The Diels-Alder approach towards cannabinoids

Article abstract of DOI:10.1055/s-2005-870008

Starting from the efficient synthesis of benzopyrans by base-catalyzed condensation reactions between substituted 2-hydroxybenzaldehydes and α,β-unsaturated aldehydes, thermal, Lewis acid catalyzed and enantioselective organo-promoted Diels-Alder reactions towards the tricyclic cannabinoid system are presented. The procedures are exemplified by the synthesis of a pentacycle and various tricycles respectively, in up to 95% enantiomeric excess and provide a versatile entry to this group of natural products with tetrahydrocannabinol (THC) being the most prominent one. Most published strategies are based on the formation of the tricyclic system by condensation between readily available phenols and monoterpenes, whereas we present a novel approach to cannabinoid derivatives based on a modular synthesis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-870008

1888
FEATURE ARTICLE
The Diels–Alder Approach towards Cannabinoids
T
he
Diels–Alder
e
A
pproach t
r
owards
C
annabinoid
h
ard Lesch,a Jakob Toräng,a Martin Nieger,b Stefan Bräse*c
a
Kekulé-Institut für Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universität Bonn,
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
b
c
Institut für Anorganische Chemie der Rheinischen Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn,
Germany
Institut für Organische Chemie, Universität Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6088581; E-mail: braese@ioc.uka.de
Received 23 December 2004; revised 23 May 2005
Dedicated to Albert Eschenmoser on the occasion of his 80th birthday
proposed.3 While expression of the CB2 receptor is re-
stricted to the cells of the immune system, the CB1 recep-
tor can be found throughout the body. The highest CB1
concentrations have been reported in the cerebral cortex,
Abstract: Starting from the efficient synthesis of benzopyrans by
base-catalyzed condensation reactions between substituted 2-hy-
droxybenzaldehydes and a,b-unsaturated aldehydes, thermal,
Lewis acid catalyzed and enantioselective organo-promoted Diels–
Alder reactions towards the tricyclic cannabinoid system are pre- hippocampus, basal ganglia, and cerebellum. Conversely
it is almost absent in the respiratory centers, D9-THC
sented. The procedures are exemplified by the synthesis of a penta-
cycle and various tricycles respectively, in up to 95% enantiomeric
overdoses show low mortalities, a possible advantage
excess and provide a versatile entry to this group of natural products
against classical analgesics like morphine.
with tetrahydrocannabinol (THC) being the most prominent one.
Most published strategies are based on the formation of the tricyclic
system by condensation between readily available phenols and
monoterpenes, whereas we present a novel approach to cannabinoid
derivatives based on a modular synthesis.
9
10
8
OH
1
OH
C
6a
10a
7
2
Key words: natural product synthesis, cannabinoids, asymmetric
synthesis
A
4
B
H
H
6
3
4a
C5H11
O
5
C5H11
O
1a
1b
Nature has always been an important source for pharma-
ceutically interesting compounds. Many of the active
components of modern medicines are obtained by extrac-
tion from their natural sources (e. g. vancomycin) or par-
tial synthesis (e. g. Taxol). One of these compounds with
the longest history in pharmacology is morphine, the first
drug that was obtained as a pure substance in 1803 by F.
W. A. Sertürner from opium poppy (Papaver somnifer-
um).1 Its application can be traced back to at least the an-
cient Greeks, and today it is used as a final form of
analgesic for patients suffering from extreme pain. De-
spite morphine’s usefulness as a drug, it is also a potent
poison causing respiratory paralysis, thus limiting its ther-
apeutic value. There is another well-known group of psy-
chotropic compounds, isolated from Indian hemp
(Cannabis sativa var. indica). These compounds, about 60
in number, are categorized as ‘cannabinoids’, with (–)-D9-
tetrahydrocannabinol (D9-THC) (1a) being the most
prominent.2 It consists of a tricyclic 6a,7,8,10a-tetrahy-
dro-6H-benzo[c]chromene core structure. Other naturally
occurring cannabinoids are the D8-isomer 1b, (–)-canna-
bidiol (1c), or cannabinol (1d, Figure 1). Two cannab-
inoid receptors, CB1 and CB2 receptors, have been
reported, and the existence of a third receptor has been
OH
OH
C5H11
OH
C5H11
O
1c
1d
Figure 1 Four naturally occurring cannabinoids
Besides the classical cannabinoids exhibiting the tricyclic
core, other exo- and endogenous ligands have been de-
scribed. The most important exogenous ligands are ami-
noalkylindoles, such as (R)-(–)-WIN55212 (2). The
endogenous ligands consist of ethanol amides of polyun-
saturated carboxylic acids, such as anandamide (3)4
(Figure 2).
Extensive Structure Activity Relationship (SAR) studies
for the classical cannabinoids have been reported. The di-
hydropyran moiety is unnecessary for active compounds.
O
O
OH
N
H
O
N
O
N
3
2
SYNTHESIS 2005, No. 11, pp 1888–1900
x
x.
x
x
.
2
0
0
5
Advanced online publication: 29.06.2005
DOI: 10.1055/s-2005-870008; Art ID: T16104SS
© Georg Thieme Verlag Stuttgart · New York
Figure 2 The exogenous ligand (R)-(–)-WIN55212 (2) and the en-
dogenous ligand anandamide (3)

FEATURE ARTICLE
The Diels–Alder Approach towards Cannabinoids
1889
Several open-ring derivatives show significant affinity to- propyl chain. It can be longer than a pentyl chain and
wards the CB1 and CB2 receptors.5 On the other hand, can- branching on C-1¢ has been shown to improve the activity.
nabinoids, being protected at or missing the hydroxy An all-carbon chain is not a must, ethers are also accepted.
group on C-1 lack affinity towards the CB1 receptor, but While alkylation on C-2 is accepted, alkylation on C-4
retain some of their activity on the CB2 receptor.6 The loss and acylation or carboxylation on C-2 and C-4 abolishes
of CB1 affinity leads to CB2 selective ligands. The only activity. The substitution of the terpene moiety (ring C,
exceptions are esters, which are probably hydrolyzed in Figure 1) is more flexible. Monohydroxylation is tolerat-
vivo to form the active phenols.
ed and neither the double bond nor the methyl group is es-
sential for binding to the receptors. Although various
syntheses of THC have been reported,7 almost all strate-
gies are based on condensation of the aromatic ring sys-
The presence of a lipophilic side chain on C-3 is a prereq-
uisite for cannabinoid activity. The minimum length is a
Biographical Sketches
Bernhard Lesch was born and received his Diploma in Graduiertenförderung des
in Siegburg, Germany, in 2002. He is a member of the Landes
1977. He studied chemistry Graduiertenkolleg 804 and falen.
at the University of Bonn is a scholarship holder of the
Nordrhein-West-
Jakob Toräng was born in molecular biology and student at the University of
Grindsted, Denmark, in chemistry from Roskilde Bonn and is a scholarship
1975. In 2003, he obtained a University Center. Since holder of Graduiertenkolleg
master of science degree in 2003, he has been a graduate 804.
Martin Nieger was born in Edgar Niecke in Bonn. versity of Bonn. In 1995 he
Northeim, Germany, in Since 1990, he has been re- was appointed as Docent for
1959. He studied Biology sponsible for the common Chemistry (Crystallogra-
and Chemistry at the Uni- X-ray laboratory of the De- phy) at the University of
versities of Göttingen and partment of Organic Chem- Joensuu, Finland.
Bonn and received his Ph.D. istry and the Department of
in 1989, after working with Inorganic Chemistry, Uni-
Stefan Bräse was born in Scripps Research Institute professor. He is recipient of
Kiel, Germany, in 1967. He (K. C. Nicolaou) as DAAD the Orchem prize of the Ge-
studied at the Universities of fellow, he began his inde- sellschaft
Deutscher
Göttingen, Bangor (UK) pendent research career at Chemiker (2000) and the
and Marseille and received the RWTH Aachen in 1997. Lilly Lecture Award (2001).
his Ph.D. in 1995, after In June 2001, he completed His research interests in-
working with Armin de his Habilitation and moved clude asymmetric metal-
Meijere in Göttingen. After to the University of Bonn as catalyzed processes and
post-doctoral appointments a Professor of Chemistry. In combinatorial chemistry to-
at Uppsala University (Jan 2003, he moved to the Uni- wards the synthesis of bio-
E. Bäckvall) and The versity of Karlsruhe as a full logically active compounds.
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

1890
B. Lesch et al.
FEATURE ARTICLE
tem A, with preformed C systems readily available from
chiral pool-based monoterpenes (i.e. verbenol,8 p-menth-
2-ene-1,8-diol9, p-mentha-2,8-diene-1-ol10, or phellan-
drene11), or by enantioselective Diels–Alder reactions,12
while other strategies form the ring C by a Claisen rear-
rangement,13 or a Claisen condensation.14 In this article,
we present a novel approach to cannabinoids based on a
modular synthesis.
The retrosynthetic analysis of the THC-tricycle is shown
in Figure 3. According to the SAR studies discussed
above, the retro-synthetic approach was designed to be
flexible in the terpene part of the molecule, while giving
an easy entrance towards the arene, and still allowing vari-
ations in the aliphatic side chain. The envisaged synthesis
allows a combinatorial approach because many organo-
lithium and magnesium reagents (1,2-addition), a,b-un-
saturated aldehydes and ketones (condensation, Diels–
Alder reaction), and triphenylphosphonium salts (Wittig
reaction) are commercially available.
Figure 4 X-ray structure of 7a
compound forms dimers, which are stabilized by two in-
tramolecular hydrogen bonds.
In a hypothesis, the formation of 7a involves the conjugat-
ed addition of the dienolate 8 to the benzaldehyde 4a. The
phenolic hydroxy group undergoes 1,4-addition to the
a,b-unsaturated aldehyde 9 and the addition product 10
forms the lactol 7a (Scheme 2).
O
OH
O
+
OH
O
7a
O
4a
8
Figure 3 Retrosynthetic analysis of the THC-tricycle
OH
OH
The condensation of Michael acceptors with salicylic al-
dehyde (4a) to yield benzo[b]pyrans has proven to be a
versatile and flexible entrance to these compounds.15 The
application of this concept on cyclohexenones to yield
xanthenones has been reported recently.16
OH
O
O
O
9
10
Extending this procedure to senecialdehyde (5a) gave rise
to the chromene 6a (Scheme 1).17
Scheme 2 Proposed mechanism for the formation of 7a
Optimization of the reaction revealed that sodium carbon-
ate favors the formation of 6, while triethylamine favors
the formation of 7. With respect to the hydroxylated arene
in THC, several salicylic aldehydes were tested in this re-
action. All products, 6a–j and 7a–j, were isolated in ac-
ceptable yields. This issue was discussed in detail in a
previous communication.17 The results are summarized in
Table 1.17
A synthetic route to cannabinoids was established, using
chromene 6a as a model system. Thus, 6a was reacted
with the dienolate of methyl acetoacetate (11) to give the
aldol product 12, which was obtained as an orange oil af-
ter aqueous work-up. Purification of the oil was difficult,
due to dehydration of the product on silica gel. Therefore,
the crude product was refluxed in toluene with aqueous
formic acid, causing elimination, saponification, and de-
carboxylation in a one-pot procedure. The resulting diene
13 was reacted with norbornene to give the Diels–Alder
adduct 14 (Scheme 3).
Scheme 1 Synthesis benzopyrans 6a and 7a17
Surprisingly, a byproduct could be isolated from the reac-
1
tion mixture. Using H and 13C NMR spectroscopy, the
structure 7a was assigned to this compound. An X-ray
analysis of a single crystal revealed the relative configura-
tion of 7a. Both the methyl and the hydroxy group take up
equatorial positions (Figure 4). Within the crystal, the
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Diels–Alder Approach towards Cannabinoids
1891
Table 1 Synthesis of Chromenes 6a–j and 7a–j17
Benz-aldehyde
R1
R2
H
R3
H
Conditionsa
Yield 6 (%)b
Yield 7 (%)b
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
4f
H
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
C
A
B
A
B
65
19
58
13
36
4
19
46
23
36
15
44
10
46
6
H
H
H
OMe
OMe
H
H
H
H
H
OMe
OMe
H
H
H
H
H
OMe
OMe
H
81
36
0
H
H
H
NEt2
NEt2
H
H
H
0
4
OMe
OMe
Br
Br
Br
Cl
Cl
NO2
NO2
NO2
H
44
10
58
17
0
27
57
17
51
9
4f
H
4g
4g
4h
4h
4h
4i
H
Br
H
H
H
H
H
0
47
37
23
61
24c
44c
H
H
27
52
19
65
23
allyl
allyl
Ph
Ph
H
4i
H
H
4j
H
H
4j
H
H
a Conditions: A: Na2CO3 (0.5 equiv), stirring, 55 °C, 2.5 d. B: Et3N (0.5 equiv), stirring, 55 °C, 2.5 d. C: DABCO (0.5 equiv), stirring, 55 °C,
2.5 d.
b Isolated yields.
c While all other compounds were single diastereomers, 7j was obtained as a 1:1 mixture, probably differing in the relative stereochemistry of
the lactol hydroxy group.
The relative configuration of 14 was determined by X-ray dehyde with an appropriate alkyl substitution was ob-
analysis of a single crystal (Figure 5). Although this result tained by formylation of 3,5-dimethoxypentylbenzene,
seemed promising, none of the other tested dienophiles which was prepared by procedures described in litera-
(2-methoxyprop-1-ene, n-butyl vinyl ether and cyclohex- ture.18 Accordingly, 3,5-dimethoxybenzoic acid (15) was
ene) reacted with 13.
reduced with lithium aluminum hydride to the corre-
sponding benzylic alcohol 16. The product 16 was then
oxidized using pyridinium dichromate to give 3,5-
dimethoxybenzaldehyde (17). The aldehyde was reacted
Therefore, we turned our attention on a vinyl precursor
having the correct substitution pattern of THC. A benzal-
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

1892
B. Lesch et al.
FEATURE ARTICLE
OMe
OMe
LiAlH4
THF, reflux,
4 h, 97%
HO
OMe
OMe
15
16
O
OH
OMe
pyridinium-
dichromate
CH2Cl2, r.t.,
24 h, 85%
n-BuLi
THF, –78 °C to r.t.,
30 min, 90%
OMe
17
O
OMe
OMe
TosOH
C4H9
toluene, reflux,
74%
OMe
C3H7
OMe
OH
19
18
Scheme 3 Synthesis of pentacycle 14 by a Diels–Alder strategy
OMe
n-BuLi, TMEDA
THF, 0 °C to r.t., 2 h,
then DMF, r.t., 4 h,
79%,
Pd-C/H2
MeOH, r.t.,
16 h, 80%
C5H11
OMe
20
OMe
OMe
AlCl3, NaI
CH2Cl2–MeCN
0 °C → r.t., 90 min,
86%
O
OMe
O
C5H11
C5H11
OH
21
22
Scheme 4 Synthesis of 2-hydroxy-6-methoxy-4-pentylbenzaldehy-
de (22)
triphenylphosphonium bromide, respectively. The benzyl
Wittig reagent gave a 1:1 mixture of the diastereomers
24b,c, which were separated by column chromatography
(Scheme 5, Table 2).
MeO
O
MeO
O
5b
O
Figure 5 X-ray structure of 14
Na2CO3,
C5H11
O
C5H11
OH
O,
dioxane–H2
22
23
r.t., 24 h, 71%
MeO
with n-BuLi to give the benzylic alcohol 18. An acidic de-
hydration yielded the styrene 19, which was hydrogenated
to 3,5-dimethoxypentylbenzene (20). Ortho-directed met-
alation and trapping of the aryllithium compound with
DMF resulted in the aldehyde 21 after aqueous workup.
This aldehyde was finally mono-deprotected using AlCl3/
NaI, to provide benzaldehyde 22 (Scheme 4).
R2
R1
O
Ph3P+CHR1R2 Br-
5c
n-BuLi, –78 °C, 30 min,
then r.t., 30 min
93% – quant
DMF, 70 °C, 24 h
C5H11
O
24a–c
Condensation of 22 with senecialdehyde (5a) failed. This
was probably due to the lowered electrophilicity of the
benzaldehyde. This result is consistent with the observa-
tion that the p-methoxybenzaldehyde 4c gave lower yields
than the two meta-methoxy derivatives 4b,d upon reac-
tion with senecialdehyde. When the more reactive ac-
rolein (5b) was used instead of senecialdehyde, the
desired chromene 23 was obtained. This was converted
into electron rich dienes 24a–c through a Wittig reaction
with methyltriphenylphosphonium bromide and benzyl-
R1
O
MeO
H
C5H11
O
R1 = H: 25a
1 = Ph: (endo/exo)–25b
R
Scheme 5 Preparation and Thermal Diels–Alder Reactions of Die-
nes 24a–c
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Diels–Alder Approach towards Cannabinoids
1893
Table 2 Yields of Compounds 24a and 25 Prepared
could be identified by a coupling of the proton multiplet
in the HMQC spectra with two carbons at d = 47.6 and
34.7. Those carbons have a positive signal in the DEPT
spectra, identifying them as the aliphatic CH groups.
Likewise, the CH2 groups form complex multiplet struc-
tures, which generated even more difficulty as they super-
pose between 1.82 and 2.22 ppm. Therefore, the
regiochemistry of the published compound is adopted. In
the case of 25b, it was possible to identify the endo-25b
Entry
R1
H
R2
H
Yield of 24 (%) Yield of 25 (%)
a
b
c
quant
47a
62
50b
0
Ph
H
H
Ph
46a
a Both 24b,c were obtained from the Wittig reaction and separated by
column chromatography.
1
b Combined yield of 2.1:1 endo/exo mixture.
and the exo-25b adducts on the basis of H NMR and
HH-COSY spectra. This was due to the fact that C-8 is a
CH group in endo/exo-25b, which shows a significant dif-
ferent shift than the CH2 group in 25a, giving separated
signals for the protons on C-8 and C-9.
A similar diene 26a has been previously synthesized, but
not isolated, and its Diels–Alder reaction with methyl
acrylate 5d has been reported (Scheme 6).19 In this case, a
free phenol 26 was reacted with methyl acrylate (5d) to
give tricycles 27 and 28 in mediocre yields with the
isomerized 27 as the major product.
To introduce the 9-methyl group, the reaction with cro-
tonaldehyde (5e) as substrate was attempted. No reaction
was observed at room temperature. As a Lewis acid cata-
lyzed reaction is not applicable (see above), we turned our
focus on the organocatalysis of Diels–Alder reactions.
Several groups have reported the effective use of second-
ary amines as catalysts for the activation of a,b-unsaturat-
ed ketones and aldehydes in Diels–Alder reactions via the
corresponding iminium ions,20 and recently this method
has found its application in the total synthesis of (+)-
hapalindole Q.21 To test the validity of this concept on our
substrates, we tested L-proline (29a) as a readily available
chiral secondary amine with crotonaldehyde as dienophile
to introduce the 9-methyl group. The desired products
endo/exo-25c were obtained in 39% yield based on recov-
ered starting material (Scheme 7, Table 3). The slow con-
version in relation to the published examples20 with
organo-catalysts is due to the high substitution pattern of
the diene. The product was formed as a 1:~2 mixture of
endo-adducts, endo-25c and exo-adduct, exo-25c. The
diastereomers could not be separated by column chroma-
tography, but after reduction with lithium aluminum hy-
dride the resulting alcohols endo/exo-25d are separable on
silica gel. The enantiomeric excesses were only modest
(20% ee for the endo- and 25% ee for the exo-isomer). The
relative stereochemistry was assigned on the basis of
1H NMR and HH-COSY experiments. When the catalyst
29b introduced by MacMillan20a was applied, the yield
was increased and both diastereomers were obtained in
very good to excellent enantiomeric excesses (25% yield,
95% ee for endo-25d, 43% yield, 90% ee for exo-25d).
The absolute configuration of the endo-product based on
the model of MacMillan20a is 10aR, being the correct
stereochemistry for the natural THC molecule. Both cata-
lysts 29a and 29b favored the same enantiomers. Al-
though this offers the first asymmetric Diels–Alder
approach to the THC family, the diastereoselectivity as
well as the chemical yields needs further improvement. A
detailed investigation on the optimization of the chemical
yield and the diastereoselectivity using different chiral
secondary amines as well conversion to the natural prod-
uct will be the subject of further studies.
MeO2C
OH
CO2Me
OH
5d
C5H11
O
O
100 °C
27 (29%)
MeO2C
OH
C5H11
O
26
(prepared in situ)
C5H11
28 (7%)
Scheme 6 Cannabinoid synthesis according to Minami et al.19
In contrast, dienes 24a,b gave in both thermal and Lewis
acid catalyzed Diels–Alder reactions, using but-3-en-2-
one (5c) as the dienophile, the tricycles 25a,b, and no
isomerization of the double bond could be observed
(Scheme 5). This gives the opportunity to build up the ste-
reogenic center on C-10a by an enantioselective Diels–
Alder reaction. Comparing the Lewis acid catalyzed reac-
tion of 24a (28% yield) with the thermal Diels–Alder re-
action of 24a (62% yield), the thermal reaction proved to
be superior over the Lewis acid-catalyzed reaction. This
points out to an acid lability of the starting material and/or
the product. Therefore, 24b,c were only used in a thermal
Diels–Alder reaction. While the Diels–Alder adduct 25a
was isolated as a single diastereomer, the E-isomer 24b
gave a mixture of two isomers endo/exo-25b in a ~2:1 ra-
tio. In contrast to this, the Z-isomer 24c showed no turn-
over under the conditions used for 24a,b.
Neither the regio- nor the stereochemistry of 25a could be
deduced from the NMR spectra (1H, 13C, DEPT, HH-CO-
SY, HMQC, NOESY). The signals at C-10 and C-10a are
useful for assigning the stereo- and regiochemistry. Un-
fortunately, they occur at 3.72–3.79 ppm, which obstruct-
ed the deduction from the NMR spectra. These protons
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

1894
B. Lesch et al.
FEATURE ARTICLE
C-atom (positive signal), – = secondary C-atom (negative signal),
q = quaternary C-atom (no signal). IR: Perkin-Elmer FT-IR 1750.
The substances were measured in KBr pellets. MS, EI-HRMS: (EI,
70 eV, I) Kratos MS 50 (70 eV) and (EI, 70 eV, II) Thermo Quest
Finnigan MAT 95 XL (70 eV). GC analytical: Hewlett-Packard HP
5890 Serie II 12 m × 0.25 mm capillary column HP I (carrier gas
N2). X-ray analysis: Nonius Kappa CCD. TLC: Silica gel coated
aluminum plates (Merck, silica gel 60, F254). Detection under UV
light at 254 nm, displayed with molybdato phosphate (5% phospho-
molybdic acid in EtOH, dipping solution), or KMnO4 (0.45 g
KMnO4 and 2.35 g of Na2CO3 in 90 mL of H2O, dipping solution).
Elemental analysis: elementar vario EL at the Mikroanalytisches
Labor des Instituts für Organische Chemie der Universität Bonn.
Melting points were determined on a hot plate apparatus and are
corrected. Descriptions without nominated temperature were done
at r.t. Solvents, reagents and chemicals were purchased from Ald-
rich, Fluka, Janssen, and Merck. Solid materials were powdered.
EtOAc, light petroleum ether and CH2Cl2 were distilled prior to use.
Solvents for reactions for organometallic and other sensitive mate-
rials (Et2O, THF, CH2Cl2, MeCN) were dried according to standard
procedures and distilled under argon. Anhyd DMF was purchased
from Acros. All other solvents, reagents and chemicals were used as
purchased. Abbreviations: Light petroleum ether (bp 40–60 °C):
PE. Pentane: pen.
O
H
O
MeO
MeO
5e
1 equiv 29a,b
MeOH–H2O
r.t., 24 h
C5H11
O
C5H11
O
(endo/exo)–25c
24a
OH
OH
MeO
MeO
H
LiAlH4, THF, r.t.,
30 min.
+
C5H11
O
C5H11
O
(endo)–25d
(exo)–25d
O
Me
N
Bn
HO2C
29a
N
N
H2
Cl
29b
H
Scheme 7 Organo-Promoted Diels–Alder Reactions
Table 3 Yields and Enantiomeric Excesses of 25d Prepared
5-(2,2-Dimethyl-2H-chromen-3-yl)-5-hydroxy-3-oxopentanoic
Acid Methyl Ester (12)
Catalyst
Yield (%)a (ee, %)b Yield (%)a (ee, %)b Conversion
Diisopropylamine (4.55 g, 6.32 mL, 45.0 mmol) was dissolved in
anhyd THF (10 mL) under argon. The solution was cooled to
–78 °C and n-BuLi (24 mL, 1.6 M solution in hexane, 38 mmol)
was added. The flask was immersed in an ice bath and the mixture
was stirred for 30 min. At 0 °C, methyl acetoacetate (1.92 g, 1.78
mL, 16.5 mmol) was added slowly, whence the color of the solution
turned orange. After stirring for 15 min at 0 °C, 2,2-dimethyl-2H-
chromene-3-carbaldehyde (6a; 2.82 g, 15 mmol) dissolved in anhyd
THF (10 mL) was added. The cooling was removed and the mixture
was stirred for 15 min at r.t. After completion of the reaction, brine
(30 mL) and dil. H2SO4 (c = 2 mol/L) was added, the phases were
separated, and the aqueous layer was extracted with EtOAc (3 × 20
endo–25d
exo–25d
28 (25)
43 (90)
(%)
29a
29b
11 (20)
53
25 (95)
67
a Yield based on recovered starting material.
b Enantiomeric excess determined by HPLC with chiral stationary
phase (Chiralpak AS) in comparison with racemic products.
A Diels–Alder approach described towards the cannab-
inoid tricycle, exemplified by the synthesis of tricycles mL). The combined organic layers were dried (Na2SO4), the solvent
25a–d, provides a versatile entry to this fascinating group
was evaporated, and the crude product was purified by flash column
chromatography (EtOAc–PE, 1:5 to remove the starting material,
of naturally occurring compounds. Most published strate-
then EtOAc–PE, 1:1 to isolate the product) yielding 3.61 g (79%) of
gies focus on the formation of the heterocycle, with the
the title compound as a yellow oil. The NMR in CDCl3 showed
about 10% of the enol form.
cyclohexane moiety preexisting in the starting material.
However, the procedures presented in this article are espe-
cially flexible with respect to the substitution of the ter-
pene unit, because there are many dienophiles available
for Diels–Alder reactions. Moreover, the obtained prod-
ucts 25a–d still allow further derivatization. Further im-
provement of enantioselective construction of the
cyclohexane moiety by an organo-catalytic approach will
be the focus of future investigations.
1H NMR (300 MHz, CDCl3): d (keto form) = 1.44 (s, 3 H, CH3),
1.46 (s, 3 H, CH3), 2.90 (d, 3J = 3.6 Hz, 1 H, CHaHbCHOH), 2.91
(d, 3J = 8.1 Hz, 1 H, CHaHbCHOH), 3.02 (br s, 1 H, OH), 3.50 (s, 2
H, COCH2CO2CH3), 3.70 (s, 3 H, CO2CH3), 4.69 (dd, 3J = 8.1, 3.6
Hz, 1 H, CHaHbCHOH), 6.37 (s, 1 H, H-4¢), 6.77 (d, 3J = 8.1 Hz, 1
3
4
Harom), 6.83 (ddd, J = 7.3, 7.3 Hz, J = 1.1 Hz, 1 Harom), 6.99 (dd,
3J = 7.3 Hz, 4J = 1.4 Hz, 1 Harom), 7.09, (ddd, 3J = 7.8, 7.7 Hz,
4J = 1.6 Hz, 1 Harom).
13C NMR (75 MHz, CDCl3): d (keto form) = 26.0, 26.3 (+, 2 CH3),
48.8, 49.5 (–, 2 CH2), 52.4 (+, OCH3), 66.0 (+, CHOH), 77.9 [q,
OC(CH3)2], 116.1, 119.7, 120.9, 126.5, 129.2 (+, CHarom, C-4¢),
121.8, 140.9. 152.2 (q, Carom, C-3¢), 167.2 (C-1), 202.5 (C-3).
1H NMR: Bruker DP 300 (300 MHz), Bruker DP 400 (400 MHz);
d = 7.26 for CHCl3, 7.27 for benzene-d5. Description of signals:
s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, mc = centered multiplet, dd = doublet of doublet,
ddd = doublet of dd, dddd = dd of dd, dt = doublet of triplets,
dq = doublet of quartets, and tt = triplet of triplets. The spectra were
analyzed according to first order. All coupling constants are abso-
lute values. Abbreviations for signals: Carom or Harom = aromatic C
or H, Caliph or Haliph = aliphatic C or H, naph = naphthyl, Tol = tolyl.
13C NMR: Bruker DP 300 (75 MHz), Bruker DP 400 (100 MHz);
d = 77.16 for CDCl3, 128.5 for benzene-d5. The signal structure was
analyzed by DEPT and described as follows: + = primary or tertiary
MS (EI, 70 eV, I): m/z (%) = 304 (17, [M+]), 289 (81, [M+ – CH3]),
173 (100, [M+ – C5H7O4]).
HR-EIMS (EI, 70 eV, I): m/z calcd for C17H20O5: 304.1311; found:
304.1314.
(E)-4-(2,2-Dimethyl-2H-chromen-3-yl)but-3-en-2-one (13)
To a solution of 12 (1.81 g, 5.95 mmol) in toluene (25 mL), were
added formic acid (1 mL) and H2O (0.5 mL) and the mixture was
refluxed for 16 h. After cooling to r.t., the mixture was dried
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Diels–Alder Approach towards Cannabinoids
1895
(Na2CO3), the solvent was evaporated and the crude product was
purified by flash column chromatography (EtOAc–PE, 1:5) to give
1.15 g (85%) of the title compound as a yellow oil; Rf 0.49 (EtOAc–
PE, 1:5).
was generated, the precipitate was dissolved by the addition of dil.
H2SO4 (500 mL, conc. acid–H2O, 1:3). Brine (300 mL) and CH2Cl2
(300 mL) were added, and the phases were separated. The aqueous
layer was extracted with CH2Cl2 (3 × 300 mL), and the combined
organic layers were dried (MgSO4). After evaporation of the sol-
vent, 71.4 g (97%) of the title compound was obtained as a colorless
solid, pure enough for synthetic purposes. To obtain analytically
pure 16, the crude product can be recrystallized from cyclohexene ;
mp 42–43 °C; Rf 0.46 (EtOAc–PE, 1 :1).
1H NMR (300 MHz, CDCl3): d = 2.08 (br s, 1 H, OH), 3.78 (s, 6 H,
OCH3), 4.60 (s, 2 H, CH2OH), 6.37 (t, 4J = 2.3 Hz, 1 H, H-4), 6.51
(d, 4J = 2.3 Hz, 2 H, H-2, H-6).
13C NMR (75 MHz, CDCl3): d = 55.3 (+, OCH3), 65.2 (–, CH2OH),
IR (KBr): 2979, (C–Haliph), 1711 (C=O), 1586 (C=Carom) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.54 [s, 6 H, C(CH3)2], 2.31 (s, 3
H, H-1), 6.49 (d, 3J = 16.1 Hz, 1 H, H-3), 6.75, (s, 1 H, H-4¢), 6.79
3
3
4
(d, J = 8.1, 1 Harom), 6.86 (ddd, J = 7.4, 7.4 Hz, J = 1.1 Hz, 1
Harom), 7.04 (dd, 3J = 7.4 Hz, 4J = 1.7 Hz, 1 Harom), 7.10 (dd,
3J = 16.1 Hz, 4J = 0.85 Hz, 1 H, H-4), 7.09, (ddd, 3J = 7.8, 7.8 Hz,
4J = 1.4 Hz, 1 Harom).
13C NMR (75 MHz, CDCl3): d = 26.8 [+, C(CH3)2], 27.9 (+,
CH3CO), 78.5 [q, OC(CH3)2], 116.3, 121.2, 125.7, 127.3, 130.7,
139.7 (+, C-3, C-4, C-4¢, CHarom), 121.3, 126.4 (q, C-3¢, Carom),
153.1 (q, Carom–O), 197.6 (C-2).
99.6 (+, C-4), 104.5 (+, C-2, C-6), 143.3 (q, C-1), 160.9 (q, C-3, C-
5).
MS (EI, 70 eV, I): m/z (%) = 168 (100) [M+], 139, (68) [M+ – CHO).
MS (EI, 70 eV, II): m/z (%) = 228 (27, [M+]), 213 (100, [M+ –
CH3]).
HR-EIMS (EI, 70 eV, I): m/z calcd for C9H12O3: 168.0786; found:
168.0781.
HR-EIMS (EI, 70 eV, II): m/z calcd for C15H16O2: 228.1150; found:
228.1151.
3,5-Dimethoxybenzaldehyde (17)
Anal. Calcd for C15H16O2: C, 78.92; H, 7.06. Found: C, 78.91; H,
7.14.
To a solution of 3,5-dimethoxybenzylic alcohol (16; 52.6 g, 313
mmol) in CH2Cl2 (1 L) was added pyridinium dichromate (118 g,
313 mmol) via a wide-mouthed funnel and the mixture was stirred
for 24 h. The solvent was evaporated and the residue was filtered
over silica gel (eluent: EtOAc–PE, 1:1, +5% Et3N). After evapora-
tion of the solvent, the crude product was distilled under reduced
pressure to yield 44.0 g (85%) of the title compound; bp 118–
122 °C/1.9 mbar; mp 45–46 °C; Rf 0.76 (EtOAc–PE, 1:1).
1H NMR (300 MHz, CDCl3): d = 3.83 (s, 6 H, OCH3), 6.59 (t,
4J = 2.4 Hz, 1 H, H-4), 7.00 (d, 4J = 2.4 Hz, 2 H, H-2, H-6), 9.89 (s,
1 H, CHO).
3-Acetyl-6,6-dimethyl-7-oxapentacyc-
lo[14.2.1.02,15.05,14.08,13]nonadeca-4,8,10,12-tetraene (14)
A neat mixture of 13 (1.01 g, 4.43 mmol) and norbornene (834 mg,
8.86 mmol) was heated to 90 °C for 48 h and then to 60 °C for 48 h.
After cooling to r.t., the crude product was purified by flash column
chromatography, to afford 1.05 g (73%) of a mixture of the exo/exo
adduct with another diastereomer in a 90.5:9.5 ratio (13C NMR).
The exo/exo product can be obtained by recrystallization from cy-
clohexene; mp 123–125 °C; Rf 0.79 (EtOAc–PE, 1:5).
13C NMR (75 MHz, CDCl3): d = 55.6 (+, OCH3), 107.1 (+, C-2, C-
6), 107.1 (+, C-4), 138.4 (q, C-1), 161.2 (q, C-3, C-5), 191.8 (+,
CHO).
IR (KBr): 3079 (C–Harom), 2985, (C–Haliph), 1716 (C=O), 1606
(C=Carom) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.92–0.99 (m, 1 Haliph), 1.05 (s, 3
H, CH3), 1.07–1.14 (m, 2 Haliph), 1.35 (t, 3J = 9.6 Hz, 1 Haliph), 1.40–
1.45 (m, 1 Haliph), 1.44 (s, 3 H, CH3), 1.74, (dd, 3J = 10.0, 9.8 Hz, 2
H, H-2, H-15), 1.99 (s, 1 H, H-1 or H-16), 2.18 (s, 3 H, CH3C=O),
2.49 (s, 1 H, H-1 or H-16), 2.78 (ddd, 3J = 10.8, 3.0 Hz, 4J = 1.0 Hz,
1 H, H-3), 2.84 (d, 3J = 10.4 Hz, 1 H, H-14), 5.60 (dd, 3J = 3.2 Hz,
4J = 3.2 Hz, 1 H, H-4), 6.78 (dd, 3J = 8.1 Hz, 4J = 1.1 Hz, 1 H, H-9
or H-12), 6.85 (ddd, 3J = 7.5, 7.5 Hz, 4J = 1.3 Hz, 1 H, H-10 or H-
MS (EI, 70 eV, I): m/z (%) = 166 (100, [M+]), 137, (22, [M+ –
CHO]), 135 (26, [M+ – OCH3]).
HR-EIMS (EI, 70 eV, I): m/z calcd for C9H10O3: 166.0630; found:
166.0629.
1-(3,5-Dimethoxyphenyl)pentan-1-ol (18)
3,5-Dimethoxybenzaldehyde (17; 8.31 g, 50.0 mmol) was dissolved
in anhyd THF (70 mL) and cooled to –78 °C. n-BuLi (34 mL, 1.6 M
solution in hexane, 55 mmol) was added slowly via a syringe. After
the addition was complete, cooling was removed and the mixture
was stirred for 1 h. The reaction was quenched with brine (100 mL)
and the precipitate was dissolved in H2O (50 mL). The phases were
separated and the aqueous layer was extracted with EtOAc (3 × 50
mL). The combined organic layers were dried (MgSO4) and the sol-
vent was removed under reduced pressure. The crude product was
purified by flash column chromatography (EtOAc–PE, 1:5) to yield
10.1 g (90%) of the title compound as a colorless oil; Rf 0.27
(EtOAc–PE, 1:5).
3
4
11), 7.04 (ddd, J = 7.7, 7.7 Hz, J = 1.5 Hz, 1 H, H-10 or H-11),
7.19 (dd, 3J = 7.6 Hz, 4J = 1.3 Hz, 1 H, H-9 or H-12).
13C NMR (CDCl3, 100 MHz): d = 26.7, 26.8 [+, C(CH3)2], 29.3 (+,
CH), 29.4, 29.5, 33.0 (–, C-17, C-18, C-19), 37.1, 39.9, 41.9, 47.2
(+, C-1, C-2, C-15, C-16), 52.1, 52.4 (+, C-3, C-14), 77.0 (q, C-6),
117.6, 118.7, 121.1, 127.3, 129.2 (+, C-4, C-9, C-10, C-11, C-12),
127.8, 146.4 (q, C-5, C-13), 153.7 (C-8), 210.8 (q, H3CC=O).
MS (EI, 70 eV, II): m/z (%) = 322 (29, [M+]), 307 (82, [M+ – CH3]),
279 (100, [M+ – COCH3]).
HR-EIMS (EI, 70 eV, II): m/z calcd for C22H26O2: 322.1933; found:
322.1933.
IR (KBr): 3419 (br, O–H), 2999 (C–Harom), 2934 (C–Haliph), 1598
(C=Carom) cm–1.
Anal. Calcd for C22H26O2: C, 81.95; H, 8.13. Found: C, 81.40; H,
8.04.
3
1H NMR (400 MHz, CDCl3): d = 0.84 (t, J = 7.0 Hz, 3 H, CH3),
1.17–1.39 (m, 4 H, 2 CH2), 1.58–1.76 (m, 2 H, CH2), 2.68 (br s, 1
3
3,5-Dimethoxybenzylic Alcohol (16)
H, OH), 3.70 (s, 6 H, OCH3), 4.47 (dd, J = 5.9, 7.3 Hz, 1 H,
CHOH), 6.29 (t, 4J = 2.3 Hz, 1 H, H-4¢), 6.43 (d, 4J = 2.3 Hz, 2 H,
H-2¢, H-6¢).
LiAlH4 (25.0 g, 659 mmol) was suspended in anhyd THF (500 mL)
under argon. To this suspension was added 3,5-dimethoxybenzoic
acid (15; 80.0 g, 439 mmol) in anhyd THF (1 L) from a dropping
funnel. During the addition, the mixture boiled slightly. After all the
acid had been added, the mixture was refluxed for 4 h. The solution
was cooled with an ice bath and the excess of LiAlH4 was destroyed
by the addition of H2O (100 mL) (caution!). When no further H2
13C NMR (100 MHz, CDCl3): d = 13.8 (+, CH3), 22.4, 27.8, 38.5
(–, 3 CH2), 55.0 (+, OCH3), 99.0 (+, C-4¢), 103.4 (+, C-2¢, C-6¢),
147.6 (q, C-1¢), 160.6 (q, C-3¢, C-5¢).
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

1896
B. Lesch et al.
FEATURE ARTICLE
MS (EI, 70 eV, II): m/z (%) = 224 (68, [M+]), 168 (100, [M+ –
1.6 M solution in hexane, 35 mmol) was added. The mixture was
warmed to r.t., and stirred for 2 h. To this mixture was added anhyd
DMF (5.06 g, 5.38 mL, 69.2 mmol). After stirring for 4 h, brine (150
mL) was added, the layers were separated and the aqueous layer was
extracted with EtOAc (3 × 70 mL). The combined organic layers
were dried (MgSO4), and the solvent was evaporated. The crude
product was purified by flash column chromatography (EtOAc–PE,
1:1) to yield 4.18 g (79%) of the title compound as a colorless oil;
Rf 0.65 (EtOAc–PE, 1:1).
C4H8]), 167 (85, [M+ – C4H9]), 139 (100, [M+ – C5H9O]).
HR-EIMS (EI, 70 eV, II): m/z calcd for C13H20O3: 224.1413; found:
224.1415.
Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 70.19; H,
8.79.
(E)-1-(3,5-Dimethoxyphenyl)pent-1-ene (19)
p-Toluenesulfonic acid (782 mg, 4.55 mmol) was suspended in tol-
uene (150 mL) in a two-necked 500 mL flask equipped with a drop-
ping funnel and a Dean–Stark trap and the mixture was heated to
reflux. To this mixture was added slowly a solution of 18 (8.98 g,
45.5 mmol) in toluene (100 mL). After 60 min, no more H2O was
produced and the heating was removed. After cooling to r.t.,
Na2CO3 (2.5 g) was added, the mixture filtered, and the solvent was
evaporated. The residue was purified by flash column chromatogra-
phy (EtOAc–PE, 1:5) to yield 6.89 g (74%) of the title compound as
a colorless oil; Rf 0.72 (EtOAc–PE, 1:5).
IR (KBr): 3004 (C–Harom), 2933 (C–Haliph), 1648 (C=O), 1607
(C=Carom) cm–1.
3
1H NMR (300 MHz, CDCl3): d = 0.86 (t, J = 6.9 Hz, 3 H, CH3),
1.26–1.37 (m, 4 H, 2 CH2), 1.57 (tt, 3J = 7.4, 7.4 Hz, 2 H,
CH2CH2CH2), 2.55 (t, 3J = 7.2 Hz, 2 H, H-1¢), 3.83 (s, 6 H, OCH3),
6.34 (s, 2 H, H-3, H-5), 10.40 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 13.8 (+, CH3), 22.3, 30.4, 31.3,
37.0 (–, 4 CH2), 55.8 (+, OCH3), 103.9 (+, C-3, C-5), 112.2 (q, C-
4), 152.4 (q, C-1), 162.1 (q, C-2, C-6), 188.7 (+, CHO).
MS (EI, 70 eV, I): m/z (%) = 236 (54, [M+]), 180, (100, [M+ –
C4H10]).
IR (KBr): 2989 (C–Harom), 2947 (C–Haliph), 1592 (C=Carom) cm–1.
3
1H NMR (400 MHz, CDCl3): d = 1.14 (t, J = 7.4 Hz, 3 H, CH3),
1.50 (tt, 3J = 7.4, 7.4 Hz, 2 H, CH2CH2CH3), 2.19 (dt, 3J = 7.1, 7.1
Hz, 2 H, CHCH2CH2), 3.81 (s, 6 H, OCH3), 6.22 (dt, 3J = 6.7, 16.2
HR-EIMS (EI, 70 eV, I): m/z calcd for C14H20O3: 236.1413; found:
236.1414.
3
Hz, 1 H, CH=CHCH2), 6.33 (d, J = 16.2 Hz, 1 H, CH=CH), 6.34
(t, 4J = 2.2 Hz, 1 H, H-4¢), 6.52 (d, 4J = 2.2 Hz, 2 H, H-2¢, H-6¢).
Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 70.85; H,
8.52.
13C NMR (100 MHz, CDCl3): d = 13.4 (+, CH3), 22.4, 22.4, 35.0
(–, 3 CH2), 55.2 (+, OCH3), 99.1 (+, C-4¢), 104.0 (+, C-2¢, C-6¢),
129.9, 131.4 (+, C-1, C-2), 140.0 (q, C-1¢), 160.9 (q, C-3, C-5¢).
2-Hydroxy-6-methoxy-4-pentylbenzaldehyde (22)
2,6-Dimethoxy-4-pentylbenzaldehyde (21; 3.63 g, 15.4 mmol) and
NaI (5.76 g, 38.5 mmol) were dissolved in anhyd CH2Cl2–MeCN
(1:2, 150 mL) under argon. The solution was cooled to 0 °C and
AlCl3 (5.13 g, 38.5 mmol) was added. During the addition, the color
of the solution turned to dark red. Cooling was removed and the
mixture was stirred for 90 min. Brine (100 mL) and H2O (30 mL)
were added, and the pH of the mixture was adjusted to 1–2 with
H2SO4 (c = 2 mol/L). The phases were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 50 mL). The combined organ-
ic phases were dried (MgSO4), the solvent was evaporated and the
crude product was purified by flash column chromatography
(EtOAc–PE, 1:5 + 1% AcOH) to yield 2.94 g (86%) of the title com-
pound as a colorless oil; Rf 0.62 (EtOAc–PE, 1:5).
MS (EI, 70 eV, II): m/z (%) = 206 (100, [M+]), 191 (43, [M+ –
CH3]), 177 (63, [M+ – C2H5]).
HR-EIMS (EI, 70 eV, II): m/z calcd for C13H18O2: 206.1307; found:
206.1298.
Anal. Calcd for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.79; H,
8.60.
1-(3,5-Dimethoxyphenyl)pentane (20)
(E)-1-(3,5-Dimethoxyphenyl)pent-1-ene (19; 6.00 g, 29.1 mmol)
and 5% Pd/C (308 mg, 1.46 mmol) were placed in a flask, the flask
was sealed with a septum, evacuated and filled with H2. MeOH (50
mL) was added via a syringe and the mixture was stirred for 20 h.
Pd/C was recovered by filtration, the filtrate was dried (MgSO4),
and the solvent evaporated. The crude product was purified by flash
column chromatography (EtOAc–PE, 1:5) to yield 4.84 g (80%) of
the title compound as a colorless oil; Rf 0.86 (EtOAc–PE, 1:5).
IR (KBr): 2956 (C–Harom), 2932 (C–Haliph), 1646 (C=O), 1574
(C=Carom) cm–1.
3
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7.0 Hz, 3 H, CH3),
1.27–1.38 (m, 4 H, 2 CH2), 1.61 (tt, 3J = 7.5, 7.5 Hz, 2 H,
3
CH2CH2CH2), 2.54 (t, J = 7.8 Hz, 2 H, H-1¢), 3.86 (s, 6 H, 2
IR (KBr): 2998 (C–Harom), 2931 (C–Haliph), 1596 (C=Carom) cm–1.
OCH3), 6.18 (d, 4J = 0.8 Hz, 1 Harom), 6.34 (d, 4J = 0.8 Hz, 1 Harom),
3
1H NMR (400 MHz, CDCl3): d = 0.81 (t, J = 7.5 Hz, 3 H, CH3),
10.23 (s, 1 H, CHO), 11.97 (s, 1 H, OH).
1.20–1.29 (m, 4 H, 2 CH2), 1.52 (tt, 3J = 7.5, 7.5 Hz, 2 H,
CH2CH2CH2), 2.45 (t, 3J = 7.9 Hz, 2 H, H-1), 3.68 (s, 6 H, 2 OCH3),
6.21 (t, 4J = 2.1 Hz, 1 H, H-4¢), 6.26 (d, 4J = 2.1 Hz, 2 H, H-2¢, H-6¢).
13C NMR (100 MHz, CDCl3): d = 13.9 (+, CH3), 22.4, 30.1, 31.4,
37.6 (–, 4 CH2), 55.6 (+, 2 OCH3), 101.5, 109.4 (+, C-3, C-5), 109.1
(q, C-4), 155.4 (q, C-1), 162.3, 163.6 (q, C-2, C-6), 193.4 (+, CHO).
MS (EI, 70 eV, II): m/z (%) = 222 (21, [M+]), 166, (100, [M+ –
C4H10]).
13C NMR (100 MHz, CDCl3): d = 13.9 (+, CH3), 22.5, 30.9, 31.5,
36.2 (–, 4 CH2), 55.1 (+, 2 OCH3), 97.5 (+, C-4¢), 106.4 (+, C-2¢, C-
6¢), 129.9, 131.4 (+, C-1, C-2), 145.3 (q, C-1¢), 160.7 (q, C-3¢, C-5¢).
MS (EI, 70 eV, II): m/z (%) = 208 (27, [M+]), 152, (100, [M+ –
C4H10]).
HR-EIMS (EI, 70 eV, II): m/z calcd for C13H18O3: 222.1256; found:
222.1257.
Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.10; H,
8.20.
HR-EIMS (EI, 70 eV, II): m/z calcd for C13H20O2: 208.1463; found:
208.1456.
Anal. Calcd for C13H20O2: C, 74.96; H, 9.68. Found: C, 74.77; H,
9.46.
5-Methoxy-7-pentyl-2H-chromene-3-carbaldehyde (23)
2-Hydroxy-6-methoxy-4-pentylbenzaldehyde (22; 4.00 g, 18.0
mmol) and DABCO (1.01 g, 9.00 mmol) were dissolved in diox-
ane–H2O (10:1, 9 mL). To this mixture was added acrolein (5b; 2.41
mL, 2.02 g, 36.0 mmol) via syringe over a period of 24 h. After stir-
ring for further 24 h, dil. HCl (20 mL, c = 1 mol/L) and CH2Cl2 (20
mL) were added. The precipitate was dissolved in H2O and the
2,6-Dimethoxy-4-pentylbenzaldehyde (21)
To a solution of 20 (4.66 g, 22.4 mmol) in anhyd Et2O (150 mL) was
added tetramethylethylenediamine (4.02 g, 5.18 mL, 34.6 mmol)
under argon. The solution was cooled to 0 °C and n-BuLi (22 mL,
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Diels–Alder Approach towards Cannabinoids
1897
phases were separated. The aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(MgSO4), and the solvent was evaporated. The crude product was
purified by flash column chromatography (EtOAc–PE, 1:8) to yield
3.32 g (71%) of the title compound as a yellow oil, which crystal-
lized upon standing ; mp 53–55 °C; Rf 0.50 (EtOAc–PE, 1:8).
–78 °C and a solution of 23 (2.50 g, 9.62 mmol) in anhyd THF (40
mL) was added. After stirring for 30 min at –78 °C, the cooling was
removed and the mixture was stirred for 30 min. at r.t. The reaction
was quenched by the addition of silica gel, the solvent was removed
under reduced pressure and the crude product was purified by flash
column chromatography (Et2O–pen, 1:20) to obtain 1.28 g (40%) of
24b as a slightly yellow solid and 1.69 g (53%) of 24c as an oil.
IR (KBr): 3057 (C–Harom), 2955, (C–Haliph), 1666 (C=O), 1568
(C=Carom) cm–1.
24b
3
1H NMR (400 MHz, CDCl3): d = 0.90 (t, J = 6.9 Hz, 3 H, H-5¢),
Rf 0.47 (Et2O–pen, 1:20).
2.38–1.38 (m, 4 H, 2 CH2), 1.60 (tt, 3J = 7.6, 7.6 Hz, 2 H,
CH2CH2CH2), 2.54 (t, 3J = 7.8 Hz, 2 H, H-1¢), 3.87 (s, 3 H, OCH3),
4.95 (s, 2 H, H-2), 6.28 (s, 1 Harom), 6.34 (s, 1 Harom), 7.60 (s, 1 H,
H-4), 9.52 (s, 1 H, CHO).
3
1H NMR (400 MHz, CDCl3): d = 0.83 (t, J = 6.9 Hz, 3 H, H-5¢),
1.22–1.31 (m, 4 H, 2 CH2), 1.54 (tt, 3J = 7.5, 7.5 Hz, 2 H,
CH2CH2CH2), 2.46 (t, 3J = 7.9 Hz, 2 H, H-1¢), 3.76 (s, 3 H, OCH3),
4.94 (s, 2 H, H-2), 6.20 (d, 4J = 0.8 Hz, 1 H, H-4), 6.28 (d, 4J = 0.5
Hz, 1 Harom), 6.31 (d, 3J = 16.3 Hz, 1 H, CH=CHPh), 6.76 (d,
13C NMR (100 MHz, CDCl3): d = 13.9 (+, C-5¢), 22.5, 30.5, 31.4,
36.8 (–, C-1¢ to C-4¢), 55.7 (+, OCH3), 62.9 (–, C-2), 104.0, 109.0
(+, CHarom), 108.6, 128.7, 150.4 (q, C-3, C-4a, C-7), 137.2, (+, C-4),
156.8, 157.1 (q, C-5, C-9a), 189.6 (+, CHO).
3
4J = 0.5 Hz, 1 Harom), 6.82 (dd, J = 16.3, 0.8 Hz, 1 H, CH=CH),
7.14 (dddd, 3J = 7.3, 7.3 Hz, 4J = 1.1, 1.1 Hz, 1 H, p-HC6H4), 7.25
(dd, 3J = 7.7 Hz, 2 H, 2 m-HC6H4), 7.34 (d, 3J = 7.5 Hz, 2 o-HC6H4).
MS (EI, 70 eV, II): m/z (%) = 260 (100, [M+]), 231 (51, [M+ –
13C NMR (100 MHz, CDCl3): d = 14.2 (+, C-5¢), 22.7, 31.0, 31.7,
36.7 (–, C-1¢ to C-4¢), 55.8 (+, OCH3), 65.4 (–, C-2), 104.1, 108.6,
119.2, 126.4, 126.8, 127.5, 127.6, 128.2 (+, CHarom, CHolefin), 110.2,
137.5, 145.2 (q, C-3, C-4a, C-7), 154.5, 155.4 (q, C-5, C-9a).
MS (EI, 70 eV, II): m/z (%) = 334 (100, [M+]), 277 (17, [M+ –
C4H9]).
CHO]), 204 (49, [M+ – C4H10]).
HR-EIMS (EI, 70 eV, II): m/z calcd for C16H20O3: 260.1412; found:
258.1417.
Anal. Calcd for C16H20O3: C, 73.82; H, 7.74. Found: 73.34; H, 7.65.
5-Methoxy-7-pentyl-3-vinyl-2H-chromene (24a)
HR-EIMS (EI, 70 eV, II): m/z calcd for C25H26O2: 334.1933; found
Methyltriphenylphosphonium bromide (1.47 g, 4.11 mmol) was
suspended in anhyd THF (20 mL) under argon. The mixture was
cooled to –78 °C and n-BuLi (1.93 mL, 1.6 M solution in hexane,
3.08 mmol) was added slowly. During the addition, the color of the
solution turned to intense yellow. The mixture was stirred for 30
min, the cooling was removed and the mixture was again stirred for
30 min at r.t. The suspension of the Wittig reagent was cooled to
–78 °C and a solution of 23 (534 mg, 2.05 mmol) in anhyd THF (20
mL) was added. After stirring for 30 min at –78 °C, cooling was re-
moved and the mixture was stirred for 30 min at r.t. The reaction
was quenched by the addition of silica gel , the solvent was removed
under reduced pressure and the crude product was purified by flash
column chromatography (EtOAc–PE, 1:10). The title compound
was obtained (530 mg, quant) as a colorless oil; Rf 0.77 (EtOAc–PE,
1:10).
334.1929.
24c
Rf 0.55 (Et2O–pen, 1:20).
1H NMR (400 MHz, CDCl3): d = 0.82 (t, J = 6.9 Hz, 3 H, H-5¢),
3
1.20–1.29 (m, 4 H, 2 CH2), 1.51 (tt, 3J = 7.4, 7.4 Hz, 2 H,
CH2CH2CH2), 2.43 (t, 3J = 7.5 Hz, 2 H, H-1¢), 3.74 (s, 3 H, OCH3),
4.27 (s, 2 H, H-2), 6.19 (m, 2 H, H-4, CHarom), 6.21 (d, 3J = 12.4 Hz,
1 H, CH=CH), 6.44 (d, 3J = 12.4 Hz, 1 H, CH=CH), 6.75 (d, 4J = 0.6
Hz, CHarom), 7.11–7.27 (m, 5 H, C6H5).
13C NMR (100 MHz, CDCl3): d = 14.1 (+, C-5¢), 22.7, 31.0, 31.6,
36.7 (–, C-1¢ to C-4¢), 55.7 (+, OCH3), 66.8 (–, C-2), 104.1, 108.5,
121.3, 127.3, 128.2, 128.8, 129.1, 129.6 (+, CHarom, CHolefin), 110.7,
138.8, 145.1 (q, C-3, C-4a, C-7), 154.6, 155.5 (q, C-5, C-9a).
3
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 6.9 Hz, 3 H, H-5¢),
MS (EI, 70 eV, II): m/z (%) = 334 (100, [M+]), 277 (17, [M+ –
C4H9]).
1.28–1.42 (m, 4 H, 2 CH2), 1.62 (tt, 3J = 7.6, 7.6 Hz, 2 H,
CH2CH2CH2), 2.55 (t, 3J = 7.7 Hz, 2 H, H-1¢), 3.84 (s, 3 H, OCH3),
4.92 (s, 2 H, H-2), 5.07 [d, 3J = 17.6 Hz, 1 H, (E)-CH=CHH], 5.12
HR-EIMS (EI, 70 eV, II): m/z calcd for C25H26O2: 334.1933; found
334.1928.
3
4
[d, J = 10.8 Hz, 1 H, (Z)-CH = CHH], 6.29 (d, J = 0.85 Hz, 1
H
arom), 6.36 (d, 4J = 0.85 Hz, 1 Harom), 6.49 (ddd, 3J = 17.6, 10.8 Hz,
14-Acetyl-3-methoxy-5-pentyl-8-oxatricyclo[4.8.01,10.02,7]tet-
radeca-2,4,6,10-tetraene (25a)
4J = 0.57 Hz, 1 H, CH=CH2), 6.74 (s, 1 H, H-4¢).
13C NMR (75 MHz, CDCl3): d = 14.0 (+, C-5¢), 22.5, 30.8, 31.5,
36.4 (–, C-1¢ to C-4¢), 55.5 (+, OCH3), 64.8 (–, C-2), 103.8, 108.4,
118.7, 135.2 (+, CHarom, CHolefin), 109.6, 128.0, 144.9 (q, C-3, C-4a,
C-7), 111.9, (+, CH=CH2), 154.4, 155.4 (q, C-5, C-9a).
Procedure A (Lewis Acid Catalyzed): 5-Methoxy-7-pentyl-3-vinyl-
2H-chromene (24a; 247 mg, 956 mmol) and but-3-en-2-one (5c; 199
mL, 168 mg, 2.39 mmol)) were dissolved in anhyd CH2Cl2 (10 mL)
and cooled to –78 °C. At this temperature, BF3·OEt2 (12 mL, 14 mg,
96 mmol) was added to this mixture. The mixture was stirred for 5 h
at –78 °C, cooling was removed and the stirring was continued for
15 min. During this period, the color of the mixture changed from
orange to dark red. The mixture was poured into brine (15 mL), the
phases were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(MgSO4), the solvent was removed under reduced pressure and the
crude product was purified by flash column chromatography
(EtOAc–PE, 1:5) to yield 89.3 mg (28%) of the title compound as a
colorless oil.
MS (EI, 70 eV, I): m/z (%) = 258 (100, [M+]), 202 (76, [M+ –
C4H10]).
HR-EIMS (EI, 70 eV, I): m/z calcd for C25H22O2: 258.1620; found:
258.1621.
(E/Z)-5-Methoxy-7-pentyl-3-styryl-2H-chromene (24b,c)
Benzyltriphenylphosphonium bromide (6.24 g, 14.4 mmol) was
suspended in anhyd THF (150 mL) under argon. The mixture was
cooled to –78 °C and n-BuLi (8.4 mL, 1.6 M solution in hexane, 14
mmol) was added slowly. During the addition, the color of the solu-
tion turned to intense yellow. The mixture was stirred for 30 min,
the cooling was removed and the mixture was again stirred for 30
min at r.t. The suspension of the Wittig reagent was cooled to
Procedure B (Thermal): A mixture of 24a (1.58 g, 6.03 mmol) and
5c (1.06 g, 1.25 mL, 15.1 mmol) in DMF (15 mL) was heated to
70 °C for 24 h. After cooling to r.t., the mixture was diluted with
Et2O (30 mL) and H2O (40 mL), the layers were separated and the
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

1898
B. Lesch et al.
FEATURE ARTICLE
aqueous phase was extracted with Et2O (3 × 25 mL). The combined
organic layers were dried (MgSO4), the solvent was removed under
reduced pressure and the crude product was purified by flash col-
umn chromatography (EtOAc–PE, 1:5) to yield 1.22 g (62%) of the
title compound as a colorless oil; Rf 0.55 (EtOAc–PE, 1:5).
2 H, CH2CH2CH2), 1.78 (ddd, 2J = 13.1 Hz, 3J = 13.0, 11.0 Hz, 1 H,
3
2
H-13a), 2.50 (t, J = 7.8 Hz, 2 H, H-1¢), 2.85 (ddd, J = 13.1 Hz,
3J = 6.3, 2.4 Hz, 1 H, H-13b), 3.08 (ddd, 3J = 13.0, 6.3, 2.4 Hz, 1 H,
H-14), 3.48 (s, 3 H, OCH3), 3.70–3.78 (m, 2 H, H-1, H-12), 4.17 (d,
2J = 11.0 Hz, 1 H, H-9a), 4.24 (d, 2J = 11.0 Hz, 1 H, H-9b), 5.52 (dd,
4
4
3J = 2.7 Hz, J = 2.7 Hz), 6.28 (d, J = 1.3 Hz, 1 Harom), 6.76 (d,
4J = 1.3 Hz, 1 Harom), 7.01–7.06 (m, 3 H, CHarom, C6H5), 7.16–7.21
(m, 2 H, CHarom, C6H5).
3
1H NMR (400 MHz, CDCl3): d = 0.78 (t, J = 6.9 Hz, 3 H, C-5¢),
1.15–1.25 (m, 4 H, 2 CH2), 1.48 (tt, 3J = 7.5, 7.5 Hz, 2 H,
CH2CH2CH2), 1.66 (s, 3 H, CH3C=O), 1.79–2.19 (m, 4 H, H-12, H-
13), 2.40 (t, 3J = 7.9 Hz, 2 H, H-1¢), 3.70 (s, 3 H, OCH3), 3.72–3.79
(m, 2 H, H-1, H-14), 4.21 (dd, 2J = 11.3 Hz, 4J = 0.88 Hz, 1 H, H-
13C NMR (100 MHz, C6D6): d = 14.7 (+, C-5¢), 23.4, 26.2, 31.9,
32.2, 36.9 (–, C-1¢ to C-4¢, C-13), 28.8, 34.7, 43.7, 54.0 (+, C-1, C-
12, C-14, CH3C=O), 55.4 (+, OCH3), 71.2 (–, C-9), 104.7, 111.4,
127.7, 127.8, 129.0, 130.2 (CHarom, C-11), 113.2, 135.7, 140.9,
143.4 (q, C-2, C-5, C-10, Cq of C6H5), 158.0, 160.0 (q, C-3, C-7),
208.4 (q, CH3C=O).
2
9a), 4.31 (d, J = 11.3 Hz, 1 H, H-9b), 5.61–5.64 (m, 1 H, H-11),
6.17 (d, 4J = 1.4 Hz, 1 H, H-4 or H-6), 6.25 (d, 4J = 1.4 Hz, 1 H, H-
4 or H-6).
13C NMR (100 MHz, CDCl3): d = 13.9 (+, C-5¢), 22.2, 22.4, 25.3,
30.7, 31.5, 35.9 (–, C-12, C-13, C-1¢, C-2¢, C-3¢, C-4¢), 29.1 (+,
CH3C=O), 34.7, 47.6 (+, C-1, C-14), 55.2 (+, OCH3), 70.8 (–, C-9),
103.6, 110.0, 124.3 (+, C-4, C-6, C-11), 111.0, 131.5, 142.7 (q, C-
2, C-5, C-10), 157.5, 158.0 (q, C-2, C-7), 210.0 (q, CH3C=O).
MS (EI, 70 eV, II): m/z (%) = 404 (100, [M+]), 361 (54, [M+ –
CH3CO]), 334 (90, [M+ – C4H6O]).
HR-EIMS (EI, 70 eV, II): m/z calcd for C27H32O3: 404.2351; found:
404.2355.
MS (EI, 70 eV, II): m/z (%) = 328 (13, [M+]), 258 (29, [M+ –
C4H6O]), 189 (100, [M+ – C10H11O2]).
(1S/R,13S,14R)-3-Methoxy-13-methyl-5-pentyl-8-oxatricyc-
lo[4.8.01,10.02,7]tetradeca-2,4,6,10-tetraene-14-carbaldehyde
(endo/exo-25c)
HR-EIMS (EI, 70 eV, II): m/z calcd for C21H28O3: 328.2038; found:
328.2031.
To a solution of 24a (100 mg, 388 mmol) and L-proline (29a; 44.6
mg, 388 mmol) in MeOH (2 mL) were added H2O (0.1 mL) and cro-
tonaldehyde (5e; 54.4 mg, 63 mL, 776 mmol) and the mixture was
stirred at r.t. for 24 h. A sat. aq solution of NH4Cl (5 mL) and Et2O
(5 mL) were added, the phases were separated and the aqueous layer
was extracted with Et2O (3 × 10 mL). The combined organic ex-
tracts were dried (Na2SO4), the solvent was removed under reduced
pressure and the residue was purified by column chromatography to
yield 54.8 mg (55%) of the diene 24a and 22.5 mg (18%, 39% based
on recovered starting material) of endo/exo-25c as a colorless oil; Rf
0.39 (Et2O–pen, 1:10).
endo/exo-14-Acetyl-3-methoxy-5-pentyl-12-phenyl-8-oxatricyc-
lo[4.8.01,10.02,7]tetradeca-2,4,6,10-tetraene (endo/exo-25b)
(E)-Methoxy-7-pentyl-3-styryl-2H-chromene (24b; 500 mg, 1.49
mmol) and but-3-en-2-one (5c; 262 mg, (311 mL, 3.74 mmol) were
dissolved in DMF (2 mL) and heated to 70 °C under argon. After 24
h, another portion of 5c (262 mg, 311 mL, 3.74 mmol) was added
and the heating at 70 °C was continued for 24 h. The mixture was
diluted with H2O (10 mL) and Et2O (10 mL), the phases were sepa-
rated and the aqueous layer was extracted with Et2O (3 × 10 mL).
The combined organic extracts were dried (Na2SO4), the solvent
was removed under reduced pressure and the residue was purified
by column chromatography to yield 204 mg (34%) of endo-25b as
a colorless oil and 96.9 mg (16%) of exo-25b as a colorless solid.
When 29b was used as the catalyst, the catalyst was dissolved in
MeOH (0.5 mL), and dil. HCl (0.35 mL, c = 1 mol/L, 350 mmol) and
crotonaldehyde (5e, 54.4 mg, 63 mL, 776 mmol) were added and the
mixture was stirred for 5 min. A solution of 24a (100 mg, 388 mmol)
in MeOH (1.5 mL) was added and the mixture was stirred for 24 h.
After the work-up described above, the crude product was reduced
without further purification according to the procedure described
below.
endo-25b
Rf 0.44 (Et2O–pen, 1:5) .
3
1H NMR (400 MHz, C6D6): d = 0.85 (t, J = 7.0 Hz, 3 H, H-5¢),
1.20–1.27 (m, 4 H, 2 CH2), 1.35 (s, 3 H, CH3C=O), 1.54 (tt, 3J = 7.6,
7.6 Hz, 2 H, CH2CH2CH2), 2.07 (ddd, 2J = 14.0 Hz, 3J = 4.4, 4.4 Hz,
1 H, H-13a), 2.24 (ddd, 2J = 14.0 Hz, 3J = 7.5, 6.5 Hz, H-13b), 2.45
(t, 3J = 7.9 Hz, 2 H, H-1¢), 3.17 (ddd, 3J = 7.4, 7.4, 3.1 Hz, 1 H, H-
14), 3.42 (s, 3 H, OCH3), 3.71–3.79 (m, 2 H, H-1, H-12), 4.29 (d,
2J = 12.1 Hz, 1 H, H-9a), 4.46 (d, 2J = 12.1 Hz, 1 H, H-9b), 5.63 (d,
To obtain a racemic mixture, D/L-proline [(rac)-29a] was used as a
catalyst according to the procedure described for 29b.
1H NMR (400 MHz, C6D6): d = 0.97 (t, 3J = 7.0 Hz, 3 H, H-5¢), 1.07
(d, 3J = 7.3 Hz, 3 H, CHCH3), 1.33–1.40 (m, 4 H, 2 CH2), 1.67 (tt,
3J = 7.5 Hz, CH2CH2CH2), 1.83–2.00 (m, 1 H, H-12a), 2.37 (dddd,
4
3J = 3.1 Hz, 1 H, H-11), 6.22 (d, J = 1.4 Hz, 1 Harom), 6.73 (d,
3
4
2J = 19.0 Hz, J = 8.9, 4.4 Hz, J = 2.5 Hz, 1 H, H-12b), 2.58 (t,
3J = 7.8 Hz, 4J = 3.0 Hz, 2 H, H-1¢), 2.64 (qdd, 3J = 7.3, 6.8, 3.0 Hz,
1 H, H-13), 3.38–3.42 (m, 1 H, H-14), 3.43 (s, 3 H, OCH3), 3.97–
4.05 (m, 1 H, H-1), 4.21 (d, 2J = 10.9 Hz, H-9a), 4.29 (d, 2J = 10.9
4J = 1.4 Hz, 1 Harom), 7.10–7.15 (m, 5 H, C6H5).
13C NMR (100 MHz, C6D6): d = 14.7 (+, C-5¢), 23.4, 31.8, 32.4,
35.1, 36.9 (–, C-1¢ to C-4¢, C-13), 28.3, 34.5, 39.6, 49.0 (+, C-1, C-
12, C-14, CH3C=O), 55.5 (OCH3), 71.0 (C-9), 104.6, 111.5, 126.2,
126.9, 128.5, 129.0, 129.2 (+, CHarom, C-11), 112.3, 135.6, 143.2,
145.7, (q, C-2, C-5, C-10, Cq of C6H5), 158.7, 159.0 (q, C-3, C-7),
206.8 (q, CH3C=O).
3
Hz, 1 H, H-9b), 5.42 (dd, J = 6.4, 3.1 Hz, 1 H, H-11), 6.31 (d,
4J = 1.4 Hz, 1 Harom), 6.80 (d, 4J = 1.4 Hz, 1 Harom), 9.67 (d, 3J = 1.4
Hz, 1 H, CHO).
13C NMR (100 MHz, C6D6): d = 14.7 (+, C-5¢), 20.6, (+, C-13-CH3),
23.4, 29.3, 31.8, 32.4, 36.9 (–, 5 peaks, C-1¢ to C-4¢, C-12), 28.2,
29.7, 52.7 (+, C-1, C-13, C-14), 55.4 (+, OCH3), 71.2 (–, C-9),
104.6, 111.4, 126.0 (+, CHarom, C-11), 111.2, 132.1, 143.9 (q, C-2,
C-4, C-10), 158.9, 159.2 (C-3, C-7), 204 (CHO).
MS (EI, 70 eV, II): m/z (%) = 404 (44, [M+]), 334 (100, [M+ –
C4H6O]).
HR-EIMS (EI, 70 eV, II): m/z calcd for C27H32O3: 404.2351; found:
404.2351.
MS (EI, 70 eV, II): m/z (%) = 328 (34, [M+]), 258 (29, [M+ –
exo-25b
C4H6O]).
Mp 113–117 °C; Rf 0.23 (Et2O–pen, 1:5).
HR-EIMS (EI, 70 eV, II): m/z calcd for C21H28O3: 328.2038; found:
328.2033.
1H NMR (400 MHz, C6D6): d = 0.85 (t, J = 7.0 Hz, H-5¢), 1.33–
3
1.40 (m, 4 H, 2 CH2), 1.57 (s, CH3C=O), 1.59 (tt, 3J = 7.6, 7.6 Hz,
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Diels–Alder Approach towards Cannabinoids
1899
(1R/S,13S,14R)-14-Hydroxymethyl-3-methoxy-13-methyl-5-
pentyl-8-oxatricyclo[4.8.01,10.02,7]tetradeca-2,4,6,10-tetraene
(endo/exo-25d)
Crystal Structure Determinations of Compounds 7a and 14
The data were collected on a Nonius KappaCCD diffractometer at
–150 °C using MoKa radiation (l = 0.71073 Å). The structures
were solved by direct methods (SHELXS-97).22 The non-hydrogen
atoms were refined anisotropically; H-atoms were refined using a
riding model, H(O) free [full-matrix least-squares refinement on F2
(SHELXL-97)].23 Details of data collection and refinement are giv-
en in Table 4.24
Endo/exo-25c (22.5 mg, 68.6 mmol) was dissolved in anhyd THF (2
mL) under argon. LiAlH4 (approximately 100 mg) was added until
no more H2 was evolved. The mixture was stirred at r.t. for 30 min,
diluted with aq HCl (10 mL, c = 1 mol/L) and Et2O (10 mL), the
phases were separated and the aqueous phase was extracted with
Et2O (3 × 10 mL). The combined organic extracts were dried
(Na2SO4), the solvent was removed under reduced pressure and the
residue was purified by column chromatography to yield 8.4 mg
(37%) of endo-25d and 13.8 mg (61%) of exo-25d as colorless oils.
Table 4 Crystallographic Data, Structure Solution and Refinement
of 7a and 14
Compound
formula
Mr
7a
14
When 29b was used as a catalyst, the crude product of 25c was treat-
ed as described to yield 31.9 mg of 24a, 21.3 mg (17%, 25% based
on recovered starting material) of endo-25d and 37.4 mg (29%,
43% based on recovered starting material) of exo-25d.
C12H14O3
206.23
0.60 × 0.50 × 0.30
monoclinic
P21/n (No. 14)
7.0184(2)
6.0121(2)
23.7498)8)
90
C22H26O2
322.43
dimensions [mm]
crystal system
space group
a [Å]
0.50 × 0.30 × 0.10
orthorhombic
Pbca (No. 61)
9.7837(2)
17.6180(3)
20.3716(4)
90
endo-25d
Rf 0.66 (Et2O–pen, 1:1).
1H NMR (400 MHz, C6D6): d = 0.60 (t, 3J = 7.1 Hz, 3 H, H-5¢), 0.82
(d, 3J = 6.9 Hz, 3 H, CHCH3), 1.06–1.11 (m, 4 H, 2 CH2), 1.31 (tt,
3J = 7.6, 7.6 Hz, CH2CH2CH2), 1.40 (qddd, 3J = 13.4, 6.9, 5.3, 2.8
2
3
Hz, 1 H, H-13), 1.61 (ddd, J = 18.4 Hz, J = 5.3, 3.3 Hz, 1 H, H-
12a), 1.75 (dddd, 2J = 18.4 Hz, 3J = 13.4, 6.3 Hz, 4J = 3.0 Hz, 1 H,
b [Å]
3
3
H-12b), 2.21 (t, J = 7.9 Hz, 2 H, H-1¢), 2.73 (dddd, J = 5.8, 4.6,
4.6, 2.8 Hz, 1 H, H-14), 3.19, (5.8, 4J = 3.3, 3.2 Hz, 1 H, H-1), 3.85
(d, 2J = 11.1 Hz, 1 H, H-9a), 3.96 (d, 2J = 11.1 Hz, H-9b), 5.12 (dd,
3J = 5.3, 3.3 Hz, 1 H, H-11), 5.99 (d, 4J = 1.4 Hz, 1 Harom), 6.45 (d,
4J = 1.84 Hz, 1 Harom).
c [Å]
a [°]
b [°]
93.235(2)
90
90
13C NMR (100 MHz, C6D6): d = 14.7 (+, C-5¢), 20.8, (+, C-13-CH3),
23.4, 31.8, 32.4, 33.1, 39.1 (–, 5 peaks, C-1¢ to C-4¢, C-12), 36.9,
43.8 (+, C-1, C-14), 55.5 (+, OCH3), 60.3, 71.7 (–, C-9, CH2OH),
104.6, 111.3, 128.6 (+, CHarom., C-11), 112.3, 133.0, 145.5 (q, C-2,
C-4, C-10), 159.3, 159.8 (C-3, C-7).
g [°]
90
V [Å3]
1000.53(6)
4
3511.44(12)
8
Z
MS (EI, 70 eV, II): m/z (%) = 330 (28, [M+]), 258 (100, [M+ –
CH3CHOHCH=CH2]), 138 (46, [M+ – C12H16O2]).
r [g cm–3]
m [mm–1]
F(000)
1.369
1.220
HR-EIMS (EI, 70 eV, II): m/z calcd for C21H30O3: 330.2195; found:
328.2195.
0.098
0.076
440
1392
exo-25d
Rf 0.41 (Et2O–pen, 1:1).
2qmax. [°]
55
50
1H NMR (400 MHz, C6D6): d = 0.85 (t, 3J = 7.0 Hz, 3 H, H-5¢), 1.10
(d, 3J = 6.8 Hz, 3 H, CHCH3), 1.34–1.41 (m, 4 H, 2 CH2), 1.53 (ddd,
2J = 17.2 Hz, 3J = 6.1, 3.0 Hz, 1 H, H-12a), 1.58 (tt, 3J = 7.5, 7.5 Hz,
–5 £ h £ 9
–7 £ k £ 6
–30 £ l £ 30
4589
–7 £ h £ 11
–19 £ k £ 20
–24 £ l £ 24
13890
2
3
CH2CH2CH2), 2.21 (ddd, J = 17.2 Hz, J = 5.4, 2.6 Hz, 1 H, H-
3
12b), 2.28 (qddd, J = 6.8, 5.4, 3.1, 3.0 Hz, 1 H, H-13), 2.48 (t,
3J = 7.8 Hz, 2 H, H-1¢), 2.90 (dddd, 3J = 8.6, 6.0, 5.3, 3.1 Hz, 1 H,
H-14), 3.22 (dd, 2J = 10.6 Hz, 3J = 8.6 Hz, 1 H, CHaHOH), 3.32 (dd,
2J = 10.6, 3J = 5.3 Hz, 1 H, CHHbOH), 3.42, (s, 3 H, OCH3), 3.94
(ddd, 3J = 6.0 Hz, 4J = 4.0, 2.5 Hz, 1 H, H-1), 4.08 (dddd, 2J = 11.9
Hz, 4J = 2.0, 2.0, 0.8 Hz, 1 H, H-9a), 4.18 (d, 2J = 11.9 Hz, 1 H, H-
9b), 5.36 (dd, 3J = 6.1, 2.6 Hz, 1 H, H-11), 6.23 (d, 4J = 1.4 Hz, 1 H,
no. of meas. data
no. of unique data
Rint
2196
3093
0.0520
F2
0.0275
arom), 6.68 (d, 4J = 1.84 Hz, 1 H, Harom).
refinement on
F2
H
13C NMR (100 MHz, C6D6): d = 14.7 (+, C-5¢), 20.8, (+, C-13-CH3),
23.4, 31.8, 32.4, 33.1, 39.1 (–, 5 peaks, C-1¢ to C-4¢, C-12), 36.9,
43.8 (+, C-1, C-14), 55.5 (+, OCH3), 60.3, 71.7 (–, C-9, CH2OH),
104.6, 111.3, 128.6 (+, CHarom, C-11), 112.3, 133.0, 145.5 (q, C-2,
C-4, C-10), 159.3, 159.8 (C-3, C-7).
no. of parameters/
restraints
139/1
218/0
R1 [for I > 2s
(EI, 70 eV, I)]
0.0446
0.0364
MS (EI, 70 eV, II): m/z (%) = 330 (30, [M+]), 258 (100, [M+ –
C4H8O]).
wR2 (all data)
0.1275
0.0957
max/min difference
peak [e Å–3]
0.320/–0.283
0.222/–0.204
HR-EIMS (EI, 70 eV, II): m/z calcd for C21H30O3: 330.2195; found:
328.2193.
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York

1900
B. Lesch et al.
FEATURE ARTICLE
(8) Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc.
1967, 89, 4552.
(9) (a) Handrick, G. R.; Uliss, D. B.; Dalzell, H. C.; Razdan, R.
K. Tetrahedron Lett. 1979, 20, 681. (b) Stoss, P.; Merrath,
P. Synlett 1991, 553.
(10) (a) Pitt, C. G.; Seltzman, H. H.; Sayed, Y.; Twine, C. E. Jr.;
Williams, D. L. J. Org. Chem. 1979, 44, 677. (b) Nikas, S.
P.; Thakur, G. A.; Makriyannis, A. J. Labelled Compd.
Radiopharm. 2002, 45, 1065.
(11) Crombie, L.; Crombie, W. M. L.; Firth, D. F. J. Chem. Soc.,
Perkin Trans. 1 1988, 1251.
Acknowledgment
We would like to honor the fruitful cooperation and many stimula-
ting discussions in the field of cannabinoid chemistry with Profes-
sor Andreas Zimmer and Professor Christa E. Müller. We
acknowledge the help of Henning Vogt in determining the enantio-
meric excesses. Furthermore, we would like to express our gratitude
towards the DFG (Graduiertenkolleg 804 ‘Analyse von Zellfunktio-
nen durch kombinatorische Chemie und Biochemie’, fellowship to
J.T., and the SPP 1133 ‘Organocatalysis’) and the Graduiertenför-
derung Nordrhein Westphalen (fellowship to B.L.) for their financi-
al support.
(12) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von
Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.;
Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc. 1999,
121, 7582.
References
(13) Childers, W. E. Jr.; Pinnick, H. W. J. Org. Chem. 1984, 49,
5276.
(14) Fahrenholtz, K. E.; Lurie, M.; Kierstead, R. W. J. Am. Chem.
Soc. 1967, 89, 5934.
(1) Sertürner, F. W. A. Trommsdorf’s J. Pharm. 1806, 13, 234.
(2) (a) Mechoulam, R.; Gaoni, Y. J. Am. Chem. Soc. 1965, 87,
3273. (b) Palmer, S. L.; Thakur, G. A.; Makriyannis, A.
Chem. Phys. Lip. 2002, 121, 3.
(15) (a) Satoh, Y.; Stanton, J. L.; Hutchison, A. J.; Libby, A. H.;
Kowalski, T. J.; Lee, W. H.; White, D. H.; Kimble, E. F. J.
Med. Chem. 1993, 36, 3580. (b) Kaye, P. T.; Nocanda, X.
W. J. Chem. Soc., Perkin Trans. 1 2000, 1331.
(c) Takadate, A.; Masuda, T.; Murata, C.; Shibuya, M.;
Isobe, A. Chem. Pharm. Bull. 2000, 48, 256. (d) Shiraishi,
M.; Aramaki, Y.; Seto, M.; Imoto, H.; Nishikawa, Y.;
Kanzaki, N.; Okamoto, M.; Sawada, H.; Nishimura, O.;
Baba, M.; Fujino, M. J. Med. Chem. 2000, 43, 2049.
(e) Ravichandran, S. Synth. Commun. 2001, 31, 1233.
(f) Kaye, P. T.; Nocanda, X. W. J. Chem Soc., Perkin Trans.
1 2002, 1318.
(16) (a) Lesch, B.; Bräse, S. Angew. Chem. Int. Ed. 2004, 43, 115;
Angew. Chem. 2004, 116, 118. (b) Lee, K. Y.; Kim, J. M.;
Kim, J. N. Bull. Korean Chem. Soc. 2003, 24, 17; Chem.
Abstr. 2003, 139, 52830.
(17) Lesch, B.; Toräng, J.; Vanderheiden, S.; Bräse, S. Adv.
Synth. Catal. 2005, 347, 555.
(3) (a) Di Marzo, V.; Breivogel, C. S.; Tao, Q.; Bridgen, D. T.;
Razdan, R. K.; Zimmer, A. M.; Zimmer, A.; Martin, B. R. J.
Neurochem. 2000, 75, 2434. (b) Breivogel, C. S.; Griffin,
G.; Di Marzo, V.; Martin, B. R. Mol. Pharmacol. 2001, 60,
155. (c) Steffens, S.; Veillard, N. R.; Arnaud, C.; Pelli, G.;
Burger, F.; Staub, C.; Zimmer, A.; Frossard, J.-L.; Mach, F.
Nature 2005, 434, 782.
(4) For reviews on endocannabinoid signalling, see: (a) Di
Marzo, V.; Deutsch, D. G. Neurobiol. Dis. 1998, 5, 386.
(b) Porter, A. C.; Felder, C. C. Pharm. Ther. 2001, 90, 45.
(c) Maccarone, M.; Finazzi-Agró, A. Cell Death Diff. 2003,
10, 946. (d) Piomelli, D. Nat. Rev. Neurosci. 2003, 4, 873.
(e) Wendeler, M.; Kolter, T. Angew. Chem. Int. Ed. 2003,
42, 2938; Angew. Chem. 2003, 115, 3044. (f) Battista, N.;
Fezza, F.; Maccarone, M. Curr. Neurovas. Res. 2004, 1,
129. (g) De Petrocellis, L.; Cascio, M. G.; Di Marzo, V. Brit.
J. Pharmacol. 2004, 141, 765.
(5) For a review on cannabinoid receptors and (ant)agonists,
see: Howlett, A. C.; Barth, F.; Bonner, T. I.; Cabral, G.;
Casellas, P.; Devane, W. A.; Felder, C. C.; Herkenham, M.;
Mackie, K.; Martin, B. R.; Mechoulam, R.; Pertwee, R. G.
Pharmacol. Rev. 2002, 54, 161.
(6) Sun, H.; Mahadevan, A.; Razdan, R. K. Tetrahedron Lett.
2004, 45, 615.
(7) For a review on cannabinoid synthesis, see: (a) Razdan, R.
K. Total Synth. Nat. Prod. 1981, 4, 185. For a selection of
relevant literature, see: (b) Gaoni, Y.; Mechoulam, R. J. Am.
Chem. Soc. 1964, 86, 1646. (c) Mechoulam, R.; Gaoni, Y. J.
Am. Chem. Soc. 1965, 87, 3273. (d) Gaoni, Y.; Mechoulam,
R. Tetrahedron 1966, 22, 1481. (e) Petrzilka, T.; Haefliger,
W.; Sikemeier, C.; Ohloff, G.; Eschenmoser, A. Helv. Chim.
Acta 1967, 50, 719. (f) Jen, T. Y.; Hughes, G. A.; Smith, H.
J. Am. Chem. Soc. 1967, 89, 4551. (g) Tietze, L.-F.; von
Kiedrowski, G.; Harms, K.; Clegg, W.; Sheldrick, G. Angew.
Chem., Int. Ed. Engl. 1980, 19, 134; Angew. Chem. 1980, 92,
130. (h) Tietze, L.-F.; von Kiedrowski, G.; Berger, B.
Angew. Chem., Int. Ed. Engl. 1982, 21, 221; Angew. Chem.
1982, 94, 222. (i) Tius, M. A.; Xueqin, G.; Kerr, M. A. J.
Chem. Soc., Chem. Commun. 1989, 62. (j) Tietze, L.-F.;
von Kiedrowski, G.; Fahlbush, K. G.; Voss, E. Org. Synth.
1990, 69, 31. (k) Tius, M. A.; Kannangara, G. S. K.
Tetrahedron 1992, 48, 9173.
(18) Barbosa, L. C. A.; Ferreira, M. L.; Demuner, A. J.; da Silva,
A. A.; de Cássia Pereira, R. Quim. Nova 2001, 24, 751;
Chem. Abstr. 2001, 136, 382963.
(19) Minami, T.; Matsumoto, Y.; Nakamura, S.; Koyanagi, S.;
Yamaguchi, M. J. Org. Chem. 1992, 57, 167.
(20) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243. (b) Northrup, A. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.
(c) Ramachary, D. B.; Anebouselvy, K.; Chowdari, N. S.;
Barbas, C. F. III J. Org. Chem. 2004, 69, 5838.
(d) Ramachary, D. B.; Barbas, C. F. III Chem. Eur. J. 2004,
10, 5323. (e) Wabnitz, T. C.; Saaby, S.; Jørgensen, K. A.
Org. Biomol. Chem. 2004, 2, 828.
(21) Kinsmann, A. C.; Kerr, M. A. J. Am. Chem. Soc. 2003, 125,
14120.
(22) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467.
(23) Sheldrick, G. M. SHELXL-97; University of Göttingen:
Germany, 1997.
(24) Crystallographic data (excluding structure factors) for the
structures reported in this work have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-258378 (7a) and CCDC-258379
(14), respectively. Copies of the data can be obtained free of
charge on application to The Director, CCDC, 12 Union
Road, Cambridge, UK.
Synthesis 2005, No. 11, 1888–1900 © Thieme Stuttgart · New York