Discovery of highly potent analgesic activity of isopulegol-derived (2R,4aR,7R,8aR)-4,7-dimethyl-2-(thiophen-2-yl)octahydro-2H-chromen-4-ol

Article abstract of DOI:10.1007/s00044-016-1573-3

A large set of chiral heterocyclic compounds with the octahydro-2H-chromene scaffold was first obtained by a reaction of (?)-isopulegol and (+)-neoisopulegol with furan-2-carbaldehyde, thiophene-2-carbaldehyde and their derivatives and isomers in the pres

Full text of DOI:10.1007/s00044-016-1573-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1573-3
ORIGINAL RESEARCH
Discovery of highly potent analgesic activity of isopulegol-derived
(2R,4aR,7R,8aR)-4,7-dimethyl-2-(thiophen-2-yl)octahydro-2H-
chromen-4-ol
Ekaterina Nazimova1,2 Alla Pavlova1 Oksana Mikhalchenko1 Irina Il’ina1,2 Dina Korchagina1
•
•
•
•
•
Tat’yana Tolstikova1 Konstantin Volcho1,2 Nariman Salakhutdinov1,2
•
•
Received: 3 September 2015 / Accepted: 7 April 2016
Ó Springer Science+Business Media New York 2016
Abstract A large set of chiral heterocyclic compounds
with the octahydro-2H-chromene scaffold was first
obtained by a reaction of (-)-isopulegol and (?)-
neoisopulegol with furan-2-carbaldehyde, thiophene-2-
carbaldehyde and their derivatives and isomers in the
presence of montmorillonite K10 clay. Most of the (-)-
isopulegol-derived compounds exhibited a significant
analgesic activity in the acetic acid-induced writhing test.
Compound 3b obtained by a reaction of (-)-isopulegol
with thiophene-2-carbaldehyde demonstrated a significant
analgesic effect in this test within 15 min after oral
administration at the dose of 1 mg/kg and retains the effect
for at least 24 h. Compound 3b exhibited analgesic activity
in the hot plate test also. A change in the sulfur atom
position in the aromatic ring was found to lead to the effect
reversal in the hot plate test.
Introduction
Although pain is the most common symptom for which
patients seek medical attention (Wolff et al., 2011), the
treatment of pain is still inadequate and continues to be a
substantial worldwide public health concern, especially in
the case of cancer-related pain (Juniper et al., 2009) and
chronic non-cancer pain (Reinecke et al., 2015). Therefore,
the development of effective analgesic compounds of novel
structural types for pain relief is required.
Recently, we have found that several heterocyclic
compounds 1 (Scheme 1) with the hexahydro-2H-chro-
mene scaffold that were synthesized by reactions of
monoterpenoid 2 with aromatic aldehydes in the presence
of montmorillonite K10 clay exhibit a pronounced anal-
gesic activity in in vivo tests (Mikhalchenko et al., 2013a,
b; Il’ina et al., 2014; Pavlova et al., 2015). Compound 2
can be obtained from a monoterpenoid (-)-verbenone in
three stages, which is not a trivial task due to the formation
of a complex reaction mixture at the last stage (Ardashov
et al., 2007; Stekrova et al., 2013).
Keywords Terpene Á Chromene Á Isopulegol Á
Analgesic activity Á Acetic acid-induced writhing test Á
Hot plate test
It is known that compounds with the octahydro-2H-
chromene scaffold 3 which are similar to 1 can be syn-
thesized in one stage via a reaction of commercially
available (-)-isopulegol 4 with aldehydes using various
catalytic systems, including para-toluenesulfonic acid
placed onto silica gel (Macedo et al., 2010), I2 (Silva and
Quintiliano, 2009) and montmorillonite clays (Baishya
et al., 2013; Anikeev et al., 2013; Timofeeva et al., 2015).
The aim of the present study was to synthesize com-
pound 3 containing heteroaromatic furan and thiophene
substituents and investigate their analgesic activity. The
choice of this type of substituents was based on the pres-
ence of furan and thiophene moieties in a number of
compounds with a significant analgesic activity (Nelson
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-016-1573-3) contains supplementary
material, which is available to authorized users.
& Konstantin Volcho
volcho@nioch.nsc.ru
1
Novosibirsk Institute of Organic Chemistry, Siberian Branch,
Russian Academy of Sciences, Lavrentjev Av., 9,
Novosibirsk, Russian Federation 630090
2
Novosibirsk State University, Pirogova 2, Novosibirsk,
Russian Federation 630090
123

Med Chem Res
Scheme 1 Synthesis of compounds 1 and 3
et al., 2012; Thur et al., 2012; Guerrero et al., 2009; Joshi
et al., 2009; Sarigol et al., 2015). Moreover, the products
with these substituents can be considered as the analogs of
earlier synthesized compounds with pronounced analgesic
activity which contain hydroxy or methoxy groups in the
aromatic ring (Il’ina et al., 2014; Pavlova et al., 2015).
Usually, the (4R)-diastereomer predominated in the
reaction mixtures, except a reaction with 5-nitrofuran-2-
carbaldehyde 3d where the (4S)-isomer was the major
product (Table 1). Given the lack of an explicit depen-
dence of the stereoisomer ratio on the donor–acceptor
properties of substituents, it may be supposed that the
isomer ratio is mainly affected by steric factors.
In some cases, we were able to isolate individual (4R)-
and/or (4S)-diastereomers. In particular, we obtained the
(4R)- and (4S)-isomers 3d and 3g as well as the (4R)-
isomer 3b.
Chemistry
Previously, the synthesis of compounds 3a and 3b con-
taining non-substituted furan and thiophene rings
(Scheme 2) was performed in a study (Baishya et al., 2013)
through a reaction of (-)-isopulegol 4 with aldehydes 5a
and 5b using montmorillonite K10 clay as a catalyst under
microwave irradiation with the yield of 56 and 50 %,
respectively. Compounds 3a and 3b were formed as mix-
tures of two diastereomers differing in the fourth position
(Scheme 2), with the predominance of the (R)-isomer.
We found that conducting these reactions in the pres-
ence of K10 clay at room temperature without microwave
irradiation requires slightly more time but significantly
increases the yield of products 3a and 3b, which amounted
to 86 and 78 %, respectively. The reactions were carried
out without solvent; complete conversion of isopulegol was
achieved within 1 h (Table 1); the products were isolated
by column chromatography on silica gel.
According to GC–MS analysis of reaction mixtures, in
almost all cases, the formation of several minor products
with molecular weights corresponding to those of com-
pound 3, but with the loss of a water molecule, was
detected. We could not separate these compounds with a
purity required to determine their structure. To confirm the
structure of these compounds, we searched for a catalyst
system that would lead to their preferable formation. These
compounds appeared to form with a high yield during the
˚
reaction in the presence of TsOH and 4A molecular sieves
in refluxing toluene. After production and subsequent iso-
lation by column chromatography, we obtained a mixture
of double-bond position isomers 6 and 7 (Scheme 3) at the
9:1 ratio that were minor products of the reaction con-
ducted in the presence of K10 clay.
A possible mechanism for the formation of compounds
3, 6 and 7 is depicted in Scheme 4 and includes the attack
of a protonated aldehyde group on the alcohol group of
(-)-isopulegol 4, followed by carbocyclization with
involvement of an isopropylene double bond. The resulting
intermediate can further either interact with a water
Introduction of a methyl group (3c, 3e, 3f) or bromine (3g,
3h) into the aldehyde aromatic ring led to an increase in the
reaction time to 1.5–2 h. When nitro-substituted aldehydes
3d and 3i were used as reactants, the reaction rate was equal
to that observed for unsubstituted aldehydes 3a and 3c.
Scheme 2 Synthesis of compounds 3a–i
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Med Chem Res
Table 1 Synthesis of compounds 3a–i via interaction of (-)-isopulegol 4 with different aldehydes
Entry
Aldehyde
Reaction time (min)
Product (yield, %)
Ratio of 4R/4Sa
1
2
3
4
5
6
7
8
9
a
5a; X = O; R3 = R4 = R5 = H
5b; X = S; R3 = R4 = R5 = H
60
60
3a (86)
3b (78)
3c (65)
3d (54)
3e (80)
3f (69)
3g (76)
3h (74)
3i (50)
3:1
5:1
5c; X = O; R3 = R4 = H; R5 = Me
5d; X = O; R3 = R4 = H; R5 = NO2
5e; X = S; R3 = R4 = H; R5 = Me
5f; X = S; R3 = Me; R4 = R5 = H
5g; X = S; R3 = R4 = H; R5 = Br
5h; X = S; R3 = R5 = H; R4 = Br
5i; X = S; R3 = R4 = H; R5 = NO2
90
3.5:1
1:1.5
4.5:1
10:1
6.5:1
3:1
60
120
120
120
120
60
1:1
1
The ratio of diastereomers (S)/(R) for products of type 3 was determined from the H NMR spectrum of corresponding reaction mixture
Scheme 3 Synthesis of
compounds 6 and 7
Scheme 4 Possible mechanism of formation of compounds 3, 6 and 7
molecule to form diastereomers (4R(S))-3 or undergo
deprotonation to form compounds 6 and 7.
reaction time was 60 min, and the yields were 61 and
63 %, respectively. It should be noted that the yields in
both cases were slightly lower than those upon the use of
isomeric aldehydes 3a and 3b.
Compounds 8a and 8b, which are isomers of compounds
3a and 3b differing in the heteroatom position in an aro-
matic substituent, were synthesized by reacting (-)-isop-
ulegol 4 with aldehydes 9a and 9b (Scheme 5). The
The relative and absolute configurations of monoter-
penoids and their derivatives are well known to be capable
of exerting a decisive influence on their biological activity
(Pavlova et al., 2013; Ardashov et al., 2011). To obtain
other diastereomers of compounds 3a and 3b, we synthe-
sized a mixture of (?)-neoisopulegol 11 and (-)-isopule-
gol 4 by oxidation of (-)-isopulegol 4 to isopulegone 10
followed by reduction (Scheme 6). Compound 11 was
isolated from the epimer mixture by column chromatog-
raphy. A reaction of (?)-neoisopulegol 11 with furan-2-
Scheme 5 Synthesis of compounds 8a,b
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Med Chem Res
Scheme 6 Synthesis of (?)-neoisopulegol 11 and its interaction with aldehydes 5a,b
carbaldehyde 5a in the presence of K10 clay resulted in the
formation of compound with the octahydrochromene
scaffold 12a (41 %, 4R:4S = 1:1.5) and monoterpenoid
diol 13 (19 %) obviously formed by the reaction of 11 with
water. Analogous interaction with thiophene-2-carbox-
aldehyde 5b led to formation of 12b in 75 % yield
(4R:4S = 1:1). Complete conversion of monoterpenoid 11
in both cases was achieved in 60 min.
of (4R)- and (4S)-isomers in acid-induced writhing test, and
the effect observed in the hot plate test for (4R)-3b was not
statistically significant.
Compounds 3e and 3f containing a methyl group at the
fifth and the third positions of the thiophene ring, respec-
tively, exhibited the analgesic activity in the acetic acid-
induced writhing test only. Analgesic activity in this test
was also found in the (4R)-diastereomer of 5-bromo-sub-
stituted compound 3g. In the case of the (4S)-diastereomer,
the observed effect appeared not to be statistically signifi-
cant. Compound 3h with a bromine atom at the fourth
position of the aromatic ring was significantly more
effective in acid-induced writhing test, but it did not have a
statistically significant analgesic effect in the hot plate test.
Nitro-containing compound 3i exhibited analgesic effect in
acid-induced writhing test.
Thus, we first synthesized a large set of chiral hetero-
cyclic compounds with the octahydro-2H-chromene scaf-
fold, containing heteroaromatic substituents.
Biology
The analgesic activity of the compounds in a dose of
10.0 mg/kg (oral administration) was studied in the stan-
dard experimental pain models, namely in the acetic acid-
induced writhing (0.75 % acetic acid, 0.1 ml for one ani-
mal, intraperitoneally) and hot plate (thermal stimulation,
T = 54 0.5 °C) tests (Koster et al., 1959; Eddy and
Leimbach, 1953). Agents were administered 1 h before
testing. Diclofenac sodium in the dose of 10.0 mg/kg was
used as a reference drug. The mixtures of diastereomers at
the carbon atom bonded with the methyl and hydroxyl
groups were used without separation. We also tested the
individual stereoisomers in cases we obtained them.
Table 2 presents the analgesic activity data.
Therefore, most of the compounds prepared by inter-
action of (-)-isopulegol 4 with furan-2-carbaldehyde,
thiophene-2-carbaldehyde and their derivatives exhibited a
potent analgesic activity in the acetic acid-induced writhing
test. In all cases when the activity of individual diastere-
omers was tested, their analgesic effect was comparable.
Only compound 3b exhibited analgesic activity in both
used animal models: in acid-induced writhing and in the
hot plate test.
Compound 8a, like its isomer differing in the heteroa-
tom position in the aromatic ring 3a, had no analgesic
activity (Table 2). The result of testing compound 8b, an
isomer of the most active compound 3b, was unexpected.
Instead of the analgesic effect previously observed for
compound 3b in the hot plate test, the use of compound 8b
led to statistically significant manifestation of hyperalgesia
in this test. Thus, a change in the sulfur atom position in the
aromatic ring appeared to lead to the effect reversal in the
hot plate test. Compound 8b did not influence on
the numbers of writhing induced by acetic acid
administration.
Compound 3a obtained by interaction of isopulegol 4
with furfural 5a exhibited no analgesic activity. Compound
3c with a methyl substituent at the fifth position also had no
activity. At the same time, the replacement of a methyl
group by a nitro group in the case of compound 3d led to a
significant analgesic effect in the acetic acid-induced wri-
thing test, with both diastereomers being effective.
Unlike compound 3a, its sulfur-containing analog 3b
had a statistically significant analgesic effect in both used
models. Interestingly, the individual (4R)-3b stereoisomer
was somewhat less effective than the 5:1 original mixture
Compounds 12a and 12b derived from (?)-neoisop-
ulegol 11 exhibited no analgesic activity in both tests
123

Med Chem Res
Table 2 Analgesic activity of compounds 3a–i, 8a,b, 12a,b and sodium diclofenac (10 mg/kg dose)
Compound
Acetic acid-induced writhing test
Hot plate test
Control
Control
Mean SD (pain inhibition, %)a
Mean SD (protection, %)b
3a
11.1 0.6
9.6 0.9
8.9 0.7
9.8 0.5
11.1 0.7
11.1 0.7
10.9 0.5
10.9 0.5
10.0 0.7
10.0 0.7
9.6 0.9
11.1 0.7
7.9 1.1
7.9 1.1
8.4 1.5
8.1 0.5
10.1 1.9
9.8 1.3
14.4 1.7
9.8 0.8
19.9 2.5
3b
4.3 1.1 (55)#
5.6 0.8 (37)*
8.1 1.2
4.8 1.2 (57)§
6.4 1.5 (42)*
6.6 0.5 (39)§
7.0 0.6 (36)§
7.4 0.6 (26)*
6.6 1.4
13.1 1.2 (34)*
15.1 2.0
(4R)-3b
11.5 1.1
13.3 1.4
12.1 1.3
12.1 1.3
18.4 2.1
18.4 2.1
13.4 1.8
13.4 1.8
9.8 0.8
3c
16.0 2.2
(4S)-3d
15.1 1.2
(4R)-3d
17.9 2.3
3e
17.4 2.4
3f
12.8 1.7
(4R)-3g
20.3 3.8
(4S)-3g
14.5 2.3
3h
3.6 1.5 (63)#
7.5 1.2 (32)*
7.3 0.9
13.6 1.7
3i
12.1 1.3
19.4 2.7
19.4 2.7
14.0 1.2
13.4 1.6
9.6 1.6
14.5 1.6
8a
13.9 1.0
10.5 1.0 (-46)#
8b
8.9 0.9
12a
5.3 1.7
17.5 2.1
12b
7.6 1.1
5.0 1.1 (50)§
11.5 0.9
15.6 2.4 (62)#
Diclofenac sodium
#
§
* p \ 0.05; p \ 0.01; p \ 0.001 in comparison with control
a
% of pain inhibition = (tcontrol - texp)/tcontrol 9 100 %
b
% of protection = (texp - tcontrol)/tcontrol 9 100 %
(Table 2), indicating importance of the trans-junction of
rings for the analgesic effect in compound 3b.
comparable analgesic effect in both tests. Further lowering
the dose to 0.5 mg/kg results in the disappearance of the
analgesic effect. Based on these data, we may conclude that
the optimal dose for 3b is 1 mg/kg.
Compound 3b (Fig. 1) that demonstrated the analgesic
activity in both tests was studied for the effect–dose
dependence (Table 3). As seen from the presented data,
compound 3b at doses of 1, 5 and 10 mg/kg has a
Acute toxicity of compound 3b was investigated at
single intragastric administration in mice at a doses of 500,
1000, 2500 and 4500 mg/kg. Doses of 500, 1000 and
2500 mg/kg did not influence behavior and physiological
state of animals. Administration of 4500 mg/kg of the
studied compound caused the labored breathing and
movement in animals in the first day. Two animals were
died on the second and third day (33 % of total number of
animals). Therefore, the LD50 for compound 3b was found
Fig. 1 Structure of the most
promising compound 3b
Table 3 Analgesic activity of compound 3b in various doses
Dose (mg/kg)
Acetic acid-induced writhing test
Hot plate test
Control
Mean SD (pain inhibition, %)a
Control
Mean SD (protection, %)b
0.5
1
10.1 0.7
8.4 0.6
8.4 0.6
9.6 0.9
7.4 1.3
15.8 1.6
10.4 1.2
10.4 1.2
9.8 0.8
20.3 2.2
2.4 0.8 (71)§
4.9 1.0 (42)#
4.3 1.1 (55)#
16.5 1.9 (59)*
16.3 1.6 (57)*
13.1 1.2 (34)*
5
10
#
§
* p \ 0.05; p \ 0.01; p \ 0.001 in comparison with control
a
% of pain inhibition = (tcontrol - texp)/tcontrol 9 100 %
b
% of protection = (texp - tcontrol)/tcontrol 9 100 %
123

Med Chem Res
The minimum dose at which compound 3b retained a
high efficacy in both tests was found to be 1 mg/kg. Given
a low acute toxicity (LD50 [ 4500 mg/kg), compound 3b
exhibits a wide therapeutic index, which is unique for
analgesic medications. Compound 3b exhibits the anal-
gesic activity in the acetic acid-induced writhing test within
15 min after oral administration at the dose of 1 mg/kg,
with the effect being retained for at least 24 h.
Table 4 Time-dependent analgesic effect of compound 3b in 1 mg/
kg dose in acetic acid-induced writhing test
Time
Control
Mean SD
(pain inhibition, %)a
15 min
30 min
60 min
2 h
10.0 0.3
10.0 0.3
10.0 0.3
10.0 0.3
10.1 0.7
10.1 0.7
10.1 0.7
10.1 0.7
§
4.1 1.4 (59)§
7.3 0.7 (27)#
5.3 1.3 (47)#
5.6 0.8 (44)§
7.3 0.5 (28)#
5.0 1.4 (50)#
4.0 0.9 (60)§
5.6 1.0 (45)#
3 h
4 h
Experimental
Chemistry
5 h
24 h
#
* p \ 0.05; p \ 0.01; p \ 0.001 in comparison with control
a
% of pain inhibition = (tcontrol - texp)/tcontrol 9 100 %
All the chemicals and reagents were of commercial grade.
As the catalyst, we used K10 clay (Aldrich). The clay was
calcined at 105 °C for 3 h immediately before use. CH2Cl2
b
% of protection = (texp - tcontrol)/tcontrol 9 100 %
was passed through calcined Al2O3. (-)-Isopulegol
to exceed 4500 mg/kg, indicating a low acute toxicity of
the compound. For comparison, the LD50 of diclofenac
sodium is 370 mg/kg (Syubaev et al., 1986).
31
(½aŠ - 49.1 (c = 2.6, CHCl3)) was purchased from
D
Aldrich.
All product yields are given for isolated compounds.
Column chromatography (CC): silica gel (SiO2; 60–200 l;
Macherey–Nagel); hexane/EtOAc 100:0 ? 0:100; Agilent
7890A gas chromatograph equipped with a quadrupole
mass spectrometer Agilent 5975C as a detector; quartz
column HP-5MS (copolymer 5 % diphenyl–95 %
dimethylsiloxane) of length 30 m, internal diameter
0.25 mm and stationary phase film thickness 0.25 lm was
used for the analysis; optical rotation: polAAr 3005 spec-
trometer, CHCl3 soln; HR-MS: DFS-Thermo-Scientific
spectrometer in a full scan mode (15–500 m/z, 70 eV
The next step of the research was to study the time-
dependent analgesic effect of compound 3b at the dose of
1 mg/kg. A significant analgesic effect was observed as
soon as 15 min after oral administration of the agent and
was retained for at least 24 h (Table 4). Importantly,
compound 3b, in contrast to opioid analgesics (Bihel et al.,
2015), has no signs of hyperalgesia throughout the
experiment.
Conclusion
1
electron-impact ionization, direct sample introduction); H
and 13C NMR: Bruker DRX-500 apparatus at 500.13 MHz
(1H) and 125.76 MHz (13C), J in Hz; and structure deter-
minations by analyzing the 1H NMR spectra, including
In summary, a large set of chiral heterocyclic compounds
with the octahydro-2H-chromene scaffold, containing
heteroaromatic substituents, was first synthesized by
interaction of (-)-isopulegol 4 with furan-2-carbaldehyde
5a, thiophene-2-carbaldehyde 5b and their derivatives and
isomers in the presence of montmorillonite K10 clay. Two
more products with the octahydro-2H-chromene scaffold
but with another ring junction were obtained by reactions
of (?)-neoisopulegol 11 with aldehydes 5a and 5b.
Most of the (-)-isopulegol 4 derived compounds
exhibited a potent analgesic activity in the acetic acid-in-
duced writhing test, but only compound 3b that was
obtained by the reaction with thiophene-2-carbaldehyde 5b
exhibited a potent analgesic activity in hot plate test too. A
change in the sulfur atom position in the aromatic ring
upon transition from 3b to 8b leads to the effect reversal in
the hot plate test. Compounds 12a and 12b synthesized
from (?)-neoisopulegol 11 had no analgesic activity in
both tests.
1
1H–1H double resonance spectra and H–1H 2D homonu-
clear correlation, J-modulated 13C NMR spectra (JMOD)
and 13C–1H 2D heteronuclear correlation with one-bond
and long-range spin–spin coupling constants (C–H COSY,
1J(C,H) = 160 Hz, COLOC, 2,3J(C,H) = 10 Hz).
Numeration for carbon atoms used for assignment in
NMR spectra is presented in Fig. 2 with compound (R)-3c
as an example.
Fig. 2 Numeration for NMR
spectra
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Med Chem Res
Reaction of isopulegol 4 with aldehydes on clay K10:
general procedure
C-3); 43.73 (t, C-4); 69.00 (s, C-5); 49.21 (d, C-6); 22.38 (t,
C-7); 34.24 (t, C-8); 31.13 (d, C-9); 41.03 (t, C-10); 154.72
(s, C-11); 141.91 (d, C-12); 109.81 (d, C-13); 106.40 (d,
C-14); 28.09 (q, C-15); 22.05 (q, C-16). HR-MS: 250.1559
(M?, C15H22O3?; calc. 250.1563).
An appropriate aldehyde was added to a suspension of clay
K10 in CH2Cl2 (10 ml), and then, a solution of isopulegol 4
in CH2Cl2 (10 ml) was added. The solvent was distilled
off. The mixture was stored at r.t. for the required period of
time. Then ethyl acetate (15 ml) was added. The catalyst
was filtered off, the solvent was distilled off, and the
residue was separated on a SiO2 column.
(2R,4R(S),4aR,7R,8aR)-4,7-Dimethyl-2-(thiophen-2-yl)oc-
tahydro-2H-chromen-4-ol (3b) The reaction of isopule-
gol 4 (0.400 g) and thiophene-2-carbaldehyde 5b (0.290 g)
in the presence of clay K10 (1.3 g) for 60 min led to
compound 3b ((R):(S) = 5:1) (0.543 g, 78 %).
1
(R)-3b. H NMR (CDCl3): 0.87–0.96 (m, 1H, Ha-8);
0.93 (d, J(16,9) = 6.7 Hz, 3H, H-16); 1.03 (dddd,
Reactions of isopulegol 4 with aldehydes 5a–i
and 9a,b on clay K10
J(7a,7e) = J(7a,8a) = 12.8 Hz,
J(7a,6a) = 12.2 Hz,
J(7a,8e) = 3.3 Hz, 1H, Ha-7); 1.11 (ddd, J(10a,10e) =
12.2 Hz, J(10a,9a) = 12.2 Hz, J(10a,1a) = 10.8 Hz, 1H,
Ha-10); 1.26 (d, J(15,4a) = 0.8 Hz, 3H, H-15); 1.30 (ddd,
(2R,4R(S),4aR,7R,8aR)-2-(Furan-2-yl)-4,7-dimethyloc-
tahydro-2H-chromen-4-ol (3a) The reaction of isopule-
gol 4 (0.400 g) and furan-2-carbaldehyde 5a (0.250 g) in
the presence of clay K10 (1.3 g) for 60 min led to com-
pound 3a ((R):(S) = 3:1) (0.558 g, 86 %).
J(6a,7a) = 12.2 Hz,
3.3 Hz, 1H, Ha-6); 1.40–1.52 (m, 1H, Ha-9); 1.72 (ddddd,
J(8e,8a) = 12.8 Hz, J(8e,7a) = J(8e,9a) = J(8e,7e) =
3.3 Hz, J(8e,10e) = 2.0 Hz, 1H, He-8); 1.89 (ddq,
J(4a,4e) = 12.7 Hz, J(4a,3a) = 11.8 Hz, J(4a,15) =
J(6a,1a) = 10.2 Hz,
J(6a,7e) =
(R)-3a.1H NMR (CDCl3): 0.85–0.94 (m, 1H, Ha-8); 0.90
(d, J(16,9) = 6.6 Hz, 3H, H-16); 0.97–1.06 (m, 1H, Ha-7);
1.07 (ddd, J(10a,10e) = J(10a,9a) = 12.2 Hz, J(10a,1a) =
10.8 Hz, 1H, Ha-10); 1.23 (d, J(15,4a) = 0.6 Hz, 3H,
H-15); 1.28 (ddd, J(6a,7a) = 12.2 Hz, J(6a,1a) = 10.2 Hz,
J(6a,7e) = 3.2 Hz, 1H, Ha-6); 1.38–1.48 (m, 1H, Ha-9);
1.70 (dm, J(8e,8a) = 13.0 Hz, 1H, He-8); 1.92 (dd,
J(4e,4a) = 12.8 Hz, J(4e,3a) = 2.4 Hz, 1H, He-4); 1.92
(dm, J(7e,7a) = 13.0 Hz, 1H, He-7); 1.95–2.02 (m, 2H,
Ha-4, He-10); 3.24 (ddd, J(1a,10a) = 10.8 Hz, J(1a,
6a) = 10.2 Hz, J(1a, 10e) = 4.3 Hz, 1H, Ha-1); 4.49 (dd,
J(3a,4a) = 11.8 Hz, J(3a,4e) = 2.4 Hz, 1H, Ha-3); 6.24
(dd, J(14,13) = 3.3 Hz, J(14,12) = 0.7 Hz, 1H, H-14);
6.28 (dd, J(13,14) = 3.3 Hz, J(13,12) = 1.8 Hz, 1H,
H-13); 7.33 (dd, J(12,13) = 1.8 Hz, J(12,14) = 0.7 Hz,
H-12). 13C NMR (CDCl3): 77.34 (d, C-1); 70.00 (d, C-3);
45.70 (t, C-4); 70.44 (s, C-5); 51.84 (d, C-6); 22.87 (t, C-7);
34.17 (t, C-8); 31.31 (d, C-9); 41.22 (t, C-10); 154.21 (s,
C-11); 141.98 (d, C-12); 109.90 (d, C-13); 106.43 (d,
C-14); 21.03 (q, C-15); 21.98 (q, C-16). HR-MS: 250.1559
(M?, C15H22O3?; calc. 250.1563).
(S)-3a. 1H NMR (CDCl3): 0.84–0.94 (m, 1H, Ha-8);
0.89 (d, J(16,9) = 6.6 Hz, 3H, H-16); 1.04 (ddd,
J(10a,10e) = J(10a,9a) = 12.2 Hz, J(10a,1a) = 11.2 Hz,
1H, Ha-10); 1.10–1.22 (m, 2H, Ha-6, Ha-7); 1.23 (s, 3H,
H-15); 1.40–1.50 (m, 1H, Ha-9); 1.67–1.74 (m, 1H, He-8);
1.75–1.83 (m, 2H, He-4, He-7); 1.94–2.02 (m, 2H, Ha-4,
He-10); 3.55 (ddd, J(1a,10a) = 11.2 Hz, J(1a,6a) =
9.7 Hz, J(1a,10e) = 4.3 Hz, 1H, Ha-1); 4.83 (dd,
J(3a,4a) = 12.0 Hz, J(3a,4e) = 2.2 Hz, 1H, Ha-3); 6.22
(dd, J(14,13) = 3.3 Hz, J(14,12) = 0.7 Hz, 1H, H-14);
6.27 (dd, J(13,14) = 3.3 Hz, J(13,12) = 1.8 Hz, 1H,
H-13); 7.33 (dd, J(12,13) = 1.8 Hz, J(12,14) = 0.7 Hz,
1H, H-12). 13C NMR (CDCl3): 75.45 (d, C-1); 68.12 (d,
0.8 Hz, 1H, Ha-4); 1.93 (dm, J(7e,7a) = 12.8 Hz, 1H,
He-7); 2.01 (ddm, J(10e,10a) = 12.2 Hz, J(10e,1a) =
4.3 Hz, 1H, He-10); 2.05 (dd, J(4e,4a) = 12.7 Hz,
J(4e,3a) = 2.2 Hz, 1H, He-4); 3.27 (ddd, J(1a,10a) =
10.8 Hz, J(1a, 6a) = 10.2 Hz, J(1a,10e) = 4.3 Hz, 1H,
Ha-1); 4.69 (ddd, J(3a,4a) = 11.8 Hz, J(3a,4e) = 2.2 Hz,
J(3a,14) = 0.7 Hz, 1H, Ha-3); 6.93 (dd, J(13,12) =
5.0 Hz, J(13,14) = 3.5 Hz, 1H, H-13); 6.95 (ddd,
J(14,13) = 3.5 Hz, J(14,12) = 1.2 Hz, J(14, 3a) =
0.7 Hz, 1H, H-14); 7.21 (dd, J(12,13) = 5.0 Hz, J(12,14)
= 1.2 Hz, 1H, H-12). 13C NMR (CDCl3): 77.51 (d, C-1);
72.39 (d, C-3); 49.76 (t, C-4); 70.61 (s, C-5); 51.83 (d,
C-6); 22.89 (t, C-7); 34.21 (t, C-8); 31.34 (d, C-9); 41.27 (t,
C-10); 145.37 (s, C-11); 124.47 (d, C-12); 126.24 (d,
C-13); 123.45 (d, C-14); 21.13 (q, C-15); 22.02 (q, C-16).
HR-MS: 266.1332 (M?, C15H22O2S?; calc. 266.1335).
1
(S)-3b. H NMR (CDCl3): 0.92 (d, J(16,9a) = 6.7 Hz,
3H, H-16); 1.06–1.22 (m, 3H, Ha-6, Ha-7, Ha-10); 1.23 (s,
3H, H-15); 1.83 (dd, J(4a,4e) = 13.7 Hz, J(4a,3a) =
11.5 Hz, 1H, Ha-4); 1.77–1.85 (m, 1H, He-7); 3.59 (ddd,
J(1a,10a) = 11.2 Hz, J(1a,10e) = 4.3 Hz, 1H, Ha-1); 5.04
(ddd, J(3a,4a) = 11.5 Hz, J(3a,4e) = 2.4 Hz, J(3a,14) =
0.7 Hz, 1H, Ha-3); 7.19 (dd, J(12,13) = 5.0 Hz,
1
J(12,14) = 1.2 Hz, 1H, H-12). Other signals in H NMR
spectrum of minor isomer (S)-3b were overlapped with the
signals of (R)-3b. 13C NMR (CDCl3): 75.66 (d, C-1); 70.59
(d, C-3); 47.87 (t, C-4); 69.29 (s, C-5); 49.20 (d, C-6);
22.39 (t, C-7); 34.28 (t, C-8); 31.16 (d, C-9); 41.09 (t,
C-10); 146.06 (s, C-11); 124.17 (d, C-12); 126.22 (d,
C-13); 123.31 (d, C-14); 28.08 (q, C-15); 22.08 (q, C-16).
HR-MS: 266.1332 (M?, C15H22O2S?; calc. 266.1335).
123

Med Chem Res
(2R,4R(S),4aR,7R,8aR)-4,7-Dimethyl-2-(5-methylfuran-2-
yl)octahydro-2H-chromen-4-ol (3c) The reaction of
isopulegol 4 (0.300 g) and 5-methylfuran-2-carbaldehyde
5c (0.210 g) in the presence of clay K10 (1.0 g) for 90 min
gave rise starting isopulegol 4 (0.020 g) and compound 3c
((R):(S) = 3.5:1) (0.312 g, 65 %). Yield is calculated
based on converted 4.
(0.280 g) in the presence of clay K10 (1.2 g) for 60 min
led to compound 3d (0.120 g of (R)-isomer and 0.188 g of
mixture (R):(S) = 1:11; 54 %).
27:1
D
(R)-3d. ½aŠ
? 27.2 (c 0.272, CHCl3). 1H NMR
(CDCl3): 0.87–0.95 (m, 1H, Ha-8); 0.92 (d, J(16,
9) = 6.5 Hz, 3H, H-16); 1.02 (dddd, J(7a,7e) =
J(7a,8a) = 13.0 Hz,
J(7a,6a) = 12.2 Hz,
J(7a,8e) =
(R)-3c. 1H NMR (CDCl3): 0.86–0.95 (m, 1H, Ha-8);
0.91 (d, J(16, 9) = 6.5 Hz, 3H, H-16); 1.02 (dddd,
3.3 Hz, 1H, Ha-7); 1.07 (ddd, J(10a,10e) = J(10a,9a)
= 12.2 Hz, J(10a,1a) = 10.9 Hz, 1H, Ha-10); 1.26 (d,
J(15,4a) = 0.7 Hz, 3H, H-15); 1.31 (ddd, J(6a,7a) =
12.2 Hz, J(6a,1a) = 10.3 Hz, J(6a,7e) = 3.3 Hz, 1H, Ha-
6); 1.39–1.50 (m, 1H, Ha-9); 1.72 (ddddd, J(8e,8a)
= 13.0 Hz, J(8e,7a) = J(8e,9a) = J(8e, 7e) = 3.3 Hz,
J(8e,10e) = 2.0 Hz, 1H, He-8); 1.89 (ddq, J(4a,4e) =
12.7 Hz, J(4a, 3a) = 12.1 Hz, J(4a,15) = 0.7 Hz, 1H, Ha-
4); 1.93 (dm, J(7e,7a) = 13.0 Hz, others J B 3.5 Hz, 1H,
He-7); 1.98 (dddd, J(10e,10a) = 12.2 Hz, J(10e,1a) =
4.3 Hz, J(10e,9a) = 3.7 Hz, J(10e,8e) = 2.0 Hz, 1H, He-
10); 2.03 (dd, J(4e,4a) = 12.7 Hz, J(4e,3a) = 2.2 Hz, 1H,
He-4); 3.26 (ddd, J(1a,10a) = 10.9 Hz, J(1a,6a) = 10.3 Hz,
J(1a,10e) = 4.3 Hz, 1H, Ha-1); 4.55 (dd, J(3a,4a) =
12.1 Hz, J(3a,4e) = 2.2 Hz, 1H, Ha-3); 6.49 (dd,
J(14,13) = 3.8 Hz, J(14,3a) = 0.7 Hz, 1H, H-14); 7.24 (d,
J(13,14) = 3.8 Hz, 1H, H-13). 13C NMR (CDCl3): 77.85 (d,
C-1); 69.98 (d, C-3); 45.70 (t, C-4); 70.19 (s, C-5); 51.76 (d,
C-6); 22.83 (t, C-7); 34.11 (t, C-8); 31.30 (d, C-9); 41.10 (t,
C-10); 157.90 (s, C-11); 151.47 (s, C-12); 112.17 (d, C-13);
109.48 (d, C-14); 20.99 (q, C-15): 21.97 (q, C-16). HR-MS:
J(7a,7e) = J(7a,8a) = 12.8 Hz,
J(7a,6a) = 12.2 Hz,
J(7a,8e) = 3.2 Hz, 1H, Ha-7); 1.08 (ddd, J(10a,10e)
= J(10a,9a) = 12.2 Hz, J(10a,1a) = 10.8 Hz, 1H, Ha-10);
1.23 (d, J(15,4a) = 0.8 Hz, 3H, H-15); 1.29 (ddd,
J(6a,7a) = 12.2 Hz, J(6a,1a) = 10.2 Hz, J(6a,7e) = 3.3 Hz,
1H, Ha-6); 1.38–1.50 (m, 1H, Ha-9); 1.71–1.74 (dm,
J(8e,8a) = 12.8 Hz, 1H, He-8); 1.90–1.95 (m, 1H, He-7);
1.91 (dd, J(4e,4a) = 12.8 Hz, J(4e,3a) = 2.2 Hz, 1H, He-4);
1.95–2.02 (m, 1H, He-10); 1.99 (ddq, J(4a,4e) = 12.8 Hz,
J(4a,3a) = 11.8 Hz, J(4a,15) = 0.8 Hz, 1H, Ha-4); 2.25 (d,
J(17,13) = 1.0 Hz, 3H, H-17); 3.24 (ddd, J(1a,10a) =
10.8 Hz, J(1a,6a) = 10.2 Hz, J(1a,10e) = 4.2 Hz, 1H, Ha-
1); 4.43 (dd, J(3a,4a) = 11.8 Hz, J(3a,4e) = 2.2 Hz, 1H, Ha-
3); 5.87 (dq, J(13,14) = 3.1 Hz, J(13,17) = 1.0 Hz, 1H,
H-13); 6.13 (d, J(14,13) = 3.1 Hz, 1H, H-14). 13C NMR
(CDCl3): 77.34 (d, C-1); 70.08 (d, C-3); 45.66 (t, C-4); 70.62
(s, C-5); 51.94 (d, C-6); 22.96 (t, C-7); 34.25 (t, C-8); 31.40
(d, C-9); 41.35 (t, C-10); 152.48 (s, C-11); 151.84 (s, C-12);
105.95 (d, C-13); 107.51 (d, C-14); 21.14 (q, C-15); 22.04 (q,
C-16); 13.47 (q, C-17). HR-MS: 264.1722 (M?, C16H24O3
295.1428 (M?, C15H21O5N?; calc. 295.1414).
?
;
27:3
D
calc. 264.1720).
(S)-3d. ½aŠ
? 57.6 (c 1.00, CHCl3). 1H NMR
(S)-3c. 1H NMR (CDCl3): 0.86–0.95 (m, 1H, Ha-8); 0.90
(d, J(16,9) = 6.5 Hz, 3H, H-16); 1.01–1.09 (m, 1H, Ha-
10); 1.11–1.21 (m, 2H, Ha-6, Ha-7); 1.24 (s, 3H, H-15);
1.38–1.50 (m, 1H, Ha-9); 1.68–1.74 (m, 1H, He-8); 1.78
(dd, J(4e,4a) = 13.7 Hz, J(4e,3a) = 2.2 Hz, 1H, He-4);
1.78–1.83 (m, 1H, He-7); 1.95–2.02 (m, 2H, Ha-4, He-10);
2.25 (s, 3H, H-17); 3.55 (ddd, J(1a,10a) = 11.2 Hz,
J(1a,6a) = 9.7 Hz, J(1a,10e) = 4.2 Hz, 1H, Ha-1); 4.77
(dd, J(3a,4a) = 12.0 Hz, J(3a,4e) = 2.2 Hz, 1H, Ha-3);
5.86 (dq, (J(13,14) = 3.1 Hz, J(13,17) = 1.0 Hz, 1H,
H-13); 6.11 (d, J(14,13) = 3.1 Hz, 1H, H-14). 13C NMR
(CDCl3): 75.48 (d, C-1); 68.21 (d, C-3); 43.72 (t, C-4);
69.17 (s, C-5); 49.23 (d, C-6); 22.47 (t, C-7); 34.32 (t, C-8);
31.22 (d, C-9); 41.16 (t, C-10); 152.98 (s, C-11); 151.74 (s,
C-12); 105.86 (d, C-13); 107.51 (d, C-14); 28.21 (q, C-15);
22.11 (q, C-16); 13.50 (q, C-17). HR-MS: 264.1722 (M?,
C16H24O3?; calc. 264.1720).
(CDCl3): 0.87–0.96 (m, 1H, Ha-8); 0.90 (d, J(16,9) =
6.6 Hz, 3H, H-16); 1.02 (ddd, J(10a,10e) = J(10a,9a)
= 12.1 Hz, J(10a,1a) = 11.2 Hz, 1H, Ha-10); 1.10–1.21
(m, 2H, Ha-6, Ha-7); 1.25 (s, 3H, H-15); 1.41–1.51 (m, 1H,
Ha-9); 1.72 (dm, J(8e,8a) = 13.0 Hz, others J B 4.0 Hz,
1H, He-8); 1.77–1.82 (m, 1H, He-7); 1.86 (dd,
J(4a,4e) = 13.6 Hz, J(4a,3a) = 11.3 Hz, 1H, Ha-4); 1.91
(dd, J(4e,4a) = 13.6 Hz, J(4e,3a) = 3.0 Hz, 1H, He-4);
1.94 (dddd, J(10e,10a) = 12.1 Hz, J(10e,1a) = 4.2 Hz,
J(10e,9a) = 3.7 Hz, J(10e,8e) = 2.0 Hz, 1H, He-10);
3.57 (ddd, J(1a,10a) = 11.2 Hz, J(1a,6a) = 9.6 Hz,
J(1a,10e) = 4.2 Hz, 1H, Ha-1); 4.91 (dd, J(3a,4a) =
11.3 Hz, J(3a,4e) = 3.0 Hz, 1H, Ha-3); 6.47 (dd,
J(14,13) = 3.7 Hz, J(14,3a) = 0.6 Hz, 1H, H-14); 7.23
(d, J(13,14) = 3.7 Hz, 1H, H-13). 13C NMR (CDCl3):
75.88 (d, C-1); 68.25 (d, C-3); 43.69 (t, C-4); 68.74 (s,
C-5); 49.18 (d, C-6); 22.32 (t, C-7); 34.17 (t, C-8); 31.11
(d, C-9); 40.89 (t, C-10); 158.72 (s, C-11); 151.50 (s,
C-12); 112.21 (d, C-13); 109.54 (d, C-14); 27.97 (q, C-15);
22.01 (q, C-16). HR-MS: 295.1428 (M?, C15H21O5N?;
calc. 295.1414).
(2R,4R(S),4aR,7R,8aR)-4,7-Dimethyl-2-(5-nitrofuran-2-yl)
octahydro-2H-chromen-4-ol (3d) The reaction of isop-
ulegol 4 (0.300 g) and 5-nitrofuran-2-carbaldehyde 5d
123

Med Chem Res
(2R,4R(S),4aR,7R,8aR)-4,7-Dimethyl-2-(5-methylthiophen-
2-yl)octahydro-2H-chromen-4-ol (3e) The reaction of
isopulegol 4 (0.300 g) and 5-methylthiophene-2-carbalde-
hyde 5e (0.250 g) in the presence of clay K10 (1.1 g) for
120 min gave rise to starting isopulegol 4 (0.034 g) and
compound 3e ((R):(S) = 4.5:1) (0.386 g, 80 %). Yield is
calculated based on converted 4.
(q, C-16); 15.13 (q, C-17). HR-MS: 280.1491 (M?,
C16H24O2S?; calc. 280.1492).
(2R,4R(S),4aR,7R,8aR)-4,7-Dimethyl-2-(3-methylthiophen-2-
yl)octahydro-2H-chromen-4-ol (3f) The reaction of isop-
ulegol 4 (0.300 g) and 3-methylthiophene-2-carbaldehyde
5f (0.250 g) in the presence of clay K10 (1.1 g) for
120 min led to compound 3f ((R):(S) = 10:1) (0.381 g,
69 %).
1
(R)-3e. H NMR (CDCl3): 0.87–0.96 (m, 1H, Ha-8); 0.92
(d, J(16,9a) = 6.6 Hz, 3H, H-16); 1.02 (dddd, J(7a,7e) =
J(7a,8a) = 12.8 Hz, J(7a,6a) = 12.2 Hz, J(7a,8e) = 3.3 Hz,
1H, Ha-7); 1.09 (ddd, J(10a,10e) = J(10a,9a) = 12.3 Hz,
J(10a,1a) = 10.8 Hz, 1H, Ha-10); 1.25 (d, J(15,4a) =
0.8 Hz, 3H, H-15); 1.28 (ddd, J(6a,7a) = 12.2 Hz,
(R)-3f. 1H NMR (CDCl3): 0.88–0.97 (m, 1H, Ha-8); 0.92
(d, J(16,9a) = 6.6 Hz, 3H, H-16); 1.03 (dddd,
J(7a,7e) = J(7a,8a) = 12.8 Hz,
J(7a,6a) = 12.1 Hz,
J(7a,8e) = 3.3 Hz, 1H, Ha-7); 1.11 (ddd, J(10a,10e) =
J(10a,9a) = 12.2 Hz, J(10a,1a) = 10.8 Hz, 1H, Ha-10);
1.28 (d, J(15,4a) = 0.7 Hz, 3H, H-15); 1.31 (ddd,
J(6a,1a) = 10.2 Hz,
J(6a,7e) = 3.3 Hz,
1H,
Ha-6);
1.39–1.52 (m, 2H, Ha-9, OH); 1.72 (ddddd, J(8e,8a) =
12.8 Hz, J(8e,7a) = J(8e,9a) = J(8e,7e) = 3.3 Hz, J(8e,10e)
= 2.0 Hz, 1H, He-8); 1.86 (ddq, J(4a,4e) = 12.7 Hz,
J(4a,3a) = 11.7 Hz, J(4a,15) = 0.8 Hz, 1H, Ha-4); 1.93
(dddd, J(7e,7a) = 12.8 Hz, J(7e,6a) = J(7e,8a) = J(7e,8e) =
3.3 Hz, 1H, He-7); 1.99 (dm, J(10e,10a) = 12.3 Hz, 1H,
He-10); 2.01 (dd, J(4e,4a) = 12.7 Hz, J(4e,3a) = 2.2 Hz, 1H,
He-4); 2.42 (d, J(17,13) = 1.1 Hz, 3H, H-17); 3.24 (ddd,
J(6a,7a) = 12.1 Hz,
J(6a,1a) = 10.2 Hz,
J(6a,7e) =
3.3 Hz, 1H, Ha-6); 1.40–1.53 (m, 2H, Ha-9, OH); 1.72
(ddddd, J(8e,8a) = 12.9 Hz, J(8e,7a) = J(8e,9a) = -
J(8e,7e) = 3.3 Hz, J(8e,10e) = 2.0 Hz, 1H, He-8); 1.85
(ddq,
J(4a,4e) = 12.7 Hz,
J(4a,3a) = 11.7 Hz,
J(4a,15) = 0.7 Hz, 1H, Ha-4); 1.91–1.97 (m, 1H, He-7);
1.95 (dd, J(4e,4a) = 12.7 Hz, J(4e,3a) = 2.4 Hz, 1H, He-
4); 1.99 (dm, J(10e,10a) = 12.2 Hz, 1H, He-10); 2.19 (s,
3H, H-17); 3.26 (ddd, J(1a,10a) = 10.8 Hz, J(1a,6a)
= 10.2 Hz, J(1a,10e) = 4.3 Hz, 1H, Ha-1); 4.71 (dd,
J(3a,4a) = 11.7 Hz, J(3a,4e) = 2.4 Hz, 1H, Ha-3); 6.75
J(1a,10a) = 10.8 Hz,
J(1a,6a) = 10.2 Hz,
J(1a,10e) =
4.3 Hz, 1H, Ha-1); 4.59 (dd, J(3a,4a) = 11.7 Hz, J(3a,4e) =
2.2 Hz, 1H, Ha-3); 6.56 (dq, J(13,14) = 3.4 Hz, J(13,17) =
1.1 Hz, 1H, H-13); 6.73 (d, J(14,13) = 3.4 Hz, 1H, H-14). 13
C
(d,
J(13,12) = 5.0 Hz,
1H,
H-13);
7.09
(d,
NMR (CDCl3): 77.43 (d, C-1); 72.54 (d, C-3); 49.58 (t, C-4);
70.69 (s, C-5); 51.89 (d, C-6); 22.93 (t, C-7); 34.26 (t, C-8);
31.38 (d, C-9); 41.35 (t, C-10); 142.89 (s, C-11); 139.12 (s,
C-12); 124.26 (d, C-13); 123.50 (d, C-14); 21.17 (q, C-15);
22.04 (q, C-16); 15.16 (q, C-17). HR-MS: 280.1491 (M?,
C16H24O2S?; calc. 280.1492).
J(12,13) = 5.0 Hz, 1H, H-12). 13C NMR (CDCl3): 77.63
(d, C-1); 71.09 (d, C-3); 49.70 (t, C-4); 70.64 (s, C-5);
51.91 (d, C-6); 22.94 (t, C-7); 34.26 (d, C-9); 41.32 (t,
C-10); 138.34 (s, C-11); 122.92 (d, C-12); 129.72 (d,
C-13); 133.29 (s, C-14); 21.09 (q, C-15); 22.03 (q, C-16);
13.63 (q, C-17). HR-MS: 280.1488 (M?, C16H24O2S?;
calc. 280.1492).
(S)-3e. 1H NMR (CDCl3): 0.86–0.97 (m, 1H, Ha-8); 0.91
(d, J(16,9a) = 6.5 Hz, 3H, H-16); 1.05 (ddd,
J(10a,10e) = J(10a,9a) = 12.2 Hz, J(10a,1a) = 11.2 Hz,
1H, Ha-10); 1.11–1.20 (m, 2H, Ha-6, Ha-7); 1.23 (s, 3H,
H-15); 1.41–1.52 (m, 1H, Ha-9); 1.72 (dm,
J(8e,8a) = 13.1 Hz, 1H, He-8); 1.76–1.84 (m, 1H, He-7);
1.80 (dd, J(4a,4e) = 13.7 Hz, J(4a,3a) = 11.5 Hz, 1H, Ha-
4); 1.90 (dd, J(4e,4a) = 13.7 Hz, J(4e,3a) = 2.4 Hz, 1H,
He-4); 1.98 (dddd, J(10e,10a) = 12.2 Hz, J(10e,1a) =
4.2 Hz, J(10e,9a) = 3.3 Hz, J(10e,8e) = 2.0 Hz, 1H, He-
10); 2.41 (d, J(17,13) = 1.1 Hz, 3H, H-17); 3.55 (ddd,
J(1a,10a) = 11.2 Hz, J(1a,6a) = 9.7 Hz, J(1a,10e) =
4.2 Hz, 1H, Ha-1); 4.93 (dd, J(3a,4a) = 11.5 Hz,
J(3a,4e) = 2.4 Hz, 1H, Ha-3); 6.55 (dq, J(13,14) =
3.4 Hz, J(13,17) = 1.1 Hz, 1H, H-13); 6.72 (d,
J(14,13) = 3.4 Hz, 1H, H-14). 13C NMR (CDCl3): 75.57
(d, C-1); 70.68 (d, C-3); 47.66 (t, C-4); 69.34 (s, C-5);
49.22 (d, C-6); 22.40 (t, C-7); 34.31 (t, C-8); 31.17 (d,
C-9); 41.14 (t, C-10); 143.54 (s, C-11); 138.74 (s, C-12);
124.22 (d, C-13); 123.36 (d, C-14); 28.08 (q, C-15); 22.08
1
(S)-3f. H NMR (CDCl3): 0.91 (d, J(16,9a) = 6.6 Hz,
3H, H-16); 1.16–1.21 (m, 1H, Ha-6); 1.23 (s, 3H, H-15);
2.21 (s, 3H, H-17); 3.58 (ddd, J(1a,10a) = 11.3 Hz,
J(1a,6a) = 9.7 Hz, J(1a,10e) = 4.3 Hz, 1H, Ha-1); 5.07
(dd, J(3a,4a) = 10.8 Hz, J(3a,4e) = 3.1 Hz, 1H, Ha-3);
7.08 (d, J(12,13) = 5.0 Hz, 1H, H-12). Other signals in 1H
NMR spectrum of minor isomer (S)-3f were overlapped
with the signals of (R)-3f. 13C NMR (CDCl3): 75.76 (d,
C-1); 69.10 (d, C-3); 47.64 (t, C-4); 69.39 (s, C-5); 49.23
(d, C-6); 22.45 (t, C-7); 34.33 (t, C-8); 31.21 (d, C-9);
41.15 (t, C-10); 138.92 (s, C-11); 122.69 (d, C-12); 126.03
(d, C-13); 133.43 (s, C-14); 28.09 (q, C-15); 22.09 (q,
C-16), 13.63 (q, C-17). HR-MS: 280.1488 (M?,
C16H24O2S?; calc. 280.1492).
(2R,4R(S),4aR,7R,8aR)-2-(5-Bromothiophen-2-yl)-4,7-
dimethyloctahydro-2H-chromen-4-ol (3g) The reac-
tion of isopulegol 4 (0.300 g) and 5-bromothiophene-2-
carbaldehyde 5g (0.370 g) in the presence of clay K10
123

Med Chem Res
(1.4 g) for 120 min led to compound 3g (0.443 g of (R)-
isomer and 0.069 g of (S)-isomer; (R):(S) = 6.4:1; 76 %).
of isopulegol 4 (0.300 g) and 4-bromothiophene-2-car-
baldehyde 5h (0.370 g) in the presence of clay K10 (1.4 g)
for 120 min led to compound 3h ((R):(S) = 3:1) (0.499 g,
74 %).
26:9
D
(R)-3g. ½aŠ
- 65.2 (c 0.276, CHCl3). 1H NMR
(CDCl3): 0.87–0.96 (m, 1H, Ha-8); 0.92 (d, J(16,9a) =
1
6.6 Hz,
3H,
H-16);
1.02
(dddd,
J(7a,7e) =
J(7a,8e) =
(R)-3h. H NMR (CDCl3): 0.87–0.96 (m, 1H, Ha-8);
0.93 (d, J(16,9a) = 6.6 Hz, 3H, H-16); 1.02 (dddd,
J(7a,8a) = 12.8 Hz,
J(7a,6a) = 12.2 Hz,
3.3 Hz, 1H, Ha-7); 1.09 (ddd, J(10a,10e) = J(10a,9a)
= 12.2 Hz, J(10a,1a) = 10.8 Hz, 1H, Ha-10); 1.25 (d,
J(15,4a) = 0.8 Hz, 3H, H-15); 1.28 (ddd, J(6a,7a) =
12.2 Hz, J(6a,1a) = 10.2 Hz, J(6a,7e) = 3.3 Hz, 1H, Ha-
6); 1.37–1.50 (m, 2H, Ha-9, OH); 1.72 (dm, J(8e,8a)
= 12.8 Hz, others J \ 3.5 Hz, 1H, He-8); 1.81 (ddq,
J(7a,7e) = J(7a,8a) = 12.8 Hz,
J(7a,6a) = 12.1 Hz,
J(7a,8e) = 3.2 Hz, 1H, Ha-7); 1.10 (ddd, J(10a,10e)
= J(10a,9a) = 12.2 Hz, J(10a,1a) = 11.1 Hz, 1H, Ha-
10); 1.26 (d, J(15,4a) = 0.7 Hz, 3H, H-15); 1.29 (ddd,
J(6a,7a) = 12.1 Hz,
J(6a,1a) = 10.1 Hz,
J(6a,7e) =
3.2 Hz, 1H, Ha-6); 1.39–1.50 (m, 1H, Ha-9); 1.56 (br.s,
OH); 1.72 (dm, J(8e,8a) = 12.8 Hz, others J \ 3.5 Hz,
1H, He-8); 1.82 (ddq, J(4a,4e) = 12.7 Hz, J(4a,3a)
= 11.7 Hz, J(4a,15) = 0.7 Hz, 1H, Ha-4); 1.93 (dddd,
J(4a,4e) = 12.7 Hz,
J(4a,3a) = 11.8 Hz,
J(4a,15) =
0.8 Hz, 1H, Ha-4); 1.92 (dddd, J(7e,7a) = 12.8 Hz,
J(7e,6a) = J(7e,8a) = J(7e,8e) = 3.3 Hz, 1H, He-7); 1.98
(dddd,
J(10e,10a) = 12.2 Hz,
J(10e,1a) = 4.3 Hz,
J(7e,7a) = 12.8 Hz,
J(7e,6a) = J(7e,8a) = J(7e,8e) =
J(10e,9a) = 3.7 Hz, J(10e,8e) = 2.0 Hz, 1H, He-10);
2.01 (dd, J(4e,4a) = 12.7 Hz, J(4e,3a) = 2.2 Hz, 1H, He-
4); 3.24 (ddd, J(1a,10a) = 10.8 Hz, J(1a,6a) = 10.2 Hz,
J(1a,10e) = 4.3 Hz, 1H, Ha-1); 4.59 (ddd, J(3a,4a) =
11.8 Hz, J(3a,4e) = 2.2 Hz, J(3a,14) = 0.8 Hz, 1H, Ha-
3); 6.68 (dd, J(14,13) = 3.8 Hz, J(14,3a) = 0.8 Hz, 1H,
H-14); 6.86 (d, J(13,14) = 3.8 Hz, 1H, H-13). 13C NMR
(CDCl3): 77.58 (d, C-1); 72.53 (d, C-3); 49.42 (t, C-4);
70.54 (s, C-5); 51.84 (d, C-6); 22.89 (t, C-7); 34.20 (t, C-8);
31.35 (d, C-9); 41.23 (t, C-10); 147.17 (s, C-11); 111.45 (s,
C-12); 129.01 (d, C-13); 123.55 (d, C-14); 21.16 (q, C-15);
22.02 (q, C-16); HR-MS: 345.0442 (M?, C15H21O2SBr?;
3.2 Hz, 1H, He-7); 1.99 (dddd, J(10e,10a) = 12.8 Hz,
J(10e,1a) = 4.3 Hz, J(10e,9a) = 3.7 Hz, J(10e,8e) =
2.0 Hz, 1H, He-10); 2.01 (dd, J(4e,4a) = 12.7 Hz,
J(4e,3a) = 2.2 Hz, 1H, He-4); 3.26 (ddd, J(1a,10a) =
11.1 Hz, J(1a,6a) = 10.1 Hz, J(1a,10e) = 4.3 Hz, 1H,
Ha-1); 4.62 (ddd, J(3a,4a) = 11.7 Hz, J(3a,4e) = 2.2 Hz,
J(3a,14) = 0.8 Hz, 1H, Ha-3); 6.86 (dd, J(14,12)
= 1.5 Hz, J(14,3a) = 0.8 Hz, 1H, H-14); 7.11 (d,
J(12,14) = 1.5 Hz, 1H, H-12). 13C NMR (CDCl3): 77.65
(d, C-1); 72.07 (d, C-3); 49.54 (t, C-4); 70.52 (s, C-5);
51.82 (d, C-6); 22.89 (t, C-7); 34.20 (t, C-8); 31.36 (d,
C-9); 41.22 (t, C-10); 146.74 (s, C-11); 121.72 (d, C-12);
108.88 (s, C-13); 126.11 (d, C-14); 21.16 (q, C-15); 22.02
(q, C-16). HR-MS: 345.0445 (M?, C15H21O2SBr?; calc.
345.0440).
calc. 345.0440).
27:0
D
(S)-3g. ½aŠ
? 36.5 (c 0.768, CHCl3). 1H NMR
(CDCl3): 0.87–0.97 (m, 1H, Ha-8); 0.91 (d, J(16,9a) =
6.6 Hz, 3H, H-16); 1.04 (ddd, J(10a,10e) = J(10a,9a)
= 12.2 Hz, J(10a,1a) = 11.2 Hz, 1H, Ha-10); 1.08–1.19
(m, 2H, Ha-6, Ha-7); 1.22 (s, 3H, H-15); 1.41–1.51 (m, 1H,
Ha-9); 1.74 (dd, J(4a,4e) = 13.5 Hz, J(4a,3a) = 11.6 Hz,
1H, Ha-4); 1.69–1.75 (m, 1H, He-8); 1.77–1.83 (m, 1H, He-
7); 1.90 (dd, J(4e,4a) = 13.5 Hz, J(4e,3a) = 2.4 Hz, 1H,
He-4); 1.97 (dddd, J(10e,10a) = 12.2 Hz, J(10e,1a) =
4.2 Hz, J(10e,9a) = 3.8 Hz, J(10e,8e) = 2.0 Hz, 1H, He-
10); 3.55 (ddd, J(1a,10a) = 11.2 Hz, J(1a,6a) = 9.7 Hz,
J(1a,10e) = 4.2 Hz, 1H, Ha-1); 4.94 (ddd, J(3a,4a) =
11.6 Hz, J(3a,4e) = 2.4 Hz, J(3a,14) = 0.8 Hz, 1H, Ha-
3); 6.66 (dd, J(14,13) = 3.8 Hz, J(14,3a) = 0.8 Hz, 1H,
H-14); 6.85 (d, J(13,14) = 3.8 Hz, 1H, H-13). 13C NMR
(CDCl3): 75.69 (d, C-1); 70.75 (d, C-3); 47.50 (t, C-4);
69.21 (s, C-5); 49.18 (d, C-6); 22.37 (t, C-7); 34.25 (t, C-8);
31.15 (d, C-9); 41.02 (t, C-10); 147.92 (s, C-11); 111.02 (s,
C-12); 128.96 (d, C-13); 123.38 (d, C-14); 28.07 (q, C-15);
22.06 (q, C-16). HR-MS: 345.0442 (M?, C15H21O2SBr?;
calc. 345.0440).
1
(S)-3h. Some signals in H NMR spectrum of minor
isomer (S)-3h were overlapped with the signals of (R)-3h.
1H NMR (CDCl3): 0.88–0.97 (m, 1H, Ha-8); 0.92 (d,
J(16,9a) = 6.6 Hz, 3H, H-16); 1.01–1.21 (m, 3H, Ha-10,
Ha-6, Ha-7); 1.24 (s, 3H, H-15); 1.40–1.51 (m, 1H, Ha-9);
1.75 (dd, J(4a,4e) = 13.6 Hz, J(4a,3a) = 11.6 Hz, 1H, Ha-
4); 1.70–1.83 (m, 2H, He-8, He-7); 1.90–2.02 (m, 2H, He-4,
He-10); 3.57 (ddd, J(1a,10a) = 11.1 Hz, J(1a,6a) =
9.7 Hz, J(1a,10e) = 4.3 Hz, 1H, Ha-1); 4.97 (ddd, J(3a,4a)
= 11.6 Hz, J(3a,4e) = 2.3 Hz, J(3a,14) = 0.8 Hz, 1H, Ha-
3); 6.85 (dd, J(14,12) = 1.5 Hz, J(14,3a) = 0.8 Hz, 1H,
H-14); 7.09 (d, J(12,14) = 1.5 Hz, 1H, H-12). 13C NMR
(CDCl3): 75.79 (d, C-1); 70.29 (d, C-3); 47.57 (t, C-4);
69.26 (s, C-5); 49.21 (d, C-6); 22.40 (t, C-7); 34.27 (t, C-8);
31.19 (d, C-9); 41.03 (t, C-10); 147.49 (s, C-11); 121.45 (d,
C-12); 108.85 (s, C-13); 125.89 (d, C-14); 28.11 (q, C-15);
22.08 (q, C-16). HR-MS: 345.0445 (M?, C15H21O2SBr?;
calc. 345.0440).
(2R,4R(S),4aR,7R,8aR)-4,7-Dimethyl-2-(5-nitrothiophen-
2-yl)octahydro-2H-chromen-4-ol (3i) The reaction of
(2R,4R(S),4aR,7R,8aR)-2-(4-Bromothiophen-2-yl)-4,7-
dimethyloctahydro-2H-chromen-4-ol (3h) The reaction
isopulegol
4
(0.400 g)
and
5-nitrothiophene-2-
123

Med Chem Res
carbaldehyde 5i (0.410 g) for 60 min in the presence of
clay K10 (1.6 g) led to compound 3i (0.167 g of (R)-iso-
mer, 0.233 g of mixture (R):(S) = 1:6; 50 %).
isopulegol 4 (0.300 g) and furan-3-carbaldehyde 9a
(0.190 g) in the presence of clay K10 (1.0 g) for 60 min
led to compound 8a (0.178 g of (R)-isomer, 0.050 g of (S)-
27:3
(R)-3i. ½aŠ
? 17.9 (c 0.312, CHCl3). 1H NMR
isomer and 0.072 g of mixture (R):(S) = 8:1; 61 %).
26:4
D
(CDCl3): 0.86–0.95 (m, 1H, Ha-8); 0.93 (d,
(R)-8a. ½aŠ
? 4.3 (c 0.326, MeOH). 1H NMR
D
J(16,9a) = 6.6 Hz, 3H, H-16); 1.01 (dddd, J(7a,7e) =
(CDCl3): 0.87–0.96 (m, 1H, Ha-8); 0.92 (d, J(16,9) =
6.5 Hz, 3H, H-16); 1.03 (dddd, J(7a,7e) = J(7a,8a) =
13.0 Hz, J(7a,6a) = 12.2 Hz, J(7a,8e) = 3.2 Hz, 1H, Ha-
J(7a,8a) = 12.8 Hz,
J(7a,6a) = 12.1 Hz,
J(7a,8e) =
3.4 Hz, 1H, Ha-7); 1.09 (ddd, J(10a,10e) = J(10a,9a) =
12.2 Hz, J(10a,1a) = 10.9 Hz, 1H, Ha-10); 1.26 (d,
J(15,4a) = 0.7 Hz, 3H, H-15); 1.29 (ddd, J(6a,7a) =
12.1 Hz, J(6a,1a) = 10.2 Hz, J(6a,7e) = 3.2 Hz, 1H,
Ha-6); 1.39–1.50 (m, 1H, Ha-9); 1.72 (dm, J(8e,8a) =
12.8 Hz, others J \ 3.5 Hz, 1H, He-8); 1.75 (ddq, J(4a,4e)
= 12.8 Hz, J(4a,3a) = 11.9 Hz, J(4a,15) = 0.7 Hz, 1H,
Ha-4); 1.92 (dddd, J(7e,7a) = 12.8 Hz, J(7e,6a) =
J(7e,8a) = J(7e,8e) = 3.2 Hz, 1H, He-7); 1.99 (dddd,
J(10e,10a) = 12.2 Hz, J(10e,1a) = 4.3 Hz, J(10e,9a) =
3.7 Hz, J(10e,8e) = 1.9 Hz, 1H, He-10); 2.04 (dd,
J(4e,4a) = 12.8 Hz, J(4e,3a) = 2.2 Hz, 1H, He-4); 3.27
(ddd, J(1a,10a) = 10.9 Hz, J(1a,6a) = 10.2 Hz, J(1a,10e)
= 4.3 Hz, 1H, Ha-1); 4.65 (ddd, J(3a,4a) = 11.9 Hz,
J(3a,4e) = 2.2 Hz, J(3a,14) = 0.9 Hz, 1H, Ha-3); 6.82
(dd, J(14,13) = 4.2 Hz, J(14,3a) = 0.9 Hz, 1H, H-14);
7.75 (d, J(13,14) = 4.2 Hz, 1H, H-13). 13C NMR (CDCl3):
77.81 (d, C-1); 72.38 (d, C-3); 49.42 (t, C-4); 70.25 (s,
C-5); 51.68 (d, C-6); 22.78 (t, C-7); 34.09 (t, C-8); 31.25
(d, C-9); 41.04 (t, C-10); 154.79 (s, C-11); 150.56 (s,
C-12); 128.17 (d, C-13); 121.75 (d, C-14); 21.01 (q, C-15);
21.95 (q, C-16). HR-MS: 311.1185 (M?, C15H21O2SBr?;
calc. 311.1186).
(S)-3i. 1H NMR (CDCl3): 0.88–0.97 (m, 1H, Ha-8); 0.92
(d, J(16,9a) = 6.5 Hz, 3H, H-16); 1.05 (ddd, J(10a,10e)
= J(10a,9a) = 12.1 Hz, J(10a,1a) = 11.2 Hz, 1H, Ha-10);
1.09–1.20 (m, 2H, Ha-6, Ha-7); 1.24 (s, 3H, H-15);
1.41–1.52 (m, 1H, Ha-9); 1.67 (dd, J(4a,4e) = 13.4 Hz,
J(4a,3a) = 11.6 Hz, 1H, Ha-4); 1.72 (dm, J(8e,8a) =
13.1 Hz, others J \ 3.5 Hz, 1H, He-8); 1.77–1.83 (m, 1H,
He-7); 1.95 (dd, J(4e,4a) = 13.4 Hz, J(4e,3a) = 2.4 Hz,
1H, He-4); 1.97 (dm, J(10e,10a) = 12.1 Hz, others
J \ 4.5 Hz, 1H, He-10); 3.58 (ddd, J(1a,10a) = 11.2 Hz,
J(1a,6a) = 9.7 Hz, J(1a,10e) = 4.2 Hz, 1H, Ha-1); 5.01
(ddd, J(3a,4a) = 11.6 Hz, J(3a,4e) = 2.4 Hz, J(3a,14) =
1.0 Hz, 1H, Ha-3); 6.81 (dd, J(14,13) = 4.2 Hz,
J(14,3a) = 1.0 Hz, 1H, H-14); 7.74 (d, J(13,14) =
4.2 Hz, 1H, H-13). 13C NMR (CDCl3): 75.89 (d, C-1);
70.73 (d, C-3); 47.54 (t, C-4); 69.98 (s, C-5); 49.12 (d,
C-6); 22.28 (t, C-7); 34.14 (t, C-8); 31.08 (d, C-9); 40.83 (t,
C-10); 155.99 (s, C-11); 150.31 (s, C-12); 128.26 (d, C-13);
121.60 (d, C-14); 27.91 (q, C-15); 22.00 (q, C-16). HR-MS:
311.1185 (M?, C15H21O2SBr?; calc. 311.1186).
7);
1.07
(ddd,
J(10a,10e) = J(10a,9a) = 12.2 Hz,
J(10a,1a) = 10.8 Hz, 1H, Ha-10); 1.25 (d, J(15,4a) =
0.7 Hz, 3H, H-15); 1.27 (ddd, J(6a,7a) = 12.2 Hz,
J(6a,1a) = 10.2 Hz, J(6a,7e) = 3.2 Hz, 1H, Ha-6);
1.39–1.50 (m, 1H, Ha-9); 1.72 (dm, J(8e,8a) = 13.0 Hz,
others
J B 3.5 Hz,
1H,
He-8);
1.79
(ddq,
J(4a,4e) = 12.7 Hz,
J(4a,3a) = 11.8 Hz,
J(4a,15) =
0.7 Hz, 1H, Ha-4); 1.91 (dd, J(4e,4a) = 12.7 Hz,
J(4e,3a) = 2.2 Hz, 1H, He-4); 1.92 (dm, J(7e,7a) =
13.0 Hz, others J B 3.5 Hz, 1H, He-7); 1.98 (dddd,
J(10e,10a) = 12.2 Hz, J(10e,1a) = 4.3 Hz, J(10e,9a) =
3.7 Hz, J(10e,8e) = 2.0 Hz, 1H, He-10); 3.22 (ddd,
J(1a,10a) = 10.8 Hz, J(1a,6a) = 10.2 Hz, J(1a,10e) =
4.3 Hz, 1H, Ha-1); 4.42 (dd, J(3a,4a) = 11.8 Hz, J(3a,
4e) = 2.2 Hz, 1H, Ha-3); 6.38 (dd, J(14,13) = 1.8 Hz,
J(14,12) = 0.8 Hz,
1H,
H-14);
7.34
(dd,
J(13,14) = 1.8 Hz, J(13,12) = 1.5 Hz, 1H, H-13); 7.37
(ddd, J(12,13) = 1.5 Hz, J(12,14) = 0.8 Hz, J(12,3a) =
0.5 Hz, 1H, H-12). 13C NMR (CDCl3): 77.26 (d, C-1);
69.42 (d, C-3); 48.43 (t, C-4); 70.58 (s, C-5); 51.97 (d,
C-6); 22.94 (t, C-7); 34.27 (t, C-8); 31.37 (d, C-9); 41.38 (t,
C-10); 126.72 (s, C-11); 139.03 (d, C-12); 142.93 (d,
C-13); 108.79 (d, C-14); 21.19 (q, C-15); 22.06 (q, C-16).
HR-MS: 250.1561 (M?, C15H22O3?; calc. 250.1563).
26:3
D
(S)-8a. ½aŠ
? 10.3 (c 0.812, MeOH). 1H NMR
(CDCl3): 0.87–0.96 (m, 1H, Ha-8); 0.91 (d,, J(16,9) =
6.5 Hz, 3H, H-16); 1.03 (ddd, J(10a,10e) = J(10a,9a)
= 12.1 Hz, J(10a,1a) = 11.2 Hz, 1H, Ha-10); 1.08–1.20
(m, 2H, Ha-6, Ha-7); 1.22 (s, 3H, H-15); 1.41–1.52 (m, 1H,
Ha-9); 1.72 (dm, J(8e,8a) = 13.0 Hz, 1H, He-8); 1.73 (dd,
J(4a,4e) = 13.6 Hz, J(4a,3a) = 11.5 Hz, 1H, Ha-4);
1.78–1.83 (m, 1H, He-7); 1.80 (dd, J(4e,4a) = 13.6 Hz,
J(4e,3a) = 2.5 Hz, 1H, He-4); 1.96 (dddd, J(10e,10a) =
12.1 Hz,
J(10e,1a) = 4.2 Hz,
J(10e,9a) = 3.7 Hz,
J(10e,8e) = 2.0 Hz, 1H, He-10); 3.52 (ddd, J(1a,10a) =
11.2 Hz, J(1a,6a) = 9.6 Hz, J(1a,10e) = 4.2 Hz, 1H, Ha-
1); 4.75 (dd, J(3a,4a) = 11.5 Hz, J(3a,4e) = 2.5 Hz, 1H,
Ha-3); 6.38 (dd, J(14,13) = 1.8 Hz, J(14,12) = 0.8 Hz,
1H, H-14); 7.33 (dd, J(13,14) = 1.8 Hz, J(13,12) =
1.5 Hz, 1H, H-13); 7.36 (ddd, J(12,13) = 1.5 Hz,
J(12,14) = 0.8 Hz, J(12,3a) = 0.5 Hz, 1H, H-12). 13C
NMR (CDCl3): 75.36 (d, C-1); 67.48 (d, C-3); 46.43 (t,
C-4); 69.20 (s, C-5); 49.33 (d, C-6); 22.42 (t, C-7); 34.32 (t,
C-8); 31.18 (d, C-9); 41.19 (t, C-10); 127.04 (s, C-11);
138.96 (d, C-12); 142.78 (d, C-13); 108.82 (d, C-14); 28.14
(2R,4R(S),4aR,7R,8aR)-2-(Furan-3-yl)-4,7-dimethyloc-
tahydro-2H-chromen-4-ol (8a) The reaction of
123

Med Chem Res
(q, C-15); 22.11 (q, C-16). HR-MS: 250.1561 (M?,
C-5); 49.41 (d, C-6); 22.47 (t, C-7); 34.38 (t, C-8); 31.23
(d, C-9); 41.26 (t, C-10); 143.98 (s, C-11); 120.52 (d,
C-12); 125.45 (d, C-13); 125.89 (d, C-14); 28.20 (q, C-15);
22.14 (q, C-16). HR-MS: 266.1337 (M?, C15H22O2S?;
calc. 266.1335).
C15H22O3?; calc. 250.1563).
(2R,4R(S),4aR,7R,8aR)-4,7-Dimethyl-2-(thiophen-3-yl)oc-
tahydro-2H-chromen-4-ol (8b) The reaction of isopule-
gol 4 (0.300 g) and thiophene-3-carbaldehyde 9b (0.220 g)
in the presence of clay K10 (1.1 g) for 60 min led to
compound 8b (0.216 g of (R)-isomer and 0.112 g of mix-
Synthesis of compounds 6 and 7
ture (R):(S) = 1.5:1; 63 %).
26:4
A solution of TsOH (0.032 g) in toluene (5 ml) was added
to a solution of aldehyde 5b in toluene (10 ml). Then a
solution of isopulegol 4 (0.300 g) in toluene (10 ml) and
(R)-8b. ½aŠ
? 18.0 (c 0.412, MeOH). 1H NMR
D
(CDCl3): 0.88–0.97 (m, 1H, Ha-8); 0.93 (d, J(16,9) =
6.6 Hz, 3H, H-16); 1.04 (dddd, J(7a,7e) = J(7a,8a) =
12.9 Hz, J(7a,6a) = 12.2 Hz, J(7a,8e) = 3.3 Hz, 1H, Ha-
˚
molecular sieves 4A (30 pieces) were added. The mixture
was refluxed for 60 min. The sieves were filtered off, the
solvent was distilled off, and the residue was separated on a
SiO2 column. The mixture of compounds 6 and 7 (0.407 g,
9:1; 84 %) was obtained.
7);
1.10
(ddd,
J(10a,10e) = J(10a,9a) = 12.2 Hz,
J(10a,1a) = 10.8 Hz, 1H, Ha-10); 1.27 (d, J(15,4a) =
0.8 Hz, 3H, H-15); 1.29 (ddd, J(6a,7a) = 12.2 Hz,
J(6a,1a) = 10.2 Hz, J(6a,7e) = 3.3 Hz, 1H, Ha-6);
1.40–1.52 (m, 1H, Ha-9); 1.73 (ddddd, J(8e,8a) = 12.9 Hz,
(2R,4aS,7R,8aR)-7-Methyl-4-methylene-2-(thiophen-2-
yl)octahydro-2H-chromene (6) 1H NMR (CDCl3): 0.95
(d, J(16,9a) = 6.5 Hz, 3H, H-16); 1.00 (dddd, J(8a,8e) =
13.0 Hz, J(8a,7a) = 13.0 Hz, J(8a,9a) = 12.2 Hz, J(8a,7e)
= 3.7 Hz, 1H, Ha-8); 1.20 (ddd, J(10a,10e) =
J(10a,9a) = 12.2 Hz, J(10a,1a) = 11.0 Hz, 1H, Ha-10);
1.27 (dddd, J(7a,7e) = J(7a,8a) = 13.0 Hz, J(7a,6a) =
11.7 Hz, J(7a,8e) = 3.7 Hz, 1H, Ha-7); 1.44–1.55 (m, 1H,
Ha-9); 1.74 (dddd, J(8e,8a) = 13.0 Hz, J(8e,7a) = 3.7 Hz,
J(8e,7e) = 3.3 Hz, J(8e,10e) = 2.0 Hz, 1H, He-8);
1.81–1.88 (m, 1H, Ha-6); 1.90 (dddd, J(7e,7a) = 13.0 Hz,
J(7e,8a) = J(7e,6a) = 3.7 Hz, J(7e,8e) = 3.3 Hz, 1H,
He-7); 2.01 (dddd, J(10e,10a) = 12.2 Hz, J(10e,1a) =
J(10e,9a) = 4.1 Hz, J(10e,8e) = 2.0 Hz, 1H, He-10); 2.50
(ddm, J(4a,4e) = 13.1 Hz, J(4a,3a) = 11.4 Hz, 1H, Ha-4);
2.61 (dd, J(4e,4a) = 13.1 Hz, J(4e,3a) = 2.6 Hz, 1H, He-
4); 3.13 (ddd, J(1a,10a) = 11.0 Hz, J(1a,6a) = 9.8 Hz,
J(1a,10e) = 4.1 Hz, 1H, Ha-1); 4.63 (ddd, J(3a,4a) =
11.4 Hz, J(3a,4e) = 2.6 Hz, J(3a,14) = 0,7 Hz, 1H, Ha-3);
4.69, 4.81 (2 m, all J B 2.2 Hz, 2H, H-15); 6.95 (dd,
J(13,12) = 5.0 Hz, J(13,14) = 3.5 Hz, 1H, H-13); 6.98
(ddd, J(14,13) = 3.5 Hz, J(14,12) = 1.3 Hz, J(14,3a) =
0.7 Hz, 1H, H-14); 7.22 (dd, J(12,13) = 5.0 Hz,
J(12,14) = 1.3 Hz, 1H, H-12). 13C NMR (CDCl3): 81.96 (d,
C-1); 76.35 (d, C-3); 44.24 (t, C-4); 145.59 (s, C-5); 46.24
(d, C-6); 25.97 (t, C-7); 34.02 (t, C-8); 31.38 (d, C-9); 41.28
(t, C-10); 147.54 (s, C-11); 124.41 (d, C-12); 126.28 (d,
C-13); 123.40 (d, C-14); 105.99 (t, C-15); 22.11 (q, C-16).
HR-MS: 248.1230 (M?, C15H20OS?; calc. 248.1229).
J(8e,7a) = J(8e,9a) = J(8e,7e) = 3.3 Hz,
J(8e,10e) =
2.0 Hz, 1H, He-8); 1.81 (ddq, J(4a,4e) = 12.8 Hz,
J(4a,3a) = 11.8 Hz, J(4a,15) = 0.8 Hz, 1H, Ha-4); 1.93
(dddd, J(7e,7a) = 12.9 Hz, J(7e,6a) = J(7e,8a) = J(7e,8e)
= 3.3 Hz, 1H, He-7); 1.97 (dd, J(4e,4a) = 12.8 Hz,
J(4e,3a) = 2.2 Hz, 1H, He-4); 2.00 (dddd, J(10e,10a) =
12.2 Hz, J(10e,1a) = 4.2 Hz, J(10e,9a) = 3.7 Hz, J(10e,8e)
= 2.0 Hz, 1H, He-10); 3.25 (ddd, J(1a,10a) = 10.8 Hz,
J(1a,6a) = 10.2 Hz, J(1a,10e) = 4.2 Hz, 1H, Ha-1); 4.53
(dd, J(3a,4a) = 11.8 Hz, J(3a,4e) = 2.2 Hz, 1H, Ha-3); 7.06
(dd, J(14,13) = 5.0 Hz, J(14,12) = 1.2 Hz, 1H, H-14); 7.18
(ddd, J(12,13) = 3.0 Hz, J(12,14) = 1.2 Hz, J(12,3a) =
0.8 Hz, 1H, H-12); 7.25 (dd, J(13,14) = 5.0 Hz, J(13,12) =
3.0 Hz, 1H, H-13). 13C NMR (CDCl3): 77.36 (d, C-1); 72.84
(d, C-3); 49.16 (t, C-4); 70.71 (s, C-5); 52.04 (d, C-6); 22.97
(t, C-7); 34.31 (t, C-8); 31.39 (d, C-9); 41.42 (t, C-10); 143.36
(s, C-11); 120.78 (d, C-12); 125.61 (d, C-13); 125.87 (d,
C-14); 21.21 (q, C-15); 22.08 (q, C-16). HR-MS: 266.1337
(M?, C15H22O2S?; calc. 266.1335).
(S)-8b. 1H NMR (CDCl3): 0.88–0.97 (m, 1H, Ha-8);
0.92 (d, J(16,9) = 6.6 Hz, 3H, H-16); 1.06 (ddd,
J(10a,10e) = J(10a,9a) = 12.1 Hz, J(10a,1a) = 11.2 Hz,
1H, Ha-10); 1.12–1.21 (m, 2H, Ha-6, Ha-7); 1.23 (s, 3H,
H-15); 1.41–1.53 (m, 1H, Ha-9); 1.74 (dd, J(4a,4e) =
13.7 Hz, J(4a,3a) = 11.7 Hz, 1H, Ha-4); 1.78–1.84 (m,
1H, He-7); 1.70–1.76 (m, 1H, He-8); 1.88 (dd,
J(4e,4a) = 13.7 Hz, J(4e,3a) = 2.5 Hz, 1H, He-4);
1.97–2.01 (m, 1H, He-10); 3.55 (ddd, J(1a,10a) = 11.2 Hz,
J(1a,6a) = 9.6 Hz, J(1a,10e) = 4.2 Hz, 1H, Ha-1); 4.87
(dd, J(3a,4a) = 11.7 Hz, J(3a,4e) = 2.5 Hz, 1H, Ha-3);
7.06 (dd, J(14,13) = 5.0 Hz, J(14,12) = 1.3 Hz, 1H,
H-14); 7.17 (ddd, J(12,13) = 3.0 Hz, J(12,14) = 1.3 Hz,
J(12,3a) = 0.8 Hz, 1H, H-12); 7.24 (dd, J(13,14) =
5.0 Hz, J(13,12) = 3.0 Hz, 1H, H-13). 13C NMR (CDCl3):
75.49 (d, C-1); 71.01 (d, C-3); 47.19 (t, C-4); 69.34 (s,
(2R,7R,8aR)-4,7-Dimethyl-2-(thiophen-2-yl)-3,5,6,7,8,8a-
(7) 1H
hexahydro-2H-chromene
NMR
(CDCl3):
0.83–0.95 (m, 1H, Ha-8); 0.92 (d, J(16,9a) = 6.6 Hz, 3H,
H-16); 1.04 (ddd, J(10a,10e) = J(10a,9a) = 12.2 Hz,
J(10a,1a) = 11.2 Hz, 1H, Ha-10); 1.54–1.73 (m, 3H, Ha-7,
He-8, Ha-9); 1.69 (m, all J B 2.5 Hz, 3H, H-15); 2.07–2.16
(m, 2H, He-4, He-10); 2.49 (ddm, J(4a,4e) = 16.5 Hz,
123

Med Chem Res
1
J(4a,3a) = 10.8 Hz, 1H, Ha-4); 2.67–2.74 (m, 1H, He-7);
4.12–4.18 (m, 1H, Ha-1); 4.77 (ddd, J(ddd, J(3a,4a) =
10.8 Hz, J(3a,4e) = 3.2 Hz, J(3a,14) = 0.7 Hz, 1H, Ha-3);
6.94 (dd, J(13,12) = 5.0 Hz, J(13,14) = 3.5 Hz, 1H,
H-13); 6.98 (ddd, J(14,13) = 3.5 Hz, J(14,12) = 1.2 Hz,
J(14,3a) = 0.7 Hz, 1H, H-14); 7.21 (dd, J(12,13) =
5.0 Hz, J(12,14) = 1.2 Hz, 1H, H-12). 13C NMR (CDCl3):
76.45 (d, C-1); 71.13 (d, C-3); 39.19 (t, C-4); 121.46 (s,
C-5); 131.39 (s, C-6); 26.43 (t, C-7); 34.95 (t, C-8); 30.91
(d, C-9); 42.65 (t, C-10); 146.08 (s, C-11); 124.34 (d,
C-12); 126.30 (d, C-13); 123.45 (d, C-14); 18.05 (q, C-15);
21.87 (q, C-16).
19 %). The H and 13C NMR spectra of diol 13 coincided
with the literature data (Kocovsky et al., 1999).
1
(S)-12a. H NMR (CDCl3): 0.81 (d, J(16,9) = 6.5 Hz,
3H, H-16); 0.83–0.92 (m, 1H, Ha-8); 1.06 (ddd,
J(10a,10e) = 14.0 Hz,
J(10a,1e) = 3.0 Hz,
J(6a,7a) = 12.5 Hz,
J(10a,9a) = 12.3 Hz,
1H,
1H,
Ha-10);
Ha-6);
1.38
1.41
(dm,
(d,
J(15,4a) = 0.8 Hz, 3H, H-15); 1.54–1.63 (m, 1H, Ha-7);
1.63 (ddd, J(4e,4a) = 12.9 Hz, J(4e,3a) = 2.5 Hz,
J(4e,6a) = 1.2 Hz, 1H, He-4); 1.67–1.79 (m, 3H, He-7,
He-8, Ha-9); 1.97 (dm, J(10e,10a) = 14.0 Hz, others
J B 4.5 Hz, 1H, He-10); 2.07 (ddq, J(4a,4e) = 12.9 Hz,
J(4a,3a) = 12.3 Hz, J(4a,15) = 0.8 Hz, 1H, Ha-4); 3.80
(m,
J(3a,4a) = 12.3 Hz, J(3a,4e) = 2.5 Hz, 1H, Ha-3); 6.25
(ddd, J(14,13) = 3.2 Hz, J(14,12) = 0.9 Hz,
J(14,3a) = 0.7 Hz, 1H, H-14); 6.30 (dd,
all
J B 3.0 Hz,
1H,
He-1);
4.46
(dd,
Synthesis of (1)-neoisopulegol 11
A solution of (-)-isopulegol 4 (3.47 g) in CH2Cl2 (10 ml)
was added dropwise during 10 min to a slurry of PCC
(pyridinium chlorochromate, 11.26 g) in CH2Cl2 (50 ml).
The mixture was stirred for 5 h at r.t.; then Et2O (60 ml)
was added, the sediment was filtered through the column
with SiO2, and the solvent was distilled off. Isopulegone 10
(2.70 g, 79 %) was obtained.
J(13,14) = 3.2 Hz, J(13,12) = 1.8 Hz, 1H, H-13); 7.35
(dd, J(12,13) = 1.8 Hz, J(12,14) = 0.9 Hz, 1H, H-12).
13C NMR (CDCl3): 73.86 (d, C-1); 70.77 (d, C-3); 39.03 (t,
C-4); 71.02 (s, C-5); 46.59 (d, C-6); 21.29 (t, C-7); 34.19 (t,
C-8); 26.04 (d, C-9); 40.12 (t, C-10); 154.60 (s, C-11);
142.01 (d, C-12); 109.95 (d, C-13); 106.39 (d, C-14); 27.00
(q, C-15); 22.06 (q, C-16). HR-MS: 250.3335 (M?,
C15H22O3?; calc. 250.3334).
NaBH4 (1.34 g) was added to a solution of 10 (2.70 g)
in MeOH (10 ml). The mixture was stirred at r.t. for 2.5 h,
and then, 3.5 % HCl was added before pH 3 was reached.
MeOH was distilled off, and then water (5 ml) was added.
The product was extracted by Et2O. The solution was dried
over Na2SO4. The solvent was distilled off which gave rise
to 2.39 g (87 %) mixture of (-)-isopulegol 4 and (?)-
1
(R)-12a. H NMR (CDCl3): 0.81 (d, J(16,9) = 6.5 Hz,
3H, H-16); 0.84–0.94 (m, 1H, Ha-8); 1.04 (ddd,
J(10a,10e) = 14.0 Hz,
J(10a,9a) = 12.3 Hz,
J(10a,1e) = 2.9 Hz, 1H, Ha-10); 1.22 (s, 3H, H-15);
1.22–1.27 (m, 1H, Ha-6); 1.47–1.56 (m, 3H, He-4, 2H-7);
neoisopulegol 11 (1.7:1). (?)-Neoisopulegol 11 (0.73 g,
30;6
1.67–1.79
(m,
2H,
He-8,
Ha-9);
1.99
(dd,
21 %; ½aŠ
? 28.5 (c 0.498, C6H14)) was isolated by
D
J(4a,4e) = 13.8 Hz, J(4a,3a) = 12.1 Hz, 1H, Ha-4); 1.97
(dm, J(10e,10a) = 14.0 Hz, 1H, He-10); 4.19 (ddd,
J(1e,10a) = 2.9 Hz, J(1e,6a) & J(1e,10e) & 2.7 Hz, 1H,
He-1); 4.80 (dd, J(3a,4a) = 12.1 Hz, J(3a,4e) = 2.5 Hz,
column chromatography on SiO2, and (-)-isopulegol 4
1
(1.32 g) was also obtained. The H and 13C NMR spectra
of (?)-neoisopulegol 11 coincided with the literature data
(Moreira and Correa 2003).
1H,
Ha-3);
6.23
(ddd,
J(14,13) = 3.2 Hz,
J(14,12) = 0.9 Hz, J(14,3a) = 0.7 Hz, 1H, H-14); 6.29
(dd, J(13,14) = 3.2 Hz, J(13,12) = 1.8 Hz, 1H, H-13);
7.34 (dd, J(12,13) = 1.8 Hz, J(12,14) = 0.9 Hz, 1H,
H-12). 13C NMR (CDCl3): 71.54 (d, C-1); 68.99 (d,
C-3); 38.24 (t, C-4); 71.19 (s, C-5); 46.20 (d, C-6); 23.60 (t,
C-7); 34.48 (t, C-8); 25.87 (d, C-9); 39.92 (t, C-10); 155.19
(s, C-11); 141.91 (d, C-12); 109.88 (d, C-13); 106.36 (d,
C-14); 28.88 (q, C-15); 22.11 (q, C-16). HR-MS: 250.3335
Reaction of (1)-neoisopulegol 11 with aldehydes
5a,b on clay K10: general procedure
An appropriate aldehyde was added to a suspension of clay
K10 in CH2Cl2 (10 ml); then, a solution of neoisopulegol
11 in CH2Cl2 (10 ml) was added. The solvent was distilled
off. The mixture was stored at r.t. for 60 min. Then ethyl
acetate (15 ml) was added. The catalyst was filtered off, the
solvent was distilled off, and the residue was separated on a
SiO2 column.
(M?, C15H22O3?; calc. 250.3334).
27:5
D
Compound 13. ½aŠ
- 10.4 (c 0.154, CHCl3). 1H NMR
(CDCl3): 0.86 (d, J(10,3) = 6.3 Hz, 3H, H-10); 0.87–0.94
(m, 1H, H-4); 1.04 (ddd, J(2a,2e) = 14.1 Hz,
J(2a,3a) = 12.4 Hz, J(2a,1e) = 2.3 Hz, 1H, Ha-2); 1.15
(2S,4S(R),4aR,7R,8aS)-2-(Furan-2-yl)-4,7-dimethyloctahy-
dro-2H-chromen-4-ol (12a) The reaction of (?)-neoisop-
ulegol 11 (0.200 g) and furan-2-carbaldehyde 5a (0.125 g) in
the presence of clay K10 (0.7 g) led to compound 12a
((S):(R) = 1.5:1) (0.133 g, 41 %) and (1S,2R,5R)-2-(2-hy-
(ddd,
J(6a,5a) = 11.7 Hz,
J(6a,5e) = 4.8 Hz,
J(6a,1e) = 2.3 Hz, 1H, Ha-6); 1.21 (s, 3H) and 1.34 (s,
3H)– H-8 and H-9; 1.63–1.71 (m, 2H, H-5); 1.74–1.84 (m,
3H, He-2, Ha-3, H’-4); 4.39 (m, all J B 3.0 Hz, 1H, He-1).
droxypropan-2-yl)-5-methylcyclohexanol
13
(0.042 g,
123

Med Chem Res
13C NMR (CDCl3): 68.01 (d, C-1); 42.44 (t, C-2); 25.52 (d,
C-3); 34.77 (t, C-4); 20.14 (t, C-5); 48.30 (d, C-6); 73.19 (s,
C-7); 28.78 and 28.82 (2q, C-8, C-9); 22.07 (q, C-10).
Biology
Animals
(2S,4S(R),4aR,7R,8aS)-4,7-Dimethyl-2-(thiophen-2-yl)oc-
tahydro-2H-chromen-4-ol (12b) The reaction of (?)-
neoisopulegol 11 (0.200 g) and thiophene-2-carbaldehyde
5b (0.145 g) in the presence of clay K10 (0.7 g) led to
compound 12b ((S):(R) = 1:1) (0.258 g, 75 %).
All studies were carried out on non-breeding albino mice
(male) weighting 20–25 g, 8 animals in each group (SPF-
vivarium of the Institute of Cytology and Genetics of the
Siberian Branch of the Russian Academy of Sciences).
Mice were maintained at 22–25 °C on a 12-h light–dark
cycle with food and water available ad libitum. All work
with animals was performed in strict accordance with the
legislation of the Russian Federation, the regulations of the
European Convention for the Protection of Vertebrate
Animals Used for Experimental and Other Scientific Pur-
poses, and the requirements and recommendations of the
Guide for the Care and Use of Laboratory Animals.
1
(S)-12b. H NMR (CDCl3): 0.84 (d, J(16,9) = 6.6 Hz,
3H, H-16); 0.90 (dddd, J(8a,8e) = J(8a,7a) = J(8a,9a) =
12.8 Hz, J(8a,7e) = 3.0 Hz, 1H, Ha-8); 1.07 (ddd,
J(10a,10e) = 13.9 Hz, J(10a,9a) = 12.0 Hz, J(10a,1e) =
2.9 Hz, 1H, Ha-10); 1.39 (dm, J(6a,7a) = 12.8 Hz, others
J B 3.5 Hz, 1H, Ha-6); 1.44 (d, J(15,4a) = 0.7 Hz, 3H, H-
15); 1.59 (dddd, J(7a,7e) = J(7a,6a) = J(7a,8a) =
12.8 Hz, J(7a,8e) = 3.2 Hz, 1H, Ha-7); 1.73 (ddd,
J(4e,4a) = 13.0 Hz,
J(4e,3a) = 2.7 Hz,
J(4e,6a) =
Analgesic tests
1.2 Hz, 1H, He-4); 1.71–1.81 (m, 3H, He-7, He-8, Ha-9);
1.95 (ddd, J(4a,4e) = 13.0 Hz, J(4a,3a) = 11.8 Hz,
J(4a,15) = 0.7 Hz, 1H, Ha-4); 1.98 (dm, J(10e,10a) =
13.9 Hz, others J B 4.0 Hz, 1H, He-10); 3.83 (m, all
J B 3.0 Hz, 1H, He-1); 4.67 (ddd, J(3a,4a) = 11.8 Hz,
J(3a,4e) = 2.7 Hz, J(3a,14) = 0.8 Hz, 1H, Ha-3); 6.93
(dd, J(13,12) = 5.0 Hz, J(13,14) = 3.5 Hz, 1H, H-13);
Agents were dissolved in saline containing 0.5 % Tween
80 just before use and were administered per os, 1 h before
testing. Saline was administered per os in blank mice
(control group), 1 h before testing. Analgesic activity of
test agents was assessed using acetic acid-induced writhing
test and hot plate test.
6.96
(ddd,
J(14,13) = 3.5 Hz,
J(14,12) = 1.3 Hz,
In the acetic acid-induced writhing test, the pain reaction
was determined by the number of abdominal convulsions,
recorded from the 5th to the 8th min following the acetic acid
injection (0.75 %, 0.1 ml/mouse) (Koster et al., 1959). The
percentage of pain reaction inhibition was calculated
according to the following equation: % inhibition =
100 9 (A - B)/A, where A is the mean number of writhes in
the control group, and B is the mean number of writhes in the
test group.
J(14,3a) = 0.8 Hz, 1H, H-14); 7.21 (dd, J(12,13) =
5.0 Hz, J(12,14) = 1.3 Hz, 1H, H-12). 13C NMR (CDCl3):
73.92 (d, C-1); 73.24 (d, C-3); 43.58 (t, C-4); 71.13 (s, C-5);
46.42 (d, C-6); 21.36 (t, C-7); 34.21 (t, C-8); 26.10 (d, C-9);
40.20 (t, C-10); 145.92 (s, C-11); 124.36 (d, C-12); 126.24 (d,
C-13); 123.33 (d, C-14); 27.02 (q, C-15); 22.10 (q, C-16).
HR-MS: 266.1334 (M?, C15H22O2S?; calc. 266.1335).
1
(R)-12b. H NMR (CDCl3): 0.83 (d, J(16,9) = 6.6 Hz,
3H, H-16); 0.83–0.95 (m, 1H, Ha-8); 1.05 (ddd,
J(10a,10e) = 14.0 Hz, J(10a,9a) = 12.0 Hz, J(10a,1e) =
2.9 Hz, 1H, Ha-10); 1.20 (s, 3H, H-15); 1.23–1.28 (m, 1H,
Ha-6); 1.50–1.56 (m, 2H, H-7); 1.65 (ddd, J(4e,4a) =
13.9 Hz, J(4e,3a) = 2.7 Hz, J(4e,6a) = 1.4 Hz, 1H, He-4);
1.70–1.80 (m, 2H, He-8, Ha-9); 1.84 (dd, J(4a,4e) =
13.9 Hz, J(4a,3a) = 11.7 Hz, 1H, Ha-4); 1.95–2.10 (m, 1H,
He-10); 4.22 (ddd, J(1e,10a) = 2.9 Hz, J(1e,6a) &
J(1e,10e) & 2.7 Hz, 1H, He-1); 5.02 (ddd, J(3a,4a) =
11.7 Hz, J(3a,4e) = 2.7 Hz, J(3a,14) = 0.7 Hz, 1H, Ha-3);
6.92 (dd, J(13,12) = 4.9 Hz, J(13,14) = 3.5 Hz, 1H, H-13);
In the hot plate test, animals were placed individually on
a metallic plate warmed to 54 0.5 °C, and the time until
either licking of the hind paw or jumping occurred was
recorded by a stopwatch (Eddy and Leimbach, 1953).
Acute toxicity
Acute toxicity studies were performed on non-breeding
albino mice (male) weighting 20–25 g (6 animals in each
group). The agent 3b was dissolved in saline containing
0.5 % Tween 80 just before use and administered per os in
doses of 500, 1000, 2500 and 4500 mg/kg. The toxicity
was evaluated from the clinical picture of poisoning and
survival of animals for 14 days (EPA, 2002).
6.95
(ddd,
J(14,13) = 3.5 Hz,
J(14,12) = 1.3 Hz,
J(14,3a) = 0.7 Hz, 1H, H-14); 7.19 (dd, J(12,13) =
4.9 Hz, J(12,14) = 1.3 Hz, 1H, H-12). 13C NMR (CDCl3):
71.63 (d, C-1); 71.54 (d, C-3); 42.85 (t, C-4); 71.44 (s, C-5);
46.12 (d, C-6); 23.69 (t, C-7); 34.50 (t, C-8); 25.93 (d, C-9);
40.01 (t, C-10); 146.67 (s, C-11); 124.09 (d, C-12); 126.24 (d,
C-13); 123.20 (d, C-14); 28.78 (q, C-15); 22.16 (q, C-16).
HR-MS: 266.1334 (M?, C15H22O2S?; calc. 266.1335).
Statistical data processing was carried out using a Sta-
tistica 6.0 program.
Acknowledgments Authors are grateful to the Russian Foundation
for Basic Research (Grant No 13-03-00206a) for the financial support.
123

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