Efficient synthesis of cannabigerol, grifolin, and piperogalin via alumina-promoted allylation

Article abstract of DOI:10.1021/acs.jnatprod.0c00131

The synthesis of three phenolic natural products has been accomplished with unprecedented efficiency using a new alumina-promoted regioselective aromatic allylation reaction. Cannabigerol and grifolin were prepared in one step from the inexpensive 5-alkyl-resorcinols olivetol and orcinol. Piperogalin was synthesized, for the first time, via two sequential allylations of orcinol with geraniol and prenol.

Full text of DOI:10.1021/acs.jnatprod.0c00131

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Article
Efficient Synthesis of Cannabigerol, Grifolin, and Piperogalin via
Alumina-Promoted Allylation
Nicholas G. Jentsch, Xiong Zhang, and Jakob Magolan*
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ABSTRACT: The synthesis of three phenolic natural products has been accomplished with unprecedented efficiency using a new
alumina-promoted regioselective aromatic allylation reaction. Cannabigerol and grifolin were prepared in one step from the
inexpensive 5-alkyl-resorcinols olivetol and orcinol. Piperogalin was synthesized, for the first time, via two sequential allylations of
orcinol with geraniol and prenol.
Scheme 1. Previous Syntheses of CBG
annabigerol (CBG, 3) is a nonpsychotropic minor
1
Ccannabinoid produced by Cannabis sativa.
CBG is
reported to be an α2-adrenoceptor agonist, a 5HT1A receptor
antagonist,2 and an activator of TRPV1 and TRPV2 ion
channels.3 It has also been shown to stimulate appetite,4 act as
a neuroprotective agent in mouse models of Huntington’s
disease,5 inhibit colon carcinogenesis,6 act as an anti-
inflammatory in the context of colitis,7 and inhibit nausea.8
A 2008 report by Appendino and co-workers demonstrated
that 3 and other cannabinoids had potent antimicrobial activity
against Staphylococcus aureus.9 We recently became interested
in further exploring the antimicrobial potential of 3 and its
synthetic analogues.10 This required efficient synthetic access
to the CBG scaffold.
RESULTS AND DISCUSSION
■
be attributed to variability between the silica used in our
laboratories.
These results prompted an investigation into alternative
reaction conditions for this process. In the context of
heterogeneous synthetic methods development research,14,15
Two syntheses of 3 have been previously reported, both
proceeding via C-alkylation of olivetol (1) with geraniol (2)
(Scheme 1). In 1995, Baek and co-workers treated these two
substrates with boron trifluoride etherate on silica in CH2Cl2
to afford 3 in 29% yield (Scheme 1).11 One year later,
Morimoto and co-workers reported the use of p-toluenesul-
fonic acid in CHCl3 to obtain 3 from the same two substrates
in 40% yield,12 following a similar procedure to one described
in 1969 by Mechoulam and Yagen.13 However, in our hands,
both of these methods produced lower yields than those
reported (Scheme 1). Our inability to achieve appreciable
yields following the procedure of Baek and co-workers might
Received: February 4, 2020
© XXXX American Chemical Society and
American Society of Pharmacognosy
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Table 1. Optimization of Alumina-Promoted CBG Synthesis
alumina
a
a
entry
type
amt (g)
solvent
1 (mmol)
2 (mmol)
3 (%)
34
12
4
39
53
22
15
4 (%)
1
2
3
4
5
6
7
8
acidic
neutral
basic
acidic
acidic
acidic
acidic
acidic
acidic
acidic
2
2
2
2
2
1
2
2
2
2
0
hexanes
hexanes
hexanes
hexanes
hexanes
hexanes
heptanes
DCE
1
1
1
1
1.5
1.5
1.5
1.5
1.5
1.5
1
1
1
1.5
1
1
1
1
1
11
2
1
13
12
13
13
10
2
b
67 (62 )
9
10
11
CH3CN
MeOH
DCE
9
0
0
1
1
0
0
none
1.5
a
b
1
Yield determined by H NMR spectroscopy with CH2Br2 as an internal standard. Isolated yield after chromatography.
Scheme 2. Current Synthesis and Four Previous Syntheses of Grifolin (5)
we recently identified the pairing of activated acidic alumina
with hydrophobic solvents such as hexanes or 1,2-dichloro-
ethane (DCE) as useful conditions for promoting an indole
alkylation reaction.16 When analogous conditions were applied
to the reaction of 1 with 2, a relatively selective and clean
formation of 3 in 34% yield (Table 1, entry 1) was observed.
The only other observable product was digeranylated
compound 4, in 11% yield. The optimization of this process
is summarized in Table 1. Acidic alumina was found to be
superior to basic and neutral aluminas (entries 1−3) and DCE
was found to be a preferred solvent (entries 6−10). Byproduct
4, which was formed in 10% yield could be readily removed
using silica chromatography. Ultimately, 3 was obtained in
62% isolated yield using the following reaction conditions
(entry 8): treatment of 2 with excess 1 (1.5 equiv) in DCE at
reflux temperature (83 °C) for 6 h in the presence of acidic
alumina (2 g/mmol with respect to 2). This constitutes the
most efficient synthesis of this natural product reported to
date. Notably, CBG is of industrial significance as a substrate
for a bioenzymatic synthesis of tetrahydrocannabinol
(THC).17
Cannabigerol is structurally analogous to grifolin (5), a
natural product isolated in 1950 by Hirata from the mushroom
Grifola confluens (Scheme 2).18 Bioactivity investigations of 5
have shown it to be a tyrosinase inhibitor,19 an antioxidant,20
an antihistamine agent,21 an antitumor agent,22−25 an
antimicrobial,15 hypocholesterolemic,26 a carbonic anhydrase
inhibitor,27 and an inhibitor of nitric oxide production.28 We
hypothesized that a simple one-step synthesis of 5 was possible
using a process analogous to the cannabigerol synthesis.
Indeed, after a cursory optimization of substrate ratios it was
found that a refluxing mixture of farnesol (1.0 mmol), orcinol
(6, 3.0 mmol), and acidic alumina (2.0 g) in DCE afforded 5 in
37% isolated yield after a 7 h reaction time (Scheme 2). This
simple one-step process compares favorably with four previous
syntheses of this compound, which utilized reaction sequences
ranging from four to seven steps (Scheme 2).29−32
Seeking to further demonstrate the utility of this alumina-
promoted allylation reaction, a third natural product,
piperogalin (8), was selected for synthesis. Pierogalin was
isolated in 1995 from Peperomia galioides33 and later from
Peperomia obtusifolia but had yet to be accessed via chemical
B
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1
synthesis (Scheme 3).34 Compound 8 showed antiparasitic
activity against Leishmania and Trypanosoma cruzi.35 As
used without further purification. H NMR spectra were acquired at
700 MHz with a default digital resolution (Bruker parameter:
̈
FIDRES) of 0.15 Hz/point. Coupling constants, therefore, have
uncertainties of 0.30 Hz. Chemical shifts in 1H NMR and 13C NMR
spectra are reported in parts per million (ppm) with reference to
residual CHCl3 (δH 7.26) and CDCl3 (δC 77.16). Peak multiplicities
are reported using the following abbreviations: s, singlet; d, doublet; t,
triplet; q, quartet; dd, doublet of doublets; m, multiplet. Reaction
progress was monitored by TLC (EMD Chemicals, Inc., silica gel 60
F254). TLC plates were developed via capillary action in hexanes−
EtOAc solvent mixtures, visualized under UV light followed by p-
anisaldehyde stain. An automated flash chromatography system
(Teledyne CombiFlash Rf 200) was used for the purification of
compounds on silica gel (40−60 μM particle size).
Scheme 3. Synthesis of Piperogalin
Cannabigerol (3). To a solution of geraniol (2,173.5 μL, 1.0
mmol) and olivetol (1, 270.4 mg, 1.5 mmol) in DCE (5 mL) was
added acidic alumina (2.0 g). The heterogeneous mixture was stirred
at reflux temperature for 6 h, then cooled to ambient temperature, and
filtered through a Celite plug. The filter cake was rinsed with EtOAc
(3 × 10 mL portions), and the filtrate was concentrated in vacuo to
afford a yellow oil. This residue was purified via chromatography
using silica gel eluted with hexanes and EtOAc. Product-rich fractions
were pooled and evaporated to afford 1 (162 mg, 62%) as a yellow oil:
illustrated in Scheme 3, the two-step sequence began with a
geranylation of 6. In this case, the reaction was run on a 4
mmol scale with a reduced alumina loading of 0.5 g/mmol to
facilitate magnetic stirring of the heterogeneous reaction
mixture. The reaction required 24 h in refluxing DCE and
afforded cannabigerocin (7) in 47% isolated yield. Next,
prenylation of 7 was initially low yielding in DCE and required
some effort to optimize solvent, reaction temperature, and
substrate ratios. Ultimately, 8 was obtained in 57% yield when
the reaction was run in heptanes, with 1.5 equiv of prenol
(9)and 1.5 g/mmol of alumina relative to 7, and the
temperature was maintained at 80 °C for 14 h. Considerably
reduced yields were observed when the reaction was
performed at 98 °C, the reflux temperature of heptanes, as 8
appeared to be prone to further reactions resulting in complex
1
Rf = 0.49 (EtOAc−hexanes, 30:70); H NMR (700 MHz, CDCl3) δ
6.25 (2H, s), 5.27 (1H, td, J = 7.1, 1.0 Hz), 5.05 (3H, m), 3.39 (2H,
d, J = 7.1 Hz), 2.46 (2H, t, J = 7.8 Hz), 2.11 (2H, q, J = 7.4 Hz), 2.06
(2H, d, J = 7.4 Hz), 1.81 (3H, s), 1.68 (3H, s), 1.60 (3H, s), 1.56
(2H, q, J = 7.2 Hz), 1.36−1.28 (4H, m), 0.89 (3H, t, J = 6.9 Hz);
DEPTQ 13C NMR (176 MHz, CDCl3) δ 154.9 (C), 142.9 (C), 139.1
(C), 132.2 (C), 123.9 (CH), 121.8 (CH), 110.7 (C), 108.5 (CH),
39.8 (CH2), 35.7 (CH2), 31.6 (CH2), 30.9 (CH2), 26.5 (CH2), 25.8
(CH3), 22.7 (CH2), 22.4 (CH2), 17.8 (CH3), 16.3 (CH3), 14.2
(CH3). These NMR spectroscopic data matched those in a previous
report.36
Grifolin, (E)-2-(3,7-Dimethylocta-2,6-dien-1-yl)-5-methylben-
zene-1,3-diol (5). To a solution of farnesol (251 μL, 1.0 mmol)
and orcinol (6, 372 mg, 3.0 mmol) in DCE (5 mL) was added acidic
alumina (2.0 g). The heterogeneous mixture was stirred at reflux
temperature for 7 h, then cooled to ambient temperature, and filtered
through a Celite plug. The filter cake was rinsed with EtOAc (3 × 10
mL portions), and the filtrate was concentrated in vacuo to afford a
yellow oil. This residue was purified via chromatography using silica
gel eluted with hexanes and EtOAc. Product-rich fractions were
pooled, and the solvent was evaporated to afford 5 (121 mg, 37%) as
a yellow oil: Rf = 0.57 (EtOAc−hexanes, 25:75); 1H NMR (700 MHz,
CDCl3) δ 6.25 (2H, s), 5.48 (2H, s), 5.29 (1H, t, J = 7.0 Hz), 5.12
(2H, q, J = 7.1 Hz), 3.42 (2H, d, J = 7.1 Hz), 2.21 (3H, s), 2.10 (2H,
q, J = 6.9 Hz), 2.09−2.07 (4H, m), 2.01−1.99 (2H, m), 1.83 (3H, s),
1.70 (3H, s), 1.63 (3H, s), 1.61 (3H, s); DEPTQ 13C NMR (176
MHz, CDCl3) δ 154.9 (C), 138.9 (C), 137.5 (C), 135.7 (C), 131.4
(C), 124.5 (CH), 123.7 (CH), 121.9 (CH), 110.7 (C), 109.2 (CH),
39.8 (CH2), 39.8 (CH2), 26.8 (CH2), 26.5 (CH2), 25.8 (CH3), 22.3
(CH2), 21.1 (CH3), 17.8 (CH3), 16.3 (CH3), 16.1 (CH3). These
NMR spectroscopic data matched those in two previous reports.30,37
Cannabigerorcin, (E)-2-(3,7-Dimethylocta-2,6-dien-1-yl)-5-
methylbenzene-1,3-diol (7). To a solution of geraniol (2, 838 μL,
4.0 mmol) and orcinol (6, 617 mg, 6.0 mmol) in DCE was added
acidic alumina (2.0 g). The heterogeneous mixture was stirred at
reflux temperature for 24 h, cooled to ambient temperature, and
filtered through a Celite plug. The filter cake was rinsed with EtOAc
(3 × 15 mL portions), and the filtrate was concentrated in vacuo to
afford a yellow oil. This residue was purified via chromatography
using a silica gel eluted with hexanes and EtOAc. Product-rich
fractions were pooled, and the solvent was evaporated to afford 7
(492 mg, 47%) as a yellow oil: Rf = 0.41 (EtOAc−hexanes, 25:75);
1H NMR (700 MHz, CDCl3) δ 6.24 (2H, s), 5.28−5.26 (1H, m),
1
mixtures of unidentified byproducts evident in the crude H
NMR spectrum. Overall, this regioselective geranylation and
prenylation sequence offered the first total synthesis of 8 in
27% overall yield in two steps from 6.
In conclusion, we have demonstrated the utility of a new
regioselective alumina-promoted allylation reaction of resorci-
nols that has enabled efficient syntheses of the natural products
cannabigerol, grifolin, and piperogalin. While the mechanism
of this reaction remains under examination in our laboraotry,
we suspect that the allylation occurrs via an alumina-templated
electrophilic aromatic substitution process. Mechanistic
investigations and broad explorations of the scope of this
allylation chemistry are underway will be reported in future
manuscripts, as will the application of this chemistry to the
synthesis of novel cannabinoid analogues in the context of
preclinical drug discovery.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Alumina was purchased
from Millipore Sigma (activated, acidic, Brockmann I, catalogue no.
199966; activated neutral, Brockmann I, catalogue no. 199974;
activated, basic, Brockmann I, catalogue no. 199443). Activated
aluminas are typically sold at the Brockmann I grade, which
corresponds to a water content of 1−1.5%. Freshly purchased
alumina was used in this study. Reduced reaction yields were obtained
when using alumina that had been stored under air for several months.
High reaction yields could be regained by drying alumina at 200 °C
under high vacuum for several hours prior to use.
5.07 (2H, s), 5.05 (1H, d, J = 6.9 Hz), 3.39 (2H, d, J = 7.1 Hz), 2.21
(3H, s), 2.10 (2H, dd, J = 7.3, 6.9 Hz), 2.06 (2H, dd, J = 8.7, 6.3 Hz),
1.81 (3H, s), 1.68 (4H, s), 1.59 (3H, s); DEPTQ 13C NMR (175
MHz, CDCl3) δ 154.8 (C), 139.0 (C), 137.6 (C), 132.1 (C), 123.8
Substrates were purchased from AKScientific and used as obtained.
Solvents were purchased from Fisher Scientific, reagent grade, and
C
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(CH), 121.7 (CH), 110.5 (C), 109.1 (CH), 39.7 (CH2), 26.4 (CH2),
25.7 (CH3), 22.2 (CH2), 21.1 (CH3), 17.7 (CH3), 16.2 (CH3). These
NMR spectroscopic data matched those in two previous reports.38,39
Piperogalin, (E)-2-(3,7-Dimethylocta-2,6-dien-1-yl)-5-methyl-4-
(3-methylbut-2-en-1-yl)benzene-1,3-diol (8). To a solution of
cannabigerorcin (7, 78 mg, 0.3 mmol) and prenol (9, 20.3 μL, 0.2
mmol) in heptanes (3.0 mL) was added acidic alumina (300 mg).
The reaction was heated to 80 °C for 14 h, cooled to ambient
temperature, and filtered through a Celite pad. The filter cake was
rinsed with EtOAc (3 × 10 mL), and the filtrate was concentrated in
vacuo to afford a yellow oil. This residue was purified via
chromatography using silica gel eluted with hexanes and EtOAc.
Product-rich fractions were pooled, and the solvent was evaporated to
afford 8 (37.5 mg, 57%) as a yellow oil: Rf = 0.46 (EtOAc−hexanes,
1:6); 1H NMR (700 MHz, CDCl3) δ 6.27 (1H, s), 5.38 (1H, s), 5.25
(1H, t, J = 7.0 Hz), 5.14 (1H, t, J = 6.4 Hz), 5.06 (1H, t, J = 6.4 Hz),
4.90 (1H, s), 3.40 (2H, d, J = 7.0 Hz), 3.29 (2H, d, J = 7.0 Hz), 2.21
(3H, s), 2.11 (2H, q, J = 7.5 Hz), 2.07−2.04 (2H, m), 1.81 (3H, s),
1.80 (3H, s), 1.73 (3H, s), 1.68 (3H, s), 1.59 (3H, s); DEPTQ 13C
NMR (176 MHz, CDCl3) δ 153.6 (C), 152.8 (C), 138.8 (C), 135.4
(C), 133.7 (C), 132.1 (C), 124.0 (CH), 122.6 (CH), 122.1 (CH),
118.2 (C), 111.5 (C), 109.9 (CH), 39.8 (CH2), 26.5 (CH2), 25.9
(CH3), 25.8 (CH3), 25.7 (CH2), 22.7 (CH2), 20.0 (CH3), 18.0
(CH3), 17.8 (CH3), 16.3 (CH3). These NMR spectroscopic data
matched both reports of isolated natural piperogalin.33,34
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AUTHOR INFORMATION
Corresponding Author
■
Jakob Magolan − Department of Biochemistry and Biomedical
Sciences, McMaster University, Hamilton, ON, Canada L8N
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mcmaster.ca
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Nicholas G. Jentsch − Department of Biochemistry and
Biomedical Sciences, McMaster University, Hamilton, ON,
Canada L8N 3Z5
Xiong Zhang − Department of Biochemistry and Biomedical
Sciences, McMaster University, Hamilton, ON, Canada L8N
3Z5
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jnatprod.0c00131
Notes
The authors declare the following competing financial
interest(s): J.M., N.G.J. and X.Z. are inventors on a patent
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ACKNOWLEDGMENTS
■
This work was made possible by preliminary investigations
supported by the National Science Foundation, Grant No.
1301506. N.G.J. received support from the Michael G.
DeGroote Centre for Medicinal Cannabis Research at
McMaster University. X.Z. was funded by a fellowship from
the Chinese Scholarship Council. We are grateful for generous
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