Effect of chiral polyhydrochromenes on cannabinoid system

Article abstract of DOI:10.1007/s00044-019-02294-9

A set of chiral polyhydrochromenes was synthesized by clay-catalyzed reactions of monoterpenoids (?)-isopulegol, (+)-neoisopulegol and (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 5 with aromatic and heteroaromatic aldehydes. These compou

Full text of DOI:10.1007/s00044-019-02294-9

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-019-02294-9
ORIGINAL RESEARCH
Effect of chiral polyhydrochromenes on cannabinoid system
Nikolai S. Li-Zhulanov1,2 Irina V. Il’ina1,2 Andrea Chicca3 Patricia Schenker3 Oksana S. Patrusheva1
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Ekaterina V. Nazimova1 Dina V. Korchagina1 Mikhail Krasavin4 Konstantin P. Volcho
Nariman F. Salakhutdinov1,2
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Received: 5 October 2018 / Accepted: 23 January 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
A set of chiral polyhydrochromenes was synthesized by clay-catalyzed reactions of monoterpenoids (−)-isopulegol,
(+)-neoisopulegol and (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 5 with aromatic and heteroaromatic
aldehydes. These compounds resemble in structure phytocannabinoids, some of them demonstrated analgesic activity
in vivo. Polyhydrochromenes containing amino groups were obtained through the interaction of (−)-isopulegol with 5-
hydroxymethylfurfural, followed by substitution of hydroxy-group with bromine and further reaction with amines. The
ability of all synthesized compounds to influence the endocannabinoid system was studied for the first time. Although the
polyhydrochromenes did not significantly bind to CB1 and CB2 cannabinoid receptors and did not inhibit MAGL activity at
the concentration of 10 µM, isopulegol derivative 2i containing 3-bromothiophene substituent inhibited FAAH activity with
an IC50 value of 7.6 µM. Thus, this compound may increase endocannabinoid system activity.
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Keywords CB1 CB2 Anandamide Fatty acid amide hydrolase (FAAH) Monoacylglycerol lipase (MAGL) Isopulegol
Aldehyde
Introduction
are controlled by the hydrolytic activity of fatty acid amide
hydrolase (FAAH) for AEA and monoacylglycerol lipase
(MAGL) for 2-AG (Makriyannis 2014). Cannabinoid
receptors are involved in the regulation of nausea, obesity,
pain, anxiety, depression, and neurodegenerative disorders
(Khurana et al. 2017).
The endocannabinoid system consists of two type of G-
protein coupled receptors (CB1 and CB2) and a group of
neuromodulatory lipids derived from arachidonic acid,
anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG)
(Aghazadeh Tabrizi et al. 2016). Endocannabinoid levels
The most known exocannabinoid ligands are phyto-
cannabinoids. Cannabidiol and Δ9-tetrahydrocannabinol
(Fig. 1) isolated from Cannabis and combining mono-
terpenoid fragment with para-menthane structure and
aromatic ring are the most abundant phytocannabinoids
with pronounced biological effects (Woodhams et al.
2017; Dos Santos et al. 2015; Javid et al. 2016). In par-
ticular, pronounced analgesic effect of phytocannabinoids
attracts special attention due to their ability to control
neuropathic pain (King et al. 2017; Walter et al. 2016).
Earlier we have found that several heterocyclic com-
pounds 1 and 2 (Fig. 1) also containing para-menthane
and aromatic moieties and synthesized by interaction of
monoterpenoid alcohols with aldehydes possess high
analgesic activity in vivo along with low acute toxicity
(Mikhalchenko et al. 2013; Il’Ina et al. 2014; Pavlova
et al. 2015; Pavlova et al. 2016; Nazimova et al. 2016;
Pavlova et al. 2017). For compound 1a, it was shown the
Supplementary information The online version of this article (https://
doi.org/10.1007/s00044-019-02294-9) contains supplementary
material, which is available to authorized users.
* Konstantin P. Volcho
volcho@nioch.nsc.ru
1
Novosibirsk Institute of Organic Chemistry, Lavrentjev av. 9,
Novosibirsk, Russian Federation630090
2
Novosibirsk State University, Pirogova st. 1, Novosibirsk, Russian
Federation630090
3
Institute of Biochemistry and Molecular Medicine, NCCR
TransCure, University of Bern, Bühlstrasse 28, 3012
Bern, Switzerland
4
Saint Petersburg State University, Saint Petersburg, Russian
Federation199034

Medicinal Chemistry Research
Fig. 1 Structures of
cannabinoids and compounds 1
and 2
loss of analgesic effect in presence of the selective CB1
receptor antagonist rimonabant (Pavlova et al. 2017). It
means that the endocannabinoid system may be involved
in the mechanism of action of this compound. At the same
time, the ability of these compounds to effect cannabinoid
system was not studied yet. The only published data
concern competition binding of a small set of dimethyl-
substituted compounds of type 2 with CB1 and CB2 can-
nabinoid receptor subtypes (Slater et al. 2018). Among
these compounds, only 2a was marginally active against
these receptors with ~20% displacement of radioligand at
10 µM concentration.
et al. 2016). The products were formed as a mixture of
diastereomers at C-4.
It was found recently that the use of BF3·Et2O/H2O
system for reaction of monoterpenoid alcohols with alde-
hydes led to formation of fluorine containing compounds 4
along with compounds of type 2 (Scheme 2) (Mikhalchenko
et al. 2016; Patrusheva et al. 2016). Thus, compounds 2m
and 4a were obtained by the reaction of (−)-isopulegol with
3,4,5-trimethoxybenzaldehyde (Mikhalchenko et al. 2016).
In addition to these compounds, in this work fluorine con-
taining compounds 4b–f, as well as hydroxyl containing
analogues 2n–p were synthesized.
The goal of this work is to study whether compounds of
types 1 and 2 having different substituents at aromatic/
heteroaromatic ring can interact with cannabinoid system.
Acid-catalyzed reactions of isopulegol with aromatic/
heteroaromatic aldehydes allow one to obtain octahy-
drochromenes with various substituents in the aromatic
ring excluding amine-containing substituent. To synthe-
size these compounds, three step approaches has been
elaborated in the current work (Scheme 3). At first step,
compound 2q was synthesized by clay catalyzed reaction
of (−)-isopulegol with 5-hydroxymethylfurfural obtained
from fructose in accordance with (Tian et al. 2013). The
individual stereoisomer (R)-2q and mixture of (R)-2q and
(S)-2q (dr 1.0) were isolated by column chromatography.
Then, bromide 2r was synthesized by the reaction of (R)-
2q or mixture 2q with PBr3. This compound appeared to
be unstable at room temperature and was involved in the
reaction with a set of secondary amines without separa-
tion, giving amine-containing compounds 2s–v.
The last group of monoterpenoid based compounds was
synthesized from diol 5, obtained in three stages from
(−)-verbenone in accordance with (Il’ina et al. 2007). Clay
catalyzed reaction of monoterpenoid 5 with a set aldehydes
led to formation of compound 1a and its analogues 1b–e
(Scheme 4).
Thus, large set of chiral octahydrochromenes belonging
to four structural types, 1, 2, 3 and 4, has been synthesized
from monoterpenoid alcohols (−)-isopulegol, (+)-neoiso-
pulegol and compound 5.
Results and discussion
Chemistry
Compounds of types 1 and 2 can be synthesized by acid-
catalyzed interaction of monoterpenoids with aldehydes
(Patrusheva et al. 2018). Although different catalysts,
including TsOH/SiO2 (Macedo et al. 2010), BF3·Et2O
(Bondalapati et al. 2011), Sc(OTf)3 (Yadav et al. 2010), I2
(Silva and Quintiliano 2009), and zeolites (Stekrova et al.
2015) can be applied for these transformations, the most
often catalysts used are clays (Baishya et al. 2013; Stekrova
et al. 2015; Timofeeva et al. 2015; Timofeeva et al. 2016;
Sidorenko et al. 2018a; Sidorenko et al. 2018b). Earlier, we
obtained a set of compounds 2b–l by clay K10 catalyzed
reactions of (−)-isopulegol with heteroaromatic aldehydes
(Scheme 1) (Nazimova et al. 2016; Nazimova et al. 2017).
These octahydrochromene derivatives with heteroaromatic
substituents demonstrated high analgesic activity in vivo.
Compounds 3a, b were synthesized by (+)-neoisopulegol
reactions with corresponding aldehydes (Nazimova

Medicinal Chemistry Research
Scheme 1 Synthesis of 2b-l and
3a, b; dr is the 4R/4S
diastereomers ratio (Nazimova
et al. 2016)
Biology
presence of test compounds (10 µM) as previously reported
(Chicca et al. 2017). We found, that isopulegol derivative 2i
containing 3-bromothiophene substituent inhibited FAAH
activity with an IC50 value (50% inhibiting concentration)
of 7.6 1.5 µM (Fig. 4a). In agreement with the inhibition
of FAAH, compound 2i also inhibited AEA uptake in living
U937 cells with an IC50 value of 15.1 2.1 µM (Fig. 4b).
None of the other compounds inhibited FAAH activity or
AEA uptake at the concentration of 10 µM (Suppl. Figs 1
and 2). Note, that high in vivo analgesic activity of com-
pound 2i in acetic acid-induced writhing test (10 mg/kg
dose, mice) was recently reported (Nazimova et al. 2016). It
is known, that FAAH inhibition attenuates neuropathic pain
(Jhaveri et al. 2006) and gastric ulceration (Naidu et al.
2009) in rodents. Thus, the analgesic effect of 2i may be
caused, at least partly, by FAAH inhibition. The potent and
selective AEA uptake inhibitor WOBE437 (Chicca et al.
2017) exerted analgesic and anti-inflammatory effects at the
dose of 10 mg/kg in a model of chronic inflammation in
BALB/C mice (monoarthitis of the knee) (Reynoso-Moreno
et al. 2018). At the same time, structurally similar com-
pounds 2e and 2h also demonstrated an analgesic effect
(Nazimova et al. 2016), do not influence cannabinoid sys-
tem, which implies the existence of other mechanisms of
action.
The ability of substituted polyhydrochromenes 1–4 to bind
to CB1 and CB2 receptors was studied with a radioactivity-
based binding assay. The experiments were performed
using membrane preparations overexpressing hCB1 and
hCB2 using [3H]CP55,940 as a competitive ligand as pre-
viously reported (Chicca et al. 2017). While the classic CB1
receptor agonist (R)-WIN55,212-2 (Showalter et al. 1996)
decreased [3H]CP55,940 signal to 10%, all tested chro-
menes did not significantly bind to CB1 receptor at the
screening concentration of 10 μM (Fig. 2).
In the case of CB2 receptor, five compounds (1a, 2b, 2k,
4a, and 4d) marginally interacted with the receptor leading
to a 15–25% displacement of the [3H]CP55,940 (Fig. 3).
Compounds 2b and 2k are furan-containing analogues of
recently studied chromenol 2a (Slater et al. 2018), which
demonstrated similar activity. Compounds 4a and 4d con-
tain fluorine atom, their counterparts with hydroxy group
2m and 2p were not active. Note, that just for compound 1a
it was shown the loss of analgesic effect in vivo in presence
of rimonabant (Pavlova et al. 2017).
As all tested compounds did not show significant inter-
action with CB receptors at 10 µM concentration, we also
studied their ability to influence AEA and 2-AG hydrolysis.
FAAH is primarily responsible for AEA degradation and
indirectly involved in AEA uptake (Chicca et al. 2012;
Nicolussi et al. 2014; Chicca et al. 2017), thus its inhibition
leads to increasing endocannabinoid system activity. FAAH
activity was measured using U937 cell homogenate in the
2-AG activity is terminated by enzymatic hydrolysis
primarily mediated by MAGL and MAGL inhibitors pro-
duce antinociceptive effects (Kinsey et al. 2013; Aghazadeh
Tabrizi et al. 2018). None of our compounds showed a
significant inhibition of MAGL activity at the concentration

Medicinal Chemistry Research
Scheme 2 Synthesis of 2b, e,
m–p and 4a–f; dr is 4S/4R the
diastereomers ratio
of 10 µM, unlike the classic MAGL inhibitor JZL184
(Kinsey et al. 2013), which was used as a positive control
(Suppl. Fig. 3).
through calcined Al2O3. (–)-Isopulegol (½αŠ31 = − 21 (c 0.4,
D
CHCl3)) was purchased from Aldrich. (+)-Neoisopulegol
½αŠ30;6 = +29 (c 0.498, C6H14) was synthesized according to
D
(Chavan et al. 1993) from (–)-isopulegol (Aldrich), the
content of the main substance was not less than 98.0%.
(1R,2R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-
Conclusion
1,2-diol 5 (½αŠ30;6 = –49.1 (c 0.26, CHCl3)) was synthesized
D
Large set of chiral hydrochromenes was synthesized by
clay-catalyzed reactions of monoterpenoids (−)-isopulegol,
(+)-neoisopulegol and (1R,2R,6S)-3-methyl-6-(prop-1-en-
2-yl)cyclohex-3-ene-1,2-diol 5 with aromatic and hetero-
aromatic aldehydes. It is known that some of these com-
pounds possess analgesic activity with possible
involvement of cannabinoid system. Amine-containing
derivatives were obtained through the interaction of
(−)-isopulegol with 5-hydroxymethylfurfural, followed by
substitution of hydroxy-group with bromine and further
reaction with amines.
The ability of all synthesized compounds to influence the
endocannabinoid system was studied for the first time. We
found, that all these chromene derivatives do not bind to
CB1 receptor at the concentration of 10 µM concentration.
Five compounds (1a, 2b, 2k, 4a, and 4d) marginally
interact at the same concentration with CB2 receptor leading
to 15–25% displacement of the radioligand. Moreover, all
tested compounds do not affect MAGL activity. At the
same time, isopulegol derivative 2i containing 3-
bromothiophene substituent inhibits FAAH activity with
an IC50 value of 7.6 µM, and thus may increase endo-
cannabinoid system activity. Taking into account that
FAAH inhibition attenuates various types of pain, it can be
assumed that earlier found analgesic effect of 2i may be
caused, at least partly, by FAAH inhibition.
according to (Il’ina et al. 2007) from (–)-verbenone
(Aldrich), the content of the main substance was not less
than 98.0%.
Column chromatography: silica gel (SiO2; 60–200 μ;
Macherey-Nagel); hexane/EtOAc 100:0 → 0:100. GC/MS
(purity control and products analysis): Agilent 7890A with
a quadrupole mass spectrometer Agilent 5975C as a
detector, HP-5MS quartz column, 30,000 × 0.25 mm, He (1
atm) as carrier gas. Optical rotation: polAAr 3005 spectro-
meter, CHCl3 soln. HR-MS: DFS-Thermo-Scientific spec-
trometer in a full scan mode (15–500 m/z, 70 eV electron-
1
impact ionization, direct sample introduction). H and 13C
NMR: Bruker DRX-500 apparatus at 500.13 MHz (1H) and
125.76 MHz (13C) and Bruker Avance-III 600 apparatus at
600.30 MHz (1H) and 150.95 MHz (13C) in CDCl3 or
CDCl3/CD3OD; chemical shifts δ in ppm rel. to residual
CHCl3 (δ (H) 7.24, δ (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 homo-
nuclear correlation (COSY, NOESY); J-modulated 13C
NMR spectra (JMOD), and 13C–1H 2D heteronuclear cor-
relation with one-bond and long-range spin-spin coupling
1
1
constants (C–H COSY, J(C,H) = 135 Hz; HSQC, J(C,H)
= 145 Hz; COLOC, 2,3J(C,H) = 10 Hz; HMBC, 2,3J(C,H)
= 7 Hz). All the target compounds reported in this paper
have the purity of at least 95%. Please note that numeration
of atoms in the compounds (see SI) is given for assigning
the signals in the NMR spectra and does not coincide with
that for the names according to the nomenclature of
compounds.
Materials and methods
Chemistry
Spectral and analytical studies were carried out at the
Collective Chemical Service Center of the Siberian Branch
of the Russian Academy of Sciences.
Compounds 2a–l were obtained from (–)-isopulegol and
corresponding aldehydes in the presence of montmorillonite
K10 according to the described procedures (Nazimova et al.
2016) in the following yields: 2b (86%, dr 3.0), 2c (65%, dr
All commercially available compounds and solvents were
reagent grade and were used without further treatment
unless otherwise noted. As the catalyst, we used mon-
tmorillonite K10 clay (Aldrich). The clay was calcinated at
105oC for 3 h immediately before use. CH2Cl2 was passed

Medicinal Chemistry Research
Scheme 3 Synthesis of 2q and
2s–v; dr is 4R/4S the
diastereomers ratio
3.5), 2d (54%, dr 0.67), 2e (78%, dr 5.0), 2f (80%, dr 4.5),
2g (69%, dr 10.0), 2h (76%, dr 6.5), 2i (74%, dr 3.0), 2j
(50%, dr 1.0), 2k (61%, dr 8.0), 2l (63%, dr 1.5).
Compounds 3a, 3b were obtained from (+)-neoisopu-
legol and corresponding aldehydes in the presence of
montmorillonite K10 according to the described procedures
(Nazimova et al. 2016) in the following yields: 3a (41%, dr
0.67), 3b (75%, dr 1.0).
Compounds 4a and 2m were obtained from (–)-iso-
pulegol and 3,4,5-trimethoxybenzaldehyde in the presence
of BF3·Et2O/H2O system according to the described pro-
cedures (Mikhalchenko et al. 2016) in the following yields:
4a (76%, dr 0.29), 2m (15%, dr 5.0).
Compound 1a (29%, dr 5.0) was obtained from diol 5
and 3-hydroxy-4-methoxybenzaldehyde in the presence of
montmorillonite K10 according to the described procedures
(Il’ina et al. 2011).
Compounds 1c, 1e were obtained from diol 5 and cor-
responding aldehydes in the presence of montmorillonite
K10 according to the described procedures (Pavlova et al.
2016) in the following yields: 1c (42%, dr 3.3), 1e (54%, dr
2.8).
in CH2Cl2 (5 ml) under vigorous stirring. Resulting cloudy
solution of BF3·Et2O was added dropwise to the mixture of
aldehyde and (–)-isopulegol, and then the reaction mixture
was stirred for required time period at 2 °C. Then 10%
NaHCO3 solution was added, the layers were separated and
the aqueous phase was extracted with CH2Cl2 (2 × 15 ml).
The combined organic layers were dried over Na2SO4, fil-
tered and concentrated. Reaction mixture was separated on
a SiO2 column (hexane/EtOAc 100:0–0:100 as eluent).
General procedure 2 for compounds 2s–v synthesis (GP 2)
The mixture of 2q (3 eqv.), PBr3 (1 eqv.) and NaHCO3 (4
eqv.) in 5 ml Et2O was stirred at 0 °C for 45 min. Then an
appropriate amine (21 eqv.) was added and mixture was
stirred at 0 °C for 2.5 h. The residue was filtered off, the
solvent was distilled off, and the reaction mixture was
separated on a SiO2 column (hexane/EtOAc 100:0–0:100 as
eluent).
General procedure 3 for compounds 1b, 1d synthesis (GP 3)
The solution of diol 2 and an appropriate aldehyde in
CH2Cl2 (10 ml) was added to a suspension of K10 in
CH2Cl2 (10 ml). The solvent was distilled off. The mixture
was stored at r.t. for the required period of time. Then ethyl
acetate (10 ml) was added. The catalyst was filtered off, the
solvent was distilled off, and the residue was separated on a
SiO2 column (hexane/EtOAc 100:0–0:100 as eluent).
General procedure 1 for compounds 2n–e and 4b–f
synthesis (GP 1)
(–)-Isopulegol (2.4 mmol) and aldehyde (2.9 mmol) were
dissolved in CH2Cl2 (5 ml) and cooled to 2 °C. Then water
(17.8 mmol) was added to the BF3·Et2O (3.6 mmol) solution

Medicinal Chemistry Research
Scheme 4 Synthesis of 1a–e; dr
is the 4S/4R diastereomers ratio
3
(2R,4S,4aR,7R,8aR)-4-Fluoro-4,7-dimethyl-2-
phenyloctahydro-2H-chromene 4b and (2R,4R
(S),4aR,7R,8aR)-4,7-Dimethyl-2-phenyloctahydro-2H-
chromen-4-ol 2n
10), 1.16–1.34 (m, 2H, Ha-6, Ha-7), 1.34 (d, 3H, J17,F
=
21.5, Me-17), 1.46–1.57 (m, 1H, Ha-9), 1.61 (ddd, 1H, 3J4a,
F = 38.6, J4a,4e = 14.2, J4a,3a = 11.8, Ha-4), 1.76 (dm, 1H,
J8e,8a = 13.2, the others J < 3.5 Hz, He-8), 1.86–1.92 (m,
1H, He-7), 2.01 (dm, 1H, J10e,10a = 12.2, the others J < 4.5
Hz, He-10), 2.10 (ddd, 1H, J4e,4a = 14.2, J4e,F = 9.3, J4e,3a
= 2.4, He-4), 3.55–3.62 (m, 1H, Ha-1), 4.86 (dd, 1H, J3a,4a
3
Compound (S)-4b (0.475 g, 70%) and 2n (0.135 g, 20%, dr
0.22) were obtained from (–)-isopulegol and benzaldehyde
according to the GP1. Compound (R)-4b formed only in
trace amounts. The reaction was carried out for 120 min.
= 11.8, J3a,4e = 2.4, Ha-3), 7.50 (br.d, 2H, J12,13 = J16,15
=
8.9, H-12, H-16), 8.16 (br.d, 2H, J13,12 = J15,16 = 8.9, H-13,
The H and 13C NMR spectra of 2n correspond to the lit-
H-15). NMR 13C (125 MHz, CDCl3, δ, ppm, JC,F, Hz):
1
2
erature data (Yadav et al. 2010).
75.77 (d, C-1), 73.64 (d, C-3), 45.64 (t, J = 21.5, C-4),
1
2
93.01 (s, J = 172.3, C-5), 48.33 (d, J = 20.1, C-6), 22.34
(t, 3J = 2.6, C-7), 34.23 (t, C-8), 31.05 (d, C-9), 40.97 (t, C-
10), 149.78 (s, C-11), 126.35 (d, C-12, C-16), 123.47 (d, C-
1
(S)-4b NMR H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.89–
0.99 (m, 1H, Ha-8), 0.95 (d, 3H, J18,9 = 6.6, Me-18), 1.06–
1.15 (m, 1H, Ha-10), 1.17–1.36 (m, 2H, Ha-6, Ha-7), 1.35
2
13, C-15), 147.07 (c, C-14), 24.07 (q, J = 24.8, C-17),
3
(d, 3H, J17,F = 21.4, Me-17), 1.46–1.58 (m, 1H, Ha-9),
22.06 (q, C-18). ½αŠ25:3 = 56.4 (c 0.47, CHCl3). HRMS: m/z
D
1.72 (ddd, 1H, 3J4a,F = 39.4, J4a,4e = 14.2, J4a,3a = 11.8, Ha-
4), 1.73–1.79 (m, 1H, He-8), 1.90 (dm, 1H, J7e,7a = 13.1, the
others J < 3.5 Hz, He-7), 2.03 (dm, 1H, J10e,10a = 12.2, the
calcd. for C17H22O3NF: 307.1578. Found: 307.1580.
The NMR spectra were recorded for the mixture (S)-2o and
(R)-2o isomers (1:0.70)
3
others J < 4.5 Hz, He-10), 2.09 (ddd, 1H, J4e,4a = 14.2, J4e,
F = 9.6, J4e,3a = 2.4, He-4), 3.56–3.62 (m, 1H, Ha-1), 4.77
(dd, 1H, J3a,4a = 11.8, J3a,4e = 2.4, Ha-3), 7.22–7.26 (m, 1H,
H-14), 7.29–7.37 (m, 4H, H-12, H-13, H-15, H-16). NMR
13C (125 MHz, CDCl3, δ, ppm, JC,F, Hz): 75.71 (d, C-1),
1
(S)-2o NMR H (600 MHz, CDCl3, δ, ppm, J/Hz): 0.88–
0.98 (m, 1H, Ha-8), 0.93 (d, 3H, J18,9 = 6.6, Me-18), 1.06–
1.21 (m, 3H, Ha-7, Ha-6, Ha-10), 1.22 (c, 3H, Me-17), 1.42–
1.54 (m, 1H, Ha-9), 1.57 (dd, 1H, J4a,4e = 13.8, J4a,3a =
11.7, Ha-4), 1.71–1.77 (m, 1H, He-8), 1.80–1.85 (m, 1H,
He-7), 1.85 (dd, 1H, J4e,4a = 13.8, J4e,3a = 2.4, He-4), 1.96–
2.03 (m, 1H, He-10), 3.56–3.61 (m, 1H, Ha-1), 4.89 (dd, 1H,
J3a,4a = 11.7, J3a,4e = 2.4, Ha-3), 7.50 (br.d, 2H, J12,13
J16,15 = 8.8, H-12, H-16), 8.15 (br.d, 2H, J13,12 = J15,16
2
1
74.64 (d, C-3), 45.77 (t, J = 21.4, C-4), 93.36 (s, J =
171.5, C-5), 48.48 (d, 2J = 20.3, C-6), 22.42 (t, 3J = 2.0, C-
7), 34.36 (t, C-8), 31.11 (d C-9), 41.16 (t, C-10), 142.30 (s,
C-11), 125.79 (d, C-12, C-16), 128.25 (d, C-13, C-15),
2
127.27 (d, C-14), 24.20 (q, J = 24.9, C-17), 22.12 (q, C-
=
=
18). ½αŠ25:3 = 58.3 (c 0.33, CHCl3). HR-MS: m/z calcd. for
D
C15H20O4: 264.1356. Found: 264.1358.
8.8, H-13, H-15). NMR 13C (150 MHz, CDCl3, δ, ppm):
75.47 (d, C-1), 73.64 (d, C-3), 47.99 (t, C-4), 69.22 (s, C-5),
49.23 (d, C-6), 22.37 (t, C-7), 34.24 (t, C-8), 31.14 (d, C-9),
41.09 (t, C-10), 150.51 (s, C-11), 126.41 (d, C-12, C-16),
123.41 (d, C-13, C-15), 146.88 (c, C-14), 28.08 (q, C-17),
22.10 (q, C-18). HRMS: m/z calcd. for C17H23O4N:
305.1622. Found: 305.1618.
(2R,4S,4aR,7R,8aR)-4-Fluoro-4,7-dimethyl-2-(4-nitrophenyl)
octahydro-2H-chromene (S)-4c and (2R,4S(R),4aR,7R,8aR)-
4,7-dimethyl-2-(4-nitrophenyl)octahydro-2H-chromen-4-ol
2o
Compounds (S)-4c (0.480 g, 60%) and 2o (0.198 g, 25%, dr
1.5) were obtained from (–)-isopulegol and 4-
nitrobenzaldehyde according to the GP1. The reaction
was carried out for 120 min.
1
(R)-2o NMR H (600 MHz, CDCl3, δ, ppm, J/Hz): 0.88–
0.99 (m, 1H, Ha-8), 0.94 (d, 3H, J18,9 = 6.6, Me-18), 1.00–
1.08 (m, 1H, Ha-7), 1.11–1.18 (m, 1H, Ha-10), 1.28–1.33
(m, 1H, Ha-6,), 1.30 (c, 3H, Me-17), 1.42–1.54 (m, 1H, Ha-
9), 1.64 (br.dd, 1H, J4a,4e = 12.8, J4a,3a = 12.0, Ha-4), 1.71–
1.77 (m, 1H, He-8), 1.92 (dd, 1H, J4e,4a = 12.8, J4e,3a = 2.3,
He-4), 1.91–1.96 (m, 1H, He-7), 1.96–2.03 (m, 1H, He-10),
1
(S)-4c NMR H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.88–
0.98 (m, 1H, Ha-8), 0.94 (d, 3H, J18,9 = 6.6, Me-18), 1.11
(dddd, 1H, J10a,10e ≈ J10a,1a ≈ J10a,9a = 12.2, J10a,F = 1.5, Ha-

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2i
2j
2l
2m
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2t
4f
1a
1c
1e
2c
2k
2s
2v 3a
4a
4c
4e
1b
1d
2b
2d
4R-2e
2g 2h
2n 2o 2p 2q
2u
3b
4b
4d
CTRL
4S-2e
[WIN55]
Fig. 2 CB1 receptor binding in CHO membranes (WIN55,212 and compounds, 10 μM)
3.28 (ddd, 1H, J1a,6a ≈ J1a,10a = 10.5, J1a,10e = 4.2, Ha-1),
4.53 (dd, 1H, J3a,4a = 12.0, J3a,4e = 2.3, Ha-3), 7.49 (br.d,
2H, J12,13 = J16,15 = 8.8, H-12, H-16), 8.16 (br.d, 2H, J13,12
= J15,16 = 8.8, H-13, H-15). NMR 13C (150 MHz, CDCl3, δ,
ppm): 77.41 (d, C-1), 75.55 (d, C-3), 50.08 (t, C-4), 70.62
(s, C-5), 51.82 (d, C-6), 22.86 (t, C-7), 34.18 (t, C-8), 31.30
(d, C-9), 41.26 (t, C-10), 149.62 (s, C-11), 126.42 (d, C-12,
C-16), 123.49 (d, C-13, C-15), 147.04 (c, C-14), 21.16 (q,
C-17), 22.05 (q, C-18). HRMS: m/z calcd. for C17H23O4N:
305.1622. Found: 305.1618.
10), 42.49 (d, C-11), 28.34 and 29.04 (2t, C-12, C-16),
25.99, 26.08 and 26.48 (3t, C-13, C-14, C-15), 24.51 (q, 2J
= 25.2, C-17), 22.10 (q, C-18). HRMS: m/z calcd. for
C17H28OF: 267.2119. Found: 267.2112.
(R)-4d NMR 1H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.90 (d,
3H, J18,9 = 6.6, Me-18), 1.29 (d, 3H, 3J17,F = 23.4, Me-17),
2.95 (ddd, 1H, J1a,10a ≈ J1a,6a ≈ 10.5, J1a,10e = 4.3, Ha-1),
3.02 (br.dd, 1H, J3a,4a = 11.8, J3a,11 = 6.2, Ha-3), the
remaining proton signals are overlapping multiplets at 0.81–
1.50, 1.57–1.74, and 1.78–1.96 ppm. NMR 13C (125 MHz,
CDCl3, δ, ppm, JC,F, Hz): 76.91 (d, 3J = 9.8, C-1), 78.91 (d,
(2R,4S(R),4aR,7R,8aR)-2-Cyclohexyl-4-fluoro-4,7-
dimethyloctahydro-2H-chromene 4d and
(2R,4S,4aR,7R,8aR)-2-cyclohexyl-4,7-dimethyloctahydro-2H-
chromen-4-ol 2p
2
1
3J = 11.1, C-3), 42.41 (t, J = 19.6, C-4), 95.55 (s, J =
171.7, C-5), 50.25 (d, 2J = 19.1, C-6), 23.19 (t, C-7), 33.98
(t, C-8), 31.24 (d, C-9), 41.32 (t, C-10), 42.59 (d, C-11),
29.05 and 28.50 (2t, C-12, C-16), 25.99, 26.07 and 26.45
(3t, C-13, C-14, C-15), 19.58 (q, 2J = 26.2, C-17), 22.05 (q,
C-18). HRMS: m/z calcd. for C17H28OF: 267.2119. Found:
267.2112.
Compounds 4d (0.417 g, 60%, dr 2.0) and (S)-2p (0.105 g,
15%) were obtained from (–)-isopulegol and cyclohex-
anecarbaldehyde according to the GP1. The reaction was
carried out for 120 min. The 1H and 13C NMR spectra of 2p
correspond to the literature data (Yadav et al. 2010).
The NMR spectra were recorded for the mixture (S)-4d
(2R,4S(R),4aR,7R,8aR)-4-Fluoro-2-(furan-2-yl)-4,7-
dimethyloctahydro-2H-chromene 4e
1
and (R)-4d isomers (1:0.5). The most signals NMR H of
these two isomers overlapped (are the same), separately we
managed to observe some signals only.
Compounds 4e (0.417 g, 70%, dr 7.3) and 2b (0.105 g,
20%, dr 0.5) were obtained from (–)-isopulegol and furan-
2-carbaldehyde according to the GP1. The reaction was
carried out for 120 min. The 1H and 13C NMR spectra of 2b
correspond to the literature data (Nazimova et al. 2016).
(S)-4d NMR 1H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.89 (d,
3H, J18,9 = 6.6, Me-18), 1.29 (d, 3H, 3J17,F = 21.5, Me-17),
3.27–3.33 (m, 1H, Ha-1), 3.38 (ddd, 1H, J3a,4a = 11.7, J3a,11
= 6.8, J3a,4e = 2.0, Ha-3), the remaining proton signals are
overlapping multiplets at 0.81–1.50, 1.57–1.74, and 1.78–
1.96 ppm. NMR 13C (125 MHz, CDCl3, δ, ppm, JC,F, Hz):
The NMR spectra were recorded for the mixture (S)-4e and
(R)-4e isomers (1:0.1)
2
1
75.21 (d, C-1), 76.61 (d, C-3), 40.72 (t, J = 21.6, C-4),
(S)-4e NMR H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.85–
1
2
93.43 (s, J = 170.8, C-5), 48.85 (d, J = 20.3, C-6), 22.41
0.95 (m, 1H, Ha-8), 0.91 (d, 3H, J16,9 = 6.6, Me-16), 1.05
(dddd, 1H, J10a,10e = J10a,1a = J10a,9a = 12.2, J10a,F = 1.5,
(t, 3J = 2.8, C-7), 34.37 (t, C-8), 31.09 (d, C-9), 41.20 (t, C-

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j
]
e
e
4
o
u
d
4
2i
2
2l
2m
5
2f
2t
4f
1a
1c
1e
2c
2e
2k
2s
2v 3a
4a
4c
1b
1d
2b
2d
4R
2g 2h
2n
2
2p 2q
2
3b
4b
RL
5
-
-2
4S
N
CT
[WI
Fig. 3 CB2 binding in CHO membranes (WIN and compounds, 10 μM)
3
Ha-10), 1.16–1.36 (m, 2H, Ha-6, Ha-7), 1.36 (d, 3H, J15,F
(2R,4S(R),4aR,7R,8aR)-4-Fluoro-4,7-dimethyl-2-(thiophen-2-
yl)octahydro-2H-chromene 4f
= 21.4, Me-15), 1.43–1.55 (m, 1H, Ha-9), 1.69–1.76 (m,
1H, He-8), 1.84–1.90 (m, 1H, He-7), 1.95–2.10 (m, 3H, 2H-
4, He-10), 3.52–3.59 (m, 1H, Ha-1), 4.77-4.84 (m, 1H, Ha-
3), 6.24 (ddd, 1H, J14,13 = 3.3, J14,12 = 0.9, J14,3a = 0.7, H-
14), 6.29 (dd, 1H, J13,14 = 3.3, J13,12 = 1.8, H-13), 7.35 (dd,
1H, J12,13 = 1.8, J12,14 = 0.9, H-12). NMR 13C (125 MHz,
CDCl3, δ, ppm, JC,F, Hz): 75.71 (d, C-1), 68.21 (d, C-3),
Compounds 4f (0.416 g, 60%, dr 3.5) and 2e (0.205 g, 30%,
dr 0.29) were obtained from (–)-isopulegol and thiophene-
2-carbaldehyde according to the GP1. The reaction was
1
carried out for 60 min. The H and 13C NMR spectra of 2e
correspond to the literature data (Nazimova et al. 2016).
2
1
41.43 (t, J = 21.9, C-4), 93.04 (s, J = 171.7, C-5), 48.29
(d, J = 20.3, C-6), 22.36 (t, J = 2.6, C-7), 34.21 (t, C-8),
2
3
The NMR spectra were recorded for the mixture (S)-4f and
(R)-4f isomers (1:0.2)
31.06 (d, C-9), 40.92 (t, C-10), 154.10 (s, C-11), 142.13 (d,
2
C-12), 109.91 (d, C-13), 106.73 (d, C-14), 24.14 (q, J =
1
24.8, C-15), 21.03 (q, C-16). HRMS: m/z calcd. for
(S)-4f NMR H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.87–
C15H21O2F: 252.1520. Found: 252.1517.
0.97 (m, 1H, Ha-8), 0.93 (d, 3H, J16,9 = 6.6, Me-16), 1.04–
1.12 (m, 1H, Ha-10), 1.17–1.34 (m, 2H, Ha-6, Ha-7), 1.36
1
3
(R)-4e NMR H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.92
(d, 3H, J15,F = 21.5, Me-15), 1.44–1.55 (m, 1H, Ha-9),
(d, 3H, J16,9 = 6.6, Me-16), 1.06–1.15 (m, 1H, Ha-10),
1.71–1.78 (m, 1H, He-8), 1.86 (ddd, 1H, 3J4a,F = 39.0, J4a,4e
= 14.1, J4a,3a = 11.6, Ha-4), 1.85-1.91 (m, 1H, He-7), 2.02
(dm, 1H, J10e,10a = 12.2, the others J < 4.5 Hz, He-10), 2.20
3
1.39 (dd, 3H, J15,F = 23.2, J15,4a = 0.8, Me-15), 1.43–
1.53 (m, 1H, Ha-9), 1.54–1.62 (m, 1H, Ha-6), 1.89–1.95
(m, 1H, He-7), 2.18–2.26 (m, 1H, H-4), 3.18–3.24 (m, 1H,
Ha-1), 4.45 (dm, 1H, J3a,4a = 12.1, the others J < 2.5 Hz,
Ha-3), 6.26 (ddd, 1H, J14,13 = 3.3, J14,12 = 0.9, J14,3a = 0.7,
H-14), 6.31 (dd, 1H, J13,14 = 3.3, J13,12 = 1.8, H-13), 7.36
(dd, 1H, J12,13 = 1.8, J12,14 = 0.9, H-12), the remaining
proton signals are overlapped by the signals of the main
isomer (S)-4e at 0.85-0.95, 1.69–1.76 and 1.95–2.10 ppm.
NMR 13C (125 MHz, CDCl3, δ, ppm, JC,F, Hz): 77.43 (d,
3
(ddd, 1H, J4e,4a = 14.1, J4e,F = 9.5, J4e,3a = 2.4, He-4),
3.55–3.62 (m, 1H, Ha-1), 5.01 (dd, 1H, J3a,4a = 11.6, J3a,4e
= 2.4, Ha-3), 6.94 (dd, 1H, J13,12 = 5.0, J13,14 = 3.5, H-13),
6.96 (ddd, 1H, J14,13 = 3.5, J14,12 = 1.3, J14,3a = 0.8, H-14),
7.21 (dd, 1H, J12,13 = 5.0, J12,14 = 1.3, H-12). NMR 13C
(125 MHz, CDCl3, δ, ppm, JC,F, Hz): 75.94 (d, C-1), 70.71
2
1
(d, C-3), 45.54 (t, J = 21.5, C-4), 93.23 (s, J = 171.8, C-
5), 48.32 (d, 2J = 20.3, C-6), 22.38 (t, 3J = 2.6, C-7), 34.27
(t, C-8), 31.10 (d, C-9), 41.00 (t, C-10), 145.42 (s, C-11),
124.43 (d, C-12), 126.32 (d, C-13), 123.55 (d, C-14), 24.13
(q, 2J = 24.8, C-15), 22.07 (q, C-16). HRMS: m/z calcd. for
C15H21OFS: 268.1292. Found: 268.1288.
3
2
3J = 9.9, C-1), 70.05 (d, J = 12.7, C-3), 43.09 (t, J =
21.1, C-4), 94.51 (s, 1J = 173.2, C-5), 49.76 (d, 2J = 19.5,
C-6), 23.12 (t, C-7), 33.82 (t, C-8), 31.22 (d, C-9), 41.06
(t, C-10), 153.68 (s, C-11), 142.18 (d, C-12), 109.99 (d,
C-13), 106.70 (d, C-14), 19.31 (q, 2J = 26.0, C-15), 21.98
(q, C-16). HRMS: m/z calcd. for C15H21O2F: 252.1520.
Found: 252.1517.
(R)-4f NMR 1H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.94 (d,
3H, J16,9 = 6.6, Me-16), 1.04–1.17 (m, 2H, Ha-7, Ha-10),

Medicinal Chemistry Research
A
B
120
120
100
80
60
40
20
0
100
80
60
WOBE437
40
20
0
URB597
IC50= 15.1 2.1 µM
2i
IC50= 7.6 1.5 µM
2i
-9
-8
-7
-6
-5
-4
-8
-7
-6
-5
-4
Log (compound) [M]
Log (compound) [M]
Fig. 4 a FAAH activity in the presence of 2i or URB597 measured in U937 cell homogenate. tInh 15’, AEA 100 nM 15’, 400 rpm, 37 °C, U937 1
Mio/mL. b AEA uptake in the presence of 2i or WOBE437 measured in U937 living cells. tInh 15’, AEA 100 nM 15’, 37 °C, U937 2 Mio/mL
3
1.42 (dd, 3H, J15,F = 23.3, J15,4a = 0.8, Me-15), 1.91–1.96
(m, 1H, He-7), 2.08–2.23 (m, 2H, 2H-4), 3.21–3.27 (m, 1H,
Ha-1), 4.61–4.69 (m, 1H, Ha-3), 6.92–6.98 (m, 2H, H-13,
H-14), 7.23 (dd, 1H, J12,13 = 5.0, J12,14 = 1.3, H-12), the
remaining proton signals are overlapped by the signals of
the main isomer (S)-4f at 0.87–1.01, 1.44–1.57, 1.70–1.78
and 1.99–2.06 ppm. NMR 13C (125 MHz, CDCl3, δ, ppm,
JC,F, Hz): 77.60 (d, 3J = 9.8, C-1), 72.47 (d, 3J = 12.6, C-3),
residue was separated on a SiO2 column to afford (R)-2q
(0.502 g, 16%) and mixture of (R)-2q and (S)-2q isomers
(0.218 g, 7%, dr 1.0).
1
(S)-2q NMR H (600 MHz, CDCl3, δ, ppm, J/Hz): 0.84–
0.93 (m, 1H, Ha-8), 0.89 (d, 3H, J16,9 = 6.6, Me-16), 0.97–
1.05 (m, 1H, Ha-10), 1.10–1.19 (m, 2H, Ha-6, Ha-7), 1.23 (s,
3H, Me-15), 1.39–1.47 (m, 1H, Ha-9), 1.67–1.73 (m, 1H,
He-8), 1.79 (dd, 1H, J4e,4a = 13.7, J4e,3a = 2.2, He-4), 1.90
(dm, 1H, J7e,7a = 13.2, the others J < 3.5 Hz, He-7), 1.92–
2
1
47.00 (t, J = 20.3, C-4), 94.59 (s, J = 173.0, C-5), 49.75
(d, J = 19.5, C-6), 23.15 (t, C-7), 33.87 (t, C-8), 31.26 (d,
2
C-9), 41.13 (t, C-10), 145.42 (s, C-11), 124.74 (d, C-12),
126.32 (d, C-13), 123.67 (d, C-14), 19.41 (q, J = 25.9, C-
15), 22.02 (q, C-16). HRMS: m/z calcd. for C15H21OFS:
268.1292. Found: 268.1288.
1.97 (m, 1H, He-10), 1.94 (dd, 1H, J4a,4e = 13.7, J4a,3a =
2
12.0, Ha-4), 3.52–3.57 (m, 1H, Ha-1), 4.52 (s, 2H, 2H-17),
4.80 (dd, 1H, J3a,4a = 12.0, J3a,4e = 2.2, Ha-3), 6.15–6.18
(m, 2H, H-13, H-14). NMR 13C (150 MHz, CDCl3, δ, ppm):
75.55 (d, C-1), 68.18 (d, C-3), 43.57 (t, C-4), 69.05 (s, C-5),
49.18 (d, C-6), 22.39 (t, C-7), 34.22 (t, C-8), 31.15 (d, C-9),
41.00 (t, C-10), 154.63 (s, C-11), 153.54 (d, C-12), 108.11
(d, C-13), 107.41 (d, C-14), 28.08 (q, C-15), 22.07 (q, C-
16), 57.38 (t, C-17). HRMS: m/z calcd. for C16H24O4:
280.1675. Found: 280.1672.
5-Hydroxymethylfurfural (5-(hydroxymethyl)furan-2-
carbaldehyde)
A solution of fructose (10.8 g), SnCl4 (1.50 g), TBAB (1.92
g) in DMSO (60 ml) was heated at 100 °C for 2 h in air.
Then, a saturated NaHCO3 solution was added and product
was extracted with EtOAc (6 × 20 ml). The combined
organic layers was washed twice with 20 ml brine and dried
over Na2SO4. The solvent was distilled off and of 5-
(hydroxymethyl)furan-2-carbaldehyde (1.58 g, 21%) was
obtained.
1
(R)-2q NMR H (600 MHz, CDCl3, δ, ppm, J/Hz): 0.84–
0.93 (m, 1H, Ha-8), 0.90 (d, 3H, J16,9 = 6.6, Me-16), 0.95–
1.03 (m, 1H, Ha-7), 1.04–1.10 (m, 1H, Ha-10), 1.29 (s, 3H,
Me-15), 1.38–1.46 (m, 1H, Ha-9), 1.45–1.51 (m, 1H, Ha-6),
1.64–1.70 (m, 1H, He-8), 1.75–1.82 (m, 1H, He-7), 1.95–2.00
(m, 1H, He-10), 2.01 (dd, 1H, J4e,4a = 12.4, J4e,3a = 2.4, He-4),
2.08 (dd, 1H, J4a,4e = 12.4, J4a,3a = 11.8, Ha-4), 3.28–3.33 (m,
1H, Ha-1), 4.47 (dd, 1H, J3a,4a = 11.8, J3a,4e = 2.4, Ha-3), 4.54
(s, 2H, 2H-17), 6.19–6.21 (m, 2H, H-13, H-14). NMR 13C
(150 MHz, CDCl3, δ, ppm): 77.13 (d, C-1), 69.85 (d, C-3),
40.80 (t, C-4), 75.89 (s, C-5), 48.91 (d, C-6), 23.03 (t, C-7),
34.07 (t, C-8), 31.26 (d, C-9), 41.26 (t, C-10), 154.06 (s, C-
11), 153.63 (d, C-12), 108.23 (d, C-13), 107.44 (d, C-14),
18.15 (q, C-15), 22.01 (q, C-16), 57.34 (t, C-17). HRMS: m/z
calcd. for C16H24O4: 280.1675. Found: 280.1672.
(2R,4R(S),4aR,7R,8aR)-2-(5-(Hydroxymethyl)furan-2-yl)-4,7-
dimethyloctahydro-2H-chromen-4-ol 2q
5-(Hydroxymethyl)furan-2-carbaldehyde (1.17 g) and the
solution of (−)-isopulegol (1.72 g in 10 ml CH2Cl2) were
added to the suspension of K10 clay (3 g in 20 ml CH2Cl2).
The solvent was distilled off. The mixture was stored at r.t.
for 2 h and then ethyl acetate (15 ml) was added. The cat-
alyst was filtered off, the solvent was distilled off, and the

Medicinal Chemistry Research
(2R,4R,4aR,7R,8aR)-4,7-Dimethyl-2-(5-((4-methylpiperidin-
1-yl)methyl)furan-2-yl)octahydro-2H-chromen-4-ol 2s
ppm): 77.32 (d, C-1), 70.08 (d, C-3), 45.73 (t, C-4), 70.47
(s, C-5), 51.88 (d, C-6), 22.90 (t, C-7), 34.22 (t, C-8), 31.34
(d, C-9), 41.26 (t, C-10), 153.73 (s, C-11), 152.34 (s, C-12),
108.17 (d, C-13), 106.93 (d, C-14), 21.08 (q, C-15), 22.01
(q, C-16), 52.01 (t, C-17), 53.70 (t, C-18, C-21), 23.32 (t, C-
19, C-20). HRMS: m/z calcd. for C20H31NO3: 333.2304.
Found: 333.2299.
According to the GP2 the reaction of (R)-2q (0.191 g) and
4-methylpiperidine (0.475 g) gave compound 2s (0.135 g,
55%).
1
(R)-2s NMR H (600 MHz, CDCl3, δ, ppm, J/Hz): 0.85–
0.94 (m, 1H, Ha-8), 0.88 (d, 3H, J23,20 = 6.2, Me-23), 0.90
(d, 3H, J16,9 = 6.6, Me-16), 0.97–1.05 (m, 1H, Ha-7), 1.06
(ddd, 1H, J10a,10e = J10a,9a = 12.2, J10a,1a = 11.1, Ha-10),
1.20–1.32 (m, 4H, Ha-6, H-19, H-20, H-21), 1.23 (s, 3H,
Me-15), 1.38–1.47 (m, 1H, Ha-9), 1.54–1.60 (m, 2H,
H-19’, H-21’), 1.70 (dm, 1H, J8e,8a = 12.9, the others J <
3.6 Hz, He-8), 1.87–2.00 (m, 6H, 2H-4, He-7, He-10,
H-18, H-22), 2.81–2.88 (m, 2H, H-18’, H-22’), 3.21 (ddd,
1H, J1a,10a = 11.1, J1a,6a = 10.2, J1a,10e = 4.3, Ha-1), 3.45
(S)-2t NMR 1H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.88 (d,
3H, J16,9 = 6.5, Me-16), 1.11–1.17 (m, 1H, Ha-6), 1.22 (s,
3H, Me-15), 1.72–1.81 (m, 2H, 2H-4), 3.49–3.55 (m, 1H,
Ha-1), 3.56 (d, 1H, 2J = 14.0) and 3.59 (d, 1H, 2J = 14.0) –
2H-17 (AB system), 4.79 (dd, 1H, J3a,4a = 12.0, J3a,4e = 2.3,
Ha-3), 6.07 (d, 1H, J13,14 = 3.1, H-13), 6.14 (d, 1H, J14,13
=
3.1, H-14), the remaining proton signals are overlapped by
the signals of the main isomer (R)-2t at 0.83–0.93, 0.97–
1.10, 1.35–1.47, 1.66–1.77 and 2.47–2.55 ppm. NMR 13C
(125 MHz, CDCl3, δ, ppm): 75.44 (d, C-1), 68.20 (d, C-3),
43.74 (t, C-4), 69.03 (s, C-5), 49.23 (d, C-6), 22.41 (t, C-7),
34.29 (t, C-8), 31.17 (d, C-9), 41.08 (t, C-10), 152.26 (s, C-
12), 108.12 (d, C-13), 106.97 (d, C-14), 28.14 (q, C-15),
22.07 (q, C-16), 51.99 (t, C-17), 53.65 (t, C-18, C-21),
23.32 (t, C-19, C-20), we could not assign the signal of C-
11 with certainty. HRMS: m/z calcd. for C20H31NO3:
333.2304. Found: 333.2299.
2
2
(d, 1H, J = 14.1) and 3.50 (d, 1H, J = 14.1) –2H-17
(AB system), 4.48 (dd, 1H, J3a,4a = 9.0, J3a,4e = 5.2,
Ha-3), 6.10 (d, 1H, J13,14 = 3.2, H-13), 6.18 (d, 1H, J14,13
= 3.2, H-14). NMR 13C (150 MHz, CDCl3, δ, ppm): 77.35
(d, C-1), 70.08 (d, C-3), 45.69 (t, C-4), 70.60 (s, C-5),
51.91 (d, C-6), 22.93 (t, C-7), 34.23 (t, C-8), 31.37 (d,
C-9), 41.26 (t, C-10), 153.90 (s, C-11), 151.50 (s, C-12),
109.21 (d, C-13), 106.98 (d, C-14), 21.15 (q, C-15), 22.04
(q, C-16), 55.16 (t, C-17), 53.50 and 53.36 (t, C-18,
C-22), 33.98 and 33.99 (t, C-19, C-21) 30.40 (d, C-20),
21.70 (q, C-23). HRMS: m/z calcd. for C22H35NO3:
361.2617. Found: 361.2612.
(2R,4R,4aR,7R,8aR)-4,7-Dimethyl-2-(5-(morpholinomethyl)
furan-2-yl)octahydro-2H-chromen-4-ol 2u
According to the GP2 the reaction of (R)-2q (0.231 g) and
morpholine (0.493 g) gave compound 2u (0.242 g, 84%).
(2R,4R(S),4aR,7R,8aR)-4,7-Dimethyl-2-(5-(pyrrolidin-1-
ylmethyl)furan-2-yl)octahydro-2H-chromen-4-ol 2t
1
(R)-2u NMR H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.78–
According to the GP2 the reaction of 2q (0.150 g, dr 1.0)
and pyrrolidine (0.266 g) gave compound 2t (0.128 g, 72%,
dr 4.0).
0.88 (m, 1H, Ha-8), 0.84 (d, 3H, J16,9 = 6.6, Me-16), 0.90–
0.99 (m, 1H, Ha-7), 1.00 (ddd, 1H, J10a,10e = J10a,9a = 12.2,
J10a,1a = 11.0, Ha-10), 1.16 (s, 3H, Me-15), 1.22 (ddd, 1H,
J6a,7a = 12.2, J6a,1a = 10.2, J6a,7e = 3.2, Ha-6), 1.31–1.43
(m, 1H, Ha-9), 1.64 (dm, 1H, J8e,8a = 12.8, the others J <
3.5 Hz, He-8), 1.84–1.95 (m, 4H, 2H-4, He-7, He-10), 2.36–
2.41 (m, 4H, 2H-18, 2H-21), 3.16 (ddd, 1H, J1a,10a = 11.0,
The NMR spectra were recorded for the mixture (R)-2t and
(S)-2t isomers (1:0.25)
1
2
(R)-2t NMR H (500 MHz, CDCl3, δ, ppm, J/Hz): 0.84–
J1a,6a = 10.2, J1a,10e = 4.3, Ha-1), 3.40 (d, 1H, J = 14.0)
0.93 (m, 1H, Ha-8), 0.89 (d, 3H, J16,9 = 6.5, Me-16), 0.95–
1.09 (m, 2H, Ha-7, Ha-10), 1.21 (s, 3H, Me-15), 1.26 (ddd,
1H, J6a,7a = 12.2, J6a,1a = 10.2, J6a,7e = 3.2, Ha-6), 1.35–
1.47 (m, 1H, Ha-9), 1.69 (dm, 1H, J8e,8a = 12.8, the others J
< 3.5 Hz, He-8), 1.72–1.77 (m, 4H, 2H-19, 2H-20), 1.87–
1.99 (m, 4H, 2H-4, He-7, He-10), 2.48–2.54 (m, 4H, 2H-18,
2H-21), 3.20 (ddd, 1H, J1a,10a = 11.0, J1a,6a = 10.2, J1a,10e
and 3.44 (d, 1H, 2J = 14.0) –2H-17 (AB system), 3.60–3.65
(m, 4H, 2H-19, 2H-20), 4.41 (dd, 1H, J3a,4a = 10.5, J3a,4e
=
3.6, Ha-3), 6.06 (d, 1H, J13,14 = 3.2, H-13), 6.12 (d, 1H,
J14,13 = 3.2, H-14). NMR 13C (125 MHz, CDCl3, δ, ppm):
77.20 (d, C-1), 69.88 (d, C-3), 45.55 (t, C-4), 70.12 (s, C-5),
51.69 (d, C-6), 22.76 (t, C-7), 34.11 (t, C-8), 31.20 (d, C-9),
41.14 (t, C-10), 154.17 (s, C-11), 150.45 (s, C-12), 109.36
(d, C-13), 106.82 (d, C-14), 20.91 (q, C-15), 21.89 (q, C-
16), 55.01 (t, C-17), 52.92 (t, C-18, C-21), 66.51 (t, C-19,
2
= 4.3, Ha-1), 3.54 (d, 1H, 2J = 14.0) and 3.60 (d, 1H, J =
14.0) –2H-17 (AB system), 4.46 (dd, 1H, J3a,4a = 10.0,
J3a,4e = 4.3, Ha-3), 6.08 (d, 1H, J13,14 = 3.1, H-13), 6.16 (d,
1H, J14,13 = 3.1, H-14). NMR 13C (125 MHz, CDCl3, δ,
C-20). ½αŠ27:3 = −7.0 (c 0.74, CHCl3). HRMS: m/z calcd.
D
for C20H31NO4: 349.2253. Found: 349.2248.

Medicinal Chemistry Research
1
(2R,4R,4aR,7R,8aR)-2-(5-((Dibutylamino)methyl)furan-2-yl)-
4,7-dimethyloctahydro-2H-chromen-4-ol 2v
(R)-1b NMR H (600 MHz, CDCl3 + CD3OD, δ, ppm, J/
Hz): 1.27 (s, 3H, Me-15), 1.62 (br.d, 1H, J4e,4a = 14.0, He-
4), 1.65–1.70 (m, 1H, Ha-6), 1.77 (br.s, 3H, Me-16), 1.98–
2.03 (m, 2H, H-7), 2.07 (dd, 1H, J4a,4e = 14.0, J4a,3a = 12.0,
Ha-4), 3.92 (br.s, 1H, He-10), 4.23 (br.t, 1H, J1e,6a < 2.5, He-
1), 4.84 (dd, 1H, J3a,4a = 12.0, J3a,4e = 2.4, Ha-3), 5.54–5.57
(m, 1H, H-8), 6.23 (d, 1H, J14,13 = 3.2, H-14), 6.28 (dd, 1H,
J13,14 = 3.2, J13,12 = 1.9, H-13), 7.34 (d, 1H, J12,13 = 1.9, H-
12) NMR 13C (150 MHz, CDCl3 + CD3OD, δ, ppm): 75.35
(d, C-1), 69.27 (d, C-3), 37.57 (t, C-4), 70.47 (s, C-5), 38.21
(d, C-6), 24.40 (t, C-7), 124.17 (d, C-8), 131.70 (s, C-9),
70.36 (d, C-10), 154.28 (s, C-11), 142.17 (d, C-12), 109.94
(d, C-13), 106.97 (d, C-14), 28.36 (q, C-15), 20.71 (q, C-
16). HR-MS: m/z calcd. for C15H20O4: 264.1356. Found:
264.1358.
According to the GP2 the reaction of (R)-2q (0.170 g) and
dibutylamine (0.542 g) gave compound 2v (0.112 g, 48%).
1
(R)-2v NMR H (600 MHz, CDCl3, δ, ppm, J/Hz): 0.85–
0.94 (m, 1H, Ha-8), 0.87 (t, 6H, J21,20 = J25,24 = 7.4, Me-21,
Me-25), 0.90 (d, 3H, J16,9 = 6.6, Me-16), 0.98–1.06 (m, 1H,
Ha-7), 1.07 (ddd, 1H, J10a,10e = J10a,9a = 12.2, J10a,1a = 11.1,
Ha-10), 1.22–1.31 (m, 5H, Ha-6, 2H-20, 2H-24), 1.24 (s,
3H, Me-15), 1.39–1.47 (m, 5H, Ha-9, 2H-19, 2H-23), 1.71
(dm, 1H, J8e,8a = 12.8, He-8), 1.89–2.01 (m, 4H, 2H-4, He-
7, He-10), 2.35–2.43 (m, 4H, 2H-18, 2H-22), 3.23 (ddd, 1H,
J1a,10a = 11.1, J1a,6a = 10.2, J1a,10e = 4.3, Ha-1), 3.58 (d, 1H,
2
2J = 15.3) and 3.60 (d, 1H, J = 15.3) – 2H-17, 4.46 (dd,
1H, J3a,4a = 11.2, J3a,4e = 2.8, Ha-3), 6.07 (d, 1H, J13,14
=
(2S,4S(R),4aR,8R,8aR)-2-(Furan-3-yl)-4,7-dimethyl-
3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol 1d
3.1, H-13), 6.18 (d, 1H, J14,13 = 3.1, H-14). NMR 13C (150
MHz, CDCl3, δ, ppm): 77.33 (d, C-1), 70.11 (d, C-3), 45.73
(t, C-4), 70.61 (s, C-5), 51.92 (d, C-6), 22.93 (t, C-7), 34.23
(t, C-8), 31.37 (d, C-9), 41.28 (t, C-10), 153.48 (s, C-11),
152.37 (s, C-12), 108.65 (d, C-13), 107.01 (d, C-14), 21.13
(q, C-15), 22.05 (q, C-16), 49.99 (t, C-17), 53.43 (t, C-18,
C-22), 29.02 (t, C-19, C-23), 20.54 (t, C-20, C-24), 13.95 (t,
According to the GP3 the reaction of diol 5 (0.30 g, dr 1.0),
furan-3-carbaldehyde (0.17 g) and montmorillonite K10
(1.0 g) for 45 min gave compound 1d (0.243 g, 63% on
converted 5, dr 1.4). The conversion of the diol 5 was 78%.
C-21, C-25). ½αŠ27:3 = −8.2 (c 0.34, CHCl3). HRMS: m/z
(S)-1d NMR 1H (500 MHz, CDCl3/CD3OD, δ, ppm, J/Hz):
1.41 (d, 3H, J15,4a = 0.7, Me-15), 1.60 (ddd, 1H, J4e,4a =
D
calcd. for C24H41NO3: 391.3086. Found: 391.3081.
13.3, J4e,3a = 2.7, J4e,6a = 1.2, He-4), 1.72 (m, 3H, all J ≤
2.5 Hz, Me-16), 1.72–1.77 (m, 1H, Ha-6), 1.92 (ddq, 1H,
J4a,4e = 13.3, J4a,3a = 12.1, J4a,15 = 0.7, Ha-4), 2.04–2.10
(m, 2H, 2H-7), 3.71 (dd, 1H, J1e,10e = 2.4, J1e,6a = 2.2, He-
1), 3.78 (br.s, 1H, He-10), 4.37 (dd, 1H, J3a,4a = 12.1, J3a,4e
= 2.7, Ha-3), 5.53–5.57 (m, 1H, H-8), 6.32 (dd, 1H, J14,13
= 1.8, J14,12 = 0.8, H-14), 7.28 (dd, 1H, J13,14 = 1.8, J13,12
= 1.5, H-13), 7.32 (ddd, 1H, J12,13 = 1.5, J12,14 = 0.8, J12,3a
= 0.6, H-12). NMR 13C (125 MHz, CDCl3/CD3OD, δ,
ppm): 77.77 (d, C-1), 70.27 (d, C-3), 40.86 (t, C-4), 70.33
(s, C-5), 38.27 (d, C-6), 22.49 (t, C-7), 124.42 (d, C-8),
131.09 (s, C-9), 70.09 (d, C-10), 126.26 (s, C-11), 139.11
(d, C-12), 142.86 (d, C-13), 108.77 (d, C-14), 26.58 (q, C-
15), 20.45 (q, C-16). HRMS: m/z calcd. for C15H20O4:
264.1356. Found: 264.1357.
(2S,4S(R),4aR,8R,8aR)-2-(Furan-2-yl)-4,7-dimethyl-
3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol 1b
According to the GP3 the reaction of diol 5 (0.30 g), furan-
2-carbaldehyde (0.17 g) and montmorillonite K10 (1.0 g)
for 45 min gave compound 1b (0.268 g, 63% on converted
5, dr 1.0). The conversion of the diol 5 was 90%.
NMR spectra were recorded for a mixture (S)-1b and (R)-1b
(1.0: 0.75)
1
(S)-1b NMR H (600 MHz, CDCl3 + CD3OD, δ, ppm, J/
Hz): 1.48 (s, 3H, Me-15), 1.70 (br.d, 1H, J4e,4a = 13.3, He-
4), 1.77 (br.s, 3H, Me-16), 1.78–1.83 (m, 1H, Ha-6), 2.13–
2.22 (m, 3H, Ha-4, 2H-7), 3.80 (br.t, 1H, J1e,6a ≈ J1e,10e
2.2, He-1), 3.91 (br.s, 1H, He-10), 4.49 (dd, 1H, J3a,4a
12.4, J3a,4e = 2.4, HHa-3), 5.60–5.63 (m, 1H, H-8), 6.26 (d,
1H, J14,13 = 3.2, HH-14), 6.29 (dd, 1H, J13,14 = 3.2, J13,12
≈
=
NMR spectra (R)-1d were recorded for a mixture (S)-1d and
(R)-1d (1.0:2.0)
=
1.9, H-13), 7.35 (d, 1H, J12,13 = 1.9, H-12). NMR 13C (150
MHz, CDCl3 + CD3OD, δ, ppm): 77.80 (d, C-1), 70.89 (d,
C-3), 38.55 (t, C-4), 70.77 (s, C-5), 38.54 (d, C-6), 22.52 (t,
C-7), 124.77 (d, C-8), 131.24 (s, C-9), 70.39 (d, C-10),
153.71 (s, C-11), 142.27 (d, C-12), 110.02 (d, C-13),
107.03 (d, C-14), 26.96 (q, C-15), 20.61 (q, C-16). HR-MS:
m/z calcd. for C15H20O4: 264.1356. Found: 264.1358.
(R)-1d NMR 1H (500 MHz, CDCl3, δ, ppm, J/Hz): 1.23 (s,
3H, Me-15), 1.62 (ddd, J4e,4a = 14.1, J4e,3a = 2.6, J4e,6a
=
1.3, He-4), 1.65–1.70 (m, 1H, Ha-6), 1.78 (m, 3H, all J ≤ 2.5
Hz, Me-16), 1.81 (dd, 1H, J4a,4e = 14.1, J4a,3a = 11.8, Ha-4),
1.92–2.01 (m, 2H, 2H-7), 3.90 (br.s, 1H, He-10), 4.20 (dd,
1H, J1e,10e = 2.4, J1e,6a = 2.2, He-1), 4.76 (dd, 1H, J3a,4a
=
11.8, J3a,4e = 2.6, Ha-3), 5.53–5.56 (m, 1H, H-8), 6.35

Medicinal Chemistry Research
(dd, 1H, J14,13 = 1.8, J14,12 = 0.8, H-14), 7.32 (dd, 1H,
J13,14 = 1.8, J13,12 = 1.5, H-13), 7.34 (ddd, 1H, J12,13 = 1.5,
J12,14 = 0.8, J12,3a = 0.5, H-12). NMR 13C (125 MHz,
CDCl3, δ, ppm): 75.17 (d, C-1), 68.73 (d, C-3), 40.33 (t, C-
4), 70.67 (s, C-5), 38.10 (d, C-6), 24.44 (t, C-7), 124.06 (d,
C-8), 131.70 (s, C-9), 70.50 (d, C-10), 126.68 (s, C-11),
139.05 (d, C-12), 142.84 (d, C-13), 108.85 (d, C-14), 28.25
(q, C-15), 20.72 (q, C-16). HRMS: m/z calcd. for C15H20O4:
264.1356. Found: 264.1357.
NMR 13C (125 MHz, CDCl3, δ, ppm): 75.31 (d, C-1), 69.20
(d, C-3), 37.08 (t, C-4), 69.99 (s, C-5), 37.78 (d, C-6), 24.22
(t, C-7), 123.83 (d, C-8), 131.58 (s, C-9), 69.93 (d, C-10),
152.45 (s, C-11), 151.73 (s, C-12), 105.81 (d, C-13), 107.83
(d, C-14), 27.83 (q, C-15), 20.49 (q, C-16), 13.25 (q, C-17).
HR-MS: m/z calcd. for C16H22O4: 278.1513. Found:
278.1514.
6 NMR 1H (500 MHz, CDCl3, δ, ppm, J/Hz): 1.79 (m, 3H,
all J ≤ 2.5 Hz, Me-16), 1.93 (dddq, 1H, J7e,7a = 17.8, J7e,6a
(2S,4S(R),4aR,8R,8aR)-4,7-dimethyl-2-(5-methylfuran-2-yl)-
3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol 1e
= 6.3, J7e,8 = 5.4, J7e,16 = 1.5, He-7), 2.25 (d, 3H, J17,13 =
1.0, Me-17), 2.30 (dd, 1H, J4e,4a = 14.1, J4e,3a = 2.7, He-4),
2.34 (ddm, 1H, J7a,7e = 17.8, J7a,6a = 10.8, Ha-7), 2.51 (ddd,
1H, J6a,7a = 10.8, J6a,7e = 6.3, J6a,1e = 2.1, Ha-6), 2.79 (ddt,
1H, J4a,4e = 14.1, J4a,3a = 12.0, J4a,15 = 2.0, Ha-4), 3.71 (dd,
1H, J1e,10e = 2.4, J1e,6a = 2.1, He-1), 3.93 (br.s, 1H, He-10),
4.36 (dd, 1H, J3a,4a = 12.0, J3a,4e = 2.7, Ha-3), 4.80 (dd, 1H,
J15,4a = 2.0, J15,15’ = 1.8, H-15), 4.89 (dd, 1H, J15’,4a = 2.0,
J15’,15 = 1.8, H’-15), 5.58–5.61 (m, 1H, H-8), 5.88 (dq, 1H,
J13,14 = 3.1, J13,17 = 1.0, H-13), 6.15 (d, 1H, J14,13 = 3.1, H-
14). NMR 13C (125 MHz, CDCl3, δ, ppm): 80.48 (d, C-1),
73.93 (d, C-3), 34.09 (t, C-4), 146.32 (s, C-5), 36.94 (d, C-
6), 26.19 (t, C-7), 124.67 (d, C-8), 131.37 (s, C-9), 70.28 (d,
C-10), 152.12 (s, C-11), 152.05 (s, C-12), 106.02 (d, C-13),
107.96 (d, C-14), 110.11 (t, C-15), 20.81 (q, C-16), 13.49
(q, C-17). HR-MS: m/z calcd. for C16H20O3: 260.1407.
Found: 278.1405.
According to the GP3 the reaction of diol 5 (0.40 g), 5-
methylfuran-2-carbaldehyde (0.26 g) and montmorillonite
K10 (1.3 g) for 150 min gave compounds 1e (0.359 g, 58%
on converted 5, dr 1.5), (2S,4aS,8R,8aR)-7-methyl-4-
methylene-2-(5-methylfuran-2-yl)-3,4,4a,5,8,8a-hexahydro-
2H-chromen-8-ol 6 (0.025 g, 5% on converted 5) and
(2S,4S,4aR,8S,8aR)-4,7-dimethyl-2-(5-methylfuran-2-yl)-
3,4,4a,5,8,8a-hexahydro-2H-4,8-epoxychromene 7 (0.029
g, 5% on converted 5). The conversion of the diol 5 was
93%.
NMR spectra were recorded for a mixture (S)-1e and (R)-1e
(1.0: 0.75)
(S)-1e NMR 1H (500 MHz, CDCl3/CD3OD, δ, ppm, J/Hz):
1.47 (s, 3H, Me-15), 1.64 (ddd, 1H, J4e,4a = 13.3, J4e,3a
=
7 NMR 1H (500 MHz, CDCl3, δ, ppm, J/Hz): 1.39 (s, 3H,
Me-15), 1.73 (m, 3H, all J ≤ 2.5 Hz, Me-16), 1.78 (dd, 1H,
J4e,4a = 13.0, J4e,3a = 4.2, He-4), 1.99 (dd, 1H, J4a,4e = 13.0,
J4a,3a = 11.0, Ha-4), 2.09 (br.d, 1H, J6,7 = 5.7, H-6), 2.26 (d,
2.5, J4e,6a = 1.2, He-4), 1.77 (m, 3H, all J ≤ 2.5 Hz, Me-16),
1.84 (br.t, 1H, J6a,7 = 8.3, Ha-6), 2.12–2.18 (m, 2H, 2H-7),
2.21 (dd, 1H, J4a,4e = 13.3, J4a,3a = 12.4, Ha-4), 2.25 (d, 3H,
J17,13 = 1.0, Me-17), 3.79 (dd, 1H, J1e,10e = 2.4, J1e,6a = 2.1,
He-1), 3.83 (br.s, 1H, He-10), 4.46 (dd, 1H, J3a,4a = 12.4,
J3a,4e = 2.5, Ha-3), 5.59–5.63 (m, 1H, H-8), 5.90 (dq, 1H,
J13,14 = 3.1, J13,17 = 1.0, H-13), 6.17 (d, 1H, J14,13 = 3.1, H-
14). NMR 13C (125 MHz, CDCl3/CD3OD, δ, ppm): 78.83
(d, C-1), 71.60 (d, C-3), 38.49 (t, C-4), 70.79 (s, C-5), 39.08
(d, C-6), 23.23 (t, C-7), 125.06 (d, C-8), 131.76 (s, C-9),
70.49 (d, C-10), 152.77 (s, C-11), 152.57 (s, C-12), 106.59
(d, C-13), 108.61 (d, C-14), 26.89 (q, C-15), 20.90 (q, C-
16), 13.56 (q, C-17). HR-MS: m/z calcd. for C16H22O4:
278.1513. Found: 278.1514.
3H, J17,13 = 1.0, Me-17), 2.34 (ddm, 1H, J7,7’ = 18.8, J7,6
=
5.7, H-7), 2.51 (dm, 1H, J7’,7 = 18.8, H’-7), 4.24 (br.s, 1H,
He-10), 4.38 (br.s, 1H, H-1), 5.07 (dd, 1H, J3a,4a = 11.0,
J3a,4e = 4.2, Ha-3), 5.12–5.16 (m, 1H, H-8), 5.87 (dq, 1H,
J13,14 = 3.1, J13,17 = 1.1, H-13), 6.13 (d, 1H, J14,13 = 3.1, H-
14). NMR 13C (125 MHz, CDCl3, δ, ppm): 80.97 (d, C-1),
67.34 (d, C-3), 42.94 (t, C-4), 83.02 (s, C-5), 45.44 (d, C-6),
28.14 (t, C-7), 120.73 (d, C-8), 139.57 (s, C-9), 80.27 (d, C-
10), 152.19 (s, C-11), 152.09 (s, C-12), 105.90 (d, C-13),
108.07 (d, C-14), 21.55 (q, C-15), 20.84 (q, C-16), 13.45 (q,
C-17). HR-MS: m/z calcd. for C16H20O3: 260.1407. Found:
278.1405.
(R)-1e NMR 1H (500 MHz, CDCl3, δ, ppm, J/Hz): 1.18 (s,
3H, Me-15), 1.53 (ddd, 1H, J4e,4a = 14.0, J4e,3a = 2.5, J4e,6a
= 1.4, He-4), 1.61 (br.t, 1H, J6a,7 = 8.8, Ha-6), 1.70 (m, 3H,
all J ≤ 2.5 Hz, Me-16), 1.89–1.96 (m, 2H, 2H-7), 1.98 (dd,
Biology
CB1R and CB2R binding assays
1H, J4a,4e = 14.0, J4a,3a = 12.1, Ha-4), 2.18 (d, 3H, J17,13
1.0, Me-17), 3.81 (br.s, 1H, He-10), 4.12 (dd, 1H, J1e,10e
2.4, J1e,6a = 2.1, He-1), 4.70 (dd, 1H, J3a,4a = 12.1, J3a,4e
2.5, Ha-3), 5.46–5.50 (m, 1H, H-8), 5.80 (dq, 1H, J13,14
=
=
=
=
Receptor binding experiments were performed with mem-
brane preparations as previously reported (Chicca et al.
2017). Briefly, clean membranes expressing hCB1 or hCB2
were resuspended in binding buffer (50 mM Tris-HCl, 2.5
3.1, J13,17 = 1.0, H-13), 6.05 (d, 1H, J14,13 = 3.1, H-14).

Medicinal Chemistry Research
mM EDTA, 5 mM MgCl2, 0.5% fatty acid-free bovine
serum albumin (BSA), pH 7.4) and incubated with vehicle
or compounds at the concentration of 10 µM in presence of
0.5 nM of [3H]CP55,940 for 90 min at 30 °C. Non-specific
binding was determined in presence of 10 μM WIN55,512.
After incubation, membranes were filtered through a pre-
soaked 96-well microplate bonded with GF/B filters under
vacuum and washed twelve times with 150 μl of ice-cold
binding buffer. The filters were dried under air drier and
then added with 45 µl of Microscint 20 scintillation cocktail.
The radioactivity was measured using a Packard Tri-Carb
2100 TR scintillation counter. All experiments were per-
formed at least in two independent experiments each per-
formed in triplicate and data are reported as mean values
SD.
and incubated for 15 min at 37 °C under shaking (400 rpm).
The uptake process was stopped by rapid filtration onto a
96-well microplate bonded with GF/C filters under vacuum
and washed 3 times with 150 µl of ice-cold PBS supple-
mented with 1% BSA fatty acid free. The filters were dried
under air drier and then added with 45 µl of Microscint
20 scintillation cocktail. The radioactivity was measured
using a Packard Tri-Carb 2100 TR scintillation counter. All
experiments were performed in two independent experi-
ments each performed in triplicate and data are reported as
mean values SD.
Acknowledgements Synthetic part of this work was supported by
Russian Science Foundation (grant 15-13-00017). Authors would like
to acknowledge the Multi-Access Chemical Service Center SB RAS
for spectral and analytical measurements. AC thanks Prof. Juerg
Gertsch for the continuous support on his research activity and
inspiring discussions.
FAAH and MAGL assays
Compliance with ethical standards
FAAH and MAGL assays were performed as previously
described (Chicca et al. 2017). Briefly, the assays were
performed using U937 cell homogenate (100 μg) which
were diluted in 200 μl of Tris-HCl 10 mM, EDTA 1 mM,
pH 8 containing 0.1% fatty acid-free BSA. Compounds
were added at the screening concentration of 10 µM and
pre-incubated for 30 min at 37 °C under shaking (400 rpm).
URB597 (0.1 µM) and JZL184 (1 µM) were used as positive
controls for complete FAAH and MAGL inhibition,
respectively. Then, 100 nM of AEA containing 1 nM of
[ethanolamine-1-3H]AEA as a tracer for FAAH or 10 μM of
2-OG containing 1 nM of [glycerol-1,2,3-3H]2-OG was
added to the homogenates and incubated for 15 min at 37 °C
under shaking (400 rpm). The reaction was stopped by
adding 400 μl of ice-cold CHCl3: MeOH (1:1). Samples
were vortexed and rapidly centrifuged at 16,000×g for 10
min at 4 °C. The aqueous phases were collected, transferred
to scintillation tubes and mixed with 3 ml of Ultima Gold
scintillation liquid. The radioactivity associated with the
[3H]glycerol formation was measured for tritium content by
liquid scintillation spectroscopy. Compounds were tested in
two independent experiments, each performed in triplicates
and data are reported as mean values SD.
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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