- Constituents of Cannabis sativa L. An improved method for the synthesis of dl-cannabichromene
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A new procedure was developed for the synthesis of cannabichromene (III) which involves reflux of equimolar amounts of olivetol (I), citral (II) and t-butylamine in toluene for 9 hours. The purification of III was best achieved by sodium borohydride reduction of unreacted II followed by column chromatography on 1% sodium hydroxide impregnated silica gel 60-PF. The yield of III (62.0%) was much higher than that reported in the literature.
- ElSohly,Boeren,Turner
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- Synthesis of Cannabinoids: "in Water" and "on Water" Approaches: Influence of SDS Micelles
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We have proven that the biomimetic-like synthesis of cannabinoids from citral and the corresponding phenolic counterpart may well be carried out using water as a solvent. The influence of different additives such as surfactants was also analyzed. Rationalization of the reaction mode and regiochemistry of the processes were provided in terms of "on water"and "in water"reactions. The same reactions were conducted in organic media using Ga(III) salts as catalysts. Worthy of being underlined, an unprecedented formal [2+2+2] process was found to occur between two citral molecules and the corresponding phenolic species in both aqueous and organic environments. Computational studies were performed in order to gain a comprehensive mechanistic and energetic understanding of the different steps of this singular process. Finally, the influence of SDS micelles in the chemical behavior of olivetol and citral was also pursued using PGSE diffusion and NOESY NMR studies. These data permitted to tentatively propose the existence of a mixed micelle between olivetol and SDS assemblies.
- Quílez Del Moral, José F.,Ruiz Martínez, Cristina,Pérez Del Pulgar, Helena,Martín González, Juan Eduardo,Fernández, Ignacio,López-Pérez, José Luis,Fernández-Arteaga, Alejandro,Barrero, Alejandro F.
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- Cannabichromene is a cannabinoid CB2 receptor agonist
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Background and Purpose: Cannabichromene (CBC) is one of the most abundant phytocannabinoids in Cannabis spp. It has modest antinociceptive and anti-inflammatory effects and potentiates some effects of Δ9-tetrahydrocannabinol in vivo. How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at cannabinoid CB1 and CB2 receptors. Experimental Approach: AtT20 cells stably expressing haemagglutinin-tagged human CB1 and CB2 receptors were used. Assays of cellular membrane potential and loss of cell surface receptors were performed. Key Results: CBC activated CB2 but not CB1 receptors to produce hyperpolarization of AtT20 cells. This activation was inhibited by a CB2 receptor antagonist AM630, and sensitive to Pertussis toxin. Application of CBC reduced activation of CB2, but not CB1, receptors by subsequent co-application of CP55,940, an efficacious CB1 and CB2 receptor agonist. Continuous CBC application induced loss of cell surface CB2 receptors and desensitization of the CB2 receptor-induced hyperpolarization. Conclusions and Implications: CBC is a selective CB2 receptor agonist displaying higher efficacy than tetrahydrocannabinol in hyperpolarizing AtT20 cells. CBC can also recruit CB2 receptor regulatory mechanisms. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB2 receptor-mediated modulation of inflammation.
- Udoh, Michael,Santiago, Marina,Devenish, Steven,McGregor, Iain S.,Connor, Mark
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- Total syntheses of cannabicyclol, clusiacyclol A and B, iso-eriobrucinol A and B, and eriobrucinol
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Total syntheses of a series of chromane natural products that contain a cyclobutane ring are described. A unified theme in the strategy employed for all these syntheses is an oxa-[3 + 3] annulation for constructing the chromane nucleus and a stepwise cationic [2 + 2] cycloaddition for the cyclobutane formation. More importantly, the two reactions could be rendered in tandem, thereby providing an expeditious approach to this family of natural products.
- Yeom, Hyun-Suk,Li, Hui,Tang,Hsung, Richard P.
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- A Total Synthesis of (±)-Rhododaurichromanic Acid A via an Oxa-[3+3] Annulation of Resorcinols
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Development of an oxa-[3+3] annulation of vinyliminium salts with resorcinols as a 1,3-diketo equivalent is described. This annulation constitutes a cascade of Knoevenagel condensation-oxa-electrocyclization leading to a direct access to chromenes. A series of attempts was made to demonstrate its synthetic utility in natural product synthesis, culminating in a total synthesis of (±)-rhododaurichromanic acid A that also featured an intramolecular Gassman-type cationic [2+2] cycloaddition.
- Luo, Guo-Ying,Wu, Hao,Tang, Yu,Li, Hui,Yeom, Hyun-Suk,Yang, Ka,Hsung, Richard P.
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- Photochemistry of Cannabidiol (CBD) Revised. A Combined Preparative and Spectrometric Investigation
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Cannabis is a plant with an astonishing ability to biosynthesize cannabinoids, and more than 100 molecules belonging to this class have been isolated. Among them in recent years cannabidiol (CBD) has received the interest of pharmacology as the major nonpsychotropic cannabinoid with many potential clinical applications. Although the reactivity of CBD has been widely investigated, only little attention has been given to the possible photodegradation of this cannabinoid, and the data available in the literature are outdated and, in some cases, conflicting. The aim of the present work is providing a characterization of the photochemical behavior of CBD in organic solvents, through a detailed GC-MS analyses, isolation, and NMR characterization of the photoproducts obtained.
- Caprioglio, Diego,Franco, Chiara,Mannucci, Barbara,Merli, Daniele,Porta, Alessio,Profumo, Antonella,Protti, Stefano,Salamone, Stefano,Seccamani, Paolo
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supporting information
p. 2858 - 2865
(2021/11/12)
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- METHODS FOR PREPARING CANNABINOIDS AND RELATED INSTRUMENTS
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Methods and instrumentation for converting cannabidiol (CBD) and CBD-like compounds to other naturally-occurring or synthetic cannabinoids, such as THC, CBN and/or CBC, which processes may be solvent-free, Generally, the conversion of CBD is carried out in the presence of a Lewis acid, an oxidant or both, which may be present in catalytic amounts. A reaction may be a two-phase reaction with the Lewis acid present on a support material in a column or similar chamber through which CBD passes and is converted to the cannabinoids. The reactions allow direction of relative yields of certain cannabinoid products by altering the identity of the acid reagent.
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Paragraph 0046
(2021/10/15)
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- CANNABICHROMENE COMPOSITIONS AND METHODS OF SYNTHESIZING CANNABICHROMENE
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Compositions having enhanced cannabichromene (CBC) and abnormal cannabichromene (CBCab) concentrations are disclosed herein as are methods of synthesizing CBC and CBCab. Relative to conventional methods, the methods of the present disclosure may: (i) be better suited to large-scale conditions in that they do not require dangerous and/or toxic solvents and/or reagents; (ii) provide product mixtures with enhanced CBCab concentrations; (iii) provide CBC at higher yield; (iv) provide easier to purify product mixtures comprising CBC; (v) provide product mixtures that comprise unique ratios of CBCab relative to other cannabinoids; and/or (vi) provide product mixtures with reduced THC concentrations.
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Paragraph 0080; 0083
(2021/07/02)
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- Antioxidant function of phytocannabinoids: Molecular basis of their stability and cytoprotective properties under UV-irradiation
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In this contribution, a comprehensive study of the redox transformation, electronic structure, stability and photoprotective properties of phytocannabinoids is presented. The non-psychotropic cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and psychotropic tetrahydrocannabinol (THC) isomers and iso-THC were included in the study. The results show that under aqueous ambient conditions at pH 7.4, non-psychotropic cannabinoids are slight or moderate electron-donors and they are relatively stable, in the following order: CBD > CBG ≥ CBN > CBC. In contrast, psychotropic Δ9-THC degrades approximately one order of magnitude faster than CBD. The degradation (oxidation) is associated with the transformation of OH groups and changes in the double-bond system of the investigated molecules. The satisfactory stability of cannabinoids is associated with the fact that their OH groups are fully protonated at pH 7.4 (pKa is ≥ 9). The instability of CBN and CBC was accelerated after exposure to UVA radiation, with CBD (or CBG) being stable for up to 24 h. To support their topical applications, an in vitro dermatological comparative study of cytotoxic, phototoxic and UVA or UVB photoprotective effects using normal human dermal fibroblasts (NHDF) and keratinocytes (HaCaT) was done. NHDF are approx. twice as sensitive to the cannabinoids’ toxicity as HaCaT. Specifically, toxicity IC50 values for CBD after 24 h of incubation are 7.1 and 12.8 μM for NHDF and HaCaT, respectively. None of the studied cannabinoids were phototoxic. Extensive testing has shown that CBD is the most effective protectant against UVA radiation of the studied cannabinoids. For UVB radiation, CBN was the most effective. The results acquired could be used for further redox biology studies on phytocannabinoids and evaluations of their mechanism of action at the molecular level. Furthermore, the UVA and UVB photoprotectivity of phytocannabinoids could also be utilized in the development of new cannabinoid-based topical preparations.
- Vacek, Jan,Vostalova, Jitka,Papouskova, Barbora,Skarupova, Denisa,Kos, Martin,Kabelac, Martin,Storch, Jan
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p. 258 - 270
(2021/02/05)
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- Cannabichromene, Related Phytocannabinoids, and 5-Fluoro-cannabichromene Have Anticonvulsant Properties in a Mouse Model of Dravet Syndrome
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Cannabis-based products are increasingly being used to treat refractory childhood epilepsies such as Dravet syndrome. Cannabis contains at least 140 terpenophenolic compounds known as phytocannabinoids. These include the known anticonvulsant compound cannabidiol (CBD) and several molecules showing emergent anticonvulsant properties in animal models. Cannabichromene (CBC) is a phytocannabinoid frequently detected in artisanal cannabis oils used in the community by childhood epilepsy patients. Here we examined the brain and plasma pharmacokinetic profiles of CBC, cannabichromenic acid (CBCA), cannabichromevarin (CBCV), and cannabichromevarinic acid (CBCVA) following intraperitoneal administration in mice. The anticonvulsant potential of each was then tested against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome. All phytocannabinoids within the CBC series were readily absorbed and showed substantial brain penetration (brain-plasma ratios ranging from 0.2 to 5.8). Anticonvulsant efficacy was evident with CBC, CBCA, and CBCVA, each significantly increasing the temperature threshold at which Scn1a+/- mice had a generalized tonic-clonic seizure. We synthesized a fluorinated derivative of CBC (5-fluoro-CBC), which showed improved brain penetration relative to the parent CBC molecule but not any greater anticonvulsant effect. Since CBC and derivatives are anticonvulsant in a model of intractable pediatric epilepsy, they may constitute part of the mechanism through which artisanal cannabis oils are anticonvulsant in patients.
- Anderson, Lyndsey L.,Ametovski, Adam,Lin Luo, Jia,Everett-Morgan, Declan,McGregor, Iain S.,Banister, Samuel D.,Arnold, Jonathon C.
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p. 330 - 339
(2021/01/26)
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- METHODS OF SYNTHESIZING HIGH-PURITY CANNABICYCLOL AND ARTIFICIAL RESINS COMPRISING CANNABICYCLOL
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Compositions having enhanced cannabicyclol (CBL) or CBL derivative concentrations are disclosed herein as are methods of synthesizing CBL and CBL derivative in high-purity form. Relative to conventional methods, the methods of the present disclosure may: (i) be better suited to large-scale conditions in that they do not require dangerous and/or toxic solvents and/or reagents; (ii) be more tolerant of complex starting compositions, such as cannabinoid extracts, isolates and/or distillates; (iii) provide CBL and/or CBL derivative at higher yield; (iv) provide easier methods to purify product mixtures comprising CBL and/or CBL derivative; (v) provide product mixtures that comprise unique ratios of CBL or CBL derivative relative to other cannabinoids; (vi) provide product mixtures with reduced THC concentrations and/or (vii) provide artificial resins having of a mixture cannabinoids that cannot be produced by extracting cannabis plant material.
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Paragraph 00171
(2021/07/02)
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- PREPARING AND MODIFYING MEROTERPENE POLYKETIDES, KETONES, AND LACTONES FOR CANNABINOID SEMISYNTHESIS
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Provided herein are processes, including semi-synthetic, and synthetic processes for preparing cannabinoids, and cannabinoid compositions provided thereby.
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(2021/08/20)
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- METHODS OF PREPARING SYNTHETIC CANNABICHROMENE AND CANNABICITRAN AND DERIVATIVES THEREOF
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The present disclosure relates to the preparation of synthetic cannabinoid derivatives of Formulae I and II, and compositions made therefrom.
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Paragraph 00158-00159; 00169-00170; 00173; 00176; 00179; ...
(2021/11/06)
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- METHODS FOR SYNTHESIS OF CANNABINOID COMPOUNDS
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The present invention provides simple synthetic routes for the preparation of cannabinoid compounds such as CBD, CBDV, THC, THCV, CBN, HU-308, CBG, CBC, and derivatives thereof, which are stereoselective and provide the desired cannabinoid compound in high yield.
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Paragraph 0066-0067
(2020/03/02)
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- CHROMENIC PHYTOCANNABINOIDS, THEIR SYNTHESIS AND USE IN TREATMENT OR PREVENTION OF DISEASE
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The present invention relates to a compound of the formula (I) or a solvate or co-crystal thereof wherein: - R is selected from the group consisting of: a C1-C6 alkyl, a C2-C8 alkenyl moiety, a C4-C12 dienyl or a C6-C18 trienyl moiety; - R1 is a C1-C6 alkyl moiety; - R2 is selected from the group consisting of: H and a C1-C6 alkyl moiety; - R3 is selected from the group consisting of: H and a C1-C6 alkyl moiety; - R4 is selected from the group consisting of: H, a C1-C6 alkyl moiety and a benzyl moiety. The present invention also relates to a process for producing said compound of the formula (I), or a solvate or co-crystal thereof, as well as a pharmaceutical composition comprising said compound of the formula (I), or a solvate or co-crystal thereof and at least one excipient. The present invention also relates to a compound of the formula (I), or a solvate or co-crystal thereof, for use in the treatment or prevention of a disease or condition.
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Paragraph 0055-0057; 0058
(2020/07/07)
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- One-Pot Total Synthesis of Cannabinol via Iodine-Mediated Deconstructive Annulation
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The thermal degradation of cannabichromene (CBC, 3) is dominated by cationic reactions and not by the pericyclic rearrangements observed in model compounds. The rationalization of these differences inspired the development of a process that coupled, in an aromatization-driven single operational step, the condensation of citral and alkylresorciniols to homoprenylchromenes and their in situ deconstructive annulation to benzo[c]chromenes. This process was applied to a total synthesis of cannabinol (CBN, 5) and to its molecular editing.
- Caprioglio, Diego,Mattoteia, Daiana,Minassi, Alberto,Pollastro, Federica,Lopatriello, Annalisa,Muňoz, Eduardo,Taglialatela-Scafati, Orazio,Appendino, Giovanni
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supporting information
p. 6122 - 6125
(2019/08/20)
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- Biomimetic Cannabinoid Synthesis Revisited: Batch and Flow All-Catalytic Synthesis of (±)-ortho-Tetrahydrocannabinols and Analogues from Natural Feedstocks
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Using a combination of Au nanoparticle-catalyzed oxidation under an O2 atmosphere and a Ti-doped montmorillonite (Ti-MMT)-catalyzed tandem arylation/double cyclization, we developed an original and highly selective method for the synthesis of ortho-tetrahydrocannabinol derivatives from simple substrates. The reaction sequence could be performed in two steps in batch mode or in a single operation in continuous-flow reactors. The abnormal regioselectivity was proposed to be the result of the non-innocent role of the MMT support, TiIV cation coordination, and a Lewis acid-assisted Br?nsted acid (LBA) mechanism.
- Giorgi, Pascal D.,Liautard, Virginie,Pucheault, Mathieu,Antoniotti, Sylvain
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supporting information
p. 1307 - 1311
(2018/04/02)
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- Enzymological evidence for cannabichromenic acid biosynthesis
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An enzyme involved in the biosynthesis of cannabichromenic acid was identified in young leaves of Cannabis sativa. The enzyme, named cannabichromenic acid synthase, catalyzed the oxidocyclization of cannabigerolic acid to cannabichromenic acid. The biosynthetic mechanism for the formation of cannabichromenic acid was similar to those of Δ1- tetrahydrocar nabinolic acid and cannabidiolic acid.
- Morimoto,Komatsu,Taura,Shoyama
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p. 854 - 867
(2007/10/03)
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- A new approach to dl-cannabichromene
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Natural dl-cannabichromene was synthesized in 6 steps from methyl 5-methoxy-2-methyl-7-pentyl-2H-chromen-2-acetate prepared by the cyclization of 2-hydroxy-6-methoxy-4-pentylbenzaldehyde with dimethyl isopropylidenemalonate.
- Yamaguchi,Shouji,Kuroda
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p. 305 - 308
(2007/10/02)
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- Process for preparing cannabichromene
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The preparation of cannabichromene (CBC) and homologues thereof by condensation of citral with a substituted resorcinol in the presence of a primary amine, and the use of these compounds to induce hypothermia and reduce inflammation in mammals, is disclosed. Preferably, the cannabichromene is administered as a novel composition, in combination with a pharmaceutically acceptable diluent carrier. A new compound 2-methyl-2(4-methyl-pent-3-enyl)-5-hydroxy-7-methylchromene (CBC-C1).
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- Das Prinzip der minimalen chemischen Distanz (PMCD)
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Die Ableitung der Isoprenregel, der Mechanismus der Umlagerung von Tetrahydrodicyclopentadien zu Adamantan, fuenf Colchicinsynthesen sowie die Synthese von C16-Hexaquinacen, Morphin und Strychnin werden durch das Prinzip der minimalen chemischen Distanz (PMCD) als Optimierungsprobleme formulierbar und zu Fragen, die mit Computern in der Regel in weniger als einer Sekunde loesbar sind.Das Prinzip der minimalen chemischen Distanz beruht auf einer algebraischen Theorie der konstitutionellen Chemie.Das PMCD, ein Korollar des wohlbekannten Prinzips der minimalen Strukturaenderung, ist eine quantitative heuristische Regel, welche bei der computer-unterstuetzten kombinatorischen Loesung einer Vielfalt chemischer Probleme nuetzlich ist.Dazu zaehlen insbesondere die Strukturanalyse, die Untersuchung von Reaktionsmechanismen und die Syntheseplanung.
- Jochum, Clemens,Gasteiger, Johann,Ugi, Ivar
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p. 503 - 513
(2007/10/02)
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