ACS Chemical Neuroscience
Research Article
7-(5-Fluoropentyl)-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-
chromen-5-ol (5-Fluoro-CBC, 11). Subjecting 5-(5-fluoropentyl)-
benzene-1,3-diol (14, 327 mg, 1.65 mmol) to the general procedure
gave, following purification by flash column chromatography, the title
compound (158 mg, 31%) as a yellow oil. Rf = 0.76 (hexanes/EtOAc,
Table 3. Parameters for LC-MS/MS Detection of
Cannabinoids
plasma
a
a
molecular parent > daughter
LOQ
brain LOQ
(ng/mg brain)
1
compound
CBC
weight
ions (m/z)
(μg/mL)
80:20); H NMR (400 MHz, CDCl3) δ 6.61 (d, J = 10.0 Hz, 1H),
314.5
315.20 > 193.25
315.20 > 81.25
333.45 > 277.35
0.01−20
0.03−0.25
6.25 (s, 1H), 6.11 (s, 1H), 5.50 (d, J = 10.0 Hz, 1H), 5.12−5.07 (m,
1H), 4.72 (brs, 1H), 4.43 (dt, J = 47.3, 6.2 Hz, 2H), 2.49−2.45 (m,
2H), 2.16−2.05 (m, 2H), 1.77−1.67 (m, 3H), 1.67 (s, 3H), 1.66−
1.58 (m, 3H), 1.57 (s, 3H), 1.46−1.39 (m, 2H), 1.38 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 154.3, 151.2, 144.3, 131.8, 127.5,
5-fluoro-
CBC
333.2
0.01−10
0.05−1
333.45 > 211.10
359.10 > 341.25
359.10 > 316.00
287.00 > 165.15
287.00 > 231.20
287.00 > 81.15
329.35 > 163.25
329.35 > 311.30
329.35 > 285.20
1
124.3, 116.9, 109.3, 107.8, 107.2, 84.2 (d, JC−F = 164.1 Hz), 78.4,
CBCA
CBCV
358.4
286.4
0.005- 10
0.05−4
0.05−1
41.2, 35.9, 30.7, 30.4 (d, 2JC−F = 19.5 Hz), 26.4, 25.8, 25.0 (d, 3JC−F
=
5.5 Hz), 22.9, 17.8 ppm; IR νmax 3140, 2965, 2929, 2858, 1622, 1575,
1429, 1575, 1429, 1081, 830, 774 cm−1; LCMS (ESI+): 333.2 ([M +
H]+, 100%), 355.3 ([M + Na]+, 5%).
0.01−10
CBCVA
330.4
0.01−20
0.05−4
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
a
LOQ, Limit of Quantification. Range from lower to upper limits.
1H and 13C NMR spectra and LCMS trace for 5-fluoro-
temperatures were compared using Mantel−Cox log-rank test, and p
< 0.05 was considered statistically significant. No significant sex
differences were observed, so groups were combined across sex.
Experimental time points were based on determined time-to-peak
plasma and brain concentrations from our pharmacokinetic studies.
Experimental time points used were as follows: 45 min, 5-fluoro-CBC;
30 min, CBC and CBCA; 15 min, CBCV and CBCVA, which were
administered after the 5 min acclimation period.
AUTHOR INFORMATION
Corresponding Author
■
Jonathon C. Arnold − Brain and Mind Centre, Discipline of
Pharmacology, Faculty of Medicine and Health, and Lambert
Initiative for Cannabinoid Therapeutics, The University of
Sydney, Sydney, NSW 2050, Australia;
Synthesis of Cannabichromene (CBC) and 5-Fluoro-canna-
bichrome (5-fluoro-CBC). All reactions were performed under an
atmosphere of nitrogen unless otherwise specified. Analytical thin-
layer chromatography was performed using Merck aluminum-backed
silica gel 60 F254 (0.2 mm) plates (Merck; Darmstadt, GER), which
were visualized using shortwave (254 nm) UV fluorescence. Flash
chromatography was performed using a Biotage Isolera Spektra One
and Biotage SNAP KP-Sil silica cartridges, with gradient elution
terminating at the solvent combination indicated for each compound.
Nuclear magnetic resonance spectra (NMR) were recorded at 298 K
using an Agilent 400 MHz spectrometer. The data are reported as
chemical shift (δ ppm) relative to the residual protonated solvent
resonance, multiplicity (s = singlet, br s = broad singlet, d = doublet,
br d = broad doublet, t = triplet, q = quartet, app quin. = apparent
quintet, m = multiplet), coupling constants (J Hz), relative integral,
and assignment. Assignment of carbon signals for the parent
compounds was assisted by correlation spectroscopy (COSY),
distortionless enhancement by polarization transfer (DEPT),
heteronuclear single quantum coherence (HSQC), and heteronuclear
multiple-bond correlation (HMBC) experiments where necessary.
General Procedure for the Synthesis of CBC and 5-fluoro-
CBC. Using a modified procedure, a flame-dried reaction vessel was
charged with the appropriate resorcinol (5 mmol, 1 equiv), citral (1,
1.09 mL, 6 mmol, 1.2 equiv), ethylenediamine diacetate (225 mg,
1.25 mmol, 0.25 equiv), and toluene (50 mL).51 The solution was
heated at reflux for 6 h before being cooled to ambient temperature,
and the solvent was removed under reduced pressure. The resulting
crude oils were purified via flash column chromatography.
Authors
Lyndsey L. Anderson − Brain and Mind Centre, Discipline of
Pharmacology, Faculty of Medicine and Health, and Lambert
Initiative for Cannabinoid Therapeutics, The University of
Adam Ametovski − Brain and Mind Centre, Lambert
Initiative for Cannabinoid Therapeutics, and School of
Chemistry, Faculty of Science, The University of Sydney,
Sydney, NSW 2050, Australia
Jia Lin Luo − Brain and Mind Centre, Lambert Initiative for
Cannabinoid Therapeutics, and School of Psychology, Faculty
of Science, The University of Sydney, Sydney, NSW 2050,
Australia
Declan Everett-Morgan − Lambert Initiative for Cannabinoid
Therapeutics, The University of Sydney, Sydney, NSW 2050,
Australia
Iain S. McGregor − Brain and Mind Centre, Discipline of
Pharmacology, Faculty of Medicine and Health, and School
of Psychology, Faculty of Science, The University of Sydney,
Sydney, NSW 2050, Australia
Samuel D. Banister − Brain and Mind Centre, Lambert
Initiative for Cannabinoid Therapeutics, and School of
Chemistry, Faculty of Science, The University of Sydney,
2-Methyl-2-(4-methylpent-3-en-1-yl)-7-pentyl-2H-chromen-5-ol
(CBC, 7). Subjecting olivetol (13, 900 mg, 5 mmol) to the general
procedure gave, following purification by flash column chromatog-
raphy, the title compound (556 mg, 35%) as a yellow oil. Rf = 0.74
(hexanes/EtOAc, 80:20); NMR (400 MHz, CD3OD) δ 6.65 (dd, J =
10.1 Hz, 1H), 6.17 (d, J = 1.5 Hz, 1H), 6.10 (d, J = 1.5 Hz, 1H), 5.47
(d, J = 10.1 Hz, 1H), 5.15−5.11 (m, 1H), 92.47−2.41 (m, 2H), 2.17−
2.06 (m, 2H), 1.67 (s, 3H), 1.67−1.63 (m, 2H), 1.66−1.53 (m, 2H),
1.58 (s, 6H), 1.39−1.29 (m, 4H), 1.35 (s, 3H), 0.92 (t, J = 7.1 Hz,
3H) ppm. All spectral data is consistent with that previously reported
Complete contact information is available at:
Author Contributions
L.L.A., J.C.A., S.D.B., and I.S.M. contributed to the conception
and design of the study. L.L.A., A.A., J.L.L., and D.E.M.
337
ACS Chem. Neurosci. 2021, 12, 330−339