2.5,
J10,5e 1.5, J10,4 1.3 Hz, H-10), 1.98 (1H, dddq; 2J 17.6, J5e,6a 5.3, J5e,4
5.3, J5e,10 1.5 Hz, H-5e), 2.22 (1H, dddqd; 2J 17.6, J5a,6a 11.0, J5a,4
2.5, J5a,10 2.5, J5a,2e 1.2 Hz, H-5a), 2.35 (1H, ddd; 2J 12.7, J11,12 7.8,
J11,12 6.9, H-11), 2.39 (1H, ddd; 2J 12.7, J11 ,12 7.8, J11 ,12 6.6, H-
110), 2.71 (1H, dddd; J6a,5a 11.0, J6a,5e 5.3, J6a,1e 2.0, J6a,8 0.7 Hz, H-
0
0
0
0
5. Hennemann, J.; Schatton, W. Parkinsonism Treatment. Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim, Frankfurt am Main, Germany, 2008; 10.1002/
14356007.a19 001.pub2.
6a), 3.17 (1H, d; 2J 13.5 Hz, H-9), 3.19 (1H, d; J 13.5 Hz, H-90),
2
3.84 (1H, br d; J2e,1e 3.1 Hz, H-2e), 3.87 (1H, dd; J1e,2e 3.1, J1e,6a
2.0 Hz, H-1e), 5.02 (2H, s; H-8), 5.60 (1H, ddq; J4,5e 5.3, J4,5a 2.5,
J4,10 1.3 Hz, H-4). 13C NMR, dC: 71.62 (d; C-1), 71.97 (d; C-2),
131.79 (s; C-3), 124.88 (d; C-4), 25.28 (t; C-5), 37.10 (d; C-6),
145.14 (s; C-7), 114.18 (t; C-8), 37.17 (t; C-9), 20.59 (q; C-10),
32.95 (t; C-11), 22.26 (t; C-12), 13.31 (q; C-13). HR-MS: 241.1253
(M+ꢃH, C13H21O2S; calcd 241.1257).
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