Synthesis and analgesic activity of monoterpenoid-derived 2-aryl-4,4,7-trimethyl-4a,5,8,8a-tetrahydro-4H-benzo[d][1,3]dioxin-8-ols

Article abstract of DOI:10.1007/s00044-013-0772-4

A new series of chiral heterocyclic compounds with frameworks of different types were synthesized by reactions of verbenol epoxide with aromatic aldehydes in the presence of montmorillonite clay. The analgesic activity of compounds with frameworks of 2-aryl-4,4,7-trimethyl-4a,5,8,8a-tetrahydro-4H-benzo[d][1,3] dioxin-8-ol type was studied in vivo. The majority of these compounds showed a significant analgesic activity in the acetic acid-induced writhing test; two compounds also showed analgesic activity in the hot-plate test. ED₅₀ in acetic acid-induced writhing test for compound where aryl is 4-chlorophenyl substituent was determined to be 4.5 mg/kg. Compound with 4-nitrophenyl substituent demonstrated high analgesic activity in both tests. Springer Science+Business Media 2013.

Full text of DOI:10.1007/s00044-013-0772-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:1709–1717
DOI 10.1007/s00044-013-0772-4
ORIGINAL RESEARCH
Synthesis and analgesic activity of monoterpenoid-derived 2-aryl-
4,4,7-trimethyl-4a,5,8,8a-tetrahydro-4H-benzo[d][1,3]dioxin-8-ols
•
Svetlana Kurbakova Irina Il’ina Alla Pavlova
•
•
•
Dina Korchagina Olga Yarovaya Tat’yana Tolstikova
•
•
•
Konstantin Volcho Nariman Salakhutdinov
Received: 14 May 2013 / Accepted: 27 August 2013 / Published online: 12 September 2013
Ó Springer Science+Business Media New York 2013
Abstract A new series of chiral heterocyclic compounds
with frameworks of different types were synthesized by
reactions of verbenol epoxide with aromatic aldehydes in the
presence of montmorillonite clay. The analgesic activity of
compounds with frameworks of 2-aryl-4,4,7-trimethyl-
4a,5,8,8a-tetrahydro-4H-benzo[d][1,3]dioxin-8-ol type was
studied in vivo. The majority of these compounds showed a
significant analgesic activity in the acetic acid-induced
writhing test; two compounds also showed analgesic activity
in the hot-plate test. ED50 in acetic acid-induced writhing test
for compound where aryl is 4-chlorophenyl substituent was
determined to be 4.5 mg/kg. Compound with 4-nitrophenyl
substituent demonstrated high analgesic activity in both tests.
while being the major symptom of the disease. Traditional
analgesic and anti-inflammatory agents, such as opiates,
steroids, and non-steroidal anti-inflammatory drugs all
have serious side effects, particularly at high doses taken
by chronic users (Melnikova, 2010; Kinsey et al., 2011).
The development of highly effective, low-toxic analgesics
thus remains a challenge in pharmacology and medicinal
chemistry, stimulating studies in this direction (Kankala
et al., 2013; Deep et al., 2012; Nigade et al., 2012; Ingale
et al., 2012; Tolstikova et al., 2012).
Recently, we showed that several chiral heterocyclic
compounds that formed in reactions of verbenol epoxide 1
with aromatic aldehydes containing three methoxy groups
at different positions of the aromatic ring had a considerable
analgesic activity (Mikhalchenko et al., 2013). Importantly,
compounds of different structural types showed activity,
due to which it seems promising to perform systematic
studies of biological properties for each type of framework.
Earlier, itwasshownthatepoxide1 reactedwithaldehydes
2a–d containing various substituents in the para-position of
the aromatic ring in the presence of montmorillonite clay
K10, giving compounds 3a–d with a benzodioxin framework
(Scheme 1) (Il’ina et al., 2010). These compounds that
formed as a single stereoisomer are promising for studies of
their biological activity including the analgesic activity.
The goal of this study was to synthesize heterocyclic
compounds of Type 3 with a benzodioxin framework with
various substituents in the aromatic ring and study their
analgesic activity.
Keywords Terpenoid ꢀ Heterocyclic compounds ꢀ
Benzodioxine ꢀ Analgesic activity ꢀ
Acetic acid-induced writhing test ꢀ Hot-plate test
Introduction
Pain is the most frequent cause of patient’s recourse for
medical assistance. The pain syndrome is the main reason
for a decrease in the quality-of-life of patients with the
majority of diseases and dominates in the clinical picture,
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0772-4) contains supplementary
material, which is available to authorized users.
S. Kurbakova ꢀ I. Il’ina ꢀ A. Pavlova ꢀ D. Korchagina ꢀ
O. Yarovaya ꢀ T. Tolstikova ꢀ K. Volcho (&) ꢀ
N. Salakhutdinov
Novosibirsk Institute of Organic Chemistry, Siberian Branch,
Russian Academy of Sciences, Lavrentjev av., 9,
630090 Novosibirsk, Russian Federation
e-mail: volcho@nioch.nsc.ru
Chemistry
To synthesized new compounds with a benzodioxin frame-
work, we performed the reaction of verbenol epoxide 1
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Med Chem Res (2014) 23:1709–1717
Table 1 Yields of products in the reaction of (–)-cis-verbenol
epoxide 1 with aldehydes 2e–h
Aldehyde
Yields of intermolecular productsa (%)
3
7 (5S:5R)
8, 9
2e R1 = H; R2 = Cl
2f R1 = R2 = Cl
2g R1 = H; R2 = F
11
29
10
37 (60:40)
30 (55:45)
28 (60:40)
18 (50:50)
3
–
2
–
Scheme 1 The interaction of verbenol epoxide 1 with aldehydes
2a–d
2h R1 = CF3; R2 = H 21
with aromatic aldehydes 2e–h in the presence of clay K10
(Scheme 2). The choice of substituents (halogen atoms and
CF3 group) in aldehydes was dictated by the necessity of
studying the structure–activity relationship and based on
our knowledge of the effect of the nature of substituent in
the aromatic ring on the structure of the intermolecular
products formed in reactions with verbenol epoxide 1. For
example, it was shown that the introduction of oxygen-
containing substituents in the aromatic ring of aldehyde
led to the formation of compounds with a hexahydro-2H-
chromene but not benzodioxin type of framework
(Mikhalchenko et al., 2013; Il’ina et al., 2007, 2011).
The reactions were performed in dichloromethane at
room temperature. The individual products were isolated
by column chromatography on silica gel. The yields of
intermolecular products are listed in Table 1. In addition to
the products of the reactions of 1 with aldehydes, com-
pounds 4–6, which are the products of the isomerization of
epoxide 1, formed in all instances.
a
The yields of isolated products calculated based on the consumed
aldehyde 2
(59 %). This is a good yield for reactions with such a labile
compound as verbenol epoxide 1.
Compounds 7 formed as a mixture of diastereomers at
the C-5 carbon atom (Scheme 2) in comparable amounts.
Using aldehydes 2e and 2g containing a chlorine and
fluorine atom, respectively, at the meta-position led to the
formation of small amounts of compounds 8e and 8g,
which are the products of the addition of two aldehyde
molecules to monoterpenoid 1, and to compound 9 evi-
dently formed as a result of dehydration in 7g (Fig. 1).
Thus we obtained the desired set of chiral heterocyclic
compounds 3a–h with a benzodioxin framework, which
allowed us to pass to studies of their biological activity.
Biology
Earlier, it was shown that the main intermolecular pro-
ducts formed in the reaction of verbenol epoxide 1 with
aromatic aldehydes 2a–c containing a halogen atom in the
para-position in the presence of clay K10 were products
3a–c with a benzodioxin framework (Il’ina et al., 2010).
The displacement of Cl and F atoms from para- to meta-
position led to compounds with a hexahydro-2H-chromene
framework as the main reaction products (7e, g). Com-
pounds 3e, g were obtained in minor quantities. When
dichlorobenzaldehyde 2f and 4-(trifluoromethyl)benzalde-
hyde 2h were used, compounds 3 and 7 formed in a com-
parable ratio. The highest yield of intermolecular products
was observed in the reaction with dichlorobenzaldehyde 2f
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 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). Sodium diclofenac in the same dose was
used as a reference drug.
According to the data of Table 2, among para-halogen-
substituted compounds 3a–c, compound 3b containing a
chlorine atom showed the highest analgesic activity in a
Scheme 2 The interaction of verbenol epoxide 1 with aldehydes 2e–h
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Med Chem Res (2014) 23:1709–1717
1711
Fig. 1 Structures of
compounds 8e, g, and 9
Table 2 Analgesic activity of
Compound
Substituents
Mean SD
Saline
Pain inhibition (%)
compounds 3a–h, 7e and
sodium diclofenac in the acetic
acid-induced writhing test
(10 mg/kg dose)
3a
R1 = F; R2 = H
R1 = Cl; R2 = H
R1 = Br; R2 = H
R1 = NO2; R2 = H
R1 = H; R2 = Cl
R1 = R2 = Cl
R1 = H; R2 = F
R1 = CF3; R2 = H
R1 = H; R2 = Cl
5.5 1.1
1.0 0.1
5.6 0.8
2.9 1.2
9.6 0.3
11.4 0.7
6.8 1.0
6.3 1.1
8.4 0.7
0.8 0.4
9.1 0.7
8.4 0.8
8.4 0.8
8.4 0.8
13.2 0.6
13.2 0.6
11.3 0.5
13.2 0.6
11.3 0.5
8.4 0.8
40*
88#
33
65#
27*
14
3b
3c
3d
3e
3f
3g
40*
52#
26*
90#
3h
% Of pain inhibition = (texp
tsaline)/tsaline 9 100 %
-
7e
#
* P \ 0.01; P \ 0.001 in
comparison with saline
Diclofenac sodium
dose of 10 mg/kg in the acetic acid-induced writhing test.
In this test, compound 3b was almost equal to the sodium
diclofenac reference. A displacement of the chlorine atom
to the meta-position on passing to compound 3e led to
considerable decrease in the analgesic effect, and dichloro
derivative 3f did not show any reliable degree of analgesic
activity at all. At the same time, the position of the fluorine
atom (3a and 3g) did not affect the analgesic activity of
these compounds which are both effective. Using bromo
derivative 3c did not reveal any reliable analgesic effect.
According to (Tolstikova et al., 2011), LD50 exceeds
1,000 mg/kg for 3a and is 350 mg/kg for sodium diclofe-
nac (Syubaev et al., 1986).
was determined to be 4.5 mg/kg. For comparison, ED50
was 5 mg/kg for sodium diclofenac and 155 mg/kg for
aspirin in this test (Syubaev et al., 1986). Note that, an
appreciable analgesic activity in compounds of this struc-
tural type was found for the first time.
In the hot plate test, reliable analgesic activity was found
in compounds 3d and 3e in a dose of 10 mg/kg (Table 3).
Compound 3d containing a nitro group exhibited more
pronounced analgesic activity than the sodium diclofenac
reference. It had a considerable analgesic activity in both
the acetic acid-induced writhing and hot plate tests. Com-
pound 3e showed less pronounced activity.
We also studied the analgesic activity of the compound
7e with a hexahydro-2H-chromene framework, which
formed in the highest yield among compounds of this
structural type. In the acetic acid-induced writhing test,
compound 7e was equal to 3e having a benzodioxin
framework in efficiency (Table 2), but proved inactive in
the hot plate test (in contrast to 3e) (Table 3).
Compound 3d containing a nitro group showed a pro-
nounced analgesic effect, while its analog 3h with a CF3
group was slightly less effective.
For 3b, which showed the highest analgesic activity in
the acetic acid-induced writhing test, ED50 (the ‘‘median
effective dose’’ is a dose that produces 50 % protection)
Table 3 Analgesic activity of
Compound
Substituents
Mean SD
Saline
Protection (%)
compounds 3a–h and sodium
diclofenac in the hot plate test
(10 mg/kg dose)
3a
R1 = F; R2 = H
R1 = Cl; R2 = H
R1 = Br; R2 = H
R1 = NO2; R2 = H
R1 = H; R2 = Cl
R1 = R2 = Cl
R1 = H; R2 = F
R1 = CF3; R2 = H
R1 = H; R2 = Cl
19.5 2.1
22.0 2.6
27.2 1.2
37.5 4.1
17.5 1.4
17.6 2.6
16.3 1.6
16.8 1.7
19.0 1.9
33.4 2.3
19.3 3.8
20.4 2.2
20.4 2.2
20.4 2.2
12.9 1.0
12.9 1.0
16.4 1.6
12.9 1.0
16.4 1.6
20.4 2.2
0
3b
8
3c
33
84#
36*
36
0
3d
3e
3f
3g
3h
30
14
64*
7e
#
* P \ 0.01; P \ 0.001 in
comparison with saline
Diclofenac sodium
123

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Med Chem Res (2014) 23:1709–1717
Conclusion
spectrometer in a full scan mode (15–500 m/z, 70 eV elec-
tron-impact ionization, direct sample introduction). 1H- and
13C-NMR: Bruker DRX-500 apparatus at 500.13 MHz (1H)
and 125.76 MHz (13C) in CDCl3 or CDCl3 ? CD3OD (10:1,
v/v); chemical shifts in ppm relative to residual CHCl3
((H) 7.24, (C) 76.90 ppm), J in Hz; structure determinations
by analyzing the 1H NMR spectra, including 1H–1H double
resonance spectra and 1H–1H 2D homonuclear correlation, J-
modulated 13C-NMR spectra (JMOD), and 13C–1H 2D het-
eronuclear correlation with one-bond and long-range spin–
The reactions of verbenol epoxide 1 with aromatic alde-
hydes containing a halogen atom or a CF3 group in the
presence of clay K10 gave a set of new chiral heterocyclic
compounds 3, 7–9 with frameworks of different types. The
structure and position of substituents in the aromatic ring
produced a considerable effect on the yield and distribution
of heterocyclic products.
For compounds 3e–h with a benzodioxin framework and
previously prepared compounds 3a–d, the analgesic
activity was studied on models in the acetic acid-induced
writhing test and hot plate test.
1
spin coupling constants (C–H COSY, J(C,H) = 160 Hz,
COLOC, 2,3J(C,H) = 10 Hz).
The majority of the compounds under study exhibited
pronounced analgesic activity in the acetic acid-induced
writhing test in a dose of 10 mg/kg. Compound 3b con-
taining a chlorine atom in the para-position of the aromatic
ring showed the highest pain inhibition characteristics. The
ED50 of this compound was 4.5 mg/kg.
General procedure for synthesis of (2S,4aR,8R,8aR)-2-(3-
Aryl)-4,4,7-trimethyl-4a,5,8,8a-tetrahydro-4H-
benzo[d][1,3]dioxin-8-ols
An appropriate aldehyde (4.2 lmol) was added to a sus-
pension of clay K10 (4 g) in CH2Cl2 (25 ml). A solution of
epoxide 1 (0.700 g, 4.2 lmol) in CH2Cl2 (10 ml) was
added dropwise with stirring and the reaction mixture was
stirred for 1.5 h at r.t. (20–25 °C). Then mixture of ethyl
acetate (20 ml) and acetone (20 ml) was added. The cata-
lyst was filtered off, the solvent was distilled off, and the
residue was separated on a SiO2 column. The yields of the
intermolecular products were calculated based on the
consumed aldehyde.
In the hot plate test, 3d and 3e showed the analgesic
activity; compound 3d was more effective that the sodium
diclofenac taken in the same dose. Only compound 3d
showed considerable analgesic activity in both tests.
Thus we have found analgesics 3b and 3d of a new
structural type, which are very promising for further
studies.
Experimental
Chemistry
General
With 3-chlorobenzaldehyde 2e The following compounds
were isolated: unreacted aldehyde 2e (0.270 g, conversion
54 %); intermolecular reaction products 3e (0.073 g, 11 %),
7e (S:R = 60:40) (0.253 g, 37 %) and 8e (0.260 g, 15 %);
and isomerization products (1R,2R,6S)-3-methyl-6-(prop-
1-en-2-yl)cyclohex-3-ene-1,2-diol 4 (0.129 g, 18 %), (S)-
All the chemicals reagents were of commercial grade. As
catalyst, weusedK10clay(Fluka). Theclaywascalcinatedat
110 °C for 3 h immediately before use. CH2Cl2 was passed
through calcined alumina. (–)-cis-Verbenol epoxide (1)
2-hydroxy-1-(2,2,3-trimethylcyclopent-3-enyl)ethanone
5
(0.066 g, 9 %), and (R)-2-((R)-2,2-dimethylcyclopent-3-
enyl)-2-hydroxypropanal 6 (0.010 g, 1 %). The spectral
data of 4, 5, and 6 coincided with those reported in the
literature (Il’ina et al., 2007, 2012; Ardashov et al., 2007).
20
(½aꢁ580 = -60 (c = 0.41, CHCl3)) was synthesized accord-
ing to (Il’ina et al., 2007) from (–)-verbenone (Aldrich), the
content of the main substance was not less than 98.0 %. All
product yields are given for pure compounds isolated by
column chromatography. Column chromatography: silica gel
(SiO2; 60–200 l; Macherey–Nagel), 15 g per 1 g of reaction
mixture; eluent hexane/EtOAc 100/0 ? 0/100, acetone. GC/
MS (purity control and products analysis): Agilent 7890A gas
chromatograph equipped with a quadrupole mass spectrom-
eter 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 spectrometer, CHCl3 or MeOH
soln., conc. g/100 ml. HR-MS: DFS-Thermo-Scientific
(2S,4aR,8R,8aR)-2-(3-Chlorophenyl)-4,4,7-trimethyl-4a,5,8,
8a-tetrahydro-4H-benzo[d][1,3]dioxin-8-ol 3e 1H NMR
(CDCl3): 1.26 (s, 3H, H-18); 1.51 (s, 3H, H-17); 1.53 (ddd,
J(6a,7a) = 10.8 Hz, J(6a,7e) = 6.0 Hz, J(6a,1e) = 2.
0 Hz, 1H, Ha-6); 1.80 (ddd, J(19,7a) = 2.5 Hz,
J(19,7e) = 1.5 Hz, J(19,8) = 1.5 Hz, 3H, H-19); 2.07
(dddq, J(7e,7a) = 17.8 Hz, J(7e,6a) = 6.0 Hz, J(7e,8) =
5.3 Hz, J(7e,19) = 1.5 Hz, 1H, He-7); 2.42 (dddqd,
J(7a,7e) = 17.8 Hz, J(7a,6a) = 10.8 Hz, J(7a,8) = 2.
5 Hz, J(7a,19) = 2.5 Hz, J(7a,10e) = 1.2 Hz, 1H, Ha-7);
3.88 (br.s, 1H, He-10); 4.34 (dd, J(1e,10e) = 2.3 Hz,
J(1e,6a) = 2.0 Hz, 1H, He-1); 5.65 (dm, J(8,7e) = 5.3 Hz,
123

Med Chem Res (2014) 23:1709–1717
1713
another J B 2.5 Hz, 1H, H-8); 5.75 (s, 1H, H-3); 7.23–7.28
(m, 2H, H-14, H-15); 7.31 (ddd, J(16,15) = 6.7 Hz,
J(16,14) = 2.1 Hz, J(16,12) = 1.8 Hz, 1H, H-16); 7.45
(dd, J(12,14) = 2.1 Hz, J(12,16) = 1.8 Hz, 1H, H-12).
13C-NMR (CDCl3): 75.16 (d, C-1); 95.06 (d, C-3); 74.84
(s, C-5); 34.00 (d, C-6); 22.95 (t, C-7); 125.40 (d, C-8);
130.71 (s, C-9); 70.43 (d, C-10); 140.74 (s, C-11); 126.58
(d, C-12); 134.08 (s, C-13); 128.80 (d, C-14); 129.44 (d, C-
15); 124.60 (d, C-16); 22.66 (q, C-17); 27.14 (q, C-18); 20.
(s, 3H, H-17); 1.95 (dd, J(4e,4a) = 14.9 Hz, J(4e,3a) = 2.
6 Hz, 1H, He-4); 1.94–1.97 (m, all J B 3.5 Hz, 1H, He-8); 2.
19 (dd, J(4a,4e) = 14.9 Hz, J(4a,3a) = 13.2 Hz, 1H, Ha-4);
2.39–2.42 (m; 2H, H-7); 2.43 (br.q, J(9e,18) = 7.5 Hz, 1H,
He-9); 2.57–2.61 (m, all J B 5.2 Hz, 1H, He-6); 4.54 (d,
J(1a,6e) = 5.2 Hz, 1H, Ha-1); 4.75 (dd, J(3a,4a) = 13.2 Hz,
J(3a,4e) = 2.6 Hz, 1H, Ha-3); 4.79 (br.s, 1H, H-19); 7.15 (br.
d, J(25,24) = 7.6 Hz, 1H, H-25); 7.18–7.28 (m, 4H, H-14,
H-21, H-23, H-24); 7.29 (t, J(15,14(16)) = 7.6 Hz, 1H,
H-15); 7.52 (ddd, J(16,15) = 7.6 Hz, J(16,14) & 1.5 Hz,
J(16,12) & 1.5 Hz, 1H, H-16); 7.58 (dd, J(12,14) = 2.0 Hz,
J(12,16) & 1.5 Hz, 1H, H-12). 13C-NMR (CDCl3): 76.32 (d,
C-1); 71.63 (d, C-3); 48.13 (t, C-4); 73.13 (s, C-5); 39.01 (d,
C-6); 24.40 (t, C-7); 43.30 (d, C-8); 42.60 (d, C-9); 211.43 (s,
C-10); 144.01 (s, C-11); 126.72 (d, C-12); 134.13 (s, C-13);
127.88 (d, C-14); 129.67 (d, C-15); 124.75 (d, C-16); 23.16
(q, C-17); 17.70 (q, C-18); 74.97 (d, C-19); 142.25 (s, C-20);
125.81 (d, C-21); 134.07 (s, C-22); 127.28 (d, C-23); 129.50
25
49 (q, C-19). ½aꢁD = -115.0 (c = 0.67, MeOH); HR-MS:
308.1169 (M?, C17H21ClO3?; calc. 308.1174).
(2S,4S,4aR,8R,8aR)-2-(3-Chlorophenyl)-4,7-dimethyl-
3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol ((S)-
7e) 1H NMR (CDCl3): 1.51 (s, 3H, H-17); 1.67 (ddd,
J(4e,4a) = 13.4 Hz, J(4e,3a) = 2.7 Hz, J(4e,6) = 1.1 Hz;
1H, He-4); 1.77–1.85 (m, 1H, Ha-6); 1.81 (m, all J B 2.
5 Hz, 3H, H-18); 1.83 (dd, J(4a,4e) = 13.4 Hz,
J(4a,3a) = 12.0 Hz, 1H, Ha-4); 2.12–2.18 (m, 2H, H-7); 3.
79 (dd, J(1e,10e) = 2.4 Hz, J(1e,6a) = 2.2 Hz, 1H, He-1);
3.90 (br.s, 1H, He-10); 4.39 (dd, J(3a,4a) = 12.0 Hz,
J(3a,4e) = 2.7 Hz, 1H, Ha-3); 5.63-5.66 (m, 1H, H-8);
7.15 (ddd, J(16,15) = 6.7 Hz, J(16,14) = 2.2 Hz,
J(16,12) = 1.8 Hz, 1H, H-16); 7.17–7.22 (m, 2H, H-14,
H-15); 7.27–7.30 (m, 1H, H-12). 13C-NMR (CDCl3): 77.67
(d, C-1); 76.80 (d, C-3); 43.08 (t, C-4); 70.97 (s, C-5); 38.
25 (d, C-6); 22.61 (t, C-7); 124.55 (d, C-8); 131.34 (s, C-9);
70.45 (d, C-10); 143.90 (s, C-11); 125.91 (d, C-12); 134.14
(s, C-13); 127.57 (d, C-14); 129.53 (d, C-15); 123.83 (d,
C-16); 26.96 (q, C-17); 20.67 (q, C-18). HR-MS: 308.1171
(M?, C17H21ClO3?; calc. 308.1174).
25
(d, C-24); 123.93 (d, C-25). ½aꢁD = -56.7 (c = 0.53,
MeOH); HR-MS: 430.1091 (M?, C24H24Cl2O3?; calc. 430.
1097).
With 3,4-dichlorobenzaldehyde 2f The following com-
pounds were isolated: unreacted aldehyde 2f (0.433 g,
conversion 41 %); intermolecular reaction products 3f (0.
169 g, 29 %) and 7f (S:R = 55:45) (0.180 g, 30 %); and
isomerization products 4 (0.079 g, 11 %), 5 (0.124 g,
18 %), and 6 (0.049 g, 7 %).
(2S,4aR,8R,8aR)-2-(3,4-Dichlorophenyl)-4,4,7-trimethyl-4a,
5,8,8a-tetrahydro-4H-benzo[d][1,3]dioxin-8-ol 3f 1H NMR
(CDCl3): 1.25 (s, 3H, H-18); 1.50 (s, 3H, H-17); 1.52 (ddd,
J(6a,7a) = 10.8 Hz, J(6a,7e) = 6.2 Hz, J(6a,1e) = 2.1 Hz,
1H, Ha-6); 1.80 (br.s, 3H, H-19); 2.06 (dddq, J(7e,7a) = 17.
7 Hz, J(7e,6a) = 6.2 Hz, J(7e,8) = 5.3 Hz, J(7e,19) = 1.
5 Hz, 1H, He-7); 2.38 (dddqd, J(7a,7e) = 17.7 Hz,
J(7a,6a) = 10.8 Hz, J(7a,8) = 2.5 Hz, J(7a,19) = 2.5 Hz,
J(7a,10e) = 1.3 Hz, 1H, Ha-7); 3.86 (br.s, 1H, He-10); 4.32
(dd, J(1e,10e) = 2.4 Hz, J(1e,6a) = 2.1 Hz, 1H, He-1); 5.
63 (ddq, J(8,7e) = 5.3 Hz, J(8,7a) = 2.5 Hz, J(8,19) = 1.
5 Hz, 1H, H-8); 5.72 (s, 1H, H-3); 7.26 (dd, J(16,15) = 8.
2 Hz, J(16,12) = 1.8 Hz, 1H, H-16); 7.38 (d, J(15,16) = 8.
2 Hz, 1H, H-15); 7.53 (d, J(12,16) = 1.8 Hz, 1H, H-12).
13C-NMR (CDCl3): 75.15 (d, C-1); 94.33 (d, C-3); 74.96 (s,
C-5); 33.94 (d, C-6); 22.90 (t, C-7); 125.28 (d, C-8); 130.69
(s, C-9); 70.34 (d, C-10), 139.00 (s, C-11); 128.45 (d, C-12);
132.23 and 132.56 (2 s, C-13, C-14); 130.07 (d, C-15); 125.
74 (d, C-16); 22.62 (q, C-17); 27.07 (q, C-18); 20.46 (q, C-
(2S,4R,4aR,8R,8aR)-2-(3-Chlorophenyl)-4,7-dimethyl-3,4,
4a,5,8,8a-hexahydro-2H-chromene-4,8-diol ((R)-7e) 1H
NMR (CDCl3): 1.22 (s, 3H, H-17); 1.63 (ddd, J(4e,4a) =
14.2 Hz, J(4e,3a) = 3.5 Hz, J(4e,6) = 1.3 Hz, 1H, He-4);
1.66–1.72 (m, 2H, Ha-4, Ha-6); 1.81 (m, all J B 2.5 Hz,
3H, H-18); 1.95–2.02 (m, 2H, H-7); 3.92 (br.s, 1H, He-10);
4.23 (dd, J(1e,10e) = 2.3 Hz, J(1e,6a) = 2.1 Hz, 1H, He-
1); 4.75 (dd, J(3a,4a) = 11.0 Hz, J((3a,4e) = 3.5 Hz, 1H,
Ha-3); 5.56–5.60 (m, 1H, H-8); 7.15 (ddd, J(16,15) = 6.
7 Hz, J(16,14) = 2.2 Hz, J(16,12) = 1.8 Hz, 1H, H-16);
7.17–7.24 (m, 2H, H-14, H-15); 7.27–7.30 (m, 1H, H-12).
13C-NMR (CDCl3): 75.16 (d, C-1); 75.09 (d, C-3); 42.00 (t,
C-4); 70.71 (s, C-5); 37.99 (d, C-6); 24.48 (t, C-7); 123.94
(d, C-8); 131.80 (s, C-9); 70.45 (d, C-10); 144.65 (s, C-11);
125.85 (d, C-12); 134.09 (s, C-13); 127.31 (d, C-14); 129.
45 (d, C-15); 123.88 (d, C-16); 28.27 (q, C-17); 20.77 (q,
C-18).
25
19). ½aꢁD = -101.5 (c = 0.40, MeOH); HR-MS: 342.0782
(M?, C17H20Cl2O3?; calc. 342.0784).
(2R,4S,4aR,6S,7R,8aR,9S)-2,9-Bis(3-Chlorophenyl)-4,7-dimethyl
hexahydro-2H-4,6-(epoxymethano)chromen-8(5H)-one 8e 1H
NMR (CDCl3): 1.12 (d, J(18,9) = 7.5 Hz, 3H, H-18); 1.48
(2S,4S,4aR,8R,8aR)-2-(3,4-Dichlorophenyl)-4,7-dimethyl-
3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol ((S)-
123

1714
Med Chem Res (2014) 23:1709–1717
7f) 1H NMR (CDCl3 ? CD3OD): 1.51 (s, 3H, H-17); 1.
63–1.68 (m, 1H, He-4); 1.82 (br.s, 3H, H-18); 1.80–1.89
(m, 2H, Ha-4, Ha-6); 2.11–2.18 (m, 2H, H-7); 3.80 (dd,
J(1e,10e) = 2.3 Hz, J(1e,6a) = 2.1 Hz, 1H, He-1); 3.85
(br.s, 1H, He-10); 4.43 (dd, J(3a,4a) = 12.0 Hz,
J(3a,4e) = 2.7 Hz, 1H, Ha-3); 5.63–5.67 (m, 1H, H-8); 7.
16 (dd, J(16,15) = 8.2 Hz, J(16,12) = 2.0 Hz, 1H, H-16);
7.39 (d, J(15,16) = 8.2 Hz, 1H, H-15); 7.42 (d,
J(12,16) = 2.0 Hz, 1H, H-12). 13C-NMR (CDCl3 ?
CD3OD): 77.71 (d, C-1); 75.72 (d, C-3); 41.95 (t, C-4); 69.
84 (s, C-5); 37.77 (d, C-6); 22.21 (t, C-7); 123.80 (d, C-8);
130.78 (s, C-9); 69.57 (d, C-10); 142.25 (s, C-11); 127.33
(d, C-12); 130.35 and 131.73 (2 s, C-13, C-14); 129.70 (d,
C-15); 124.77 (d, C-16); 25.87 (q, C-17); 19.91 (q, C-18).
HR-MS: 342.0788 (M?, C17H20Cl2O3?; calc. 342.0784).
6 Hz, J(12,14) = 2.5 Hz, J(12,16) = 1.8 Hz, 1H, H-12);
7.21 (br.d, J(16,15) = 7.7 Hz, 1H, H-16); 7.25–7.30 (m,
1H, H-15). 13C-NMR (CDCl3): 75.12 (d, C-1); 95.00
(4J(C,F) = 2.2 Hz, C-3); 74.77 (s, C-5); 33.98 (d, C-6); 22.
93 (t, C-7); 125.31 (d, C-8); 130.71 (s, C-9); 70.39 (d, C-
10); 141.28 (3J(C,F) = 7.1 Hz, C-11); 113.37 (2J(C,F) =
22.1 Hz, C-12); 162.66 (1J(C,F) = 245.5 Hz, C-13); 115.
52 (2J(C,F) = 21.2 Hz, C-14); 129.66 (3J(C,F) = 8.4 Hz,
C-15); 122.01 (4J(C,F) = 3.1 Hz, C-16); 22.64 (q, C-17);
24
27.12 (q, C-18); 20.47 (q, C-19). ½aꢁD = -90.8 (c = 0.83,
MeOH); HR-MS: 292.1462 (M?, C17H21FO3?; calc. 292.
1469).
(2S,4S,4aR,8R,8aR)-2-(3-Fluorophenyl)-4,7-dimethyl-3,4,
4a,5,8,8a-hexahydro-2H-chromene-4,8-diol ((S)-7g) 1H
NMR (CDCl3): 1.52 (s, 3H, H-17); 1.69 (ddd, J(4e,4a) =
13.4 Hz, J(4e,3a) = 2.8 Hz, J(4e,6a) = 1.1 Hz, 1H, He-4);
1.79–1.88 (m, 2H, Ha-4, Ha-6); 1.82 (br.s, 3H, H-18); 2.
12–2.19 (m, 2H, H-7); 3.81 (dd, J(1e,10e) = 2.3 Hz,
J(1e,6a) = 2.1 Hz, 1H, He-1); 3.92 (br.s, 1H, He-10); 4.42
(dd, J(3a,4a) = 12.0 Hz, J(3a,4e) = 2.8 Hz, 1H, Ha-3); 5.
63-5.67 (m, 1H, H-8); 6.91 (dddd, J(14, 15) = 8.0 Hz,
J(14,F) = 8.0 Hz, J(14,16) = 2.5 Hz, J(14,12) = 1.5 Hz,
1H, H-14); 7.00–7.06 (m, 2H, H-12, H-16); 7.25 (ddd,
J(15,14) = 8.0 Hz, J(15,16) = 8.0 Hz, J(15,F) = 5.6 Hz,
1H, H-15). 13C-NMR (CDCl3): 77.52 (d, C-1); 76.75
(4J(C,F) = 1.8 Hz, C-3); 43.06 (t, C-4); 71.01 (s, C-5); 38.
19 (d, C-6); 22.60 (t, C-7); 124.56 (d, C-8); 131.31 (s, C-9);
70.42 (d, C-10); 144.42 (3J(C,F) = 7.1 Hz, C-11); 112.69
(2J(C,F) = 22.1 Hz, C-12); 162.73 (1J(C,F) = 245.9 Hz,
C-13); 114.28 (2J(C,F) = 21.2 Hz, C-14); 129.76
(3J(C,F) = 8.4 Hz, C-15); 121.21 (4J(C,F) = 3.0 Hz,
C-16); 26.96 (q, C-17); 20.70 (q, C-18). HR-MS: 292.1467
(M?, C17H21FO3?; calc. 292.1469).
(2S,4R,4aR,8R,8aR)-2-(3,4-Dichlorophenyl)-4,7-dimethyl-
3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol ((R)-7f) 1H
NMR (CDCl3): 1.23 (s, 3H, H-17); 1.59–1.67 (m, 2H, H-4),
1.70 (ddd, J(6a,7a) = 10.8 Hz, J(6a,7e) = 6.2 Hz,
J(6a,1e) = 2.1 Hz, 1H, Ha-6); 1.82 (br.s, 3H, H-18); 1.88–1.
98 (m, 2H, H-7); 3.91 (br.s, 1H, He-10); 4.23 (dd,
J(1e,10e) = 2.3 Hz, J(1e,6a) = 2.1 Hz, 1H, He-1); 4.74
(dd, J(3a,4a) = 9.4 Hz, J(3a,4e) = 5.0 Hz, 1H, Ha-3); 5.
57–5.60 (m, 1H, H-8); 7.10 (dd, J(16,15) = 8.2 Hz,
J(16,12) = 2.0 Hz, 1H, H-16); 7.34 (d, J(15,16) = 8.2 Hz,
1H, H-15); 7.38 (d, J(12,16) = 2.0 Hz, 1H, H-12). 13C-
NMR (CDCl3): 75.21 (d, C-1); 74.51 (d, C-3); 41.89 (t,
C-4); 70.70 (s, C-5); 38.02 (d, C-6); 24.49 (t, C-7); 123.91
(d, C-8); 131.85 (s, C-9); 70.43 (d, C-10); 142.89 (s, C-11);
127.74 (d, C-12); 130.99 and 132.27 (2 s, C-13, C-14); 130.
12 (d, C-15); 125.10 (d, C-16); 28.30 (q, C-17); 20.77 (q,
C-18).
With 3-fluorobenzaldehyde 2g The following compounds
were isolated: unreacted aldehyde 2g (0.145 g, conversion
72 %); intermolecular reaction products 3g (0.085 g, 10 %),
7g (S:R = 60:40) (0.247 g, 28 %), 8g (0.007 g, 0.5 %),
and 9 (0.012 g, 1.5 %); and isomerization products 4 (0.
062 g, 9 %), 5 (0.069 g, 10 %), and 6 (0.012 g, 2 %).
(2S,4R,4aR,8R,8aR)-2-(3-Fluorophenyl)-4,7-dimethyl-3,4,
4a,5,8,8a-hexahydro-2H-chromene-4,8-diol ((R)-7g) 1H
NMR (CDCl3): 1.23 (s, 3H, H-17); 1.61-1.73 (m, 3H, 2H-4,
Ha-6); 1.82 (br.s, 3H, H-18); 1.95–2.05 (m, 2H, H-7); 3.93
(br.s, 1H, He-10); 4.24 (dd, J(1e,10e) = 2.4 Hz,
J(1e,6a) = 2.1 Hz, 1H, He-1); 4.78 (dd, J(3a,4a) = 11.
0 Hz, J(3a,4e) = 3.5 Hz, 1H, Ha-3); 5.57–5.60 (m, 1H,
H-8); 6.89 (dddd, J(14,15) = 8.0 Hz, J(14,F) = 8.0 Hz,
J(14,16) = 2.5 Hz, J(14,12) = 1.5 Hz, 1H, H-14); 7.00–7.
06 (m, 2H, H-12, H-16); 7.25 (ddd, J(15,14) = 8.0 Hz,
J(15,16) = 8.0 Hz, J(15,F) = 5.6 Hz, 1H, H-15). 13C-
NMR (CDCl3): 75.02 (d, C-1); 75.05 (4J(C,F) = 1.8 Hz,
C-3); 42.00 (t, C-4); 70.75 (s, C-5); 37.96 (d, C-6); 24.49 (t,
C-7); 123.95 (d, C-8); 131.76 (s, C-9); 70.42 (d, C-10);
145.19 (3J(C,F) = 7.1 Hz, C-11); 112.63 (2J(C,F) = 22.
1 Hz, C-12); 162.74 (1J(C,F) = 245.0 Hz, C-13); 114.00
(2J(C,F) = 21.2 Hz, C-14); 129.67 (3J(C,F) = 8.4 Hz,
2S,4aR,8R,8aR)-2-(3-Fluorophenyl)-4,4,7-trimethyl-4a,5,8,
8a-tetrahydro-4H-benzo[d][1,3]dioxin-8-ol 3g (1H NMR
(CDCl3): 1.25 (s, 3H, H-18); 1.51 (s, 3H, H-17); 1.53 (ddd,
J(6a,7a) = 10.8 Hz, J(6a,7e) = 6.1 Hz, J(6a,1e) = 2.
0 Hz, 1H, Ha-6); 1.79 (m, all J B 2.5 Hz, 3H, H-19); 2.06
(dddq, J(7e,7a) = 17.7 Hz, J(7e,6a) = 6.1 Hz, J(7e,8) =
5.3 Hz, J(7e,19) = 1.5 Hz, 1H, He-7); 2.38–2.47 (m, 1H,
Ha-7); 3.87 (br.s, 1H, He-10); 4.34 (dd, J(1e,10e) = 2.
3 Hz, J(1e,6a) = 2.0 Hz, 1H, He-1); 5.64 (dm, J(8,7e) =
5.3 Hz, 1H, H-8); 5.77 (s, 1H, H-3); 6.97 (dddd,
J(14,15) = 8.2 Hz, J(14,F) = 8.2 Hz, J(14,16) = 2.5 Hz,
J(14,12) = 1.6 Hz, 1H, H-14); 7.17 (ddd, J(12,F) = 9.
123

Med Chem Res (2014) 23:1709–1717
1715
C-15); 121.22 (4J(C,F) = 3.0 Hz, C-16); 28.30 (q, C-17);
0 Hz, C-3); 38.59 (t, C-4); 146.36 (s, C-5); 36.63 (d, C-6);
26.17 (t, C-7); 124.39 (d, C-8); 131.49 (s, C-9); 70.29 (d,
C-10); 144.78 (3J(C,F) = 7.1 Hz, C-11); 112.66
(2J(C,F) = 22.1 Hz, C-12); 162.86 (1J(C,F) = 245.5 Hz,
C-13); 114.21 (2J(C,F) = 21.2 Hz, C-14); 129.71
(3J(C,F) = 8.4 Hz, C-15); 121.20 (4J(C,F) = 2.9 Hz,
C-16); 110.05 (t, C-17); 20.86 (q, C-18).
20.80 (q, C-18).
(2R,4S,4aR,6S,7R,8aR,9S)-2,9-Bis(3-fluorophenyl)-4,7-dim-
ethylhexahydro-2H-4,6-(epoxymethano)chromen-8(5H)-one
8g 1H NMR (CDCl3): 1.12 (d, J(18,9) = 7.6 Hz, 3H,
H-18); 1.48 (s, 3H, H-17); 1.94–1.97 (m, all J B 3.5 Hz,
1H, He-8); 1.97 (dd, J(4e,4a) = 14.9 Hz, J(4e,3a) = 2.
6 Hz, 1H, He-4); 2.20 (dd, J(4a,4e) = 14.9 Hz, J(4a,3a) =
13.2 Hz, 1H, Ha-4); 2.40–2.47 (m, 3H, H-7, He-9); 2.59
(dm, J(6e,1a) = 5.2 Hz, another J B 3.5 Hz, 1H, He-6); 4.
55 (d, J(1a,6e) = 5.2 Hz, 1H, Ha-1); 4.77 (dd, J(3a,4a) =
13.2 Hz, J(3a,4e) = 2.6 Hz, 1H, Ha-3); 4.81 (br.s, 1H,
H-19); 6.89–6.99 (m, 3H, H-14, H-23; H-12 or H-21); 7.02
(br.d, J(H,H) = 7.7 Hz, 1H, H-16 or H-25); 7.35 (br.d,
J(H,H) = 7.7 Hz, 1H, H-25 or H-16); 7.25–7.33 (m, 2H,
H-15, H-24); 7.37 (ddd, J(H,F) = 9.8 Hz, J(H,H) = 2.
6 Hz, J(H,H) = 1.8 Hz, 1H, H-21 or H-12). 13C-NMR
(CDCl3): 76.28 (d, C-1); 71,61 (4J(C,F) = 2.0 Hz, C-3);
48.19 (d, C-4); 73.05 (s, C-5); 39.04 (d, C-6); 24.34 (t,
C-7); 43.34 (d, C-8); 42.63 (d, C-9); 211.51 (s, C-10); 144.
59 (3J(C,F) = 7.1 Hz, C-11); 112.83 (2J(C,F) = 22.1 Hz),
113.57 (2J(C,F) = 22.1 Hz), 113.94 (2J(C,F) = 21.2 Hz)
and 114.55 (2J(C,F) = 21.2 Hz)–C-12, C-14, C-21 and
C-23; 162.74 (1J(C,F) = 245.5 Hz) and 162.79
(1J(C,F) = 245.5 Hz)–C-13 and C-22; 129.75 (3J(C,F) =
8.4 Hz, C-15, C-24); 122.01 (4J(C,F) = 3.1 Hz) and 121.
16 (4J(C,F) = 3.1 Hz)–C-16 and C-25; 23.15 (q, C-17);
17.68 (q, C-18), 74.92 (4J(C,F) = 2.0 Hz, C-19); 142.83
(3J(C,F) = 7.1 Hz, C-20). HR-MS: 398.1684 (M?,
With 4-(trifluoromethyl)benzaldehyde 2h The following
compounds were isolated: unreacted aldehyde 2h (0.410 g,
conversion 44 %); intermolecular reaction products 3h (0.
131 g, 21 %) and 7h (S:R = 50:50) (0.114 g, 18 %); and
isomerization products 4 (0.031 g, 4 %), 5 (0.093 g, 13 %),
and 6 (0.066 g, 9 %).
(2S,4aR,8R,8aR)-4,4,7-Trimethyl-2-(4-(trifluoromethyl)
phenyl)-4a,5,8,8a-tetrahydro-4H-benzo[d][1,3]dioxin-
8-ol 3h 1H NMR (CDCl3): 1.26 (s, 3H, H-18); 1.53 (s,
3H, H-17); 1.55 (ddd, J(6a,7a) = 10.8 Hz, J(6a,7e) = 6.
1 Hz, J(6a,1e) = 2.0 Hz, 1H, Ha-6); 1.80 (ddd,
J(19,7a) = 2.5 Hz, J(19,7e) = 1.5 Hz, J((19,8) = 1.5 Hz,
3H, H-19); 2.08 (dddq, J(7e,7a) = 17.8 Hz, J(7e,6a) = 6.
1 Hz, J((7e,8) = 5.2 Hz, J(7e,19) = 1.5 Hz, 1H, He-7); 2.
42 (dddqd, J(7a,7e) = 17.8 Hz, J(7a,6a) = 10.8 Hz,
J(7a,8) = 2.5 Hz, J(7a,19) = 2.5 Hz, J(7a,10e) = 1.2 Hz,
1H, Ha-7); 3.89 (br.s, 1H, He-10); 4.37 (dd, J(1e,10e) = 2.
3 Hz, J(1e,6a) = 2.0 Hz, 1H, He-1); 5.65 (dm, J(8,7e) =
5.2 Hz, 1H, H-8); 5.83 (s, 1H, H-3); 7.54–7.63 (m, 4H, H-
12, H-13, H-15, H-16). 13C-NMR (CDCl3): 75.16 (d, C-1);
94.95 (d, C-3); 74.89 (s, C-5); 34.00 (d, C-6); 22.94 (t, C-
7); 125.30 (d, C-8); 130.73 (s, C-9); 70.40 (d, C-10); 142.
52 (s, C-11); 126.75 (d, C-12, C-16); 125.11 (3J(C,F) = 4.
0 Hz, C-13, C-15); 130.77 (2J(C,F) = 32.3 Hz, C-14); 22.
63 (q, C-17); 27.10 (q, C-18); 20.47 (q, C-19); 121.8
C
24H24F2O3?; calc. 398.1688).
(2S,4aS,8R,8aR)-2-(3-Fluorophenyl)-7-methyl-4-methylene-
3,4,4a,5,8,8a-hexahydro-2H-chromen-8-ol
1H NMR
9
25
(CDCl3): 1.83 (br.s, 3H, H-18); 1.96 (dddq, J(7e,7a) = 17.
8 Hz, J(7e,6a) = 6.5 Hz, J(7e,8) = 5.2 Hz, J(7e,18) = 1.
5 Hz, 1H, He-7); 2.27–2.35 (m, 1H, Ha-7); 2.33 (dd,
J(4e,4a) = 14.1 Hz, J(4e,3a) = 3.0 Hz, 1H, He-4); 2.44
(ddt, J(4a,4e) = 14.1 Hz, J(4a,3a) = 11.5 Hz, J(4a,17) =
2.0 Hz, 1H, Ha-4); 2.54 (ddd, J(6a,7a) = 10.8 Hz,
J(6a,7e) = 6.5 Hz, J(6a,1e) = 2.2 Hz, 1H, Ha-6); 3.73 dd,
J(1e,10e) = 2.4 Hz, J(1e,6a) = 2.2 Hz, 1H, He-1); 3.92
(br.s, 1H, He-10); 4.38 (dd, J(3a,4a) = 11.5 Hz,
J(3a,4e) = 3.0 Hz, 1H, Ha-3); 4.82 (dd, J(17,170) = 2.
3 Hz, J(17,4a) = 2.0 Hz, 1H, H-17); 4.92 (dd,
J(170,17) = 2.3 Hz, J(170,4a) = 2.0 Hz, 1H, H-170); 5.
61–5.65 (m, 1H, H-8); 6.93 (dddd, J(14,15) = 8.2 Hz,
J(14,F) = 8.2 Hz, J(14,16) = 2.6 Hz, J(14,12) = 1.5 Hz,
1H, H-14); 7.06 (ddd, J(12,F) = 9.5 Hz, J(12,14) = 2.
5 Hz, J(12,16) = 1.8 Hz, 1H, H-12); 7.08 (br.d,
J(16,15) = 7.5 Hz, 1H, H-16); 7.26 (ddd, J(15,14) = 8.
2 Hz, J(15,16) = 7.5 Hz, J(15,F) = 5.6 Hz, 1H, H-15).
1C-NMR (CDCl3): 80.46 (d, C-1); 79.77 (4J(C,F) = 2.
(1J(C,F) = 272.5 Hz, C-20). ½aꢁD = -80.3 (c = 0.43,
MeOH); HR-MS: 342.1334 (M?, C18H21F3O3?; calc. 342.
1437).
(2S,4S,4aR,8R,8aR)-4,7-Dimethyl-2-(4-(trifluoromethyl)
phenyl)-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol
((S) 7h) 1H NMR (CDCl3 ? CD3OD): 1.43 (s, 3H,
H-17); 1.59 (dd, J(4e,4a) = 13.4 Hz, J(4e,3a) = 2.7 Hz,
1H, He-4); 1.73 (br.s, 3H, H-18); 1.72–1.80 (m, 2H, Ha-4,
Ha-6); 2.03–2.12 (m, 2H, H-7); 3.72 (br.t,
J(1e,10e) & J(1e,6a) & 2.2 Hz, 1H, He-1); 3.78 (br.s, 1H,
He-10); 4.41 (dd, J(3a,4a) = 12.0 Hz, J(3a,4e) = 2.7 Hz,
1H, Ha-3); 5.55–5.59 (m, 1H, H-8); 7.34 (d, J(12,13) =
J(16,15) = 8.2 Hz, 2H, H-12, H-16); 7.47 (d, J(13,12) =
J(15,16) = 8.2 Hz, 2H, H-13, H-15). 13C-NMR
(CDCl3 ? CD3OD): 77.77 (d, C-1); 76.65 (d, C-3); 42.49
(t, C-4); 70.34 (s, C-5); 38.04 (d, C-6); 22.51 (t, C-7); 124.
17 (d, C-8); 131.13 (s, C-9); 69.96 (d, C-10); 145.96 (s,
C-11); 125.88 (d, C-12, C-16); 125.01 (3J(C,F) = 4.0 Hz,
123

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Med Chem Res (2014) 23:1709–1717
C-13, C-15); 129.43 (2J(C,F) = 32.3 Hz, C-14); 26.43 (q,
C-17); 20.40 (q, C-18); 123.87 (1J(C,F) = 272.5 Hz,
C-19). HR-MS: 342.1442 (M?, C18H21F3O3?; calc. 342.
1437).
injection (0.75 %, 0.1 ml/mouse) (Koster et al., 1959). The
percentage of pain reaction inhibition was calculated accord-
ing 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.
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).
The results of pharmacological testing were partly pre-
sented by us in the patent (Tolstikova et al., 2011).
Statistical data processing was carried out using a
Statistica 6.0 program.
(2S,4R,4aR,8R,8aR)-4,7-Dimethyl-2-(4-(trifluoromethyl)
phenyl)-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol
((R)-7h) 1H NMR (CDCl3 ? CD3OD): 1.15 (s, 3H,
H-17); 1.60 (d, J(4,3) = 7.3 Hz, 2H, H-4); 1.65 (ddd,
J(6a,7a) = 10.8 Hz, J(6a,7e) = 6.3 Hz; J(6a,1e) = 2.
1 Hz, 1H, Ha-6); 1.75 (br.s, 3H, H-18); 1.88–2.00 (m, 2H,
H-7); 3.82 (br.s, 1H, He-10); 4.16 (dd, J(1e,10e) = 2.4 Hz,
J(1e,6a) = 2.1 Hz, 1H, He-1); 4.78 (t, J(3,4) = 7.3 Hz,
1H, Ha-3); 5.51–5.55 (m, 1H, H-8); 7.35 (d, J(12,13) =
J(16,15) = 8.2 Hz, 2H, H-12, H-16); 7.47 (d, J(13,12) =
J(15,16) = 8.2 Hz, 2H, H-13, H-15). 13C-NMR
(CDCl3 ? CD3OD): 75.17 (d, C-1); 75.09 (d, C-3); 41.74
(t, C-4); 70.08 (s, C-5); 37.54 (d, C-6); 24.36 (t, C-7); 123.
57 (d, C-8); 131.72 (s, C-9); 70.00 (d, C-10); 146.71 (s,
C-11); 125.84 (d, C-12, C-16); 124.98 (3J(C,F) = 4.0 Hz,
C-13, C-15); 129.20 (2J(C,F) = 32.3 Hz, C-14); 27.70 (q,
C-17); 20.54 (q, C-18); 124.02 (1J(C,F) = 272.0 Hz,
C-19).
Acknowledgments Authors are grateful to the Presidium of Russian
Academy of Sciences (program N 28) and Russian Foundation for
Basic Research (Grant No. 11-03-00010a) for the financial support.
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