Synthesis and Analgesic Activity of 4,7-Dimethyl-3,4,4a,5,8,8a-Hexahydro-2-Chromen-4,8-Diols Containing Alkyl-Substituted Aromatic Moieties

Article abstract of DOI:10.1007/s10600-017-2202-1

A series of new heterocyclic compounds with the hexahydro-2H-chromene skeleton were prepared by reacting the monoterpenoid para-mentha-1,8-diene-5,6-diol with 4-alkyl-substituted aromatic aldehydes. Adding small alkyl substituents (methyl and ethyl) to the aldehyde aromatic ring increased the yields of hexahydrochromenes as compared with the analogous reaction with benzaldehyde. However, adding a branched substituent (isopropyl) and longer butyl and octyl moieties reduced the yields of the target compounds. The stereoselectivity of the reaction changed as the alkyl substituent lengthened. The analgesic activity of the obtained products was studied.

Full text of DOI:10.1007/s10600-017-2202-1

DOI 10.1007/s10600-017-2202-1
Chemistry of Natural Compounds, Vol. 53, No. 6, November, 2017
SYNTHESIS AND ANALGESIC ACTIVITY OF 4,7-DIMETHYL-
3,4,4a,5,8,8a-HEXAHYDRO-2-CHROMEN-4,8-DIOLS
CONTAINING ALKYL-SUBSTITUTED
AROMATIC MOIETIES
1*
1
1
O. S. Patrusheva, A. V. Pavlova, D. V. Korchagina,
1
1,2
1,2
T. G. Tolstikova, K. P. Volcho, and N. F. Salakhutdinov
A series of new heterocyclic compounds with the hexahydro-2H-chromene skeleton were prepared by reacting
the monoterpenoid para-mentha-1,8-diene-5,6-diol with 4-alkyl-substituted aromatic aldehydes. Adding
small alkyl substituents (methyl and ethyl) to the aldehyde aromatic ring increased the yields of
hexahydrochromenes as compared with the analogous reaction with benzaldehyde. However, adding
a branched substituent (isopropyl) and longer butyl and octyl moieties reduced the yields of the target
compounds. The stereoselectivity of the reaction changed as the alkyl substituent lengthened. The analgesic
activity of the obtained products was studied.
Keywords: monoterpenes, aldehydes, montmorillonite clay, heterocyclic compounds, analgesic activity.
Previously, we prepared a large series of compounds with the hexahydro-2H-chromene skeleton (1) by reacting the
monoterpenoid diol (4S,5R,6R)-para-mentha-1,8-diene-5,6-diol (2) with various substituted benzaldehydes in the presence of
K10 clay [1–4]. Monoterpenoid 2 was prepared from commercially available (–)-verbenone (3) in three steps [1, 5]. Compounds
of type 1 were formed as mixtures of diastereomers with respect to the methyl and hydroxyl. Studies of the biological activity
of the prepared compounds identified several promising agents with analgesic [3, 4, 6] or antiviral activity [7].
Even small changes in the substituents on the aromatic ring affect the biological properties. For example, changing
the mutual positioning of the methoxy and hydroxy substituents on the aromatic ring in compounds 4 and 5 with the
hexahydrochromene skeleton had a decisive effect on the mechanism of analgesic activity [8].
OH
H
OH
O
H
OR
OR
1
O
R
OH
H
2
4, 5
6, 7
4: R = Me, R = H; 5: R = H, R = Me
1
2
1
2
6: R = (CH ) CH ; 7: R = C(CH ) COOAlk
2 4
3
3 2
Phytocannabinoids with pronounced analgesic activity, for example, tetrahydrocannabinol (6) and its synthetic analogs,
e.g., compounds of type 7, can be considered structural analogs of type 1 compounds [9, 10]. The length and structure of the
alkyl substituent on the aromatic ring in type 7 compounds affected manifestation of an analgesic effect [11].
1) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
9 Prosp. Akad. Lavrentꢀeva, Novosibirsk, 630090, Russian Federation, fax: (383) 330 97 52, e-mail: bawos@mail.ru;
2) Novosibirsk National Research State University, 2 Pirogova St., Novosibirsk, 630090, Russian Federation. Translated
from Khimiya Prirodnykh Soedinenii, No. 6, November–December, 2017, pp. 907–911. Original article submitted February
28, 2017.
©
1066
0009-3130/17/5306-1066 2017 Springer Science+Business Media New York

The goals of the present work were to synthesize compounds with the type 1 hexahydro-2H-chromene skeleton and
alkyl substituents on the aromatic ring and to study their analgesic activity.
Our research began with the reaction of diol 2 with benzaldehyde 8a. Earlier, this reaction was studied using BF 4Et O–H O
3
2
2
[12], series of metal- and H-modified zeolites, and mesoporous silicate Ce-MCM-41 as catalysts to form product 1a with the
hexahydro-2H-chromene skeleton [13]. Benzaldehyde 8a was reacted solvent-free with diol 2 using K10 clay to compare the
results and identify trends. However, CH Cl was used to deposit the reagents evenly and then distilled at reduced pressure.
2
2
The reaction mixture was stored dry for 24 h at room temperature. This reaction procedure [14] could increase significantly
the product yield and shorten the time to reach complete conversion of starting monoterpenoid 2. The product was isolated by
column chromatography over SiO . Compound 1a was obtained in moderate yield (43%) under these conditions. According
2
to GC-MS and PMR spectroscopy, dehydration products were formed in addition to the target product. Compound 9a dominated
these (Scheme 1). The overall yield of the mixture of these products was 30%.
18
10 OH
H
OH
H
O
OH
H
O
8
OH
OH
i, ii, iii
6
iv
1
O
+
+
H
17
H
H
3
5
O
15
OH H 11
H
H
OH
R
R
R
13
(R)-1a-f
2
(S)-1a-f
9
3
CHO
19
21
19
20
1c, 8c:R =
1d, 8d: R =
1e, 8e: R =
1f, 8f: R =
19
25
19
21
R
8a-f
1a,8a: R = H, 43%, S – R 1:1; 1b,8b: R = CH , 70%, 1:1; 1c,8c: 70%, 1:1
3
1d,8d: 56%, 1:1; 1e,8e: 52%, 2.5:1; 1f,8f: 42%, 2:1
i. H O , NaOH; ii. LiAlH ; iii. K10 clay; iv. 8a-f, 20°C, K10 clay, 24 h
2
2
4
Scheme 1
Adding a short alkyl substituent to the aromatic ring increased significantly the yield of the target products. Thus,
reaction of diol 2 with 4-methylbenzaldehyde 8b in the presence of K10 clay according to the aforementioned procedure
formed 1b in 70% yield. The situation was analogous for the reaction with 4-ethylbenzaldehyde 8c. Product 1c was isolated
from the reaction mixture in 70% yield. Significant amounts of type 9 dehydration products were not detected in the reaction
mixtures after the reactions of 8b and 8c with diol 2 (Scheme 1). Apparently, this also increased the yields of type 1 compounds.
The (S)–(R) diastereomeric ratio for hexahydrochromenes 1a–c was 1:1.
The trend was broken on going to 4-isopropylbenzaldehyde 8d. The yield of target product 1d decreased to 56%
whereas that of type 9 dehydration products increased to 8%. The tendency to decrease the yield of the target product and
accumulate dehydration products persisted for the reactions with 4-butylbenzaldehyde 8e and 4-octylbenzaldehyde 8f. The
yields of target products after the reaction of diol 2 with 8e was 52%; with 8f, 42%. The overall yields of the dehydration
products were ~25% in both cases. In addition to the reduced yields, the diastereomeric ratios also changed if aldehydes 8e
and 8f were used. The (S)-diastereomer dominated (Scheme 1).
Compound 1a, which was prepared by reacting diol 2 with benzaldehyde 8a, was shown earlier to possess pronounced
analgesic activity at a dose of 10 mg/kg in the acetate writhing model. A goal of our work was to find the effects of the length
and branching of the aromatic alkyl substituent on the manifestation of analgesic activity by the type 1 hexahydro-2H-chomenes.
Analgesic activity of synthesized 1b–f was studied using pure (S)-diastereomers, which were isolated from the mixtures
by precipitation after adding small amounts of Et O. The analgesic activity of (S)-1b–f at doses of 10 mg/kg was studied using
2
standard in vivo models of tactile (hot plate) [15] and visceral pain (acetate writhing) [16]. It was found that adding alkyl
substituents to the aromatic 4-position led to the disappearance of analgesic activity regardless of the length and branching of
the aliphatic moiety.
Thus, a series of new heterocyclic compounds with the hexahydro-2H-chromene skeleton were prepared by reacting
(4S,5R,6R)-para-mentha-1,8-diene-5,6-diol (2) with 4-alkyl-substituted aromatic aldehydes 8b–f in the presence of K10
montmorillonite clay. The product yields and reaction stereoselectivity changed as the length of the alkyl substituent increased.
1067

The (S)–(R) diastereomeric ratio of the products obtained from aldehydes 8a–d was 1:1 whereas the reaction was more
stereoselective with the (S)-diastereomer dominating for aldehydes 8e and 8f with long aliphatic moieties.
EXPERIMENTAL
31
Instruments and Materials. (4S,5R,6R)-para-Mentha-1,8-diene-5,6-diol [2, [ꢁ] –49.1° (c 2.6, CHCl )] was
D
3
prepared by the previously developed procedure from (–)-verbenone [17]. Other reagents were purchased (purity >98%,
Sigma-Aldrich). Reaction mixtures were separated by column chromatography over SiO (Macherey-Nagel, 60–200 ꢂm)
2
using EtOAc (0–100%) in hexane.
Spectral and analytical studies were carried out at the Khimiya Joint Use Center, SB, RAS.
Elemental compositions of the obtained compounds were determined from mass spectra recorded on a Thermo Scientific
DFS spectrometer with full scanning in the range 0–500 m/z and electron-impact ionization at 70 eV with direct sample
introduction.
13
PMR and C NMR spectra were recorded using CD(H)Cl resonances (ꢃ 7.24, ꢃ 76.90 ppm) as standards on
3
H
C
1
13
Bruker DRX-500 (500.13 MHz for H, 125.76 MHz for C) andAV-300 spectrometers (300.13 and 75.48 MHz, respectively).
The structures of the obtained compounds were established by analyzing PMR and C NMR spectra and using H– H double
resonance and 2D heteronuclear C– H correlation spectra of direct (C–H COSY, J
13
1
1
13
1
1
= 160 Hz) and through-space
C,H
13
2,3
(C–H COLOC,
J
= 10 Hz) spin–spin coupling constants. Multiplicities of resonances in C NMR spectra were determined
C,H
from spectra recorded in J-modulation mode (JMOD). The atomic numbering given in Scheme 1 was used to describe the
13
4
PMR and C NMR spectra. AW-constant between CH -17 and H-4ax ( J
= 0.6–0.7 Hz) was observed in PMR spectra
3
Me,4ax
for the (S)-diastereomers with artificial line narrowing. This indicated that the C-5 methyl was axial. As expected, the axial
hydroxyl in the (R)-diastereomers caused a paramagnetic shift of the H-1 (ꢄꢃ = 0.41–0.44 ppm) and H-3 resonances
(ꢄꢃ = 0.34–0.36 ppm) because of 1,3-diaxial coupling.
Synthesis of 1a–f by Reacting Diol 2 with 4-Alkylbenzaldehydes 8a–f. General Method. K10 clay was calcined
beforehand at 105°C for 3 h. CH Cl was passed through a layer of Al O . CH Cl (5 mL) was added to the clay cooled to
2
2
2
3
2
2
room temperature. Then, the resulting suspension was treated with a solution of the 4-alkylbenzaldehyde in CH Cl (5 mL),
2
2
stirred, treated with a solution of diol 2 in CH Cl (5 mL). The solvent was distilled off. The resulting mixture was held at
2
2
room temperature (20°C) for 24 h and treated with EtOAc (20 mL). The catalyst was filtered off. The solvent was distilled off.
The resulting solid was separated over a column of silica gel. The isolated mixture of diastereomers was treated with Et O
2
(3–4 mL) to produce a small quantity of the pure (S)-diastereomer of product 1. The resulting precipitate was filtered off.
Compound 1a. Diol 2 (200 mg, 1.19 mmol), benzaldehyde 8a (126 mg, 1.19 mmol), and K10 clay (650 mg)
afforded 1a (140 mg, 0.51 mmol) [(S)–(R) 1:1, 43%]. Pure (S)-diastereomer (20 mg) was obtained as a precipitate by adding
Et O (3 mL) to the mixture of diastereomers. The spectral characteristics of 1a agreed with the literature [1].
2
Compound 1b. The reaction of diol 2 (200 mg, 1.19 mmol), 4-methylbenzaldehyde 8b (143 mg, 1.19 mmol), and
K10 clay (690 mg) afforded 1b (240 mg, 0.83 mmol) [(S)–(R) 1:1, 70%]. The mixture of diastereomers was treated with Et O
2
(4 mL) to produce the pure (S)-diastereomer (30 mg).
(2S,4S,4aR,8R,8aR)-4,7-Dimethyl-2-(p-tolyl)-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol [(S)-1b],
25
D
1
ꢅꢁ
–57ꢆ (c 0.20, EtOH). Í NMR spectrum (CDCl + CD OD, ꢃ, ppm, J/Hz): 1.47 (3H, s, H-17), 1.61 (1H, ddd, J = 12.0,
3 3
2.6, 1.1, H-4eq), 1.77 (3H, m, all J ꢇ 2.5, H-18), 1.79 (1H, br.t, J = 8.7, H-6ax), 1.88 (1H, dd, J = 12.0, 12.0, H-4ax), 2.10–2.17
(2H, m, H-7), 2.27 (3H, s, H-19), 3.75 (1H, dd, J = 2.3, 2.1, H-1eq), 3.84 (1H, br.s, H-10eq), 4.36 (1H, dd, J= 12.0, 2.6, H-3ax),
13
5.59–5.63 (1H, m, H-8), 7.08 (2H, d, J = 8.0, H-13, 15), 7.16 (2H, d, J = 8.0, H-12, 16). C NMR spectrum (CDCl + CD OD,
3
3
ꢃ, ppm): 77.72 (CH, C-1), 77.42 (CH, C-3), 42.76 (CH , C-4), 70.81 (C, C-5), 38.22 (CH, C-6), 22.61 (CH , C-7), 124.39
2
2
(CH, C-8), 131.24 (C, C-9), 70.20 (CH, C-10), 138.85 (C, C-11), 125.75 (CH, C-12, 16), 128.84 (CH, C-13, 15), 137.11 (C,
+
C-14), 26.72 (CH , C-17), 20.57 (CH , C-18), 20.87 (CH , C-19). Found m/z 288.1710 ꢅM (calcd for C H O 288.1720).
3
3
3
18 24 3
1
(2S,4R,4aR,8R,8aR)-4,7-Dimethyl-2-(p-tolyl)-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol [(R)-1b], Í NMR
spectrum (CDCl + CD OD, ꢃ, ppm, J/Hz): 1.18 (3H, s, H-17), 1.58 (1H, ddd, J = 14.2, 2.7, 1.2, H-4eq), 1.67 (1H, br.t, J = 8.5,
3
3
H-6ax), 1.70 (1H, dd, J = 14.2, 11.7, H-4ax), 1.77 (3H, m, all J ꢇ 2.5, H-18), 1.94–2.00 (2H, m, H-7), 2.26 (3H, s, H-19), 3.86
(1H, br.s, H-10eq), 4.18 (1H, dd, J = 2.3, 2.1, H-1eq), 4.72 (1H, dd, J = 11.7, 2.7, H-3ax), 5.53–5.57 (1H, m, H-8), 7.07 (2H,
13
d, J = 8.0, H-13, 15), 7.16 (2H, d, J = 8.0, H-12, 16). C NMR spectrum (CDCl + CD OD, ꢃ, ppm): 75.19 (CH, C-1), 75.69
3
3
(CH, C-3), 41.87 (CH , C-4), 70.43 (C, C-5), 37.77 (CH, C-6), 24.44 (CH , C-7), 123.75 (CH, C-8), 131.75 (C, C-9), 70.20
2
2
1068

(CH, C-10), 139.53 (C, C-11), 125.71 (CH, C-12, C-16), 128.79 (CH, C-13, 15), 136.83 (C, C-14), 27.97 (CH , C-17), 20.65
3
+
(CH , C-18), 20.87 (CH , C-19). Found m/z 288.1710 ꢅM (calcd for C H O 288.1720).
3
3
18 24 3
Compound 1c. The reaction of diol 2 (300 mg, 1.78 mmol) with 8c (246 mg, 1.83 mmol) in the presence of K10 clay
(1100 mg) produced 1c (382 mg, 1.26 mmol) [(S)–(R) 1:1, 71%], of which the pure (S)-diastereomer (20 mg) precipitated after
adding Et O (4 mL) to the mixture of diastereomers.
2
(2S,4S,4aR,8R,8aR)-2-(4-Ethylphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol [(S)-1c],
25
D
1
ꢅꢁ
–49.3ꢆ (c 0.13; EtOH). Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.19 (3H, t, J = 7.6, H-20), 1.50 (3H, s, H-17), 1.64
3
(1H, ddd, J = 13.3, 2.7, 1.1, H-4eq), 1.77 (3H, m, all J ꢇ 2.5, H-18), 1.83 (1H, br.t, J = 8.8, H-6ax), 1.92 (1H, dd, J = 13.3, 12.0,
H-4ax), 2.14–2.19 (2H, m, H-7), 2.60 (2H, q, J = 7.6, 2H-19), 3.79 (1H, dd, J = 2.2, 2.2, H-1eq), 3.88 (1H, br.s, H-10eq), 4.39
(1H, dd, J = 12.0, 2.7, H-3ax), 5.61–5.64 (1H, m, H-8), 7.13 (2H, d, J = 8.5, H-13, 15), 7.21 (2H, d, J = 8.5, H-12, 16).
13
C NMR spectrum (CDCl , ꢃ, ppm): 77.66 (CH, C-1), 77.45 (CH, C-3), 42.84 (CH , C-4), 71.04 (C, C-5), 38.27 (CH, C-6),
3
2
22.67 (CH , C-7), 124.52 (CH, C-8), 131.30 (C, C-9), 70.37 (CH, C-10), 139.04 (C, C-11), 125.86 (CH, C-12, 16), 127.72
2
(CH, C-13, 15), 143.56 (C, C-14), 26.88 (CH , C-17), 20.66 (CH , C-18), 28.38 (CH , C-19), 15.43 (CH , C-20). Found m/z
3
3
2
3
+
302.1868 ꢅM (calcd for C H O 302.1877).
19 26
3
(2S,4R,4aR,8R,8aR)-2-(4-Ethylphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol [(R)-1c],
1
Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.18 (3H, t, J = 7.6, H-20), 1.20 (3H, s, H-17), 1.62 (1H, ddd, J = 14.1, 2.8, 1.3,
3
H-4eq), 1.72 (1H, br.t, J = 8.5, H-6ax), 1.74 (1H, dd, J = 14.1, 11.6, H-4ax), 1.77 (3H, m, all J ꢇ 2.5, H-18), 1.96–2.02 (2H, m,
H-7), 2.58 (2H, q, J = 7.6, 2H-19), 3.90 (1H, br.d, J = 2.2, H-10eq), 4.23 (1H, dd, J = 2.2, 2.2, H-1eq), 4.75 (1H, dd, J = 11.6,
13
2.8, H-3ax), 5.55–5.58 (1H, m, H-8), 7.11 (2H, d, J = 8.5, H-13, 15), 7.21 (2H, d, J = 8.5, H-12, 16). C NMR spectrum
(CDCl , ꢃ, ppm): 75.16 (CH, C-1), 75.69 (CH, C-3), 41.89 (CH , C-4), 71.04 (C, C-5), 37.84 (CH, C-6), 24.48 (CH , C-7),
3
2
2
123.88 (CH, C-8), 131.76 (C, C-9), 70.35 (CH, C-10), 139.74 (C, C-11), 125.82 (CH, C-12, 16), 127.65 (CH, C-13, 15),
+
143.27 (C, C-14), 28.12 (CH , C-17), 20.75 (CH , C-18), 28.38 (CH , C-19), 15.44 (CH , C-20). Found m/z 302.1868 ꢅM
3
3
2
3
(calcd for C H O 302.1877).
19 26
3
Compound 1d. The reaction of diol 2 (300 mg, 1.78 mmol) with 8d (264 mg, 1.78 mmol) in the presence of K10 clay
(1130 mg) produced 1d (314 mg, 0.99 mmol) [(S)–(R) 1:1, 56%], of which the pure (S)-diastereomer (64 mg) precipitated after
adding Et O (4 mL) to the mixture of diastereomers.
2
(2S,4S,4aR,8R,8aR)-2-(4-Isopropylphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol
25
1
[(S)-1d], ꢅꢁ –56.3ꢆ (c 0.38; EtOH). Í NMR spectrum (CDCl + CD OD, ꢃ, ppm, J/Hz): 1.15 (6H, d, J = 7.0, H-20, 21),
D
3
3
1.16 (3H, s, H-17), 1.59 (1H, ddd, J = 13.4, 2.6, 1.1, H-4eq), 1.74 (3H, m, all J ꢇ 2.5, H-18), 1.78 (1H, br.t, J = 8.6, H-6ax), 1.89
(1H, dd, J = 13.4, 12.0, H-4ax), 2.08–2.15 (2H, m, H-7), 2.75–2.85 (1H, m, H-19), 3.73 (1H, dd, J = 2.4, 2.1, H-1eq), 3.80 (1H,
br.s, H-10eq), 4.35 (1H, dd, J = 12.0, 2.6, H-3ax), 5.56–5.61 (1H, m, H-8), 7.11 (2H, d, J = 8.1, H-13, 15), 7.17 (2H, d, J = 8.1,
13
H-12, 16). C NMR spectrum (CDCl + CD OD, ꢃ, ppm): 77.77 (CH, C-1), 77.45 (CH, C-3), 42.39 (CH , C-4), 70.66 (C,
3
3
2
C-5), 38.16 (CH, C-6), 22.57 (CH , C-7), 124.31 (CH, C-8), 131.14 (C, C-9), 70.05 (CH, C-10), 139.08 (C, C-11), 125.86
2
(CH, C-12, 16), 126.21 (CH, C-13, 15), 148.18 (C, C-14), 26.56 (CH , C-17), 20.47 (CH , C-18), 33.58 (CH, C-19), 23.66,
3
3
+
23.71 (2CH , C-20, 21). Found m/z 316.2027 ꢅM (calcd for C H O 316.2033).
3
20 28 3
(2S,4R,4aR,8R,8aR)-2-(4-Isopropylphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol
1
[(R)-1d], Í NMR spectrum (CDCl + CD OD, ꢃ, ppm, J/Hz): 1.14 (6H, d, J = 7.0, H-20, 21), 1.16 (3H, s, H-17), 1.57 (1H,
3
3
ddd, J = 14.2, 2.8, 1.3, H-4eq), 1.64 (1H, br.t, J = 8.7, H-6ax), 1.71 (1H, dd, J = 14.2, 11.7, H-4ax), 1.74 (3H, m, all J ꢇ 2.5,
H-18), 1.93–1.98 (2H, m, H-7), 2.75–2.85 (1H, m, H-19), 3.82 (1H, br.s, H-10eq), 4.15 (1H, dd, J = 2.3, 2.1, H-1eq), 4.69 (1H,
13
dd, J = 11.7, 2.8, H-3ax), 5.50–5.55 (1H, m, H-8), 7.10 (2H, d, J = 8.1, H-13, 15), 7.17 (2H, d, J = 8.1, H-12, 16). C NMR
spectrum (CDCl + CD OD, ꢃ, ppm): 75.19 (CH, C-1), 75.74 (CH, C-3), 41.65 (CH , C-4), 70.27 (C, C-5), 37.65 (CH, C-6),
3
3
2
24.39 (CH , C-7), 123.65 (CH, C-8), 131.69 (C, C-9), 70.05 (CH, C-10), 139.78 (C, C-11), 125.78 (CH, C-12, 16), 126.18
2
(CH, C-13, 15), 147.90 (C, C-14), 27.80 (CH , C-17), 20.54 (CH , C-18), 33.58 (CH, C-19), 23.68, 23.72 (2CH , C-20, 21).
3
3
3
+
Found m/z 316.2027 ꢅM (calcd for C H O 316.2033).
20 28
3
Compound 1e. Diol 2 (300 mg, 1.78 mmol), 8e (289 mg, 1.78 mmol), and K10 clay (1180 mg) produced 1e (305 mg,
0.92 mmol) [(S)–(R) 2.5:1, 52%], of which the pure (S)-diastereomer (95 mg) precipitated after adding Et O (4 mL) to the
2
mixture of diastereomers.
(2S,4S,4aR,8R,8aR)-2-(4-Butylphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol [(S)-1e],
25
D
1
ꢅꢁ
–85.3ꢆ (c 0.3; EtOH). Í NMR spectrum (CDCl + CD OD, ꢃ, ppm, J/Hz): 0.86 (3H, t, J = 7.4, H-22), 1.24–1.33 (2H,
3 3
m, H-21), 1.47 (3H, s, H-17), 1.47–1.55 (2H, m, H-20), 1.62 (1H, ddd, J = 13.4, 2.6, 1.1, H-4eq), 1.77 (3H, m, all J ꢇ 2.5,
H-18), 1.79 (1H, br.t, J = 8.7, H-6ax), 1.89 (1H, dd, J = 13.4, 12.0, H-4ax), 2.10–2.17 (2H, m, H-7), 2.49–2.56 (2H, m, H-19),
1069

3.76 (1H, dd, J = 2.3, 2.1, H-1eq), 3.84 (1H, br.s, H-10eq), 4.37 (1H, dd, J = 12.0, 2.6, H-3ax), 5.59–5.63 (1H, m, H-8), 7.08
13
(2H, d, J = 8.0, H-13, 15), 7.17 (2H, d, J = 8.0, H-12, 16). C NMR spectrum (CDCl + CD OD, ꢃ, ppm): 77.76 (CH, C-1),
3
3
77.52 (CH, C-3), 42.74 (CH , C-4), 70.81 (C, C-5), 38.26 (CH, C-6), 22.61 (CH , C-7), 124.41 (CH, C-8), 131.28 (C, C-9),
2
2
70.23 (CH, C-10), 138.98 (C, C-11), 125.78 (CH, C-12, 16), 128.26 (CH, C-13, 15), 142.24 (C, C-14), 26.72 (CH , C-17),
3
20.56 (CH , C-18), 35.12 (CH , C-19), 33.43 (CH , C-20), 22.11 (CH , C-21), 13.69 (CH , Ñ-22). Found m/z 312.2085
3
2
2
2
3
+
[M – H O] (calcd for C H O 312.2084).
2
21 28 2
(2S,4R,4aR,8R,8aR)-2-(4-Butylphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol [(R)-1e],
Í NMR spectrum (CDCl + CD OD, ꢃ, ppm, J/Hz): 0.85 (3H, t, J = 7.4, H-22), 1.18 (3H, s, H-17), 1.24–1.33 (2H, m, H-21),
1
3
3
1.47–1.55 (2H, m, H-20), 1.59 (1H, ddd, J = 14.1, 2.8, 1.3, H-4eq), 1.65 (1H, br.t, J = 8.8, H-6ax), 1.72 (1H, dd, J = 14.1, 11.7,
H-4ax), 1.77 (3H, m, all J ꢇ 2.5, H-18), 1.94–2.01 (2H, m, H-7), 2.49–2.56 (2H, m, H-19), 3.86 (1H, br.s, H-10eq), 4.17 (1H,
dd, J = 2.2, 2.2, H-1eq), 4.71 (1H, dd, J = 11.7, 2.8, H-3ax), 5.53–5.57 (1H, m, H-8), 7.07 (2H, d, J = 8.0, H-13, 15), 7.17 (2H,
13
d, J = 8.0, H-12, 16). C NMR spectrum (CDCl + CD OD, ꢃ, ppm): 75.21 (CH, C-1), 75.79 (CH, C-3), 41.87 (CH , C-4),
3
3
2
70.40 (C, C-5), 37.83 (CH, C-6), 24.47 (CH , C-7), 123.79 (CH, C-8), 131.78 (C, C-9), 70.23 (CH, C-10), 139.69 (C, C-11),
2
125.72 (CH, C-12, 16), 128.20 (CH, C-13, 15), 141.95 (C, C-14), 28.00 (CH , C-17), 20.63 (CH , C-18), 35.12 (CH , C-19),
3
3
2
+
33.43 (CH , C-20), 22.11 (CH , C-21), 13.69 (CH , Ñ-22). Found m/z 312.2085 [M – H O] (calcd for C H O 312.2084).
2
2
3
2
21 28 2
Compound 1f. Diol 2 (154 mg, 0.92 mmol), 8f (200 mg, 0.92 mmol), and K10 clay (708 mg) produced 1f (150 mg,
0.39 mmol) [(S)–(R) 2:1, 42%], of which the pure (S)-diastereomer (25 mg) precipitated after adding Et O (3 mL) to the
2
mixture of diastereomers.
(2S,4S,4aR,8R,8aR)- 4,7-Dimethyl-2-(4-octylphenyl)-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol [(S)-1f],
1
Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 0.86 (3H, t, J = 7.0, H-26), 1.52 (3H, s, H-17), 1.52–1.59 (2H, m, H-20), 1.67 (1H,
3
ddd, J = 13.3, 2.7, 1.1, H-4eq), 1.81 (3H, m, all J ꢇ 2.5, H-18), 1.82 (1H, br.t, J = 8.6, H-6ax), 1.92 (1H, dd, J = 13.3, 12.0,
H-4ax), 2.15–2.21 (2H, m, H-7), 2.51–2.57 (2H, m, H-19), 3.81 (1H, dd, J = 2.3, 2.0, H-1eq), 3.92 (1H, br.d, J = 2.3, H-10eq),
4.40 (1H, dd, J = 12.0, 2.7, H-3ax), 5.63–5.66 (1H, m, H-8), 7.11 (2H, d, J = 8.1, H-13, 15), 7.20 (2H, d, J = 8.1, H-12, 16),
13
other protons 1.20–1.32. C NMR spectrum (CDCl , ꢃ, ppm): 77.67 (CH, C-1), 77.56 (CH, C-3), 43.14 (CH , C-4), 71.16 (C,
3
2
C-5), 38.40 (CH, C-6), 22.68 (CH , C-7), 124.62 (CH, C-8), 131.43 (C, C-9), 70.60 (CH, C-10), 138.98 (C, C-11), 125.80
2
(CH, C-12, 16), 128.33 (CH, C-13, 15), 142.35 (C, C-14), 27.04 (CH , C-17), 20.67 (CH , C-18), 35.53 (CH , C-19), 31.37
3
3
2
(CH , C-20), 29.13, 29.19, 29.34 (all CH , C-21, 22, 23), 31.76 (CH , Ñ-24), 22.53 (CH , Ñ-25), 13.96 (CH , Ñ-26). Found
3
2
2
2
3
+
m/z 368.2808 ꢅM (calcd for C H O 368.2816).
25 38
3
(2S,4R,4aR,8R,8aR)-4,7-Dimethyl-2-(4-octylphenyl)-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol [(R)-1f],
Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 0.86 (3H, t, J = 7.0, H-26), 1.22 (3H, s, H-17), 1.52–1.59 (2H, m, H-20), 1.62
1
3
26,25
(1H, ddd, J = 14.2, 2.8, 1.3, H-4eq), 1.66–1.71 (1H, m, H-6ax), 1.77 (1H, dd, J = 14.2, 11.7, H-4ax), 1.81 (3H, m, all J ꢇ 2.5,
H-18), 1.99–2.04 (2H, m, H-7), 2.51–2.57 (2H, m, H-19), 3.93 (1H, br.s, H-10eq), 4.24 (1H, dd, J = 2.3, 2.0, H-1eq), 4.75 (1H,
dd, J = 11.7, 2.8, H-3ax), 5.57–5.60 (1H, m, H-8), 7.09 (2H, d, J = 8.1, H-13, 15), 7.20 (2H, d, J = 8.1, H-12, 16), other protons
13
1.21–1.33. C NMR spectrum (CDCl , ꢃ, ppm): 75.17 (CH, C-1), 75.74 (CH, C-3), 42.14 (CH , C-4), 70.85 (C, C-5), 38.16
3
2
(CH, C-6), 24.59 (CH , C-7), 123.99 (CH, C-8), 131.91 (C, C-9), 70.58 (CH, C-10), 139.68 (C, C-11), 125.76 (CH, C-12, 16),
2
128.27 (CH, C-13, 15), 142.06 (C, C-14), 28.39 (CH , C-17), 20.78 (CH , C-18), 35.53 (CH , C-19), 31.39 (CH , C-20),
2
3
2
2
29.13, 29.19, 29.35 (all CH , C-21, 22, 23), 31.76 (CH , Ñ-24), 22.53 (CH , Ñ-25), 13.96 (CH , Ñ-26). Found m/z 368.2808
2
2
2
3
+
ꢅM (calcd for C H O 368.2816).
25 38
3
REFERENCES
1.
I. V. Ilꢀina, K. P. Volcho, O. S. Mikhalchenko, D. V. Korchagina, and N. F. Salakhutdinov, Helv. Chim. Acta,
94, 502 (2011).
2.
3.
O. S. Mikhalchenko, D. V. Korchagina, K. P. Volcho, and N. F. Salakhutdinov, Helv. Chim. Acta, 97, 1406 (2014).
O. Mikhalchenko, I. Ilꢀina, A. Pavlova, E. Morozova, D. Korchagina, T. Tolstikova, E. Pokushalov, K. Volcho,
and N. Salakhutdinov, Med. Chem. Res., 22, 3026 (2013).
4.
5.
I. Ilꢀina, O. Mikhalchenko, A. Pavlova, D. Korchagina, T. Tolstikova, K. Volcho, and N. Salakhutdinov, Med. Chem.
Res., 23, 5063 (2014).
O. V. Ardashov, A. V. Pavlova, I. V. Ilꢀina, E. A. Morozova, D. V. Korchagina, E. V. Karpova, K. P. Volcho,
T. G. Tolstikova, and N. F. Salakhutdinov, J. Med. Chem., 54, 3866 (2011).
1070

6.
7.
8.
A. Pavlova, O. Mikhalchenko, A. Rogachev, I. Ilꢀina, D. Korchagina, Yu. Gatilov, T. Tolstikova, K. Volcho,
and N. Salakhutdinov, Med. Chem. Res., 24, 3821 (2015).
O. S. Patrusheva, V. V. Zarubaev, A. A. Shtro, Ya. R. Orshanskaya, S. A. Boldyrev, I. V. Ilꢀina, S. Yu. Kurbakova,
D. V. Korchagina, K. P. Volcho, and N. F. Salakhutdinov, Bioorg. Med. Chem., 24, 5158 (2016).
A. Pavlova, O. Patrusheva, I. Ilꢀina, K. Volcho, T. Tolstikova, and N. Salakhutdinov, Lett. Drug Des. Discovery,
14, 508 (2017).
9.
D. P. Finn and V. Chapman, Curr. Neuropharmacol., 2, 75 (2004).
10.
11.
B. Costa, Chem. Biodiversity, 4, 1664 (2007).
S. P. Nikas, R. Sharma, C. A. Paronis, S. Kulkarni, G. A. Thakur, D. Hurst, J. A. T. Wood, R. S. Gifford, G. Rajarshi,
Y. Li, J. G. Raghav, J. J. Guo, T. U. C. Jarbe, P. H. Reggio, J. Bergam, and A. Makriyannis, J. Med. Chem.,
58, 665 (2015).
12.
13.
O. S. Mikhalchenko, D. V. Korchagina, K. P. Volcho, and N. F. Salakhutdinov, Beilstein J. Org. Chem., 12, 648 (2016).
M. Stekrova, P. Maki-Arvela, N. Kumar, E. Behravesh, A. Aho, Q. Balme, K. P. Volcho, N. F. Salakhutdinov,
and D. Yu. Murzin, J. Mol. Catal. A: Chem., 410, 260 (2015).
14.
15.
16.
17.
K. P. Volcho, N. F. Salakhutdinov, and V. A. Barkhash, Zh. Org. Khim., 35, 1583 (1999).
N. B. Eddy and D. Leimbach, J. Pharmacol. Exp. Ther., 107, 385 (1953).
R. Koster, M. Anderson, and E. J. De Beer, Fed. Proc., 18, 412 (1959).
I. V. Ilꢀina, K. P. Volcho, D. V. Korchagina, V. A. Barkhash, and N. F. Salakhutdinov, Helv. Chim. Acta, 90, 353 (2007).
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