Synthesis of Phytocannabinoids

  • Michael A. Schafroth
  • Erick M. Carreira
Part of the Progress in the Chemistry of Organic Natural Products book series (POGRCHEM, volume 103)


The changing legal landscape including medicinal and recreational consumption of Cannabis sativa has led to renewed interest to study the chemistry and biology of cannabinoids. The chemistry in this chapter highlights approaches to cannabinoid total synthesis with an emphasis on the implementation of modern methods and tactics, which provide access to modified structures and enable investigations of the biology of the cannabinoid product family.


Total synthesis Synthesis Cannabinoids Stereospecific Asymmetric Enantioselective Diastereoselective Tetrahydrocannabinol Conicol Epiconicol Machaeriol Perrottetinene Bisabosqual 


  1. 1.
    Russo EB (2014) The pharmacological history of Cannabis. In: Pertwee R (ed) Handbook of Cannabis. Oxford University Press, Oxford, p 23CrossRefGoogle Scholar
  2. 2.
    Russo EB (2005) Cannabis in India: ancient lore and modern medicine. In: Mechoulam R (ed) Cannabinoids as therapeutics. Birkäuser, Basel, p 1CrossRefGoogle Scholar
  3. 3.
    Russo EB (2007) History of Cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers 4:1614CrossRefGoogle Scholar
  4. 4.
    Baron EP (2015) Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: what a long strange trip it’s been. Headache J Head Face Pain 55:885CrossRefGoogle Scholar
  5. 5.
    Brunner TF (1977) Marijuana in ancient Greece and Rome? The literary evidence. J Psychedelic Drugs 9:221CrossRefGoogle Scholar
  6. 6.
    Mechoulam R, Hanuš LO, Pertwee R, Howlett AC (2014) Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci 15:757CrossRefGoogle Scholar
  7. 7.
    Cahn RS (1930) Cannabis Indica resin. Part I. The constitution of nitrocannabinolactone (oxycannabin). J Chem Soc:986Google Scholar
  8. 8.
    For an early review see: Adams R (1942) Marihuana. Bull NY Acad Med 18:705Google Scholar
  9. 9.
    Todd AR (1946) Hashish. Experientia 2:55CrossRefGoogle Scholar
  10. 10.
    Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646CrossRefGoogle Scholar
  11. 11.
    Gaoni Y, Mechoulam R (1966) Hashish–VII: the isomerization of cannabidiol to tetrahydrocannabinols. Tetrahedron 22:1481CrossRefGoogle Scholar
  12. 12.
    Hively RL, Mosher WA, Hoffmann F (1966) Isolation of trans6-tetrahydrocannabinol from marijuana. J Am Chem Soc 88:1832CrossRefGoogle Scholar
  13. 13.
    Dalzell HC, Uliss DB, Hadnrick GR, Razdan RK (1981) Hashish: factors influencing double-bond stability in cannabinoids. J Org Chem 46:949CrossRefGoogle Scholar
  14. 14.
    Taylor EC, Lenard K, Shvo Y (1966) Active constituents of hashish. Synthesis of dl6-3,4-trans-tetrahydrocannabinol. J Am Chem Soc 88:367CrossRefGoogle Scholar
  15. 15.
    Smith MR, Kempfert KD (1977) Δ1-3,4-cis-Tetrahydrocannabinol in Cannabis sativa. Phytochemistry 16:1088Google Scholar
  16. 16.
    Gaoni Y, Mechoulam R (1964) The structure and synthesis of cannabigerol, a new hashish constituent. Proc Chem Soc:82Google Scholar
  17. 17.
    Adams R, Baker BR, Wearn RB (1940) Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. J Am Chem Soc 62:196CrossRefGoogle Scholar
  18. 18.
    Adams R, Pease DC, Clark JH (1940) Isolation of cannabinol, cannabidiol and quebrachitol from red oil of Minnesota wild hemp. J Am Chem Soc 62:2194CrossRefGoogle Scholar
  19. 19.
    ElSohly M, Gul W (2014) Constituents of Cannabis sativa. In: Pertwee R (ed) Handbook of Cannabis. Oxford University Press, Oxford, p 3CrossRefGoogle Scholar
  20. 20.
    Gertsch J, Pertwee R, Di Marzo V (2010) Phytocannabinoids beyond the Cannabis plant—do they exist? Br J Pharmacol 160:523CrossRefGoogle Scholar
  21. 21.
    Garrido L, Zubía E, Ortega MJ, Salvá J (2002) New meroterpenoids from the Ascidian Aplidium conicum. J Nat Prod 65:1328CrossRefGoogle Scholar
  22. 22.
    Muhammad I, Li XC, Dunbar DC, ElSholy MA, Khan I (2001) Antimalarial (+)-trans-hexahydrodibenzopyran derivatives from Machaerium multiflorum. J Nat Prod 64:1322CrossRefGoogle Scholar
  23. 23.
    Muhammad I, Li XC, Jacob MR, Tekwani BL, Dunbar DC, Ferreira D (2003) Antimicrobial and antiparasitic (+)-trans-hexahydrodibenzopyrans and analogues from Machaerium multiflorum. J Nat Prod 66:804CrossRefGoogle Scholar
  24. 24.
    Toyota M, Kinugawa T, Asakawa Y (1994) Bibenzyl cannabinoid and bisbibenzyl derivative from the liverwort Radula perrottetii. Phytochemistry 37:859CrossRefGoogle Scholar
  25. 25.
    Cullmann F, Becker H (1999) Prenylated bibenzyls from the liverwort Radula laxiramea. Z Naturforsch 54c:147Google Scholar
  26. 26.
    Toyota M, Shimamura T, Ishii H, Renner M, Braggins J, Asakawa Y (2002) New bibenzyl cannabinoid from the New Zealand liverwort Radula marginata. Chem Pharm Bull 50:1390CrossRefGoogle Scholar
  27. 27.
    Minagawa K, Kouzuki S, Nomura K, Yamaguchi T, Kawamura Y, Matsushima K, Tani H, Ishii K, Tanimoto T, Kamigauchi T (2001) Novel squalene synthase inhibitors I. Taxonomy, fermentation, isolation and biological activities. J Antbiot 54:890CrossRefGoogle Scholar
  28. 28.
    Minagawa K, Kouzuki S, Nomura K, Kawamura Y, Tani H, Terui Y, Nakai H (2001) Bisabosquals, novel squalene synthase inhibitors II. Physico-chemical properties and structure elucidation. J Antibiot 54:896CrossRefGoogle Scholar
  29. 29.
    Carroll AR, Bowden BF, Coll JC (1993) Studies of Australian ascidians. III. A new tetrahydrocannabinol derivative from the ascidian Synoicum castellatum. Aust J Chem 46:1079CrossRefGoogle Scholar
  30. 30.
    Simon-Levert A, Arrault A, Bontemps-Subielos N, Canal C, Bangais B (2005) Meroterpenes from the ascidian Aplidium aff. densum. J Nat Prod 68:1412CrossRefGoogle Scholar
  31. 31.
    Cressey D (2015) The Cannabis experiment. Nature 524:280CrossRefGoogle Scholar
  32. 32.
    Mechoulam R (1973) Cannabinoid chemistry. In: Mechoulam R (ed) Marijuana: chemistry, pharmacology, metabolism and clinical effects. Academic Press, New York, p 2Google Scholar
  33. 33.
    Mechoulam R, McCallum NK, Burstein S (1976) Recent advances in the chemistry and biochemistry of cannabis. Chem Rev 76:75CrossRefGoogle Scholar
  34. 34.
    Razdan RK (1981) The total synthesis of cannabinoids. In: ApSimon J (ed) The total synthesis of natural products. Wiley, New York, p 185CrossRefGoogle Scholar
  35. 35.
    Tius MA (1997) Stereospecific cannabinoid synthesis: the application of new techniques to a classical problem. In: Atta-ur-Rahman (ed) Studies in natural product chemistry. Elsevier, Amsterdam, p 185Google Scholar
  36. 36.
    Adams R, Pease DC, Cain CK, Clark JH (1940) Structure of cannabidiol. VI. J Am Chem Soc 62:2402CrossRefGoogle Scholar
  37. 37.
    Adams R, Baker BR (1940) Structure of cannabidiol. VII. J Am Chem Soc 62:2405CrossRefGoogle Scholar
  38. 38.
    Adams R, Loewe S, Pease DC, Cain CK, Wearn RB, Baker RB, Wolff H (1940) Structure of cannabidiol. VIII. J Am Chem Soc 62:2566CrossRefGoogle Scholar
  39. 39.
    Dewick PM (2012) Medicinal natural products. A biosynthetic approach, 3rd edn. Wiley, New Delhi, p 119Google Scholar
  40. 40.
    Mechoulam R, Gaoni Y (1965) A total synthesis of dl1-tetrahydrocannabinol, the active constituent of hashish. J Am Chem Soc 87:3273CrossRefGoogle Scholar
  41. 41.
    Mechoulam R, Braun P, Gaoni Y (1972) Synthesis of Δ1-tetrahydrocannabinol and related cannabinoids. J Am Chem Soc 94:6159CrossRefGoogle Scholar
  42. 42.
    Petrzilka T, Haefliger W, Sikemeier C, Eschenmoser A (1967) Synthese und Chiralität des (−)-Cannabidiols Vorläufige Mitteilung. Helv Chim Acta 50:719CrossRefGoogle Scholar
  43. 43.
    Petrzilka T, Sikemeier C (1967) Über Inhaltsstoffe des Haschisch. 2, vorläufige Mitteilung. Synthese von (−)-Δ6,1-3,4-trans-Tetrahydrocannabinol, sowie von (±)-Δ6,1-3,4-trans-Tetrahydrocannabinol. Helv Chim Acta 50:1967Google Scholar
  44. 44.
    Petrzilka T, Sikemeier C (1967) Über Inhaltsstoffe des Haschisch. 3, vorläufige Mitteilung. Umwandlung von (−)-Δ6,1-3,4-trans-Tetrahydrocannabinol in (−)-Δ1,2-3,4-trans Tetrahydrocannabinol. Helv Chim Acta 50:2111CrossRefGoogle Scholar
  45. 45.
    Petrzilka T, Haefliger W, Sikemeier C (1969) Synthese von Haschisch-Inhaltsstoffen. 4. Mitteilung. Helv Chim Acta 52:1102CrossRefGoogle Scholar
  46. 46.
    Montero J-L, Winternitz F (1975) Synthèses d’analogues des tétrahydrocannabinols. C R Hebd Seances Acad Sci Ser C 281:197Google Scholar
  47. 47.
    Dethe DH, Erande RD, Mahapatra S, Das S, Kumar BV (2015) Protecting group free enantiospecific total syntheses of structurally diverse natural products of the tetrahydrocannabinoid family. Chem Commun 51:2871CrossRefGoogle Scholar
  48. 48.
    Rickards RW, Rönneberg H (1984) Synthesis of (−)-Δ9-6a,10a-trans-tetrahydrocannabinol. Boron trifluoride catalyzed arylation by a homocuprate. J Org Chem 49:572CrossRefGoogle Scholar
  49. 49.
    Razdan RK, Dalzell HC, Handrick GR (1974) Hashish. X. Simple one-step synthesis of (−)-Δ1-tetrahydrocannabinol (THC) from p-mentha-2,8-dien-1-ol and olivetol. J Am Chem Soc 96:5860CrossRefGoogle Scholar
  50. 50.
    Razdan RK, Handrick GR (1970) Hashish. V. A stereospecific synthesis of (−)-Δ1-and (−)-Δ1(6)-tetrahydrocannabinols. J Am Chem Soc 92:6061CrossRefGoogle Scholar
  51. 51.
    Handrick GR, Uliss DB, Dalzell HC, Razdan RK (1979) The structure of valerianol, a sesquiterpenic alcohol of eremophilane type from Valeriana oil. Tetrahedron Lett 8:681CrossRefGoogle Scholar
  52. 52.
    Stoss P, Merrath P (1991) A useful approach towards Δ9-tetrahydrocannabinol. Synlett 8:553CrossRefGoogle Scholar
  53. 53.
    Razdan RK, Handrick GR, Dalzell HC (1975) A one-step synthesis of (−)-Δ1-tetrahydrocannabinol from chrysanthenol. Experientia 31:16CrossRefGoogle Scholar
  54. 54.
    This procedure was adapted from: Fahrenholtz KE, Lurie M, Kierstead RW (1967) Total synthesis of (±)-Δ9-tetrahydrocannabinol and four of its isomers. J Am Chem Soc 89:5934Google Scholar
  55. 55.
    Razdan RK, Puttick AJ, Zitiko BA, Handrick GR (1972) Hashish. VI1: conversion of (−)-Δ1(6)-tetrahydrocannabinol to (−)-Δ1(7)-tetrahydrocannabinol. Stability of (−)-Δ1- and (−)-Δ1(6)-tetrahydrocannabinols. Experientia 28:121CrossRefGoogle Scholar
  56. 56.
    William AD, Kobayashi Y (2001) A method to accomplish a 1,4-addition reaction of bulky nucleophiles to enones and subsequent formation of reactive enolates. Org Lett 3:2017CrossRefGoogle Scholar
  57. 57.
    William AD, Kobayashi Y (2002) Synthesis of tetrahydrocannabinols based on an indirect 1,4-addition strategy. J Org Chem 67:8771CrossRefGoogle Scholar
  58. 58.
    Kobayashi Y, Takeuchi A, Wang YG (2006) Synthesis of cannabidiols via alkenylation of cyclohexenyl monoacetate. Org Lett 8:2699CrossRefGoogle Scholar
  59. 59.
    Klotter F, Studer A (2015) Short and divergent total synthesis of (+)-machaeriol B, (+)-machaeriol D, (+)-Δ8-THC, and analogues. Angew Chem Int Ed 54:8547 (Angew Chem 127:8667)Google Scholar
  60. 60.
    Chou CM, Chatterjee I, Studer A (2011) Stereospecific palladium-catalyzed decarboxylative C(sp3)–C(sp2) coupling of 2,5-cyclohexadiene-1-carboxylic acid derivatives with aryl iodides. Angew Chem Int Ed 50:8614 (Angew Chem 123:8773)Google Scholar
  61. 61.
    Evans DA, Shaughnessy EA, Barnes DM (1997) Cationic bis(oxazoline)Cu(II) Lewis acid catalysts. Application to the asymmetric synthesis of ent-Δ 1-tetrahydrocannabinol. Tetrahedron Lett 38:3193CrossRefGoogle Scholar
  62. 62.
    Evans DA, Barnes DM, Johnson JS, Lectka T, von Matt P, Miller SJ, Murry JA, Norcross RD, Shaughnessy EA, Campos KR (1999) Bis(oxazoline) and bis(oxazolinyl)pyridine copper complexes as enantioselective Diels−Alder catalysts: reaction scope and synthetic applications. J Am Chem Soc 121:7582CrossRefGoogle Scholar
  63. 63.
    Trost BM, Dogra K (2007) Synthesis of (−)-Δ9-trans-tetrahydrocannabinol: stereocontrol via Mo-catalyzed asymmetric allylic alkylation reaction. Org Lett 9:861CrossRefGoogle Scholar
  64. 64.
    Schafroth MA, Zuccarello G, Krautwald S, Sarlah D, Carreira EM (2014) Stereodivergent total synthesis of Δ9-tetrahydrocannabinols. Angew Chem Int Ed 53:13898 (Angew Chem 126:14118)Google Scholar
  65. 65.
    Krautwald S, Sarlah D, Schafroth MA, Carreira EM (2013) Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes. Science 340:1065CrossRefGoogle Scholar
  66. 66.
    Krautwald S, Schafroth MA, Sarlah D, Carreira EM (2014) Stereodivergent α-allylation of linear aldehydes with dual iridium and amine catalysis. J Am Chem Soc 136:3020CrossRefGoogle Scholar
  67. 67.
    Cheng LJ, Xie JH, Chen Y, Wang LX, Zhou QL (2013) Enantioselective total synthesis of (−)-Δ8-THC and (−)-Δ9-THC via catalytic asymmetric hydrogenation and SNAr cyclization. Org Lett 15:764CrossRefGoogle Scholar
  68. 68.
    Xie JH, Zhou ZT, Kong WL, Zhou QL (2007) Ru-catalyzed asymmetric hydrogenation of racemic aldehydes via dynamic kinetic resolution: efficient synthesis of optically active primary alcohols. J Am Chem Soc 129:1868CrossRefGoogle Scholar
  69. 69.
    Crombie L (1986) Natural products of Cannabis and khat. Pure Appl Chem 58:693CrossRefGoogle Scholar
  70. 70.
    Crombie LW, Crombie ML, Firth DF (1988) Synthesis of bibenzyl cannabinoids, hybrids of two biogenetic series found in Cannabis sativa. J Chem Soc Perkin Trans 1:1263CrossRefGoogle Scholar
  71. 71.
    Song Y, Hwang S, Gong P, Kim D, Kim S (2008) Stereoselective total synthesis of (−)-perrottetinene and assignment of its absolute configuration. Org Lett 10:269CrossRefGoogle Scholar
  72. 72.
    Lee T, Kim S (2003) Efficient preparation of enantiomerically pure (E)-4-(tributylstannanyl)but-3-en-2-ol via lipase-mediated resolution. Tetrahedron Asymmetry 14:1951CrossRefGoogle Scholar
  73. 73.
    Kotame R, Hong BC, Liao JH (2009) Enantioselective synthesis of the tetrahydro-6H-benzo[c]chromenes via domino Michael–aldol condensation: control of five stereocenters in a quadruple-cascade organocatalytic multi-component reaction. Tetrahedron Lett 50:704CrossRefGoogle Scholar
  74. 74.
    Hong BC, Kotame P, Tsai CW, Liao JH (2010) Enantioselective total synthesis of (+)-conicol via cascade three-component organocatalysis. Org Lett 12:776CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Laboratorium für Organische ChemieETH ZürichZürichSwitzerland

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