One-step, stereoselective synthesis of octahydrochromanes via the Prins reaction and their cannabinoid activities

Article abstract of DOI:10.1016/j.tetlet.2018.01.040

Novel, functionalized octahydrochromane derivatives were synthesized in a single step via the Prins reaction. Enantiomerically pure (+)-isopulegol was reacted with benzaldehyde to stereoselectively yield the corresponding octahydro-2H-chromen-4-ol derivative containing five stereocenters. A total of 10 compounds were synthesized by altering the enantiomer of isopulegol and the substituted benzaldehyde, and the resulting enantiopure octahydrochromanes were screened in vitro against the cannabinoid receptor isoforms CB1 and CB2. Compounds containing an olefin at the C4 position [(+)-3c, (?)-3c, (?)-7c, (?)-9c and (?)-11c] of the octahydrochromane scaffold were found to exhibit reasonable displacement of [³H] CP55,940 from the CB receptors, whereas the corresponding hydroxy analogs [(+)-3a, (+)-3b, (?)-3a, (?)-3b and (+)-5a] had very little or no effect.

Full text of DOI:10.1016/j.tetlet.2018.01.040

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-step, stereoselective synthesis of octahydrochromanes via the Prins
reaction and their cannabinoid activities
Shuneize Slater a, Pradeep B. Lasonkar a, Saqlain Haider a, Moneerah J. Alqahtani b, Amar G. Chittiboyina a,
,
⇑
Ikhlas A. Khan a,b
a National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA
b Division of Pharmacognosy, Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel, functionalized octahydrochromane derivatives were synthesized in a single step via the Prins reac-
tion. Enantiomerically pure (+)-isopulegol was reacted with benzaldehyde to stereoselectively yield the
corresponding octahydro-2H-chromen-4-ol derivative containing five stereocenters. A total of 10 com-
pounds were synthesized by altering the enantiomer of isopulegol and the substituted benzaldehyde,
and the resulting enantiopure octahydrochromanes were screened in vitro against the cannabinoid recep-
tor isoforms CB1 and CB2. Compounds containing an olefin at the C4 position [(+)-3c, (À)-3c, (À)-7c, (À)-9c
and (À)-11c] of the octahydrochromane scaffold were found to exhibit reasonable displacement of [3H]
CP55,940 from the CB receptors, whereas the corresponding hydroxy analogs [(+)-3a, (+)-3b, (À)-3a,
(À)-3b and (+)-5a] had very little or no effect.
Received 9 November 2017
Revised 5 January 2018
Accepted 16 January 2018
Available online xxxx
Keywords:
Octahydrochromane
Prins cyclization
Enantioselectivity
Cannabinoid receptors
Ó 2018 Elsevier Ltd. All rights reserved.
Introduction
neuroprotective, and anti-inflammatory properties in humans,
and thus is protective against epilepsy, anxiety, psychosis, and
The cannabinoid receptors, CB1 and CB2, comprise part of the
endocannabinoid system (ECS) along with their endogenous
ligands and their related enzymes and transporters. This system
is involved in many human diseases and may provide potential tar-
gets in drug development.1 Various research groups have reported
that cannabinoid receptors are overexpressed in different cancers
and that cannabinoids are able to reduce tumor growth and pro-
gression by modulating cancer cell proliferation, tumor angiogen-
esis, and metastasis.2,3 CB1 receptors are mainly located in the
central nervous system (CNS) with low expression in the periph-
ery, and have been shown to protect the brain and spinal neurons
from excitotoxic damage,4 relieve gastrointestinal (GI) symptoms,5
and participate in numerous other important functions. CB2 recep-
tors are localized on immune cells and participate in the immuno-
suppressive and antinociceptive effects of the cannabinoids.6
Plant-derived cannabinoids, or phytocannabinoids, have
emerged as a major class of compounds with therapeutic potential.
Cannabis has been used medicinally for the treatment of neurolog-
ical disorders such as epilepsy.7 Cannabidiol 1a (CBD, Fig. 1), is one
of the major non-psychoactive components of Cannabis sativa and
Cannabis indica and has been proposed to possess anticonvulsive,
other CNS disorders.8
Cannabidiol 1a and tetrahydrocannabinol 1b (THC) are tetrahy-
drocannabinoids that differ only by the formation of a carbon-oxy-
gen bond in THC to form a pyran ring (Fig. 1). The machaeriols 1c
are another class of compounds that are structurally similar to
THC; however, the ring junction stereochemistry is inverted with
an additional stereocenter in the A-ring at the C9 position
(Fig. 1). Machaeriols are therefore not tetrahydrocannabinoids,
but are instead hexahydrocannabinoids. The inversion of stereo-
chemistry at these centers produce different biological properties
than those observed with THC. Hexahydrocannabinol analogs, such
as LYR-8 1d (Fig. 1), are cannabinoid-like compounds with high
similarity to the machaeriols which possess little affinity for the
CB1 and CB2 receptors, yet directly inhibit the growth of cancer
cells, induce apoptosis of cancer cells, and inhibit endothelial cell
proliferation and angiogenesis.9 Recently, Volcho10 and co-workers
reported the highly potent analgesic activity of several octahydro-
2H-chromen-4-ols derived from isopulegol. The resulting octahy-
drochromenol product of thiophene-2-carbaldehyde, isopulegol,
exhibited analgesic activity in the acetic acid-induced writhing test
as well as the hotplate test without any apparent acute toxicity.
Synthetically, these compounds have been prepared using
one-step transformations. For example, tetrahydrocannabinoid
compounds have been stereoselectively synthesized via boron
⇑
Corresponding author.
E-mail address: amar@olemiss.edu (A.G. Chittiboyina).
https://doi.org/10.1016/j.tetlet.2018.01.040
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Slater S., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.01.040

2
S. Slater et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 1. Selected biologically active compounds based on a chromane scaffold – cannabinoids, machaeriols and octahydrochromanes.
trifluoride catalyzed arylation of a homocuprate,11 whereas hex-
ahydrochromanes were prepared via hetero Diels-Alder cycloaddi-
tion.12 Octahydrochromenols were previously synthesized via the
Prins reaction of homoallylic alcohols with substituted aryl aldehy-
stereoselectivity and chirality of the homoallylic alcohols was
reported.
Keeping in mind the structural similarity between the
machaeriols and the octahydrochromanes, herein we report the
one-step synthesis of ten novel octahydrochromanes derivatives
using a stereoselective Prins cyclization as well as their biological
activities against cannabinoid receptors.
des. Lewis acids such as Sc(OTf)3 or Montmorillonite K1014 with
13
and without p-TSA10 were employed to produce octahydrochro-
manes compounds; however, little information regarding the
Results and discussion
Compounds containing a tetrahydropyran moiety are widely
used as precursors for the synthesis of biologically active com-
pounds and can be synthesized using the Prins reaction.15 The
acid-catalyzed Prins reaction of pulegols with various aldehydes
containing electron-donating and electron-withdrawing sub-
stituents is often used for the synthesis of biologically active
octahydro-2H-chromen-4-ols.16
Starting from (+)-isopulegol, (+)-2, Prins cyclization with 2,6-
dimethylbenzaldehyde (1) in the presence of a Lewis acid, resulted
in the formation of one major (À)-3a and two minor compounds
(À)-3b,c (Scheme 1). Several Lewis acids were screened, including
metal triflates, and boron trifluoride diethyl etherate (0.05 equiv.)
was found to be superior for this transformation. The stereochem-
istry of the major compound was determined by 2D-NMR and
Scheme 1. Chiral pool approach for construction of the octahydrochromane
scaffold. Reagents and conditions: a). BF3ÁOEt2 (0.05 equiv.), CH2Cl2, À40 °C to rt, 6
h, 72%, (3a:3b:3c = 3:1:2).
Fig. 2. One-pot ene, Prins reactions of (À)-citronellal with 2,6-dimethylbenzaldehyde and the formation of octahydrochromanes. Key NOE interactions are indicated by
dotted arrows. Reagents and conditions: a). BF3ÁOEt2 (0.2 equiv.), CH2Cl2, À40 °C to rt, 4.5 h, 48%, (3a:3b:5a = 3.1:1:1.2).
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S. Slater et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
NOESY experiments. Strong NOE correlations were observed
between H8a and H7 as well as H8a and H2, suggesting that H8a,
H7 and H2 were in the syn-configuration. The syn-selectivity in
the newly formed pyran ring can be envisioned as proceeding via
formation of an oxonium ion with an aryl group occupying the
equatorial position, thus both H8a and H2 are situated in the less
hindered axial positions (Fig. 2). The minor compounds (À)-3b
and (À)-3c also exhibited similar correlations, indicating the con-
served stereo-preference at the newly created centers. Strong
NOE correlations between H8a/H2 and the 4-CH3 group further
confirmed the selectivity as the S-configuration for the major com-
pound, chromanol 3a. Compound (À)-3c may either result from
the dehydration of 3a,b or be derived from competitive proton
elimination of the resulting tertiary carbocation formed after initial
cyclization (Fig. 2).
The formation of 4 from (À)-3a via metal ammonia mediated
chemo- and regio-selective hydrogenolysis17,18 (Scheme 2) further
corroborated the observed stereo-preferences in the Prins reaction
of benzaldehyde and (+)-isopulegol as (1S,3S,6S,7S,9S)-octahydro
chromanol.19
The isopulegols are intramolecular products of the ene reaction
of citronellal. In order to assess the feasibility of a one-pot ene,
Prins reactions, (À)-citronellal was subjected to the above reaction
conditions in the presence of 1. Three major isolable compounds
were formed and their structures were confirmed as (À)-3a, (À)-
3b and (+)-5a (Table 1, entry 3). Again, syn-selectivity at C8a and
C2 was observed for all three compounds, with (À)-3a formed as
the major component (Fig. 2). The distribution of these compounds
are in agreement with reported literature regarding the cyclization
of (À)-citronellal to (+)-isopulegol and (À)-neoisopulegol (3:1
ratio).20 For compound (+)-5a, the stereochemistry was deter-
mined on the basis of NOESY correlations, wherein H8a and H2
are in the syn-configuration and the S-configuration at C4 was
established on the basis of the lack of NOE correlations between
H8a/H2 and the 4-CH3 group (Fig. 2). The reaction of (À)-2 with
1, resulted in the formation of (+)-3a–c (Table 1, entry 2) while
the treatment of (+)-isopulegol with 2,3-, 2,4-dimethyl benzalde-
hydes, and 2,3,6-trimethyl benzaldehyde with 0.2 equivalents of
the Lewis acid for an extended time gave the dehydrated products,
octahydrochromanes (À)-7c, (À)-9c and (À)-11c, respectively, as
the major compounds (Table 1, entries 4–6). Trimethyl benzalde-
hyde was prepared from 3,6-dimethyl salicylaldehyde, which
was subjected to triflation using N-phenyl-bis(trifluoromethane-
sulfonimide) followed by a Pd(0) catalyzed Suzuki coupling reac-
tion with methyl boronic acid.21
All ten compounds were tested for cannabinoid activity with
CB1 and/or CB2 receptors.22 As shown in Table 2, the initial testing
of (À)-3a–c against CB1 and CB2 receptors showed that octahy-
drochromane (À)-3c, containing an olefin at the C-4 position,
was marginally active whereas both chromanols (À)-3b and (À)-
3a, were inactive. Similarly, compound (+)-5a, the product of the
one-pot ene, Prins reaction of citronellal, was also inactive. Upon
switching to the antipode (À)-pulegol (À)-2, compound (+)-3c
was found to possess higher percent displacement of the radio
ligand compared to the corresponding C-4 hydroxy analogs (+)-
3b and (+)-3a. The marginally greater activity of these chromenes
over chromanols stimulated the synthesis of additional chromene
analogs from 2,3-dimethyl (6), 2,4-dimethyl (8), and 2,3,6-tri-
methyl benzaldehydes (10). No significant difference in CB1 selec-
tivity for 2,3- and 2.6-disubstituted chromenes were observed;
however, compound (À)-9c with para-substitution showed
increased % displacement for the CB2 isoform.
Interestingly, compound (À)-11c, which is the only compound
with 3 methyl groups on the aromatic ring, has high% displacement
for CB2 receptors (74.9%) but little affinity towards the CB1 iso-
Scheme 2. Confirmation of chirality at the newly created centers. Single crystal X-
ray structure of 4 with hydrogens omitted for clarity. Reagents and conditions: a).
Na/NH3 (excess), À78 °C, 2 h, 86%.
Table 1
Substrate scope.
Entry
Reactants (ArCHO, monoterpene)
BF3ÁOEt2
Product yield (%)
Time
Equiv.
Temp.
1
2
3
4
5
6
R1,R4 = Me; R2,R3 = H; 1
R1,R4 = Me; R2,R3 = H; 1
R1,R4 = Me; R2,R3 = H; 1
R1,R2 = Me; R3,R4 = H; 6
R1,R3 = Me; R2,R4 = H; 8
R1,R2,R4 = Me; R3 = H; 10
(+)-2
0.05
0.05
0.2
0.2
0.2
À40 °C to rt
À40 °C to rt
À40 °C to rt
0 °C
0 °C
0 °C
6 h
6 h
4.5 h
12 h
12 h
12 h
(À)-3a (36%)
(+)-3a (34%)
(À)-3a (28%)
(À)-3b (12%)
(+)-3b (11%)
(À)-3b (9%)
(À)-3c (24%)
(+)-3c (20%)
(+)-5a (11%)
(À)-7c (58%)
(À)-9c (55%)
(À)-11c (62%)
(À)-2
(À)-citronellal
(+)-2
(+)-2
(+)-2
0.2
Please cite this article in press as: Slater S., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.01.040

4
S. Slater et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Table 2
with CB1 and/or CB2 selective agonist and antagonist activities
which can be explored by varying the homoallylic alcohols and
aldehydes used.
CB1 and CB2 percent displacement data for octahydrochromanes and chromenes.
Compound CB1 Receptor CB2 Receptor
Dp*
Ki (
l
M) SEM IC50
Dp*
Ki
IC50
M)
Acknowledgements
(lM)
(l
M) SEM
(
l
(À)-3c
(À)-3b
(À)-3a
(+)-3c
(+)-3b
(+)-3a
n.a.
n.a.
n.a.
n.a.
28.5
n.a.
n.a.
18.6
59.2
16.6
49.4
8.1
n.a.
68.5
13.8
8.1
We would like to thank Prof. Parcher for the editing, proof-read-
ing and valuable suggestions for improving the quality of the
manuscript. We are also thankful to Dr. Mei Wang for mass spec-
troscopy and Ms. Janet A. Lambert for biological screening against
cannabinoid receptors. This study was supported in part by United
States Department of Agriculture, Agricultural Research Service,
Specific Cooperative Agreement 58-6060-6-015. The cannabinoid
receptors activity was made possible by Grant Number
P20GM104932 from the National Institute of General Medical
Sciences (NIGMS) – United States, a component of the National
Institutes of Health (NIH) – United States.
(+)-5a
n.a.
71.9
(À)-7c
(À)-9c
(À)-11c
CP-55,940
77.6 >1.905 0.38 3.81
74.9 >0.257 0.07 0.514
0.001
0.002
0.0018
0.0036
Dp* percent displacement; n.a. not active. Compounds with ꢀ75% of Dp were
assessed for Ki and IC50
.
A. Supplementary data
form. Several of these compounds were found to be incompatible
with the assay conditions due to their hydrophobicity, in such
cases, additional DMSO (0.1–0.2%) was added to the media to over-
come solubility and without deleterious effects on the assay proto-
col and outcome.
Since the tetrahydrocannabinoid cannabidiol and the hexahy-
drocannabinoid machaeriols are reported to possess anti-cancer
activity, selected octahydrochromanes and chromenes were sub-
mitted to the NCI’s 60-cell line screening program. Unfortunately,
none of the compounds inhibited the growth of the examined can-
cer cells by a reasonable amount in spite of their marginal cannabi-
noid activities.
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.01.040.
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Please cite this article in press as: Slater S., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.01.040