A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol

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Isolation
and
characterization
of
natural CBDP
and
Δ9-THCP

In
order
to
selectively
obtain
a
cannabinoid-rich
fraction
of
FM2, n-hexane
was
used
to
extract
the
raw
material
instead
of
ethanol,
which
carries
other
contaminants
such
as
flavonoids
and
chlorophylls
along
with
cannabinoids26.
An
additional
dewaxing
step
at
−20 °C
for
48 h
and
removal
of
the
precipitated
wax
was
necessary
to
obtain
a
pure
cannabinoids
extract.
Semi-preparative
liquid
chromatography
with
a
C18 stationary
phase
allowed
for
the
separation
of
80
fractions,
which
were
analyzed
by
LC-HRMS
with
the
previously
described
method.
In
this
way,
the
fractions
containing
predominantly cannabidiphorolic
acid
(CBDPA)
and
tetrahydrocannabipgorolic
acid
(THCPA)
were
separately
subject
to
heating
at
120 °C
for
2 h
in
order
to
obtain
their
corresponding
neutral
counterparts
CBDP
and
Δ9-THCP
as
clear
oils
with
a
>95%
purity.
The
material
obtained
was
sufficient
for
a
full
characterization
by 1H
and 13C
NMR,
circular
dichroism
(CD)
and
UV
absorption.

Stereoselective
synthesis
of
CBDP
and
Δ9-THCP

(-)-trans-Cannabidiphorol
((-)-trans-CBDP)
and
(-)-trans9-tetrahydrocannabiphorol
((-)-trans9-THCP)
were
stereoselectively
synthesized
as
previously
reported
for
the
synthesis
of
(-)-trans-CBDB
and
(-)-trans9-THCB
homologs11,12,24.
Accordingly,
(-)-trans-CBDP
was
prepared
by
condensation
of
5-heptylbenzene-1,3-diol
with
(1 S,4 R)-1-methyl-4-(prop-1-en-2-yl)cycloex-2-enol,
using pTSA
as
catalyst,
for
90 min.

Longer
reaction
time
did
not
improve
the
yield
of
(-)-trans-CBDP
because
cyclization
of
(-)-trans-CBDP
to
(-)-trans9-THCP
and
then
to
(-)-trans8-THCP
occurred.
5-heptylbenzene-1,3-diol
was
synthesized
first
as
reported
in
the
Supporting
Information
(Supplementary
Fig. SI-1).
The
conversion
of
(-)-trans-CBDP
to
(-)-trans9-THCP
using
diverse
Lewis’
acids,
as
already
reported
in
the
literature
for
the
synthesis
of
the
homolog
Δ9-THC27,28,29,
led
to
a
complex
mixture
of
isomers
which
resulted
in
an
arduous
and
low-yield
isolation
of
(-)-trans9-THCP
by
standard
chromatographic
techniques.

Therefore,
for
the
synthesis
of
(-)-trans9-THCP,
its
regioisomer
(-)-trans8-THCP
was
synthesized
first
by
condensation
of
5-heptylbenzene-1,3-diol
with
(1 S,4 R)-1-methyl-4-(prop-1-en-2-yl)cycloex-2-enol,
as
described
above,
but
the
reaction
was
left
stirring
for
48 hours.
Alternatively,
(-)-trans-CBDP
could
be
also
quantitatively
converted
to
(-)-trans8-THCP
in
the
same
conditions.
Hydrochlorination
of
the
Δ8 double
bond
of
(-)-trans8-THCP,
using
ZnCl2 as
catalyst,
allowed
to
obtain
(-)-trans-HCl-THCP,
which
was
successively
converted
to
(-)-trans9-THCP
in
87%
yield
by
selective
elimination
on
position
2 of
the
terpene
moiety
using
potassium t-amylate
as
base
(Fig. 2a).

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