Mankind has long utilized Cannabis for diverse purposes. However, it has only been since the late 19th century that its individual cannabinoids began to be isolated, analyzed, and synthesized. By the mid-20th century it was discovered that many cannabinoids were asymmetric, with chirality often controlling their pharmacology. Increasingly accurate measurement and understanding of cannabinoid chirality will facilitate their synthesis and accelerate their medicinal applications.
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References
1.
HanusLO, TchilibonS, PondeDE, et al.Enantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptors. Org Biomol Chem. 2005; 3:1116–1123.
2.
ZuardiAW. History of cannabis as a medicine: a review. Revista Brasileira de Psiquiatria. 2006; 28:153–157.
3.
WoodTB, SpiveyWTN, EasterfieldTH. III.-Cannabinol. Part I. J Chem Soc Trans. 1899; 75:20–36.
4.
CahnRS. Cannabis indica resin. Part IV. The synthesis of some 2, 2-dimethyldibenzopyrans, and confirmation of the structure of cannabinol. J Chem Soc. 1933; 1400–1405.
5.
AdamsR, BakerBR, WearnRB. Structure of cannabinol. III. Synthesis of cannabinol, 1-hydroxy-3-n-amyl-6, 6, 9-trimethyl-6-dibenzopyran. J Am Chem Soc. 1940; 62:2204–2207.
6.
AdamsR, HuntM, ClarkJH. Structure of cannabidiol, a product isolated from the marijuana extract of Minnesota wild hemp. I. J Am Chem Soc. 1940; 62:196–200.
7.
AdamsR, PeaseDC, CainCK, et al.Structure of cannabidiol. VI. Isomerization of cannabidiol to tetrahydrocannabinol, a physiologically active product. Conversion of cannabidiol to cannabinol. J Am Chem Soc. 1940; 62:2402–2405.
8.
AdamsR, LoeweS, PeaseDC, et al.Structure of cannabidiol. VIII. Position of the double bonds in cannabidiol. Marijuana activity of tetrahydrocannabinols. J Am Chem Soc. 1940; 62:2566–2567.
9.
MechoulamR, ShvoY. Hashish—I The structure of cannabidiol. Tetrahedron. 1963; 19:2073–2078.
10.
GaoniY, MechoulamR. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964; 86:1646–1647.
11.
MechoulamR, GaoniY. The absolute configuration of delta-1-tetrahydro-cannabinol, the major active constituent of hashish. Tetrahedron Lett. 1967; 12:1109–1111.
12.
OttersenT, RosenqvistE, TurnerCE, et al.The crystal and molecular structure of cannabinol. Acta Chem Scand B. 1977; 31:781–787.
13.
JonesPG, FalvelloL, KennardO, et al.Cannabidiol. Acta Crystallographica. 1977; B33:3211–3214.
14.
RosenqvistE, OttersenT. The crystal and molecular structure of delta-9-tetrahydrocannabinolic acid B. Acta Chem Scand B. 1975; 29:379–384.
15.
BaekSH, SrebnikM, MechoulamR. Boron trifluoride etherate on alumina—a modified Lewis acid reagent. An improved synthesis of cannabidiol. Tetrahedron Lett. 1985; 26:1083–1086.
16.
MechoulamR, BraunP, GaoniY. A stereospecific synthesis of (−)-delta-1- and (−)-delta-1(6)-tetrahydrocannabinols. J Am Chem Soc. 1967; 89:4552–4554.
17.
ElSohlyMA, RadwanMM, GulW, et al.Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod. 2017; 103:1–36.
18.
CittiC, LincianoP, RussoF, et al.A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than delta-9-tetrahydrocannabinol: delta-9-tetrahydrocannabiphorol. Sci Rep. 2019; 9:20335.
19.
ElSohlyMA, SladeD. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci. 2005; 78:539–548.
20.
HanusLO, MeyerSM, MunozE, et al.Phytocannabinoids: a unified critical inventory. Nat Prod Rep. 2016; 33:1357–1392.
21.
SternE, GoossensL, RetailleauP, et al.Preparative enantiomeric separation of new selective CB2 receptor agonists by liquid chromatography on polysaccharide-based chiral stationary phases: determination of enantiomeric purity and assignment of absolute stereochemistry by X-ray structure analysis. Chirality. 2011; 23:389–396.
22.
MazzoccantiG, IsmailOH, D'AcquaricaI, et al.Cannabis through the looking glass: chemo- and enantio-selective separation of phytocannabinoids by enantioselective ultra high performance supercritical fluid chromatography. Chem Commun. 2017; 53:12262–12265.
23.
HanSM, PurdieN. Determination of cannabinoids by circular dichroism. Anal Chem. 1985; 57:2068–2071.
24.
KeiderlingTA. Instrumentation for vibrational circular dichroism spectroscopy: method comparison and newer developments. Molecules. 2018; 23:2404.
25.
WeberC, PuschS, SchollmeyerD, et al.Characterization of the synthetic cannabinoid MDMB-CHMCZCA. Beilstein J Org Chem. 2016; 12:2808–2815.
26.
WhitesidesGM, LewisDW. Tris[3-(tert-butylhydroxymethylene)-d-camphorato]europium(III). A reagent for determining enantiomeric purity. J Am Chem Soc. 1970; 92:6979–6980.
27.
McCrearyMD, LewisDW, WernickDL, et al.The determination of enantiomeric purity using chiral lanthanide shift reagents. J Am Chem Soc. 1974; 96:1038–1054.
28.
WilsonWK, ScallenTJ, MorrowCJ. Determination of the enantiomeric purity of mevalonolactone via NMR using a chiral lanthanide shift reagent. J Lipid Res. 1982; 23:645–652.
29.
KundeT, SchmidtBM. Microcrystal electron diffraction (MicroED) for small-molecule structure determination. Angew Chem Int Ed. 2019; 58:666–668.