Versatile solid-phase synthesis of chromenes resembling classical cannabinoids

Article abstract of DOI:10.1021/co200107s

A novel solid-phase approach toward classical cannabinoids is described. The desired tricyclic natural product analogues are assembled in only four atom economic steps: domino oxa-Michael-aldol condensation, Wittig reaction/enol-ether formation, Diels-Ald

Full text of DOI:10.1021/co200107s

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Versatile Solid-Phase Synthesis of Chromenes Resembling Classical
Cannabinoids
Dagmar C. Kapeller† and Stefan Br€ase*,†,‡
†Karlsruhe Institute of Technology, Campus North, ComPlat, Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen,
Germany
‡Karlsruhe Institute of Technology, Campus South, Institute of Organic Chemistry, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
S Supporting Information
b
ABSTRACT: A novel solid-phase approach toward classical canna-
binoids is described. The desired tricyclic natural product analogues
are assembled in only four atom economic steps: domino oxa-
Michael-aldol condensation, Wittig reaction/enol-ether formation,
DielsꢀAlder cycloaddition and cleavage. The synthesis is designed to
allow combinatorial chemistry at several stages of the sequence. The
variation of commercially available reagents at three of the reactions
(enals/enones, Wittig salts, and dienophiles) allows the introduction of
various diversity points. As proof of concept, a small library of 20 members
has been synthesized with overall yields ranging from 10% to 60%.
KEYWORDS: cannabinoids, combinatorial chemistry, domino reactions, heterocycles, natural products, solid phase synthesis
’ INTRODUCTION
addictive or psychotropic properties. Furthermore, the synthesis
of diversely modified THC-like molecules will allow to explore
the full therapeutic potential of cannabinoids, which ranges from
Parkinson’s disease and Huntington disease up to obesity and
drug dependence treatment.2e,4
THC and several analogous cannabinoid compounds have
already been prepared synthetically.5 But the methods employed
are usually quite rigid concerning modifications of the side
chains, limiting the availability of a broad range of derivatives.
To circumvent this problem, a new strategy toward the genera-
tion of cannabinoids is proposed here: combinatorial chemistry
on solid supports. It is not only compatible with various substi-
tution patterns, but also avoids extensive purification and will
allow automation later on.
Classical cannabinoids are a group of approximately 70
terpenophenolic secondary metabolites produced by Indian
hemp (Cannabis sativa var. indica). The most prominent of
these psychotropic compounds is (ꢀ)-Δ9-tetrahydrocannabinol
(Δ9-THC, Dronabinol, 1, Figure 1), which was isolated by Gaoni
and Mechoulam in 19641 and bears a tricyclic 6a,7,8,10a-tetra-
hydro-6H-benzo[c]chromene core structure.
Δ9-THC and other cannabinoids have been used in medicine
since the 1980s to treat symptoms of cancer, pain relief, and
spasticity in multiple sclerosis, or as appetite stimulants for AIDS
patients.2 Furthermore, they alleviate nausea and vomiting dur-
ing chemotherapy and are commercially available under the
trademark names of Sativex, Marinol, or Cesamet.
The physiological activities of THC and other cannabinoids
are based on their interaction with certain membrane bound
G-protein coupled cannabinoid receptors. So far two of these,
CB1 and CB2, have been confirmed.3 CB1-receptors are primarily
found in the brain with the highest concentrations in the basal
ganglia, cerebellum, and the limbic system, including the hippo-
campus. Interaction of THC with the CB1 receptor causes the
euphoric and anticonvulsive effects of cannabis. CB2-receptors
are almost exclusively located in the immune system, with the
greatest density in the spleen. They are responsible for anti-
inflammatory and other therapeutic activities.
The aim of this work is to generate a library of novel THC-
analogous structures, which will subsequently be tested for their
biological activity (e.g., interaction with CB-receptors). The
identification of receptor-selective compounds will serve to
minimize the adverse effects of existing drugs, such as their
’ RESULTS AND DISCUSSION
Our approach is designed to yield diverse THC-analogues in a
straightforward, four-step reaction sequence. It starts by reacting
salicylaldehyde (SA) motif bearing molecules attached to a poly-
styrene backbone with various Michael acceptors in a domino
oxa-Michael-aldol (DOMA) condensation (Figure 2).6
The formed 2H-chromene-3-carbaldehydes are then treated
with Wittig salts or are converted into enol-ethers, yielding in
both cases dienes of a different reactivity pattern. The diene
moieties are later on subjected to a DielsꢀAlder cycloaddition
Received: June 25, 2011
Revised:
July 29, 2011
Published: August 04, 2011
r
2011 American Chemical Society
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RESEARCH ARTICLE
Scheme 1. Immobilization of SAs on Resin 4a
Figure 1. Cannabinoids in clinical use: Dronabinol (1), Cannabidiol
(2), Nabilone (3).
a Reaction conditions: (i) 4-HSA, PPTS, DCE/toluene, 55 °C, 16 h.
(ii) 6-HSA, PPTS, DCE/toluene, 55 °C, 16 h.
4 days, chromene 8{1} was obtained in 65% yield (Scheme 2;
Table 1, Entry 1; data from [ref 6a] are included).15
Degassing of the solvent turned out to be crucial for the
reproducibility of the experiments. According to these condi-
tions, resin 5 was reacted with four other Michael acceptors
(Figure 3), resulting in chromenes 8 in yields between 38ꢀ90%
(Table 1, Entries 2ꢀ5). In all cases, except for entry 4, the purity
of the products after cleavage was above 90%, as determined
by 1H NMR of the reactions after workup. The lower yields are
probably due to prior cleavage from the resin during the DOMA
condensation.
Figure 2. General approach to THC-like structures; introduction of
diversity points.
with dienophiles, concluding the route to the tricyclic structures
typical for classical cannabinoids.
When switching to resin 6 and acrolein as Michael acceptor,
the reaction would not proceed to completion. After repeating
the DOMA condensation twice with the same batch of resin, the
ratio of product to starting material remained at 4:1, explaining
the yield of only 32% (Table 1, Entry 6). A similar result was
found for crotonaldehyde (7{3}) (Entry 7). When switching to
senecialdehyde (7{2}), no product could be found after cleavage,
only 30% of side-product 15 formed by a vinylogous aldol con-
densation were isolated.6c,16 Apparently, the DOMA condensa-
tion is dependent on the substitution pattern of the aromatic ring
and does not tolerate immobilization on position 6 very well.
To compare the results above with an analogous solution
phase approach,17 THP-protected HSAs 10+12 and reagents
7{1ꢀ3+5} were also subjected to the DOMA condensation.18
With the exceptions of acrolein and methyl vinyl ketone 7{1+5},
lower yields were observed for compound 10 substituted in
position 4 (Table 1, Entries 9ꢀ12). Furthermore, the resulting
chromenes 11 were contaminated with many side-products that
were difficult to separate. In case of substrate 12, the same trend
as in solid phase could be observed: lower yields for substitution
in position 6 and formation of side-product 14b with senecial-
dehyde (Entries 13 + 14). In conclusion, the solid phase
approach was found to be more effective, especially for sterically
demanding Michael acceptors. This is probably due to the high
actual excess of reagents,17 a feature predestined for solid phase
chemistry because of their ease of separation by filtration.
Because of the suboptimal results for the DOMA condensa-
tion with resin 6 and the consecutive low loading of 9, the
sequence was only continued with resins 8 immobilized in
position 4. The next step was either Wittig reaction with
CH3PPh3Br19 to 16{1+2} or TBS-enol ether formation yielding
18{5} (Scheme 3, left).
Our first approach was to immobilize the commercially
available 4-hydroxysalicylaldehyde (4-HSA) directly on Merri-
field resin.7 Neither treatment in 10% nor 50% TFA in CH2Cl2
released any of the attached material. Harsher conditions were
not employed, as they would limit the number of possible
functionalities to be introduced later on. The same result was
found for Wang resin.8 Attachment and cleavage with Ellman’s
acid-labile DHP-linker (4) was finally successful (Scheme 1).9
Compared to other linkers, such as the triazene one for
coupling of aniline-precursors,10 it did not require protection
of the HSAs used as starting material and could be easily pre-
pared by etherification of Merrifield resin7 (0.99 mmol/g).11 At
first, polymer 4 was treated with 4-HSA/PPTS (pyridinium
p-toluenesulfonate) to give resin 5 in a yield of up to 48%
(0.43 mmol/g) under optimized conditions (determined via
cleavage from solid supports). In addition, 6-HSA11 was immo-
bilized in 52% yield (0.46 mmol/g, 6, Scheme 1).
To generate the chromene core structure the conditions for
the DOMA condensation6 were optimized for resin 5 and
acrolein as Michael acceptor. Although there is literature pre-
cedence for solid phase syntheses of chromenes,12 the method
reported herein is to the best of our knowledge the first domino
reaction with SAs on solid supports.6a,13 Mixtures of 1,4-dioxane
or tetrahydrofuran (THF) with water for better solubility of the
base (DABCO, Na2CO3 or K2CO3) were explored. Nevertheless
only traces of product were formed under conventional heating
or ultrasound. The same was found for other basic conditions
displaying good results in solution phase (N-methylimidazole,
tetramethylguanidine,14a or pyrrolidine/benzoic acid14b). Finally,
by employing K2CO3 in 1,4-dioxane with agitation at 80 °C for
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RESEARCH ARTICLE
Scheme 2. DOMA: Solid and Solution Phasea,b
a Reaction conditions: (i) K2CO3, 1,4-dioxane, 80 °C, 4 d. b For R1, R2, R3 see Table 1.
Table 1. Yields for the DOMA Condensation: Solid and
Solution Phase
entry
substrate
product
R1
R2
R3
yield (%)
16a
26a
36a
4
5
8{1}
8{2}
8{3}
8{4}
8{5}
9{1}
9{3}
15
H
H
H
H
65a
85a,b
90a
38a,c
50a
32a
27a
25a
89d
44d
75d
67d
43d
69d
5
Me
Me
Ph
H
Me
H
Figure 3. Diversity reagents for the DOMA condensation 7{1ꢀ5}.
5
H
5
H
H
temperature (r.t.)), a further reason for choosing the solid phase
approach over the solution one.
For the DielsꢀAlder reaction, thermal conditions (80 °C)
were chosen, as Lewis or Brønsted acid catalysis would lead to
concomitant cleavage from the resin (Scheme 4).
5
5
H
Me
H
66a
76a
86a
96a
106a
116a
12
6
H
H
6
Me
H
H
6
10
10
10
10
12
12
11{1}
11{2}
11{3}
11{5}
13{1}
14b
H
H
H
Initially, the reaction of 16{1} with methyl vinyl ketone
(20{1}) as dienophile was screened in different solvents
(toluene, DMF, DCE). This resulted in comparable, almost
quantitative yields, but the best endo/exo ratios were observed
with toluene, making it the solvent of choice (Table 2, Entry 1).
Resin 16{1} was reacted with two further dienophiles
(Entries 2 + 3). But more emphasis was paid to resin 16{2}
(R1 = R2 = Me) because of its higher loading and greater
similarity to THC. It was converted to 12 different products
21{2,1ꢀ12} with all diversity reagents 20 shown in Figure 4. For
both dienes no general trend concerning the selectivity of the
DielsꢀAlder reaction could be observed. It ranged from exclu-
sively endo (maleimides 20{7 + 8}, Entries 10 + 11, 19) to mainly
exo in case of acrylonitrile (20{3}, Entry 6). Usually, diastereo-
meric mixtures favoring the endo-product were formed, which
could be separated by column chromatography in almost all cases.
This was more of an advantage, as a higher number of compounds
for later testing could be generated. In case of methyl vinyl ketone
asdienophile (Entry 4), the lower yield and increasedexo-ratiowas
caused by the endo-diastereomer being labile (starting decomposi-
tion after a few hours in the NMR tube). Generally, the endo-
products were more prone to decomposition compared to the
thermodynamically more stable exo ones.
Me
Me
H
Me
H
H
H
H
Me
H
136a
146a
H
H
a Average isolated yield after cleavage (reproducible within a 10% yield
range). b Formation of 5ꢀ10% of the vinylogous aldol condensation
product, not isolated. c Additionally, 27% of starting material were
recovered. d Isolated yield.
Again, analogous solution phase syntheses were performed,17
giving 17{1+2} and 19{5} in 80, 87, and 73% yield, respectively.
In all three cases the resulting products were not stable in pure
form and dimerized within days in the refrigerator. Accordingly,
the yields of the solid phase approach were not determined by
cleavage reaction, but by Raman spectroscopy (Scheme 3, right-
hand side). Complete disappearance of the carbonyl bands from
the starting materials (blue) compared to the products (red)
allowed an assignment of quantitative conversion. Furthermore,
resins 16{1+2} were unable to dimerize because of being immo-
bilized, resulting in far greater stability (>1 month at room
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RESEARCH ARTICLE
Scheme 3. Wittig Reaction and Enol-Ether Formation, Including Raman Spectraa
a Reaction conditions: (i) CH3PPh3Br, n-BuLi, THF, ꢀ35 °C to r.t., 2 h. (ii) Et3N, TBSOTf, CH2Cl2, ꢀ30 °C to r.t., 16 h.
Worth mentioning are compounds 21{2,11 + 12} formed
from diazocarboxylates, as such heterocyclic dihydrochromeno-
pyridazines have not been investigated concerning the CB
receptors so far (entries 14 + 15).20
with 20 structurally different members. Almost twice this amount
is available for testing, when including diastereomers and tricyclic
side-products. The chromene cannabinoids are formed in up to
60% yield employing a four step solid phase synthesis. The best
suited starting material is 4-HSA immobilized on Merrifield resin
via a THP-linker. The route itself is open to various substitution
patterns, which can simply be introduced by variation of the
starting material or reagents. The latter are cheap and commer-
cially available (Michael acceptors, Wittig salts, dienophiles).
Our solid phase approach has several advantages compared to
one in solution: higher yields because of excess of reagents,
increased stability of the intermediates (no decomposition by
dimerization possible), plus the possibility for automation.
In the future, the latter will be exploited to explore the full
potential of structural diversity. The generated library of sub-
strates will then be tested toward affinity for the cannabinoid
receptors.
Next, enol ether 18{5} was subjected to the DielsꢀAlder
reaction (Scheme 5, Entries 16ꢀ20).
The resulting tricycles 22 were at first cleaved with PPTS in
DCE/EtOH giving ketones 24 directly under concomitant loss
of the TBS-group (Entries 16ꢀ17). Unfortunately, the yield was
reduced because of diethyl acetal 25 being formed as a side-
product. When switching the solvent to THF/water, the forma-
tion of 25 was avoided, but now the TBS group was only partially
cleaved-off, mainly giving enol-ethers 23. Further treatment with
TBAF in acetonitrile finally liberated tricycles 24 in all cases
except for 23{5,11}, where side-product 26{5,11} was formed
exclusively. The latter also occurred for other dienophiles (see
footnotes f, g, i in Table 2) in 7ꢀ15% yield independent of the
cleavage conditions. In all cases, the stereochemistry of the
hydrogen atoms on the carbons of the former double bond
was anti after isomerization from enol-ethers to the ketones.
In conclusion, a combinatorial approach toward THC-like
molecules has been developed, proven by the synthesis of a library
’ EXPERIMENTAL PROCEDURES
General Procedure for Immobilization. DHP-resin 4 (6 g,
0.99 mmol/g) was dried overnight at 100 °C, then suspended in a
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Scheme 4. DielsꢀAlder Cycloaddition and Cleavagea
mixture of DCE/toluene (42/18 mL) under nitrogen. 4- or
6-HSA (4.15 g, 30.0 mmol) and PPTS (2.26 g, 9.00 mmol) were
added, and the mixture agitated at 55 °C overnight. Afterward,
the resin was filtered, washed (CH2Cl2, 2 ꢁ H2O and DMF,
2 ꢁ H2O and THF, 3 ꢁ MeOH and CH2Cl2, 4 ꢁ CH2Cl2; with
20 mL/g resin each), and dried under vacuum.
General Procedure for Cleavage. A 200 mg portion of the
resin was suspended in a 1:1 mixture of EtOH/DCE (4 mL) or a
a Reaction conditions: (i) Toluene, 80 °C, 2 d. (ii) PPTS, DCE/EtOH,
65 °C, 16 h.
Figure 4. Diversity reagents for the DielsꢀAlder cycloaddition
20{1ꢀ12}.
Table 2. Yields for the DielsꢀAlder Cycloaddition
entry
substrate
dienophile
product
R1 = R2
R4
R5, R6
R7
endo/exoa
yieldb (%)
16a
26a
36a
4
16{1}
16{1}
16{1}
16{2}
16{2}
16{2}
16{2}
16{2}
16{2}
16{2}
16{2}
16{2}
16{2}
16{2}
16{2}
18{5}
18{5}
18{5}
20{1}
20{2}
20{3}
20{1}
20{2}
20{3}
20{4}
20{5}
20{6}
20{7}
20{8}
20{9}
20{10}
20{11}
20{12}
20{1}
20{2}
20{3}
21{1,1}
21{1,2}
21{1,3}
21{2,1}
21{2,2}
21{2,3}
21{2,4}
21{2,5}
21{2,6}
21{2,7}
21{2,8}
21{2,9}
21{2,10}
21{2,11}
21{2,12}
24{5,1}
24{5,2}
23{5,3}
24{5,3}
23{5,8}
24{5,8}
23{5,11}
24{5,11}
H
C(O)Me
CO2Me
CN
H, H
H, H
H, H
H, H
H, H
H, H
H, H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
4/1
2/1
4/5
7/10
1/1
1/10
8/5
1/1
5/4
1/0
1/0
95
H
90
H
50,
50
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
C(O)Me
CO2Me
CN
5
35
66a
76a
86a
9
50
C(O)Et
CO2Me
CHO
H
70
CO2Me, H
CO2Et, H
32
29c
10
11
12
13
146a
15
16
17
18
C(O)N(H)C(O)
C(O)N(Me)C(O)
C(O)CH2CH2CH2
C(O)(CCl)2C(O)
CO2i-Pr
23
H
27
H
Tracesd
11e
30
Cl
1/1
CO2i-Pr
CO2Bn
C(O)Me
CO2Me
CN
CO2Bn
48
H, H
H
H
H
1/2
2/1
35f
51g
15h
10h
20i
12i
20j
8j
H
H, H
H
H, H
0/1
1/0
4/5
19
20
18{5}
20{8}
H
H
H
C(O)NMeC(O)
H
18{5}
20{11}
CO2i-Pr
CO2i-Pr
a Determined by H NMR of the crude product. All diastereomers apart from 21{2,5}and 21{2,10} were separable by column chromatography.
b Average isolated yield of endo- and exo-diastereomers after cleavage if not otherwise mentioned. c Cleavage in DCE/ethanol resulted in acetal formation
of the aldehyde, which was removed by the addition of p-TsOH. The isolated yield was 16% of the endo-isomer, but according to NMR of the crude
product 13% of the exo-isomer were formed as well, which were lost upon chromatography. d Complex mixture after slow conversion, the main
component being the dimer of the Wittig product. e Formation of 10% of a side product with an aromatized C-ring. f Cleavage in DCE/ethanol gives
1
g
additionally 15% of 26{5,1} and 20% of starting material (DOMA-product). Cleavage in DCE/ethanol gives additionally 22% of 25{5,1}, 7% of
26{5,1} and 20% of the DOMA-product. h Cleavage in THF/water gives additionally 8% of the DOMA-product. Cleavage in THF/water gives
i
additionally 10% of 26{5,8}. j Cleavage in THF/water gives additionally 13% of the DOMA-product.
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Scheme 5. DielsꢀAlder Cycloaddition of TBS-Enol Ether 18{5}a
a Reaction conditions: (i) Toluene, 80 °C, 2 d.
6:1 mixture of THF/water (4 mL) in case of the enol-ether path
to avoid acetal formation of the resulting ketone. Then PPTS
(100 mg, 0.400 mmol) was added, and the mixture was agitated at
65 °C overnight. The resin was separated by filtration, washed with
25 mL of EtOAc, and the filtrate concentrated. The crude product
was diluted with EtOAc (15 mL) and water (10 mL). The organic
layer was separated, and the aqueous one extracted twice with
EtOAc (15 mL). The combined organic phases were dried
(MgSO4) and concentrated under reduced pressure. After
DielsꢀAlder reactions the crude products were additionally purified
by flash chromatography to separate endo- and exo-diastereomers.
General Procedure for DOMA Condensation. A 1.00 g
portion of the resin (5 or 6) was suspended in 1,4-dioxane
(10 mL) in a 20 mL vial. Nitrogen was bubbled through for a few
minutes, before adding K2CO3 (552 mg, 4.00 mmol) and the
Michael acceptor (6.0 mmol). The vial was closed and agitated
at 80 °C for 4 d. After the second day another portion of the
Michael acceptor (1.00 mmol) was added. At the end of the
reaction, the resin was filtered, washed (as described above) and
dried under vacuum. The procedure was repeated a second time
if remaining starting material was detected after cleavage.
ꢀ30 °C. Afterwards, the reaction was agitated for 16 h, in which
the temperature was allowed to rise to r.t. The resin was separated
by filtration, washed (as described above), anddried under vacuum.
General Procedure for Wittig Reaction. Methyl triphenyl-
phosphonium bromide (1.79 g, 5.00 mmol) was suspended in
dry THF (14 mL) under nitrogen and cooled to ꢀ25 °C. n-BuLi
(3.1 mL, 5.0 mmol, 1.6 M solution in hexanes) was added (yellow
color), and the mixture stirred for 2 h (ꢀ25 °C up to r.t.).
Afterward, it was cooled to ꢀ35 °C and added to resin 8 (1.65 g),
which was previously suspended in 12 mL of dry THF, also
cooled to ꢀ35 °C. The reaction was allowed to warm up to r.t.
over the next 2 h. It was then quenched with water (2 mL),
washed (as described above), and dried under vacuum.
General Procedure for DielsꢀAlder Reaction. Resins 16
and 18 (500 mg) were dried overnight at 90 °C. They were sus-
pended in toluene (5 mL) in separate vials and nitrogen was
bubbled through for 10 min. The dienophile (5.0 mmol) was
added in each vial, the vials closed, and the reaction agitated at
80 °C for 2 days. The resins were filtered, washed (as described
above), and dried under vacuum before being cleaved.
General Procedure for Enol-Ether Formation. A 2.50 g
portion of resin 8 was dissolved in CH2Cl2 (25 mL) and flushed
with nitrogen for 5 min. Et3N (2.08 mL, 1.52 g, 15.0 mmol) was
added, followed by TBSOTf (1.70 mL, 1.98 g, 7.50 mmol) at
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures are
b
given, including the preparation of starting materials (6-HSA,10, 12),
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RESEARCH ARTICLE
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1
and H/13C NMR spectra of representative library members
(21{1,3}, 21{2,2}, 21{2,3}, 21{2,7}, 21{2,10}, 21{5,3}).
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: stefan.braese@kit.edu. Phone: +49 721 608 42902.
Author Contributions
D.C.K. and S.B. conceived and designed the project, as well as co-
wrote the manuscript. D.C.K. performed the experimental work.
Funding Sources
This work was supported by a scholarship of the Alexander-von-
Humboldt foundation.
’ ACKNOWLEDGMENT
Many thanks to Dr. T. Zebaco for his help with the NMR
measurements.
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’ ABBREVIATIONS
DABCO, 1,4-diazabicyclo[2.2.2]octane; DCE, 1,2-dichloroethane;
DOMA, domino oxa-Michael-aldol; HSA, hydroxyl-salicylic
acid; PPTS, pyridinium p-toluenesulfonate; SA, salicylaldehyde;
TBAF, tetrabutylammonium fluoride; TBSOTf, t-butyldimethyl-
silyl trifluoromethanesulfonate; THC, tetrahydrocannabinol; p-
TsOH, p-toluenesulfonic acid
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ACS Combinatorial Science
RESEARCH ARTICLE
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