A cyclotrimerization route to cannabinoids

Article abstract of DOI:10.1021/ol800589e

(Chemical Equation Presented) Three members of the cannabinoid class, cannabinol, cannabinol methyl ether, and cannabinodiol, were synthesized using a microwavemediated [2 + 2 + 2] cyclotrimerization reaction as the key step. This approach provides a high level of synthetic flexibility allowing for the facile synthesis of cannabinoid analogues.

Full text of DOI:10.1021/ol800589e

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2195-2198
A Cyclotrimerization Route to
Cannabinoids
Jesse A. Teske and Alexander Deiters*
North Carolina State UniVersity, Department of Chemistry,
Raleigh, North Carolina 27695-8204
alex_deiters@ncsu.edu
Received March 13, 2008
ABSTRACT
Three members of the cannabinoid class, cannabinol, cannabinol methyl ether, and cannabinodiol, were synthesized using a microwave-
mediated [2 + 2 + 2] cyclotrimerization reaction as the key step. This approach provides a high level of synthetic flexibility allowing for the
facile synthesis of cannabinoid analogues.
The natural cannabinoids comprise a group of more than 60
terpenophenolic compounds present in Cannabis.1 Structur-
ally, all phytocannabinoids contain a 5-alkyl (typically a five
carbon-chain) resorcinol aromatic ring that is connected at
the 2-position to a monoterpene motif. Biosynthetically, this
monoterpene unit undergoes cyclization yielding a diverse
range of natural products including cannabinol (1), canna-
binol methyl ether (2), cannabinodiol (3), ∆9-tetrahydrocan-
nabinol (THC, 4), and cannabichromene (5) (Figure 1).
Besides the well-known recreational use of the Cannabis
plant for its psychotropic effects, medicinal applications have
been known since the third millennium BC and include
antiemetic,2 analgesic,3,4 and anticonvulsant5 properties,
among others.4,6 Cannabinoids act upon two cellular recep-
Figure 1. Examples of naturally occurring cannaboids.
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10.1021/ol800589e CCC: $40.75
Published on Web 05/02/2008
2008 American Chemical Society

tor are highly desired,9,10 especially since CB2-selective
ligands should limit the side effects associated with CB1
receptor activation.8,11
available olivetol. A high level of regioselectivity in the
cyclotrimerization step will be induced through a sterically
demanding trimethylsilyl (TMS) group which can subse-
quently be removed in a traceless fashion.
First, the optimal structural features for an efficient and
regioselective [2 + 2 + 2] cyclotrimerization reaction toward
the cannabinoid core structure were delineated by synthesiz-
ing a series of model diynes (10-15) that differed in their
electronic and steric properties (Scheme 2; see the Supporting
Thus far, cannabinol derivatives have primarily been
modified at positions C-1, C-3, and C-9.10,12 Previous
syntheses of cannabinol and its derivatives have relied upon
two general strategies: (1) coupling 5-alkyl resorcinols with
suitably substituted arenes followed by pyran formation13
or (2) generating tetrahydro derivatives first via coupling of
5-alkylresorcinols with appropriate cyclohexane derivatives
followed by pyran formation and/or aromatization.10,12,14
Accessing broadly substituted C-ring analogues would
require more elaborate arene or cyclohexene starting materi-
als. In this paper, we present a flexible synthetic route to
the cannabinol core structure based on a [2 + 2 + 2]
cyclotrimerization reaction15 that is amenable to the synthesis
of various C-ring analogues from easily accessible alkyne
and nitrile precursors.
Scheme 2
.
Investigation of the [2 + 2 + 2] Cyclotrimerization
Key Step of the Diynes 10-15
In order to illustrate the feasibility of a [2 + 2 + 2]
cyclotrimerization approach, we synthesized several natural
cannabinoids including cannabinol (1), cannabinol methyl
ether (2), and cannabinodiol (3). Our synthetic strategy
toward 1-3 is depicted in Scheme 1. We envisioned the
Scheme 1. Retrosynthetic Analysis of Cannabinol (1),
Cannabinol Methyl Ether (2), and Cannabinodiol (3)
Information for diyne syntheses). These molecules were
subjected to Ru-catalyzed cyclotrimerization reactions (10
mol % of Cp*Ru(cod)Cl16) with 1-hexyne (10 equiv) under
microwave irradiation17,18 (toluene, 300 W, 10 min, sealed-
vessel). The terminal diyne 1019 delivered the cyclotrimer-
ization product 16 in a 61% yield as a 70:30 regioisomeric
cannabinoids 1-3 being derived from either 6 or 7. In turn,
these tricyclic molecules would be obtained by a regiose-
lective transition-metal-catalyzed [2 + 2 + 2] cyclotrimer-
ization reaction of an appropriately substituted diyne 8 or 9.
These diynes would be readily prepared from commercially
1
mixture of pyrans as determined by GC/MS and H NMR
analysis. The cyclotrimerization reaction of the ester analogue
1120 led to an increased regioselectivity in favor of the isomer
17a over the isomer 17b (76:24 based on 1H NMR analysis)
with a diminished yield of 31%. This result correlates well
with Yamamoto’s findings under nonmicrowave irradiation
conditions.20 The low yields in case of 10 and 11 are a result
of di- and trimerization of the diyne starting material, a
problem commonly seen in cyclotrimerization reactions of
(9) (a) Marriott, K. S.; Huffman, J. W. Curr. Top. Med. Chem. 2008, 8,
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2196
Org. Lett., Vol. 10, No. 11, 2008

reactive (terminal) diynes.16,21 The introduction of a methyl
group (R1 ) CH3) on one of the triple bonds produced a
highly efficient and regioselective cyclotrimerization reaction
delivering 18a (95:5) in 96% yield from the diyne 12. The
corresponding ester derivative 13 was converted in 71% yield
into the pyrone 19a with complete regioselectivity. These
results indicated the ability to induce high levels of regi-
oselectivity in the cyclotrimerization reaction toward the
tricyclic cannabinoid core. For the synthesis of the natural
cannabinoids, a removable regiodirecting group was desired.
Toward this goal, the TMS-derivatized diynes 14 and 15 were
prepared and investigated in the cyclotrimerization reaction.
Continuing with the trend that increased steric bulk leads to
a more efficient cyclotrimerization, both diynes 14 and 15
furnished the desired products 20a (97% yield) and 21a (81%
yield), respectively, both with complete regioselectivity.
These trends underscore the necessity to balance reactivity
and steric demand in order to achieve highly efficient [2 +
2 + 2] cyclotrimerization reactions. Diynes based on both
14 and 15 are suitable cyclotrimerization precursors for the
synthesis of 1-3, and the ability to replace the TMS group
with a hydrogen atom has previously been shown.22
Scheme 3
.
Total Synthesis of Natural Cannabinol (1) and
Cannabinol Methyl Ether (2)
Our synthesis of 1 commences with the known salicyla-
ldehyde derivative 2223 (prepared in three steps from olivetol)
which is alkylated with 3-bromo-1-trimethylsilyl-1-propyne
to give the propargyl ether 23 (89% yield, Scheme 3).
Installation of the second triple bond was accomplished by
treatment of 23 with the lithium salt of trimethylsilyldiazo-
methane24 furnishing the diyne 24 in 71% yield. Attempts
to synthesize ester-tethered diynes (as in 9) via a Corey-Fuchs
reaction (and related transformations) or a Sonogashira
coupling were unsuccesful or extremely low yielding. As in
the case of the model study with the diyne 14, the compound
24 underwent an efficient and regioselective Cp*Ru(cod)Cl-
catalyzed [2 + 2 + 2] cyclotrimerization reaction with
propargyltrimethylsilane under microwave irradiation to
deliver the pyran 25 in 88% yield as a single regioisomer.
A reaction with propyne under pressurized closed-vessel
microwave conditions was not conducted due to its low
boiling point. Removal of the aryl- and alkyl-TMS groups
was rapidly accomplished by exposure to TBAF under
microwave irradiation for 2 min to give the desilylated pyran
26 (96% yield). The next steps involved incorporation of
the gem-dimethyl substituents at the 6-position of the pyran
ring. First, a selective oxidation of the benzylic methylene
group with PCC furnished the pyrone 27 in 98% yield.25
Cannabilactones related to 27 have been shown to be
selective CB2 agonists.26 Addition of CH3Li followed by an
acid-catalyzed ring closure of the crude diol provided
cannabinol methyl ether (2), a natural product observed in
plant extracts from Cannabis satiVa,27 in 91% yield over
two steps.
Subsequent deprotection of the methylphenol with aqueous
HI (77% yield) completed the total synthesis of cannabinol
(1). The use of BBr3 in the demethylation reaction delivered
1 with an identical yield.
The developed route to cannabinol was modified to allow
for the facile synthesis of the isomeric cannabinoid, can-
nabinodiol (3).28 In this direction, demethylation of the ether
27 with aqueous HI smoothly provided the phenol 2829 in
quantitative yield (Scheme 4). Treatment of 28 with excess
MeMgBr furnished a crude triol that was subsequently
dehydrated with methanesulfonyl chloride and TEA to deliver
the methylstyrene (29) in 61% yield over two steps as well
as 22% of mesylated cannabinol. Deprotection of the
phenolic hydroxy groups with excess MeLi30 delivered
natural cannabinodiol (3) in 72% yield.28
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1988, 1357
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Soc. 1980, 102, 5253.
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Org. Lett., Vol. 10, No. 11, 2008
2197

regioselectivity. Three natural products, cannabinol (1),
cannabinol methyl ether (2), and cannabinodiol (3), were
synthesized to illustrate the flexibility of this approach to
the cannabinoid architecture. The developed cyclotrimeriza-
tion approach enables the rapid introduction of a diverse set
of substituents at the 7-, 8-, 9-, and 10-positions (see Figure
1) of the C-ring through the reaction of substituted diynes
with a variety of alkynes.17,30
Scheme 4. Total Synthesis of Cannabinodiol (3)
Acknowledgment. This research was supported by the
Donors of the American Chemical Society Petroleum
Research Fund and the Department of Chemistry at North
Carolina State University. We thank CEM Corp. for their
support.
Supporting Information Available: General cyclotrim-
In summary, we have developed a novel route to the
cannabinoid framework via a ruthenium-catalyzed microwave-
mediated [2 + 2 + 2] cyclotrimerization reaction. Several
diyne precursors for the synthesis of the tricyclic core
structure were probed to investigate the steric and electronic
effects on the [2 + 2 + 2] cyclotrimerization efficiency and
erization protocol, experimental details, and analytical data
1
as well as H NMR spectra for compounds 1-3, 12-16,
18-21, 23-27, and 29. This material is available free of
charge via the Internet at http://pubs.acs.org.
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