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The Synthetic Routes of Tetrahydrocannabinol
Gabrielle L. Abbott
Department of Chemistry and Biochemistry
Utica College, Utica, NY 13502
15 April 2014
Advanced Organic Term Paper
Professor: Dr. Michelle Boucher
2
Cannabinoids are active chemicals in Cannabis Sativa L (family: cannabinaceae) that
causes drug-like effects.12
The term cannabinoid usually refers to the typical 21-carbon
compounds, and includes both analogs and transformation products. 3 The natural synthesis of
cannabinoids takes place in Cannabis Sativa L also known as cannabis, marijuana, pot, weed,
hashish, hemp, grass or ganja.1 Cannabinoids are contained in a resin produced by the Cannabis
plant.2 Marijuana has become more common over the past four to five decades with many
Americans trying it once or using it habitually. There are a variety of reasons for using this
product whether they are deemed medical or recreational. “The illicit use of marijuana, which
started in a substantial way in the early 1960s, has continued to increase. By 1975 over 36
million Americans had tried the drug, and among the 20-24 age group over 10% were using it on
a daily basis.” 3
Currently in the United States, Cannabis is considered a controlled substance and is
classified as a Schedule I agent, meaning that it is a drug with increased potential for abuse. It is
a crime punishable by federal law to use, sell and possess this drug. However, an increasing
number of states have enacted laws on the use of both medical and recreational marijuana.
States that currently allow the legal use of medical marijuana are Alaska, Arizona, California,
Colorado, Connecticut, Delaware, The District of Columbia, Hawaii, Illinois, Maine, Maryland,
Michigan, Montana, Nevada, New Hampshire, New Jersey, New Mexico, Oregon, Rhode Island,
Vermont, and Washington. Colorado and Washington have also enacted laws allowing the
recreational use of marijuana.2
Marijuana came into use in the medical world just recently. Its main target is the central
nervous system. Researchers have recently found cannabinoid receptors in both brain and nerve
cells, as well as on immune system cells, suggesting an important role in immunity.12
Marijuana
was first introduced to patients exhibiting open
and decrease lacrimation in the eye, and
undergoing chemotherapy.123
relieve pain, relieve anxiety and
oral, inhalation, ingestion, dermal, eye, and perenteral.
where cannabinoids are quickly and easily absorbed into the bloodstream.
The main active cannabinoid in marijuana is tetrahydrocannabinol, or THC. The other
very active cannabinoid is cannabidiol, or
people “high” where as the CBD component is thought to be the more medicinal part of the
cannabis plant.2
Figure 1. delta-6-THC and CBD structures.
THC has many isomers. The most common known isomer is delta
be the essence of naturally occur
people “high”. Although very common in nature, it is also the most sy
of THC.2 This paper will concentrate
system. ∆9-THC uses the dibenzopyran numbering system while this paper will be referring to
the monoterpenoid numbering system where
was first introduced to patients exhibiting open-angle glaucoma to reduce intra
and decrease lacrimation in the eye, and also to cancer patients as an antinauseant while
It can be used to reduce nausea and vomiting, stimulate appetite,
anxiety and induce sleep.2 There are many ways to use
oral, inhalation, ingestion, dermal, eye, and perenteral.1 The most common use is inhalation
where cannabinoids are quickly and easily absorbed into the bloodstream.2
The main active cannabinoid in marijuana is tetrahydrocannabinol, or THC. The other
very active cannabinoid is cannabidiol, or CBD (Figure 1). THC is the component that gets
people “high” where as the CBD component is thought to be the more medicinal part of the
THC and CBD structures.
THC has many isomers. The most common known isomer is delta-9-THC and is thought o
be the essence of naturally occurring cannabis and is the most well known cannabinoid that gets
Although very common in nature, it is also the most synthetically derived form
concentrate on this particular isomer, by the use of a different number
THC uses the dibenzopyran numbering system while this paper will be referring to
the monoterpenoid numbering system where ∆9-THC is actually called ∆
1 –
3
aucoma to reduce intra-ocular pressure
to cancer patients as an antinauseant while
nausea and vomiting, stimulate appetite,
There are many ways to use Cannabis including
The most common use is inhalation
The main active cannabinoid in marijuana is tetrahydrocannabinol, or THC. The other
. THC is the component that gets
people “high” where as the CBD component is thought to be the more medicinal part of the
4
THC and is thought of to
most well known cannabinoid that gets
nthetically derived form
on this particular isomer, by the use of a different number
THC uses the dibenzopyran numbering system while this paper will be referring to
–THC (1).3
Figure 2. General THC structure exhibiting the two numbering systems used.
∆1 –THC is the most optically
THC (2), also known as ∆8-THC
of plants. The cis isomers of these two THC products
found in fewer then three plants. The
stable compared to the cis compounds
more stable then the delta-1 isomer because delta
acids (Figures 3 and 4). The biggest issue is that the most common natural THC product is
trans-∆1-THC but during synthesis the more stable derivatives of
often.3
Figure 3. The trans-THC isomers.
Figure 2. General THC structure exhibiting the two numbering systems used.
THC is the most optically active resin with the other physiologically active isomer being
THC (Figure 2). The delta-6 isomer is only active in a few varieties
isomers of these two THC products have been synthesized, but ha
plants. The trans isomers are thought to be more thermodynamically
compounds (3 and 4), and within the trans series, the delta
1 isomer because delta-1 is too easily isomerized when treated with
The biggest issue is that the most common natural THC product is
but during synthesis the more stable derivatives of trans-∆6-
4
3
the other physiologically active isomer being ∆6-
6 isomer is only active in a few varieties
have been synthesized, but have been
isomers are thought to be more thermodynamically
series, the delta-6 isomer is
ly isomerized when treated with
The biggest issue is that the most common natural THC product is
-THC are formed more
3
Figure 4. The cis-THC isomers.
There are many strategies in the synthesis of both
category of syntheses is stereospecific
verbenols, from chrysanthenol, from p
Menth-2-ene-1,8-diol. All of the above stated syntheses produce the
syntheses will lead to a racemic mixture of the
chosen as the starting material because it has a bulky dimethyl
to provide stereochemical control of the reactions and it is optically pure so it is open to both the
cis (+) and trans (-) syntheses.
methylene chloride and an acid catalyst like
attack by the rescorsinol would favor the side without the dimethylmethene bridge
of its bulky nature. This also prov
this reaction.3 Three oily compounds (
yield while the other racemates were found to have similar NMR spectra to the starting material.
They were also found to be quite unstable and much less polar.
isolated by chromatography where it was treated with boron trifluoride etherate in methylene
chloride at room temperature. This yielded a conversion to and 85% yield of pure
There are many strategies in the synthesis of both ∆1- and ∆
6-THC. One specific
category of syntheses is stereospecific syntheses. This category consists of synthesis from
verbenols, from chrysanthenol, from p-Menth-2,8-dien-1-ol, from carene epoxides, and from p
diol. All of the above stated syntheses produce the trans
syntheses will lead to a racemic mixture of the trans products 1 and 2. A pinane derivative was
material because it has a bulky dimethylmethylene bride that was expected
to provide stereochemical control of the reactions and it is optically pure so it is open to both the
) syntheses.5 Verbenol (5) was condensed with olivetol (
methylene chloride and an acid catalyst like p-toluenesulfonic acid.35 It was predicted that the
attack by the rescorsinol would favor the side without the dimethylmethene bridge
This also provides the stereochemical control that yields the (
Three oily compounds (7,8,9) were produced. The major product,
yield while the other racemates were found to have similar NMR spectra to the starting material.
They were also found to be quite unstable and much less polar.5 The major product,
isolated by chromatography where it was treated with boron trifluoride etherate in methylene
chloride at room temperature. This yielded a conversion to and 85% yield of pure
5
3
THC. One specific
syntheses. This category consists of synthesis from
ol, from carene epoxides, and from p-
products.3 These total
. A pinane derivative was
ene bride that was expected
to provide stereochemical control of the reactions and it is optically pure so it is open to both the
condensed with olivetol (6) in the presence of
It was predicted that the
attack by the rescorsinol would favor the side without the dimethylmethene bridge in 5, because
ides the stereochemical control that yields the (-) products of
were produced. The major product, 7, gave a 45%
yield while the other racemates were found to have similar NMR spectra to the starting material.
The major product, 7, was
isolated by chromatography where it was treated with boron trifluoride etherate in methylene
chloride at room temperature. This yielded a conversion to and 85% yield of pure 2 (this was
confirmed by IR, NMR, and TLC plating)
35%, researchers found that they could conde
etherate instead of p-toluenesulfoni
Some of the ∆6-THC product was converted into the
hydrogen chloride to the double bond and subsequent elimination steps
Figure 5. The mechanism of trans stereospecific synthesis from Verbenol.
Figure 6. The conversion of delta-6-THC into delta
confirmed by IR, NMR, and TLC plating).35
Generating a much lower yield of product
35%, researchers found that they could condense verbenol and olivetol in boron trifluoride
toluenesulfonic acid (Figure 5). This yields the same pure
THC product was converted into the ∆1-THC product by the addition of
hydrogen chloride to the double bond and subsequent elimination steps (Figure 6)
stereospecific synthesis from Verbenol.
THC into delta-1-THC.
6
Generating a much lower yield of product 2 at just
etol in boron trifluoride
. This yields the same pure trans product.
THC product by the addition of
(Figure 6).5
3
Another trans stereospecific synthesis originates from p
olivetol.3 The main product of this reaction is the
being produced. In this study instead of looking directly into the synthesis of these products,
experimenters took a closer look at the other products.
was found through gas-liquid chromatography, or GLC, tha
and abnormal cannabidiol (abn
halted at this stage if less then 0.5% boron trifuloride etherate (BF
toluenesulfonic acid (p-TSA) was
into normal and abnormal THC products (
ratio of normal to abnormal products significantly changed from 1:2 to 3:1 indicating the
transformation of abn-CBD (14
for the above transformation, a series of experiments involving the
compounds were performed.
set forth by experiment 2 in Table I.
stereospecific synthesis originates from p-Mentha-2,8
The main product of this reaction is the ∆1-THC (1) with a small amount of
being produced. In this study instead of looking directly into the synthesis of these products,
experimenters took a closer look at the other products. By delving deeper into this reaction, it
liquid chromatography, or GLC, that normal cannabidiol (
abn-CBD, 14) were formed, at first, in a fixed 1:2 ratio.
halted at this stage if less then 0.5% boron trifuloride etherate (BF3•Et2O) or wet
TSA) was employed. Following this was the conversion of
into normal and abnormal THC products (1 and 16) and iso-THC products (
ratio of normal to abnormal products significantly changed from 1:2 to 3:1 indicating the
14) to normal products was happening.3 To clarify the mechanism
for the above transformation, a series of experiments involving the normal and abnormal
compounds were performed. Compound 12 was treated with the same experimental conditions
th by experiment 2 in Table I.6
7
2,8-dien-1-ol and
) with a small amount of ∆6-THC (2)
being produced. In this study instead of looking directly into the synthesis of these products,
By delving deeper into this reaction, it
t normal cannabidiol (n-CBD, 12)
t first, in a fixed 1:2 ratio.6 The reaction
O) or wet p-
he conversion of 12 and 14
THC products (15 and 17). The
ratio of normal to abnormal products significantly changed from 1:2 to 3:1 indicating the
To clarify the mechanism
normal and abnormal
was treated with the same experimental conditions
6
It was found that for the synthesis of the
(1), 23% iso-THC (15), 2% olivetol (
compound 2 and all abnormal
under the conditions stated in experiment 1 in Table I, 34%
According to Figure 2, small amounts of
This shows that the THC/iso-THC ratios were reversed in an abnormal series. The reaction
mixture originating from compound
found that for the synthesis of the trans-delta-1 isomer, the reaction yielded 70%
), 2% olivetol (6), and 5% unreacted starting material (
and all abnormal products were not formed according to Figure 1. Compound
under the conditions stated in experiment 1 in Table I, 34% 1, 13% 15, 15%
According to Figure 2, small amounts of 2 and 6 were formed.6
THC ratios were reversed in an abnormal series. The reaction
mixture originating from compound 12 contained compounds 2 and 18, as well as
8
6
1 isomer, the reaction yielded 70% ∆1-THC
), and 5% unreacted starting material (11). Both
products were not formed according to Figure 1. Compound 14
, 15% 16, and 30% 17.
6
THC ratios were reversed in an abnormal series. The reaction
, as well as 1 and 15, after
prolonged treatment. As well, the reaction mixture
compounds 19 and 20, as well as
Figure 7. Diels-Alder Synthesis.
prolonged treatment. As well, the reaction mixture originating from compound
, as well as 16 and 17, with similar treatment (Figure 7)
9
mpound 14 contained
(Figure 7).6
3
10
On the account of sterics, the behavior of both n-CBD (12) and abn-CBD (14) can be
explained. Compound 14, unlike compound 12, shows ring closure to abnormal THC 16 that
results in huge steric interaction between the C-2 vinylic proton and the benzylic methylene of
the C5H11 group. This steric hindrance, slows the formation of compound 16 and increases the
probability of 14 undergoing cleavage resulting in either compound 17 or ion c and ion d.3
Other Approaches to the synthesis of ∆1-THC and ∆
6-THC have been found. One such
approach is a Diels-Alder Reaction in which a diene and dienophile react in an organic synthesis
to form a substituted cyclohexene product. This is also deemed a conjugate addition reaction.
The beginning of this synthesis involves an enolate being attacked by ethoxy in order to further
undergo an aldol-condensation reaction. This deprotonated enolate attacks underneath the
carbonyl of compound 31, forming an α-β-keto system (32) (Figure 8). Here, 32 undergoes the
first of two Wittig reactions, forming an intermediate containing a four-membered ring using
ylide to react. This forms product 33 (Figure 9). This compound now acts as the diene and is
reacted with CH3COCH=CH2, or the dienophile. This is known as cycloaddition, and produces a
cyclohexene compound (34) (Figure 10). The second of the two Wittig reactions converts this
product into compound 35, and then undergoes two more reactions to produce both trans-∆1-
THC and trans-∆6-THC products (compounds 1 and 2 respectively) (Figures 11 and 12). It is
important to mention that this is one of two Diels-Alder reactions that can be used to produce
synthetic trans-THC products.3
Figure 8. Aldol Condensation Reaction.
Figure 9. First Wittig Reaction.
11
Figure 10. The diene reacts with the dienophile.
Figure 11. The Second Wittig Reaction.
Figure 10. The diene reacts with the dienophile.
12
Figure 12. The final reactions leading to the
The cis isomers, compounds
generally much less thermodynamically stable then the
cannabis plant, only compound
Compound 3 is much more thermodynamically stable then compound
characterized and observed through synthetic syntheses. Sustained synthesis and
characterization of compound
reproducible synthesis of compound
Tetrahydrocannabinol
isomers and “unnatural” (bulky groups placed on different carbons to create steric hindrance)
THC products have been found in nature or being synthesized in a lab.
is an ongoing debate in the United States, scientists are ready to produce the natural and
synthetic products to provide for the masses. It has been indicated as a helpful tool in the cancer
patients undergoing chemotherapy, people with HIV/AIDS, glaucoma patients, and people with
multiple sclerosis. Cannabis Sativa L
THCs that become reproducible synthetic products.
Figure 12. The final reactions leading to the trans-THC final products.
isomers, compounds 3 and 4, are not often found and produced.
generally much less thermodynamically stable then the trans compounds. Naturally in the
cannabis plant, only compound 3, of the two cis compounds, has been recently found.
is much more thermodynamically stable then compound 4, and is both
characterized and observed through synthetic syntheses. Sustained synthesis and
characterization of compound 4 has yet to be substantial. There has been no true discovery of a
reproducible synthesis of compound 4.3
has been characterized and synthetically produced. Some of the
isomers and “unnatural” (bulky groups placed on different carbons to create steric hindrance)
THC products have been found in nature or being synthesized in a lab.3 While medical marijuana
is an ongoing debate in the United States, scientists are ready to produce the natural and
to provide for the masses. It has been indicated as a helpful tool in the cancer
patients undergoing chemotherapy, people with HIV/AIDS, glaucoma patients, and people with
Cannabis Sativa L is a powerful plant that has been found have
THCs that become reproducible synthetic products.7
13
, are not often found and produced. They are
compounds. Naturally in the
compounds, has been recently found.
, and is both
characterized and observed through synthetic syntheses. Sustained synthesis and
There has been no true discovery of a
has been characterized and synthetically produced. Some of the
isomers and “unnatural” (bulky groups placed on different carbons to create steric hindrance)
While medical marijuana
is an ongoing debate in the United States, scientists are ready to produce the natural and
to provide for the masses. It has been indicated as a helpful tool in the cancer
patients undergoing chemotherapy, people with HIV/AIDS, glaucoma patients, and people with
is a powerful plant that has been found have CBDs and
14
Works Cited
(1) Dell’Acqua, C.; Peyraube, R. IPCS INCHEM 1989.
(2) Natl. Cancer Inst. 2014.
(3) ApSimon, J. The total synthesis of natural products; Wiley: New York, 1988.
(4) The Active Ingredients of Cannabis. NCSM, 2011.
(5) Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc. 1967, 89, 4552.
(6) Razdan, R. K.; Dalzell, H. C.; Handrick, G. R. J. Am. Chem. Soc. 1974, 96, 5860.
(7) Ogborne, A. C.; Smart, R. G.; Adlaf, E. M. Can. Med. Assoc. J. 2000, 162, 1685.