The Synthetic Routes of Tetrahydrocannabinol...The Synthetic Routes of Tetrahydrocannabinol...

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


very active cannabinoid is cannabidiol, or CBD (Figure 1). THC is the component that gets


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


. THC is the component that gets


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


) 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,


They were also found to be quite unstable and much less polar.5 The major product,


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


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%


The major product, 7, was


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


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 (


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)


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


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


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


THC products have been found in nature or being synthesized in a lab.3 While medical marijuana


to provide for the masses. It has been indicated as a helpful tool in the cancer


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


There has been no true discovery of a

has been characterized and synthetically produced. Some of the


While medical marijuana


to provide for the masses. It has been indicated as a helpful tool in the cancer


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.

The Synthetic Routes of Tetrahydrocannabinol...The Synthetic Routes of Tetrahydrocannabinol...

Documents

Transcript of The Synthetic Routes of Tetrahydrocannabinol...The Synthetic Routes of Tetrahydrocannabinol...