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Cannabidiol (CBD) and tetrahydrocannabinol (THC) are literally on everyone‘s lips. The structures of these two substances are closely related but differ in their effect. Over the past years, research in the field of artificial synthesis and derivatization of cannabinoids has been flourishing. However, the term synthetic cannabinoids all too often conceals psychoactive designer drugs that bind to cannabinoid receptors and induce an (il)legal high.Plant extracts of cultivated strains of Cannabis Sativa can contain over 20% of Δ9-tetrahydrocannabinolcarboxylic acid (THCA) and cannabidiolic acid (CBDA) in dried plant mass. The biosynthesis of THCA and CBDA relies on stereoselective enzymatic conversions of the achiral polyketide olivetolic acid and the terpene derivative geranyl pyrophosphate (GPP) as achiral starting materials. It is catalyzed by THCA and CBDA synthase, respectively (<link href="#nadc20224129508-fig-0001">Figure 1).<figure xml:id="nadc20224129508-fig-0001"><figure><img alt="image" src="https://media.graphassets.com/Gc63M8sSQZi1MUZF7vVH"><figcaption><label>Abb.1: </label>Biosynthesis and main metabolism of Δ9-tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA).</figcaption></figure></figure>The psychostimulant tetrahydrocannabinol (Δ9-THC) and the nonpsychotropic cannabidiol (CBD) are formed by thermal decarboxylation. The main metabolite of Δ9-THC is the psychoactive 11-hydroxy-Δ9-THC (11-OH-THC) – this is further metabolized to the inactive 11-nor-9-carboxy-Δ9-THC (THC-CO2H) which serves as marker for substance abuse. CBD is converted to 7-hydroxy-CBD (7-OH-CBD), which, like CBD, shows neither psychological activity nor narcotic effects.1)Targeted breeding has resulted in strains that contain only THCA or CBDA, respectively. Cannabis products with a THC content of &lt;0.2% are legally available since March 2017.Cannabinoids act mainly through activating two types of G-protein-coupled receptors: the central cerebral cannabinoid receptor CB1 and the peripheral cannabinoid receptor CB2 which is almost exclusively found in the immune system.2) The interaction of THC with mitochondrial CB1 receptors effects synaptic transmission.3) This effect can be beneficial to reduce errant synaptic neurotransmission and might improve cognition in patients suffering from neurological impairments like Alzheimer’s, Parkinson’s and Huntington’s disease or neuropathic pain.However, both THC and CBD subject multiple other targets in organisms. Notably, exposure of THC to the developing brain pre- and postnatal and during (pre)adolescence as well as high dosage is associated with an increased rate of neurologically conditions.Non-psychostimulant CBD is thought to have anti-inflammatory and tissue-protective effects through promoting the antioxidant cellular defense in immune cells that are especially abundant in aging tissue. Moreover, CBD opposes the deleterious effects of THC. Thus, the individual THC and CBD contents in natural extracts isolated from cannabis plants – in addition to other minor but potentially more potent or effect-modifying phytocannabinoids as well as terpenes and terpenoids – affect clinical data. Synthetic access to phytocannabinoids makes its supply independent of regulatory restrictions, crop protection, and agroclimatic factors that affect the strains’ individual composition.4)<h2 type="main">Basic framework and first synthetic strategies</h2>THC contains a tricyclic tetrahydro dibenzopyran core structure (ABC ring system). The pyran skeleton (ring B) and cyclohexene unit (ring C) are connected trans at C6a and C10a. The two stereocenters are R-configurated. The double bond in the cyclohexene ring is positioned at C9. CBD formally consists of a (‒)-menthol unit fused to 5-pentyl-resorcinol.Most prominently, THC syntheses are achieved by Brønsted or Lewis acid catalyzed condensation of olivetol (O) with natural terpenoids.5) With respect to scalability, utilizing chiral pool feedstocks is preferred over asymmetric catalysis or auxiliaries. However, elegant asymmetric approaches have been developed to access minor, unnatural as well as the abundant cannabinoids THC and CBD.In 1964, Mechoulam and co-workers reported a seminal contribution on the structural elucidation of THC and CBD from plant extracts which sparked brought interest in the field.6) The first fully sterospecific total synthesis of (−)-Δ9-trans-THC was reported by Mechoulam, Braun and Gaoni in 1967 (<link href="#nadc20224129508-fig-0002">Figure 2).7) The synthesis proceeds via Brønsted acid-catalyzed condensation of olivetol (O) with (S)-cis-verbenol to a phenyl-α-pinene derivative that further cyclized to the thermodynamic but less active (‒)-Δ8-trans-THC isomer. Direct treatment of the starting materials with boron trifluoride dietherate yielded the identical compound in one reaction step. The Δ8-isomer was converted to the desired (‒)-Δ9-trans-THC upon sequential treatment with hydrochloric acid and sodium hydride.<figure xml:id="nadc20224129508-fig-0002"><figure><img alt="image" src="https://media.graphassets.com/4IOnC1nSCeywfeXVlQA6"><figcaption><label>Abb.2: </label>Classic syntheses of (‒)-Δ8 and Δ9-trans-THC and (‒)-CBD.</figcaption></figure></figure>Simultaneously, Petrzilka and colleagues synthesized CBD and (‒)-Δ8-trans-THC from (+)-trans-p-mentha-2,8-dien-1-ol using N,N-dimethylformamid-dineopentylacetal as activating reagent.8)Razdan used the same starting material under Lewis acid-catalyzed conditions to obtain (‒)-Δ9-trans-THC in 31 % isolated yield but as part of a complex mixture of products.9)Continuing the scouting of suitable terpenoids, Razdan and co-workers investigated p-menth-2-ene-1,8-diol as starting material.10) In contrast to previous efforts, the diol is swiftly converted into the desired (−)-Δ9-trans-THC in 28% yield in a single reaction step in the presence of zinc halides along with small amounts of side products. This approach was further optimized by Stoss and co-workers:11) Brønsted acid-catalyzed condensation of p-menth-2-ene-1,8-diol with olivetol yields the crystalline 6-hydroxy-CBD intermediate. Subsequent Lewis acid-catalyzed cyclization with zinc bromide makes (−)-Δ9-trans-THC available in 49% overall yield. Notably, the scalability of the described syntheses depends on the availability of terpenoid starting materials from the chiral pool.12)<h2 type="main">Newer syntheses</h2>In 2014, Carreira and colleagues reported a stereodivergent approach for the total synthesis of all four isomers of Δ9-tetrahydrocannabinol from the same starting materials (<link href="#nadc20224129508-fig-0003">Figure 3, top).13) The synthetic strategy relies on a key diastereoselective dual catalytic α-allylation of 5-methylhex-5-enal. The stereochemistry is dictated by an in-situ generated, chiral iridium phosphoramidite complex and Jørgensen’s pyrrolidine organocatalyst. A uniform sequence of four additional steps completes the synthesis of all possible stereoisomers of Δ9-tetrahydrocannabinol. Later the same group presented a related strategy to access the natural cis- and unnatural trans-isomer of bibenzyl (‒)-perrottetinene (PET) isolated from liverworts and subjected it to studies on major key brain receptors (Figure 3, bottom).14) (‒)-cis-PET and (‒)-trans-PET decreased basal prostaglandin levels in the brain. Increased prostaglandin levels as a result of an immune system overreaction are Δ9-trans-THC-associated side effects. Thus, PETs act similarly to the endogenous endocannabinoid 2-arachidonoylglycerol in this regard.<figure xml:id="nadc20224129508-fig-0003"><figure><img alt="image" src="https://media.graphassets.com/mdRJQAqRyq6wnT6re5mi"><figcaption><label>Abb.3: </label>Stereodivergent total synthesis of all stereoisomers of Δ9-THC (top) and (‒)-trans- and (‒)-cis-PET.</figcaption></figure></figure>Studer and Klotter reported scalable syntheses of (+)-Δ8-THC in four steps and 27% overall yield and of antimalarial agents, (+)-machaeriol B and (+)-machaeriol D, in five steps in 18% and 19% overall yield, respectively. Starting material was in each case (S)-perillic acid (<link href="#nadc20224129508-fig-0004">Figure 4, top).15) The varying aryl groups were installed by a stereospecific palladium-catalyzed, decarboxylative allylic substitution. The construction of the trans-configurated pyran skeleton was achieved through selective monodemethylation and oxycyclization in the presence of in-situ generated trimethylsilyliodide. In this sequence, a concomitant thermodynamic Δ9→Δ8-isomerization of the double bond is observed. (+)-Δ8-trans-THC was accessed by a second demethylation (R = C5H11). (+)-Machaeriol B and D were obtained through hydroboration with disiamylborane (Sia2BH) and subsequent reduction or oxidation, respectively, followed by demethylation yielding the desired natural cannabinoids.<figure xml:id="nadc20224129508-fig-0004"><figure><img alt="image" src="https://media.graphassets.com/ciitabZBQRqd0jXP5iAn"><figcaption><label>Abb.4: </label>Top: Divergent total synthesis of (+)-Δ8-THC, (+)-Machaeriol B, (+)-Machaeriol D. Bottom: Synthesis of para (−)-Δ8-THC triflate as a building block for the preparation of THC derivatives.</figcaption></figure></figure>In 2019, Studer‘s group disclosed a straightforward two-step synthesis of para-(‒)-Δ8-trans-THC triflate from (S)-cis-verbenol and phloroglucinol (Figure 4, bottom).16) The triflate serves as a expedient building block to introduce side chains at the cannabinoid core via transition metal-catalyzed cross-coupling.The synthesis of minor cannabinoids is an active area of research and may provide – in conjunction with pharmacological studies – interesting lead structures, especially with regard to the treatment of neuronal and inflammatory diseases.17)Pharmacological studies traditionally focus on the effects of the most abundant phytocannabinoids CBD and (−)-Δ9-trans-THC. Although, more than 150 phytocannabinoids have been isolated from different natural sources (cannabis plants, liverworts and fungi) till date.18) Due to the increasing use of cannabis for pain treatment and immune modulation, functional studies of immune modulation by the less available phytocannabinoids and metabolites are pertinent (<link href="#nadc20224129508-fig-0005">Figure 5).4) Limited availability and difficult isolation from plant material makes synthetic access of these compounds necessary.<figure xml:id="nadc20224129508-fig-0005"><figure><img alt="image" src="https://media.graphassets.com/Ahu4sewRnO0UCEXEGv2b"><figcaption><label>Abb.5: </label>Some minor phytocannabinoids and synthetic cannabinoids.</figcaption></figure></figure><h2 type="main">Synthetic cannabinoids</h2>Synthetic cannabinoids were initially developed to investigate the body’s endocannabinoid system, aiming to provide medical treatment for associated diseases.19) Synthetic cannabinoids have been subject of extensive pharmacological and toxicological research. Some were developed as drug candidates.Nabilone is a fully synthetic derivative of Δ9-tetrahydrocannabinol developed by Eli Lilly. Nabilone is used in exceptional cases as an antiemetic for nausea and vomiting under cytostatic or radiation therapy in the context of cancer therapy, as well as anorexia and cachexia in AIDS patients.However, by the mid-2000s, synthetic cannabinoids appeared on the market as over-the-counter replacement for cannabis. According to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), synthetic cannabinoids are the largest group of new psychoactive substances, with 209 reported between the years 2008 and 2020.20)1-Pentyl-3-naphthoylindol (JWH-018) is the first synthetic cannabinoid to be detected in a ‘legal high’ product in 2008. Till date, the EMCDDA reports 14 recognizable chemical families of synthetic cannabinoids.Many synthetic cannabinoids are much more potent compared to phytocannabinoids and act as full agonists at the cannabinoid receptors. According to the EMCDDA, the worrying trend of adulteration of low-THC and vastly abundant CBD cannabis products with synthetic cannabinoids poses an increasing risk of severe intoxication and death to consumers.<h2 type="main">Die Autorin</h2>Jola Pospech is an independent group leader at the Leibniz Institute for Catalysis (LIKAT) in Rostock. Her group conducts research in the field of transition metal and photoredox catalysis for the synthesis of biologically active molecules.<img alt="image" src="https://media.graphassets.com/tsFeoJNeQPCP3M9kW4Hi"><h2 type="main">At a glance</h2>The use of THC and CBD derivatives as therapeutics has steadily increased in recent years.The term cannabinoid describes a chemical substance that binds to cannabinoid receptors and exerts effects such as relaxation and pain relief, regardless of its structure or origin.Synthetic access to phytocannabinoids makes their access independent of agroclimatic factors, crop protection and allows structural modifications.<ul class="references" xml:id="nadc20224129508-bibl-0001" cited="no" style="numbered"><li xml:id="nadc20224129508-bib-0001">1 Cannabis and Cannabinoid Research 2016, 1, 90–101</li><li xml:id="nadc20224129508-bib-0002">2 a) E. Keimpema, V. Di Marzo, T. Harkany, Science 2021, 374, 1449–1450; b) K. Mackie, Annu. Rev. Pharmacool. Toxicol. 2006, 46, 101–122</li><li xml:id="nadc20224129508-bib-0003">3 D. Jimenez-Blasco, A. Busquets-Garcia, E. Hebert-Chatelain et al., Nature 2020, 583, 603–608</li><li xml:id="nadc20224129508-bib-0004">4 M. A. ElSohly, M. M. Radwan, W. Gul, S. Chandra, A. Galal, in Phytocannabinoids: Unraveling the Complex Chemistry and Pharmacology of Cannabis sativa (Eds.: A. D. Kinghorn, H. Falk, S. Gibbons, J. i. Kobayashi), Springer International Publishing, Cham, 2017, pp. 1–36</li><li xml:id="nadc20224129508-bib-0005">5 V. R. L. J. Bloemendal, J. C. M. van Hest, F. P. J. T. Rutjes, Org. Biomol. Chem. 2020, 18, 3203–3215</li><li xml:id="nadc20224129508-bib-0006">6 Y. Gaoni, R. Mechoulam, J. Am. Chem. Soc. 1964, 86, 1646–1647</li><li xml:id="nadc20224129508-bib-0007">7 R. Mechoulam, P. Braun, Y. Gaoni, J. Am. Chem. Soc. 1967, 89, 4552–4554</li><li xml:id="nadc20224129508-bib-0008">8 a) T. Petrzilka, W. Haefliger, C. Sikemeier, G. Ohloff, A. Eschenmoser, Helv. Chim. Acta 1967, 50, 719–723; b) T. Petrzilka, W. Haefliger, C. Sikemeier, Helv. Chim. Acta 1969, 52, 1102–1134</li><li xml:id="nadc20224129508-bib-0009">9 R. K. Razdan, H. C. Dalzell, G. R. Handrick, J. Am. Chem. Soc. 1974, 96, 5860–5865</li><li xml:id="nadc20224129508-bib-0010">10 G. R. Handrick, D. B. Uliss, H. C. Dalzell, R. K. Razdan, Tetrahedron Lett. 1979, 20, 681–684</li><li xml:id="nadc20224129508-bib-0011">11 P. Stoss, P. Merrath, Synlett 1991, 1991, 553–554</li><li xml:id="nadc20224129508-bib-0012">12 J. E. Cabaj, J. M. Lukesh, R. J. Pariza, P. M. Zizelman, Org. Process Res. Dev. 2009, 13, 358–361</li><li xml:id="nadc20224129508-bib-0013">13 M. A. Schafroth, G. Zuccarello, S. Krautwald, D. Sarlah, E. M. Carreira, Angew. Chem. Int. Ed. 2014, 53, 13898–13901</li><li xml:id="nadc20224129508-bib-0014">14 A. Chicca, M. A. Schafroth, I. Reynoso-Moreno et al., Sci. Adv. 2018, 4, eaat2166</li><li xml:id="nadc20224129508-bib-0015">15 F. Klotter, A. Studer, Angew. Chem. Int. Ed. 2015, 54, 8547–8550</li><li xml:id="nadc20224129508-bib-0016">16 G. Hoffmann, C. G. Daniliuc, A. Studer, Org. Lett. 2019, 21, 563–566</li><li xml:id="nadc20224129508-bib-0017">17 D. G. Dennis, S. D. Anand, A. J. Lopez et al., J. Org. Chem. 2022, 87, 6075–6086</li><li xml:id="nadc20224129508-bib-0018">18 L. O. Hanuš, S. M. Meyer, E. Muñoz, O. Taglialatela-Scafati, G. Appendino, Nat. Prod. Rep. 2016, 33, 1357–1392</li><li xml:id="nadc20224129508-bib-0019">19 V. L. Alves, J. L. Gonçalves, J. Aguiar, H. M. Teixeira, J. S. Câmara, Crit. Rev. Toxicol. 2020, 50, 359–382</li><li xml:id="nadc20224129508-bib-0020">20 European Monitoring Centre for Drugs and Drug Addiction (2021), Synthetic cannabinoids in Europe – a review, Publications Office of the European Union, Luxembourg: <a href="https://www.emcdda.europa.eu/system/files/publications/14035/Synthetic-cannabinoids-in-Europe-EMCDDA-technical-report.pdf" target="_blank">www.emcdda.europa.eu/system/files/publications/14035/Synthetic-cannabinoids-in-Europe-EMCDDA-technical-report.pdf</a></li></ul>

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Holy smoke – high life?

Cannabidiol (CBD) and tetrahydrocannabinol (THC) are literally on everyone‘s lips. The structures of these two substances are closely related but differ in their effect. Over the past years, research in the field of artificial synthesis and derivatization of cannabinoids has been flourishing. How...

Interskriptum

Wir Menschen sind eigenartige Gesellen. Die Weltordnung liegt in Tr&uuml;mmern, die Auswirkungen des Klimawandels werden erschreckend konkret, die Gesellschaft ist nach zwei Jahren Pandemie verunsichert, die chemische Industrie steht vor der gewaltigsten Transformation seit Jahrzehnten. Und das wichtigste Thema f&uuml;r viele scheint zu sein: Wie haltet ihr es mit dem Gendern? Manche wollen jetzt sogar die GDCh verpflichten, in der Vereinskommunikation keine Gendersonderzeichen zuzulassen. Dabei empfiehlt der im letzten Jahr verabschiedete &bdquo;Leitfaden f&uuml;r geschlechtersensible Sprache in der GDCh&ldquo; sowieso einen &auml;u&szlig;erst sparsamen Gebrauch.
In den Nachrichten aus der Chemie machen wir es so: Bei uns wird niemand zum Gendern in irgendeiner Art gezwungen, schon gar nicht mit Gendersonderzeichen. Der Anspruch der Redaktion ist im Impressum formuliert (nach ausf&uuml;hrlichen Diskussionen im Kuratorium): &bdquo;Die Nachrichten aus der Chemie wollen in ihren Texten alle Geschlechter ansprechen sowie abbilden und nutzen daf&uuml;r eine gendersensible Sprache. Wenn einzelne Sprachformen generisch verwendet werden, schlie&szlig;en diese uneingeschr&auml;nkt alle anderen Sprachformen ein.&ldquo;
Wie genau unsere Autoren, Autorinnen und auch Autor:innen diesen Anspruch verwirklichen wollen, entscheiden in letzter Instanz diese selbst. Denn gerade weil die ad&auml;quate Genderansprache f&uuml;r viele Menschen eine gesellschaftspolitisch wichtige Frage ist, halten wir in diesem Punkt eine gr&ouml;&szlig;tm&ouml;gliche Freiheit f&uuml;r geboten &ndash; und zwar f&uuml;r alle, die Beitr&auml;ge in den Nachrichten verfassen. Deshalb verzichten wir auf einen oktroyierten redaktionellen Standard und erlauben auch eine moderne vollinkludierende Genderansprache (wobei wir, haupts&auml;chlich aus Lesbarkeitsgr&uuml;nden, den Genderdoppelpunkt w&auml;hlen, keine Sternchen, Unterstriche etc.). Denn die Nachrichten aus der Chemie hatten und haben stets den Anspruch, die ganze Vielfalt der GDCh-Mitgliedschaft quer durch alle Str&ouml;mungen (wissenschaftliche, berufsst&auml;ndische und soziale) abzubilden.
Wir liegen damit nicht weit weg vom Rat f&uuml;r deutsche Rechtschreibung (auf den sich diejenigen berufen, die f&uuml;r ein Verbot der Gendersonderzeichen eintreten), der sich ebenfalls dar&uuml;ber klar ist, dass Sprache sich unabl&auml;ssig ver&auml;ndert. In dessen Empfehlung aus dem M&auml;rz 2021 hie&szlig; es n&auml;mlich zus&auml;tzlich: &bdquo;Der Rat f&uuml;r deutsche Rechtschreibung wird die weitere Schreibentwicklung beobachten. Er wird dabei insbesondere pr&uuml;fen, ob und inwieweit verschiedene Zeichen zur Erf&uuml;llung der Kriterien geschlechtergerechter oder -sensibler Schreibung geeignet sein k&ouml;nnten.&ldquo; Dabei k&ouml;nnen wir als Nachrichten aus der Chemie helfen, eben indem wir dieser Sprachentwicklung Raum geben, ohne jemanden zu bevormunden.
Im Interskriptum schreibt Nachrichten-Chefredakteur Christian Remenyi &uuml;ber Chemisches und Komisches &ndash; und was sich sonst noch so im Zettelkasten der Redaktion findet. <a href="mailto:nachrichten@gdch.de">nachrichten@gdch.de</a>

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Holy smoke – high life?

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