Lecture (5)
20/2/2013
In the last lecture we discussed the basics of cannabinoids and cannabinoids
chemistry; we gave numbers to the carbons or the single oxygen of the central pyran
ring.
Cannabinoids are hybrid substances because they are biosynthesized using two
different pathways:
1- Acetate-malonate pathway.
2- Mevalonic acid pathway.
The aromatic part of the molecule and the side chain are originating from acetate
malonate pathway, while the ten carbons originate from mevalonic acid pathway.
In general all different hybrid compounds when they are incorporating two
different pathways, at the beginning of the biosynthesis both pathways are occurring
parallel, so at the same time using the acetate malonate pathway starting with ncaproic acid in step wise addition with simultaneous decarboxylation we will obtain
the acetate originating part which is the olivetolic acid.
On the other side the mevalonic acid pathway continues, basically in the
mevalonic acid pathway we are talking about multiples of isoprene units; because we
said that the basic component of terpenoid substances is the five carbon isoprene.
Terpenoid substances in general are provided as multiples of the 5 Carbon units
isoprenes – of course there will be ± one or two carbons- which means we start with
isoprene to form the ten carbon basic unit which is geranyl pyrophosphate.
When both components are ready, then starts the combination of the two
partners: olivetolic acid with geranyl pyrophosphate to form the first intermediate
compound. There are always two components one of them is the acidic component
bearing the carboxyl group, while the other is the decarboxylated one, so the
combination of the olivetolic acid with geranyl pyrophosphate yields at first
cannabigerol-Carboxylic acid (cannabigerolic acid) which is the acidic partner.
Decarboxylation of cannabigerol Carboxylic acid will yield the cannabigerol (CBG).
We need further steps in cyclization; because in the cannabigerolic acid or
cannabigerol we don’t have the central pyran ring of the cannabidiol or βhydrocannabidiol, so different reactions are occurring. We have cannabigerol and we
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have the cannabidiol (CBD) it continues via (CBD), but of course the (CBD) is
accompanied by its acidic partner cannabidiol-carboxylic acid which is exactly the
same decarboxylated CBG. And then we will obtain two partners
tetrahydrocannabinol and the tetrahydracannabinole (THC)-carboxylic acid and the
carboxylation will yield Δ1 or Δ9 tetrahydrocannabinol,
So it goes parallel; at first biosynthesizing each component separately, then
condensation and cyclization steps via important intermediates cannabigerol and
cannabidiol and several other intermediates - don’t think that in condensation these
are the only compounds, there are several other intermediates but these are the basic
and major Intermediates of the biosynthetic pathway: CBG, CBG-carboxylic acid and
the (CBD) – and then we will obtain mono unsaturated Δ1 or Δ9 THC.
Don’t think that after synthesizing the active principle the biosynthesis will
stop, it continues after the formation of the most important (active) compound (the
mono unsaturated derivative).
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The biosynthesis continues, you can expect very simple reaction, the monounsaturated develop into di-unsaturated and at the end you will obtain two aromatic
rings, the mono unsaturated compound can be converted easily to di-unsaturated by
simple dehydrogenation reactions. So the biosynthesis doesn’t stop at this stage it
will continue. Or during the pyrolytic process it will be converted to other
intermediates, but the most important one is the Δ9-tetrahydrocannabinol and its
carboxylic acid derivative.
The continued unsaturated derivatives and the aromatic compounds loose the
biological activity, so the most potent one is the mono-unsaturated THC, and any
reaction or modification in the natural compound will result in a decrease in the
potency. Di-unsaturated or aromatic compounds will decrease the potency of the
terminal compound.
The same modifications on bioactivity can also be observed by the
modifications done the side chain, the side chain can be elongated or decreased in
length, but any decrease or elongation of the side chain or aromatic ring (which can
be hydrogenated) can be linked to loss of biological activity.
 Δ1 or Δ9 THC are biologically the most active compounds.
Don’t think that when we reach the Tetrahydrocannabinol or its carboxylic acid
derivative, the plant won’t enter in a dormancy, as biosynthetic pathways
continuously occurs, But other compounds resulting are not so important for us
(THC and its carboxylic acid are the most active constituents)
When you look at the THC structure, what further modifications can you
expect?
 Dehydrogenation
 Hydrogenation
 Oxidation
More than 60 compounds have been isolated from inactive to the most active
THC compounds, by modifying its structure. But such modification can be linked to
the loss of potency and biological activity.
The terminal structure is linked with the loss of activity. Primarily the
monounsaturated ring can be converted to di-unsaturated, and with further
dehydrogenation we convert it to aromatic ring which is associated with loss of
activity.
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We have three –CH3 groups which can also be modified to:
 Hydroxymethyl group
 Formyl group
 Carboxyl group
Aromatic ring can be hydrogenated stepwise (starting from aromatic ring→ diunsaturated→ mono-unsaturated → hexane).
There are many reactions co-occurring, but any modification after the
formation of the most active compound, will result to a loss of biological activity
(example: C5H11 .. can be oxidized, shortened, elongated,… but none of these
modifications are requested; because they’ll be linked to a loss of biological activity).
The liver is one of the organs which are responsible for the metabolism and
elimination of these compounds; it’s involved in the modification of C7 or C11 by
oxidizing them to hydroxymethyl or to carboxyl groups. At carbon no. 11, CH3 will be
converted to its alcoholic derivative, then the aldehyde form, then carboxylic acid
form, and can also be decarboxylated at the end and loose position 11 so the body
will be able to eliminate the compound by urine.
 Metabolism in the body occurs via simple oxidation reactions, and this
oxidation can occur during pyrolysis or storage, it can be converted to other
derivatives.
That was all about Cannabinoids 
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