Towards a library of chromene cannabinoids: A combinatorial approach on solid supports

Article abstract of DOI:10.1055/s-0030-1259300

A novel solid-phase synthesis towards classical cannabinoids is presented. Starting from immobilized salicylaldehydes the desired THC-analogous tricycles are obtained in four atom-economic steps including cleavage. The reagents of the employed reactions (domino oxa-Michael-aldol, Wittig, and Diels-Alder) can be varied easily, providing the basis for a combinatorial approach. Overall yields range from 20-60%. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259300

LETTER
161
Towards a Library of Chromene Cannabinoids: A Combinatorial Approach
on Solid Supports
Towards
C
hrome
n
a
e
Cannabin
g
oids via Soli
m
d
S
upports ar C. Kapeller,a Stefan Bräse*a,b
a
Karlsruhe Institute of Technology, Campus North, ComPlat, Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen,
Germany
b
Karlsruhe Institute of Technology, Campus South, Institute of Organic Chemistry, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6088581; E-mail: stefan.braese@kit.edu
Received 4 October 2010
In this work, a novel solid-phase approach to generate a li-
brary of chromene cannabinoids is presented. Contrary to
existing solution-phase syntheses,4 it is compatible with
various substitution patterns (Scheme 1) and avoids ex-
Abstract: A novel solid-phase synthesis towards classical cannab-
inoids is presented. Starting from immobilized salicylaldehydes the
desired THC-analogous tricycles are obtained in four atom-
economic steps including cleavage. The reagents of the employed
reactions (domino oxa-Michael-aldol, Wittig, and Diels–Alder) can tensive purification. Furthermore, by employing automa-
be varied easily, providing the basis for a combinatorial approach.
tion combinatorial chemistry is possible later on.
Overall yields range from 20–60%.
Our approach starts by attaching derivatized salicylalde-
Key words: cannabinoids, combinatorial chemistry, domino reac-
hydes (SA) to a polystyrene resin, followed by a domino
tions, heterocycles, solid phase synthesis
oxa-Michael-aldol (DOMA) condensation with various
Michael acceptors (Scheme 1).5
Cannabinoids are a group of almost 70 terpenophenolic
O
secondary metabolites produced by Indian hemp (Can-
O
nabis sativa). The most prominent of these compounds is
(–)-D9-tetrahydrocannabinol (D9-THC, 1, Figure 1), iso-
O
lated by Gaoni and Mechoulam in 1964.1
OH
O
2
3
OH
Ph3P
O
4
H11C5
O
1
Figure 1 (–)-D9-Tetrahydrocannabinol (1)
cleavage
X
O
O
Cannabinoids are used in medicine as antiemetics and an-
5
6
algesics for neuropathic pain (CesametTM, SativexTM
,
Scheme 1 Synthetic route; coloured dots mark possible substitution
MarinolTM). They also show promising results against
Alzheimer, Parkinson, or osteoporosis, but severe side ef-
fects (e.g. addiction) limit their use to terminal illnesses,
such as cancer, multiple sclerosis, or AIDS.2 Their mode
of action is based on two membrane-bound G-protein-
coupled receptors: CB1 located in the central nervous sys-
tem and responsible for the psychotropic and anticonvul-
sive properties and CB2, mainly found in the cells of the
immune system (analgesic, anti-inflammatory proper-
ties).3
locations
The formed 2H-chromene-3-carbaldehydes 3 are treated
with Wittig salts to give dienes 4. These are subjected to
Diels–Alder reactions, concluding the route to the tricy-
clic structures (5 and 6 after cleavage) typical for THC de-
rivatives.
For immobilization of the SA, the resin had to be modified
with a linker. The latter was required to be stable under the
reaction conditions used and allow quantitative cleavage
of the product afterwards. The best results were obtained
with Ellman’s DHP linker 9.6 It did not require further
protective groups for the starting material and could be
easily prepared by etherification of Merrifield resin7 (8,
0.99 mmol/g) with alcohol 7 (Scheme 2). Initially, 9 was
treated with 4-hydroxysalicylaldehyde (4-HSA)/PPTS8 to
give resin 10 in a yield of up to 48% (0.43 mmol/g) under
optimized conditions, as determined via cleavage.9 Later
To minimize adverse effects by increasing receptor selec-
tivity and to explore the full therapeutic potential of can-
nabinoids, it is important to generate and test a multitude
of new THC-analogous structures.
SYNLETT 2011, No. 2, pp 0161–0164
x
x.
x
x.
2
0
1
0
Advanced online publication: 05.01.2011
DOI: 10.1055/s-0030-1259300; Art ID: G25810ST
© Georg Thieme Verlag Stuttgart · New York

162
D. C. Kapeller, S. Bräse
LETTER
on, also 6-HSA, prepared in two steps from 2,6-dihydro-
xybenzoic acid,10 was immobilized in 52% yield (0.46
mmol/g, 11, Scheme 2).
O
O
i
+
10
11
R1
R2
R1
R2
O
O
O
O
O
12a–c
i
HO
O
PS
Cl
+
PS
O
O
7
8
9
i
+
ii
R1
R2
O
9
R1
R2
O
PS
PS
O
O
O
OH
13a,b
10
side reaction for R1 = R2 = Me
OH
O
O
EtO
OEt
O
OH
O
O
OH
iii
O
O
PPTS
9
DCE–EtOH
O
O
70 °C
11
14a from 10
14b from 11
15b
PS
O
=
Scheme 3 DOMA condensation and its side reaction. Reagents and
conditions: (i) K2CO3, 1,4-dioxane, 80 °C, 4 d.
Scheme 2 Immobilization of SA on solid supports. Reagents and
conditions: (i) NaH, 7, THF, r.t.; then 8, DMF; (ii) 4-HSA, PPTS,
DCE–toluene, 55 °C; (iii) 6-HSA, PPTS, DCE–toluene, 55 °C.
Table 1 DOMA Condensation
Entry
Substrate Product
R1
H
R2
H
Yield (%)a
Now, we could proceed with formation of the chromene
core structure. There are only a few examples in literature
describing the synthesis of chromenes on solid supports11
and none of them involve tandem reactions with SA.12 Ac-
cording to previous work in our group,5 mixtures of 1,4-
dioxane or THF with water for better solubility of the base
(DABCO, Na2CO3, or K2CO3) were explored with ac-
rolein as Michael acceptor. But only traces of the product
were formed under conventional heating or ultrasound.
The same was observed when using N-methylimidazole,
tetramethylguanidine,13a or pyrrolidine/benzoic acid13b
without addition of water. Finally, by employing K2CO3
in 1,4-dioxane with agitation at 80 °C for four days 12a
was obtained in 65% yield14,15 (Scheme 3; Table 1, entry
1). Some premature cleavage of the HSA occurs, as the
amount of cleaved product after performing the DOMA
condensation is less than the initial loading.
1
2
3
4
5
10
10
10
11
11
12a
12b
12c
13a
13b
65
80b
90
32
27
Me
Me
H
Me
H
H
Me
H
a Average isolated yield after cleavage.
b Formation of 5–10% of 14a; side product not isolated.
When performing the DOMA condensation with resin 11
and acrolein as Michael acceptor, the reaction was slower
compared to its regioisomer. After repeating the proce-
dure twice the ratio of product to starting material was still
only 4:1, explaining the lower yield of 32% (Table 1, en-
try 4). A similar result was found for crotonaldehyde (en-
try 5). When switching to senecialdehyde, no product
could be found after cleavage, only 30% of side product
15b formed by a vinylogous aldol condensation were iso-
lated. The same trend could be observed in analogous so-
lution-phase reactions (43% yield for acrolein and 69% of
the side product in case of senecialdehyde). Apparently,
the DOMA condensation is dependent on the substitution
pattern of the aromatic ring and does not tolerate immobi-
lization on position 6 well.
With senecialdehyde as Michael acceptor, the yield in
case of resin 10 was better (entry 2), despite the formation
of a side product 14a in amounts varying from batch to
batch (5–10%).5b The yield was best with crotonaldehyde
(90%, entry 3).
The above results were also compared to analogous solu-
tion-phase syntheses with THP-protected 4-HSA. They
gave 89%, 44%, and 75% yield, respectively, for acrolein,
sencialdehyde, and crotonaldehyde. This proves the solid-
phase approach to be more efficient in case of sterically
demanding Michael acceptors. Furthermore, without the
help of solid supports, purification of the THP-protected
2H-chromene-3-carbaldehydes (identical to 12a–c with-
out the polystyrene backbone) was difficult, as they were
contaminated with many side products. Otherwise, only
14a and residual starting material were found besides the
product.
Subjecting compounds 12a,b to standard Wittig condi-
tions, gave 16a,b, respectively (Scheme 4).16 No attempt
at cleavage was made at this step, due to the products be-
ing liable to dimerization. But disappearance of the carbo-
nyl peak in the Raman spectra indicated quantitative
conversion.
When subjecting 13a to the same conditions, no apparent
change in the Raman spectra could be observed, even after
Synlett 2011, No. 2, 161–164 © Thieme Stuttgart · New York

LETTER
Towards Chromene Cannabinoids via Solid Supports
163
and 18ab were observed. With 16b and ethyl vinyl ketone
70% of 18ba could still be isolated. In all these cases the
endo product was favored over the exo one. Equal ratios
and a yield of only 32% were found for 18bc with dime-
thyl fumarate as dienophile.
i
12a,b
quantitative
R1
R2
O
O
16a R1 = R2 = H
16b R1 = R2 = Me
Table 2 Diels–Alder Reaction and Cleavage
O
Substrate Product R3
R4
H
H
H
H
H
Yield (%)a endo/exob
i
16a
16a
16a
16b
16b
16b
16b
17a
17a
18aa
18ab
18ac
18ba
18bb
18bc
19ba
20aa
20ab
C(O)Me
CO2Me
CN
95
90
50
70
50
4:1
13a
traces
O
2:1
17a
0.8:1
1.7:1
0.1:1
1:1
Scheme 4 Wittig reaction on solid supports. Reagents and conditi-
ons: (i) MePPh3Br, n-BuLi, THF, –35 °C to r.t.
C(O)Et
CN
performing the reaction twice. Apparently, due to low
loading or the existence of impurities none or only little of
17a was formed, as conversion in solution phase proceed-
ed quantitatively.
CO2Me CO2Me 32
–
–
30
–
C(O)Et
CN
H
H
traces
traces
n.d.c
n.d.c
For the Diels–Alder reaction, thermal conditions were
chosen, as acid catalysis would lead to concomitant cleav-
age from the resin. The screening of different solvents
(toluene, DMF, DCE) gave comparable yields, but with
toluene the best endo/exo ratios were observed
(Scheme 5).17 The results for the latter conditions are
summarized in Table 2.
a Over three steps (Wittig, Diels–Alder reaction, cleavage), deter-
mined via cleavage.
b Determined by 1H NMR of the crude product. All diastereomers
apart from 18bc were separated by column chromatography.
c n.d. = not determined.
R4
Interestingly, using acrylonitrile led almost exclusively to
exo-18bb (50% yield), a trend, which could also be seen
in 18ac, although much less pronounced. Furthermore,
DIAD was used as dienophile, giving the heterocycle di-
hydrochromenopyridazine 19ba in 30% yield.18
R3
H
R4
i, ii
16a
+
R3
HO
HO
HO
O
18aa–ac
Resin 17a was also subjected to Diels–Alder conditions,
hoping that some of 13a had undergone Wittig reaction
and to see if residual 13a would react in a hetero-Diels–
Alder fashion. But after cleavage mainly the respective
2H-chromene-3-carbaldehyde was isolated (ca. 20%
yield) and only traces of 20aa and 20ab. This proves ini-
tial immobilization with 4-HSA to be superior compared
to 6-HSA.
R4
R3
H
R4
i, ii
16b
+
R3
O
18ba–bc
CO2i-Pr
N
i-PrO2C
N
In conclusion, we have developed a four-step solid-phase
synthesis of chromene cannabinoids, yielding THC ana-
logues in up to 60% yield. 4-HSA immobilized on Merri-
field resin via a THP linker has turned out to be the
starting material of choice. The route itself is open to var-
ious substitution patterns simply by variation of reagents,
which are cheap and commercially available (Michael ac-
ceptors, Wittig salts, dienophiles).
H
i-PrO2C
+
i, ii
N
N
16b
CO2i-Pr
O
19ba
R4
R3
H
HO
R4
i, ii
17a
+
In the future, the full potential of structural diversity will
be explored by introducing automation. The generated li-
brary of substrates will then be tested towards affinity for
the cannabinoid.
R3
O
20aa,ab
Scheme 5 Diels–Alder reaction and cleavage. Reagents and condi-
tions: (i) toluene, 80 °C, 2 d; (ii) PPTS, DCE–EtOH, 70 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. It contains
all experimental procedures, including those for the preparation of
When treating 16a with methyl vinyl ketone and methyl
acrylate, respectively, almost quantitative yields of 18aa
Synlett 2011, No. 2, 161–164 © Thieme Stuttgart · New York

164
D. C. Kapeller, S. Bräse
LETTER
purified by flash chromatography to separate endo- and exo-
diastereomers.
starting materials (7, 6-HSA), analogous solution-phase syntheses,
characterization of all compounds, and selected 13C NMR (9, 10, 11,
12a–c, 16a,b) and Raman (12a,b, 16a,b) spectra.
(10) For procedures see Supporting Information.
(11) (a) Oh, S.; Jang, H. J.; Ko, S. K.; Ko, Y.; Park, S. B. J. Comb.
Chem. 2010, 12, 548. (b) Review: Ziegert, R. E.; Toräng, J.;
Knepper, K.; Bräse, S. J. Comb. Chem. 2005, 7, 147.
(c) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew.
Chem. Int. Ed. 2000, 39, 734. (d) Nicolaou, K. C.; Cao, G.-
Q.; Pfefferkorn, J. A. Angew. Chem. Int. Ed. 2000, 39, 739.
(e) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao,
G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000,
122, 9939. (f) Hong, B.-C.; Chen, Z.-Y.; Chen, W.-H. Org.
Lett. 2000, 2, 2647.
(12) Shi, Y.-L.; Shi, M. Org. Biomol. Chem. 2007, 5, 1499.
(13) (a) Das, B. C.; Mohapatra, S.; Campbell, P. D.; Nayak, S.;
Mahalingam, S. M.; Evans, T. Tetrahedron Lett. 2010, 51,
2567. (b) Ibrahem, I.; Sundén, H.; Rios, R.; Zhao, G.-L.;
Córdova, A. Chimia 2009, 61, 219.
Acknowledgment
D. C. Kapeller is grateful to the Alexander-von-Humboldt founda-
tion for financial support. Many thanks to Dr. T. Zebaco for his help
with the NMR measurements.
References
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(15) General Procedure for DOMA Condensation
Resin (1.00 g) was suspended in 1,4-dioxane (10 mL) in a 20
mL vial. Nitrogen was bubbled through for a few minutes,
before addition of K2CO3 (552 mg, 4.0 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 (1.0 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.
(16) General Procedure for Wittig Reaction
Methyl triphenylphosphonium bromide (1.79 g, 5.0 mmol)
was suspended in anhydrous 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.). Afterwards, it was
cooled to –35 °C and added to the resin (1.65 g), which was
previously suspended in anhydrous THF (12 mL), also
cooled to –35 °C. The reaction was allowed to warm up to
r.t. and agitated overnight. It was quenched with H2O (2
mL), washed (as described above), and dried under vacuum.
(17) General Procedure for Diels–Alder Reaction
The resin (500 mg) was dried overnight at 90 °C. It was
suspended in toluene (5 mL) in a vial and nitrogen was
bubbled through for 10 min. The dienophile (5.0 mmol) was
added, the vial closed, and the reaction agitated at 80 °C for
2 d. The resin was filtered, washed (as described above), and
dried under vacuum before being cleaved.
(5) (a) Lesch, B.; Toräng, J.; Nieger, M.; Bräse, S. Synthesis
2005, 1888. (b) Lesch, B.; Toräng, J.; Vanderheiden, S.;
Bräse, S. Adv. Synth. Catal. 2005, 347, 555.
(6) Thompson, L. A.; Ellman, J. A. Tetrahedron Lett. 1994, 35,
9333.
(7) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
(8) General Procedure for Immobilization
DHP-resin 9 (6 g, 0.99 mmol/g) was dried overnight at
100 °C, then suspended in a mixture of DCE–toluene (42/18
mL) under nitrogen. Then, 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. Afterwards, 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.
Analytical Data for Compound 18bb
IR (ATR, platinum): 3329, 2978, 2937, 2248, 1622, 1589,
1506, 1456, 1310, 1296, 1160, 1139, 1121 cm–1. 1H NMR
(250 MHz, acetone-d6): d = 1.39 (s, 3 H, CH3), 1.43 (s, 3 H,
CH3), 1.84–2.01 (m, 1 H, CH2), 2.08–2.27 (m, 3 H, CH2),
3.00 (ddd, J = 11.5, 9.1, 3.1 Hz, 1 H, NCCH), 3.73 (br dd,
J = 9.1, 2.2 Hz, 1 H, CH), 5.80–5.88 (m, 1 H, =CH), 6.28 (d,
J = 2.5 Hz, 1 H, ArmH), 6.47 (dd, J = 8.5, 2.5 Hz, 1 H,
ArmH), 7.51 (d, J = 8.5 Hz, 1 H, ArmH), 8.32 (s, 1 H, OH)
ppm. 13C NMR (125 MHz, acetone-d6): d = 25.0, 27.6,
28.28, 28.34, 32.4, 37.3, 79.2, 106.2, 110.3, 117.7, 121.7,
125.1, 128.2, 139.6, 156.6, 159.4 ppm. MS (EI, 70 eV): m/z
(%) = 255 (43) [M+], 187 (100), 174 (27), 173 (29). HRMS
(EI): [M+] calcd for C16H17NO2: 255.1259; found: 255.1258.
Structure verified by 2D NMR.
(9) General Procedure for Cleavage
Resin (200 mg) were suspended in a 1:1 mixture of EtOH–
DCE (4 mL). Then PPTS (100 mg, 0.40 mmol) was added,
and the mixture was agitated at 70 °C overnight. The resin
was separated by filtration, washed with EtOAc (25 mL),
and the filtrate concentrated. The crude product was diluted
with EtOAc (15 mL) and H2O (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
Diels–Alder reactions the crude product was additionally
(18) Minami, T.; Matsumoto, Y.; Nakamura, S.; Koyanagi, S.;
Yamaguchi, M. J. Org. Chem. 1992, 57, 167.
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