Highly enantioselective access to cannabinoid-type tricyles by organocatalytic Diels-Alder reactions

Article abstract of DOI:10.3762/bjoc.8.160

After prosperous domino reactions towards benzopyrans, the products were used as the starting material in Lewis acid catalyzed and organocatalytic Diels-Alder reactions to build up a tricyclic system. Herein, an asymmetric induction up to 96% enantiomeric excess was obtained by the use of imidazolidinone catalysts. This approach can be utilized to construct the tricyclic system in numerous natural products, in particular the scaffold of tetrahydrocannabinol (THC) being the most representative one. Compared with other published methods, condensation with a preexisting cyclohexane moiety in the precursor is needed to gain the heterogenic tricycle systems, whereas we present a novel strategy towards cannabinoid derivatives based on a flexible modular synthesis.

Full text of DOI:10.3762/bjoc.8.160

Highly enantioselective access to cannabinoid-type
tricyles by organocatalytic Diels–Alder reactions
Stefan Bräse*1,2, Nicole Volz1, Franziska Gläser1 and Martin Nieger3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1385–1392.
1Karlsruhe Institute of Technology (KIT), Institute of Organic
Chemistry, Fritz-Haber-Weg 6, D-76131 Karlsruhe; Tel: (+49) 721
608-48581, 2Institute of Toxicology and Genetics,
Hermann-von-Helmholtz-Platz 1, D-76344
doi:10.3762/bjoc.8.160
Received: 26 May 2012
Accepted: 17 July 2012
Published: 28 August 2012
Eggenstein-Leopoldshafen, Germany and 3Laboratory of Inorganic
Chemistry, Department of Chemistry, University of Helsinki, P.O. Box
55, FIN-00014 Helsinki, Finland
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
Email:
Stefan Bräse* - braese@kit.edu
© 2012 Bräse et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
cannabinoids; Diels–Alder reaction; natural product synthesis;
organocatalysis
Abstract
After prosperous domino reactions towards benzopyrans, the products were used as the starting material in Lewis acid catalyzed
and organocatalytic Diels–Alder reactions to build up a tricyclic system. Herein, an asymmetric induction up to 96% enantiomeric
excess was obtained by the use of imidazolidinone catalysts. This approach can be utilized to construct the tricyclic system in
numerous natural products, in particular the scaffold of tetrahydrocannabinol (THC) being the most representative one. Compared
with other published methods, condensation with a preexisting cyclohexane moiety in the precursor is needed to gain the hetero-
genic tricycle systems, whereas we present a novel strategy towards cannabinoid derivatives based on a flexible modular synthesis.
Introduction
The Diels–Alder reaction is one of the most important processes addition reactions were applied to set up each of the two six-
for carbon–carbon-bond formation in organic chemistry [1,2]. membered rings of the target molecule [9,10]. As a final
Especially in the synthesis of natural products it is a widely example, Dynemicin A (3) should be mentioned, which is an
used method [3-7]. Some examples are shown in Figure 1. The enediyne consisting of a complex heterocyclic skeleton and a
first application was the total synthesis of the steroid Cortisone network of sensitive functional groups, exhibiting antitumor and
(1) in 1952 by Woodward et al. [8]. Another example, indi- antibiotic activity [11]. Three independent research groups
cating the importance of the well-known [4 + 2] cycloaddition (Schreiber, Myers and Danishefsky) successfully applied
in natural-product synthesis, is the first published total syn- [4 + 2]-cycloaddition reactions in elegant and divergent strate-
thesis of Taxol (2) by Nicolaou. Two different [4 + 2]-cyclo- gies to reach the target molecule [12-14].
1385

Beilstein J. Org. Chem. 2012, 8, 1385–1392.
MacMillan’s imidazolidinone-based organocatalysts are general
catalysts for a variety of asymmetric transformations. The first
highly enantioselective organocatalytic Diels–Alder reaction
was reported by MacMillan in his pioneering work in 2000
[17]. The activated iminium ion, formed through condensation
of imidazolidinone and an α,β-unsaturated aldehyde, underwent
reactions with various dienes to yield [4 + 2]-cycloadducts in
excellent yields and enantioselectivities.
Results and Discussion
On our way towards a metal-free total synthesis of (−)-Δ9-
tetrahydrocannabinol (4, Figure 2) we developed a convenient
organocatalytic Diels–Alder route to generate the desired
tricycle 5 of a model-system that also represents an alternative
approach to key-intermediate 6 in Danishefsky’s total synthesis
of Dynemicin A (3) [14].
Our strategy, using the [4 + 2]-cycloaddition to obtain the
cannabinoid tricycle system, is able to employ a variety of
dienophiles and, hence, provides a versatile entry to this signifi-
cant group of naturally occurring compounds [18], whereas the
achieved Diels–Alder products can be further modified to gain a
variety of heterocycles. Most published strategies are based on
the use of a preexisting cyclohexane moiety in the starting
material to form the heterogenic tricycle [19-28].
Figure 1: An assortment of natural products synthesized by
Diels–Alder reactions.
Given the importance of the Diels–Alder reaction, considerable
efforts have been directed towards increasing the reaction rate
and enantioselectivity. In the past century, catalysts that were
employed for the enantioselective synthesis of organic com-
pounds, such as pharmaceuticals, agrochemicals, or fine chemi-
cals, were either transition-metal complexes or enzymes. In the
past few years, however, organocatalysis has emerged as an
alternative approach for the catalytic production of enantiomeri-
cally pure organic compounds [15,16]. These organocatalysts
have several important advantages. They are metal-free, usually
nontoxic, stable, moisture-insensitive, and often easy to obtain.
Because of their inertness towards oxygen and moisture, the use
of absolute solvents, inert atmosphere, low temperature, etc., is,
in many instances, not required. Furthermore, due to the
absence of transition metals, organocatalytic methods are
especially attractive for the preparation of compounds that do
not tolerate metal contamination, e.g., active pharmaceutical
ingredients.
In former experiments of our group [29-31] it became apparent
that without a catalyst no conversion towards the desired prod-
uct occurred. Only the homodimer of the diene 10 could be
isolated. Metal-based Lewis acids (e.g., catechol boronates)
proved to be inefficient or too reactive. Due to the fact that
other groups have used thiourea-derivatives as successful cata-
lysts [32], we decided to test, on a model system, whether these
catalysts could increase the reaction rate based on specific
hydrogen bonds. In our initial screening we used the proven
Schreiner catalyst 1,3-bis(3,5-bis(trifluoromethyl)phenyl)thio-
urea, which gave a satisfying 60% yield. In order to optimize
the yield and to introduce chiral elements, we screened a
number of analogues. These thiourea catalysts 9a–l were easy to
obtain from the corresponding isothiocyanates 7a,b and chiral
Figure 2: Intermediates towards the total synthesis of (−)-Δ9-tetrahydrocannabinol (4).
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Beilstein J. Org. Chem. 2012, 8, 1385–1392.
amines 8a–f in a one-step synthesis (Scheme 1) [33]. The yields yields from 68% to 99% depending on the substitution of the
were good to excellent in all procedures (Table 1).
thiourea-catalyst 9a–l (Table 2).
These thioureas were used in an intermolecular Diels–Alder When the substitution of the various thioureas 9a–l is further
reaction of diene 10 [36] with acrolein (11) to obtain cannabi- compared with the obtained yields in the Diels–Alder reaction
noid tricycle 5 shown in Scheme 2.
(Table 2), the following tendencies are also observed. A notice-
able fact is that, in contrast to the thioureas with a cyclopropyl-
In all cases we only achieved one cis-diastereomer and the car- and m-halophenyl-moiety (Table 2, entries 7–9), the corres-
bonyl function was always in the 10-position. The reaction was ponding bis(trifluoromethyl)thioureas (Table 2, entries 16–18)
carried out at low temperature and high dilution to avoid the provide a higher conversion.
dimer formation of diene 10. An increase of the temperature to
40 °C resulted in a higher conversion but unfortunately no Next to the previously described thiourea catalysts, we also
enantioselectivity was observed. We obtained good to excellent analyzed iminium-ion catalysts according to MacMillan on
Scheme 1: Synthesis of thiourea catalysts 9a–l.
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Beilstein J. Org. Chem. 2012, 8, 1385–1392.
Table 1: Yields of thiourea syntheses.
Table 2: Summarized results of the Diels–Alder reaction.
Entry R1
R2
Product
Yield [%]
Entry
Catalyst
Yield [%]a
1
H
Cy
(R)-9a [34]
(S)-9a [34]
(R)-9b
99
95
99
99
99
99
99
99
99
69
62
89
99
99
99
91
99
76
1
(R)-9a
(S)-9a
(R)-9b
(S)-9b
(R)-9c
(S)-9c
(R)-9d
(S)-9e
(S)-9f
(R)-9g
(S)-9g
(R)-9h
(S)-9h
(R)-9i
(S)-9i
97
91
99
85
93
92
74
82
77
68
78
73
88
76
85
87
93
83
2
H
Cy
2
3
H
Ph
3
4
H
Ph
(S)-9b [34]
(R)-9c
4
5
H
p-BrC6H4
p-BrC6H4
cyclopropyl
m-ClC6H4
m-BrC6H4
Cy
5
6
H
(S)-9c
6
7
H
(R)-9d
7
8
H
(S)-9e
8
9
H
(S)-9f
9
10
11
12
13
14
15
16
17
18
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
(R)-9g
10
11
12
13
14
15
16
17
18
Cy
(S)-9g
Ph
(R)-9h
Ph
(S)-9h [35]
(R)-9i
p-BrC6H4
p-BrC6H4
cyclopropyl
m-ClC6H4
m-BrC6H4
(S)-9i
(R)-9j
(R)-9j
(S)-9k
(S)-9l
(S)-9k
(S)-9l
aThe conversion is quantitative with respect to 10, the byproduct is the
uncatalyzed dimer of compound 10.
Scheme 2: Organocatalytic Diels–Alder reaction with thiourea-catal-
ysis.
various model systems (Figure 3) [37]. The effect of these cata-
lysts is based on the formation of iminium ions by conden-
sation of the dienophile bearing a carbonyl group, with the steri-
cally hindered imidazole catalyst. In this way, one side is
shielded and only the other side can be attacked by the diene.
Hence, reaction rate and asymmetric induction are increased.
Figure 3: Formation of the iminium-ion.
The synthesis of imidazolidinone catalysts [38] is the premise
for the construction of the demanding amide 13, which was
afforded by the reaction of (S)-phenylalanine methyl ester
hydrochloride (12) with methylamine (Scheme 3). In the second
step of the synthesis, amide 13 was cyclized with different alde-
hydes 14 and addition of catalytic amounts of FeCl3 at high
temperatures into (2S,5S)- or (2R,5S)-imidazolidinone 15
[39,40].
To gain electron-poor catalysts for the degradation of the
dienophilic LUMO in the Diels–Alder reaction and to conse-
quently increase the reaction rate, we used aldehydes with elec-
Scheme 3: Synthesis of electron poor imidazolidinone catalysts.
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Beilstein J. Org. Chem. 2012, 8, 1385–1392.
tron-withdrawing groups in ortho-, meta- and para-positions The organocatalytic species 15 were synthesized in moderate
(Scheme 3, Table 3). Reaction with p-nitrobenzaldehyde gave yields. A conspicuous feature is that the yields of the (2S,5S)-
compound 16 in 66% yield (Figure 4).
derivatives, with the exception of the tert-butyl substituted cata-
lyst 15a (Table 3, entries 1–2), are always higher than those of
the corresponding (2R,5S)-components (Table 3, entries 3–12).
The configuration of the afforded imidazolidinone catalysts 15
could be confirmed by NOESY experiments and from their
X-ray structures (Figure 5).
Table 3: Results of the conversion of various aldehydes 14 with amide
13.
Entry (Aldehyde 14) R =
Catalyst 15
Yield [%]
1
(2R,5S)-15a
(2S,5S)-15a
35 [41]
25 [40]
t-Bu
2
3
4
(2R,5S)-15b
(2S,5S)-15b
42
52
o-NO2-C6H4
5
6
(2R,5S)-15c
(2S,5S)-15c
28
39
m-F-C6H4
7
8
(2R,5S)-15d
(2S,5S)-15d
32
43
p-F-C6H4
9
10
(2R,5S)-15e
(2S,5S)-15e
39
45
p-Br-C6H4
11
12
(2R,5S)-15f
(2S,5S)-15f
38
46
p-CN-C6H4
Figure 5: Confirmation of the relative configuration with NOESY exper-
iments and X-ray crystal structures of two imidazolidinones 15d and
15f.
Before testing the catalysts in the Diels–Alder reaction, we
analyzed a few co-catalysts with the commercially available
imidazolidinone catalyst 15h. A pentyl-substituted tricycle was
used as a model system (model system II) 19 (Scheme 4,
Table 4).
Hydrochloric acid has been proven to be the best co-catalyst
(Table 4, entry 1), providing cis-19 in good yield and with an
enantiomeric excess of 96%. Even perchloric acid and trifluoro-
acetic acid gave high enantiomeric excesses but in much poorer
yields (Table 4, entries 2 and 3). Using para-toluenesulfonic
acid also afforded cis-19 in good yield, but its enantiomeric
excess could not be determined (Table 4, entry 4). Trifluoro-
Figure 4: Crystal structure of the side product from the reaction of 13.
Scheme 4: Co-catalyst screening.
1389

Beilstein J. Org. Chem. 2012, 8, 1385–1392.
successful determination of their enantiomeric excess, Table 5
only contains results for cis-19. Except for in the case of 15a,
we observe tendencies such as the achievement of higher yields
through the use of (2S,5S)-configurated imidazolidinones 15
compared to the yields afforded by (2R,5S)-configurated cata-
lysts 15. There is an opposite trend for the enantiomeric excess,
which is also related to the steric hindrance of the phenyl
substituent, i.e., the smaller the substituent, the lower the enan-
tiomeric excess. Application of the known tert-butylimidazo-
lidinone catalyst 15a provides the highest yield (66%) and
enantiomeric excess (98% ee) with its (2S,5S)-derivate (Table 5,
Table 4: Summary of the screening of co-catalysts.
Entry Co-catalyst cis-19 trans-19
Yield [%] ee [%] Yield [%] ee [%]
1
2
3
4
5
HCl (1 M)
HClO4 (60%)
TFA
51
6
96
95
96
n.d.
—
12
10
9
91
n.d.
77
90
—
31
50
—
p-TSA·H2O
TfOH
15
—
n.d.: not determined.
methanesulfonic acid as co-catalyst only led to decomposition entry 3).
(Table 4, entry 5).
Conclusion
Under these optimized reaction conditions, we performed a In conclusion, we have demonstrated that the Diels–Alder reac-
catalyst screening with the previously synthesized imidazolidi- tion of 3-vinyl-2H-chromene with acrolein can be accelerated
none catalysts 15 to study their asymmetric induction with different thioureas, obtained in a one-step synthesis (in
(Scheme 5). As starting material we used compound 17 with the some cases with quantitative conversion). Application of imida-
THC-typical pentyl side chain. The results are summarized in zolidinone catalysts, inspired by the work of MacMillan,
Table 5.
achieved good yields up to 66% and enantiomeric excesses up
to 98%.
Table 5: Catalyst screening towards model system II 19.
Experimental
Crystal structure determinations
Entry Catalyst 15
cis-19
R =
Yield [%]
ee [%]
The single-crystal X-ray diffraction study was carried out on a
Nonius Kappa-CCD (9a, 16) or Bruker-Nonius APEXII diffrac-
tometer (9c, 9k, 9l, 15d, 15f) at 123(2) K, by using Mo Kα radi-
ation (λ = 0.71073 Å). Direct methods (SHELXS-97) [42] were
used for structure solution, and refinement was carried out with
SHELXL-97 [42] (full-matrix least-squares on F2). Hydrogen
atoms were localized by difference electron density determin-
ation and refined by using a riding model (H(N) free). The
absolute configurations of 9a, 9c, 9k, 9l were determined by
refinement of Flack’s x-parameter [43] and by using Bayesian
statistics on Bijvoet differences (Hooft’s y-parameter) [44].
1
t-Bu
(2R,5R)-15h
51
96
2
3
(2R,5S)-15a
(2S,5S)-15a
47
66
−24
−98
t-Bu
4
5
(2R,5S)-15b
(2S,5S)-15b
43
50
−89
−29
o-NO2-C6H4
m-F-C6H4
p-F-C6H4
6
7
(2R,5S)-15c
(2S,5S)-15c
47
55
−78
−38
8
9
(2R,5S)-15d
(2S,5S)-15d
48
54
−79
−37
10
11
(2R,5S)-15f
(2S,5S)-15f
52
54
−83
−43
p-CN-C6H4
The used organocatalysts, having a (S)-configured stereocenter The absolute configuration of 15d and 15f could not be deter-
in the 5-position, should prefer the formation of opposite enan- mined reliably by refinement of Flack’s x-parameter [43], nor
tiomers, compared to the commercially available (2R,5R)-15h. by using Bayesian statistics on Bijvoet differences (Hooft’s
This is indicated by negative enantiomeric excess (Table 5). y-parameter) [44]. The enantiomer was assigned by reference to
Due to low yields of diastereomer trans-19 and the less an unchanging chiral center in the synthetic procedure.
Scheme 5: Screening of imidazolidinone catalysts 15.
1390

Beilstein J. Org. Chem. 2012, 8, 1385–1392.
Semi-empirical absorption corrections were applied for 9c and 15f: colorless, C18H17N3O, M = 291.35, crystal size
9l. In 9l one CF3-group is disordered.
0.50 × 0.40 × 0.30 mm, monoclinic, space group P21 (no. 4):
a = 6.0140(1) Å, b =15.7002(4) Å, c = 8.5232(2) Å, β =
9a: colorless, C15H22N2S, M = 262.41, crystal size 95.211(2)°, V = 801.44(3) Å3, Z = 2, ρ(calc) = 1.207 Mg m−3,
0.30 × 0.10 × 0.05 mm, monoclinic, space group P21 (no. 4): F(000) = 308, μ = 0.077 mm−1, 13805 reflections (2θmax =
a = 8.5864(5) Å, b = 22.2641(17) Å, c = 8.6811(6) Å, β = 55°), 3628 unique [Rint = 0.027], 203 parameters, 2 restraints,
117.350(4)°, V = 1474.04(17) Å3, Z = 4, ρ(calc) = R1 (I > 2σ(I)) = 0.033, wR2 (all data) = 0.077, GOOF = 1.08,
1.182 Mg m−3, F(000) = 568, μ = 0.206 mm−1, 8575 reflec- largest diff. peak and hole 0.181/−0.152 e Å−3, x = −0.2(11),
tions (2θmax = 50°), 4687 unique [Rint = 0.057], 337 parameters, y = 0.8(5).
5 restraints, R1 (I > 2σ(I)) = 0.048, wR2 (all data) = 0.119,
GOOF = 1.09, largest diff. peak and hole 0.235/−0.290 e Å−3, 16: colorless, C17H17N3O3, M = 311.34, crystal size 0.30 × 0.05
x = −0.01(8), y = −0.05(5).
× 0.05 mm, monoclinic, space group P21/c (no. 14): a =
18.265(5) Å, b =10.935(2) Å, c = 7.857(2) Å, β = 101.60(1)°,
9c: colorless, C15H15BrN2S, M = 335.26, crystal size V = 1537.2(6) Å3, Z = 4, ρ(calc) = 1.345 Mg m−3, F(000) =
0.25 × 0.10 × 0.05 mm, monoclinic, space group P21 (no. 4): 656, μ = 0.094 mm−1, 4930 reflections (2θmax = 50°), 2685
a = 16.2276(4) Å, b = 5.5562(2) Å, c = 17.3953(6) Å, β = unique [Rint = 0.128], 212 parameters, 1 restraint, R1 (I > 2σ(I))
108.894(2)°, V = 1483.92(8) Å3, Z = 4, ρ(calc) = 1.501 Mg m−3, = 0.071, wR2 (all data) = 0.185, GOOF = 0.99, largest diff. peak
F(000) = 680, μ = 2.899 mm−1, 11045 reflections (2θmax = and hole 0.227/−0.247 e Å−3.
50°), 4958 unique [Rint = 0.037], 355 parameters, 5 restraints,
R1 (I > 2σ(I)) = 0.030, wR2 (all data) = 0.072, GOOF = 1.06, Crystallographic data (excluding structure factors) for the
largest diff. peak and hole 0.387/−0.504 e Å−3, x = −0.018(7), structures reported in this work have been deposited with the
y = −0.012(2).
Cambridge Crystallographic Data Centre as supplementary
publications no.’s CCDC-865479 (9a), CCDC-865480 (9c),
9k: colorless, C17H13ClF6N2S, M = 426.80, crystal size 0.20 × CCDC-865481 (9k), CCDC-865482 (9l), CCDC-965483 (15d),
0.10 × 0.05 mm, monoclinic, space group P21 (no. 4): a = CCDC-865484 (15f), and CCDC-865485 (16). Copies of
8.1359(6) Å, b =16.2464(13) Å, c = 13.9980(7) Å, β = the data can be obtained free of charge on application
92.246(4)°, V = 1848.8(2) Å3, Z = 4, ρ(calc) = 1.533 Mg m−3, to The Director, CCDC, 12 Union Road, Cambridge
F(000) = 864, μ = 0.381 mm−1, 9231 reflections (2θmax = 50°), DB2 1EZ, UK (Fax: int. code +(1223)336-033; email:
5469 unique [Rint = 0.039], 499 parameters, 5 restraints, R1 (I > deposit@ccdc.cam.ac.uk).
2σ(I)) = 0.055, wR2 (all data) = 0.116, GOOF = 1.16, largest
diff. peak and hole 0.388/−0.252 e Å−3, x = 0.07(9), y = 0.07(4).
Supporting Information
9l: colorless, C17H13BrF6N2S, M = 471.26, crystal size 0.35 ×
Supporting Information File:
0.20 × 0.10 mm, monoclinic, space group P21 (no. 4): a =
Supporting Information File 1
8.2910(7) Å, b = 16.1565(8) Å, c = 14.0204(10) Å, β =
92.073(3)°, V = 1876.9(2) Å3, Z = 4, ρ(calc) = 1.668 Mg m−3,
F(000) = 936, μ = 2.362 mm−1, 10315 reflections (2θmax =
50°), 5936 unique [Rint = 0.046], 494 parameters, 320 restraints,
R1 (I > 2σ(I)) = 0.056, wR2 (all data) = 0.125, GOOF = 1.09,
largest diff. peak and hole 1.033/−0.634 e Å−3, x = −0.014(11),
y = −0.009(6).
Experimental data for all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-160-S1.pdf]
Acknowledgements
We gratefully thank the Deutsche Forschungsgemeinschaft
15d: colorless, C17H17FN2O, M = 284.33, crystal size 0.45 × DFG (SPP 1133, Schwerpunktprogramm Organokatalyse) for
0.25 × 0.10 mm, orthorhombic, space group P212121 (no. 19): financial support.
a = 8.4559(3) Å, b = 10.5000(4) Å, c = 16.6177(5) Å, V =
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