Advertisement

The Chemistry and Pharmacology of Morphinan Alkaloids

  • A. Brossi
Part of the Proceedings in Life Sciences book series (LIFE SCIENCES)

Abstract

The chemistry of morphinan drugs is closely related to that of morphine through recognition of its structure by Robinson and Sugasawa (1933) and Schöpf and Thierfelder (1939). Real progress, however, was made when Grewe and Mondon (1948) reported a novel detailed synthesis of morphinan, the basic unit of the opium alkaloids. This accomplishment, together with the first total synthesis of morphine by Gates and Tschudi (1952), its biosynthesis from reticuline by Barton et al. (1965), the final proof of the stereochemistry of natural morphine proposed by Stork (1952) and Rapoport and Levine (1953) and confirmed by Kalvoda et al. (1955) and Goto’s (1964) work on sinomenine, set the stage for an unprecedented effort by Universities, Pharmaceutical Industries and Government Research Laboratories (NIH), to synthesize structures simpler than that of morphine. It was hoped that total synthesis would afford compounds with similar biological features but devoid of unfavourable side-effects and without the addictive properties of morphine. It was expected that the accumulated knowledge would ultimately lead to a practical synthesis of morphine accomplished 30 years later by Rice at the NIH.

Keywords

Total Synthesis Opiate Receptor Methyl Vinyl Ketone Opium Alkaloid Practical Synthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Barton DHR, Kirby GW, Steglich W, Thomas GM, Battersby AR (1965) Investigations on the biosynthesis of morphine alkaloids. J Chem Soc:2423–2438Google Scholar
  2. Beckett AH, Casy AF, Harper NJ (1956) Analgesics and their antagonists: some steric and chemical considerations. J Pharm Pharmacol 6:874–884CrossRefGoogle Scholar
  3. Belleau B (1982) The chemical regulation of biological mechanisms. In: Creighton AM, Turner S (eds) R Soc Chem, Spec Publ no 42. Burlington House, London, pp 200–221Google Scholar
  4. Belleau B, Morgan P (1974) Clastic binding on the opiate receptor. J Med Chem 17:908–909PubMedCrossRefGoogle Scholar
  5. Belleau B, Conway T, Ahmed FR, Hardy FR (1974) Importance of the nitrogen lone electron pair orientation in stereospecific opiates. J Med Chem 17:907–908PubMedCrossRefGoogle Scholar
  6. Bentley KW, Robinson R, Wain AE (1952) The reduction of thebaine and dihydrothebainone by sodium and ammonia. J Chem Soc:958–966Google Scholar
  7. Beyerman HC, Lie TS, Maat L, Buurman E, Bijsterveld EJM, Sianige HJM (1976a) A convenient synthesis of codeine and morphine. Recl Tray Chim Pays-Bas Belg 95 (1):24–25CrossRefGoogle Scholar
  8. Beyerman HC, Bommel L van, Maat L, Olieman C (1976b) Red Tray Chim Pays-Bas Belg 95:312CrossRefGoogle Scholar
  9. Beyerman HC, Leeuwen FF van, Lie TS, Maat L, Olieman C (1976c) Chemistry of opium alkaloids, part VI, A practical technique for laboratory Birch reductions. Reel Tray Chim PaysBas Belg 95(10):238–240CrossRefGoogle Scholar
  10. Blasko G, Börnyei G, Barczai-Beke M, Pechy P, Szántay C (1984) J Org Chem (press)Google Scholar
  11. Blount JF, Mohacsi E, Vane FM, Mannering GJ (1973) Isolation, X-ray analysis and synthesis of a metabolite of (-)-3-hydroxy-N-allylmorphinan. J Med Chem 16:352–355PubMedCrossRefGoogle Scholar
  12. Bogriar R, Gaál Gy, Kerekes P, Horváth G, Kovacs MT (1974) Hydroxyl group elimination in the morphine series. Org Prep Proc Int 6(6):305–311CrossRefGoogle Scholar
  13. Brossi A, Teitel S (1970) Partial 0-demethylation of aromatic substituted 3,4dihydroisoquinolines. Helv Chim Acta 53:1779–1787CrossRefGoogle Scholar
  14. Brossi A, Häfliger O, Schnider O (1955) Oxy-morphinane 6. Mitt. Die papierchromatographische Bestimmung von Morphinanderivaten und die Verfolgung ihrer Ausscheidung beim Hund. Arzneim. Forsch 5:62–66Google Scholar
  15. Brossi A, Atwell L, Jacobson AE, Rozwadowska MD, Schmidhammer H, Flippen-Anderson JL, Gilardi R (1982a) Structure-activity relationship of oxygenated morphinans VII: 5-methylated and 14-hydroxysubstituted agonists and antagonists of the 4-hydroxy-and 3,4-dioxygenated 6-morphinanone series. Helv Chim Acta 65:2394–2404CrossRefGoogle Scholar
  16. Brossi A, Hsu FL, Rice KC (1982b) A simplified synthesis of (±)-4-hydroxy-N-methylmorphinan6one. J Org Chem 47:5214–5216CrossRefGoogle Scholar
  17. Brown CE, Roerig SC, Fujimoto JM, Burger VT (1983) The structure of morphine differs between the crystalline state and aqueous solution. J Chem Soc Chem Commun:1506–1508Google Scholar
  18. Corrodi H, Hellerbach J, Züst A, Hardegger E, Schnider O (1959) Hydroxy-morphinane. Die Konfiguration der Morphinane. Helv Chim Acta 42:212–217CrossRefGoogle Scholar
  19. Feinburg AP, Creese I, Snyder SH (1976) The opiate receptor: a model explaining structure-activity relationships of opiate agonists and antagonists. Proc Natl Acad Sci USA 73:4213–4219Google Scholar
  20. Gates M, Tschudi G (1952) The synthesis of morphine. J Am Chem Soc 74:1109–1110CrossRefGoogle Scholar
  21. Gates M, Webb WG (1958) The synthesis and resolution of 3-hydroxy-N-methylisomorphinan. J Am Chem Soc 80:1186–1194CrossRefGoogle Scholar
  22. Ghosh AC, Portlock DE, Dalzell HC, Malberg C, Herligy P, Razdan RK (1983) Diels-Alder reaction of ßdihydrothebaine and its 4-phenyl ether with methyl vinyl ketone: synthesis of 6,14-exoethenomorphinans. J Org Chem 48:4137–4139CrossRefGoogle Scholar
  23. Glasel JA (1981) A comparison of solution solid state and theoretical conformations of morphine. Biochem Biophys Res Commun 102:703–709PubMedCrossRefGoogle Scholar
  24. Gordon M (1974) Annu Rep Med Chem 9:38–50CrossRefGoogle Scholar
  25. Goto K (1964) Sinomenine-an optical antipode of morphine alkaloids. Kitasato Inst, TokyoGoogle Scholar
  26. Goto K, Nambo T (1930) Sinomenine and disinomenine. Part XVI. On isobromo-sinomenine (or bromo-sinomeneine). Bull Chem Soc Jpn 5:165–169CrossRefGoogle Scholar
  27. Goto K, Sudzuki H (1929) Sinomenine and disnomenine. Part XI. On the position of the double linking in sinomenine. Bull Chem Soc Jpn 4:244–254CrossRefGoogle Scholar
  28. Grewe R, Friedrichsen W (1967) Cyclization of octahydroisoquinoline derivatives by morphinan ring closure: synthesis of dihydrothebainone. Chem Ber 100:1550–1558PubMedCrossRefGoogle Scholar
  29. Grewe R, Mondon A (1948) Synthesen in der Phenanthren-Reihe, vi.M.H: Synthese des Morphinans. Chem Ber 81:279–286CrossRefGoogle Scholar
  30. Grewe R, Fischer H, Friederichsen W (1967) Partial Birch reduction of 1-benzylisoquinoline derivatives. Chem Ber 100:1–8CrossRefGoogle Scholar
  31. Häfliger O, Brossi A, Chopard-dit-Jean LH, Walter M, Schnider O (1956) Hydroxy-Morphinane. Über ein Photooxydationsprodukt von (+)-3-Methoxy-N-methyl-morphinan. Helv Chim Acta 39:2053–2062CrossRefGoogle Scholar
  32. Heinisch G, Vieböck F (1971) Preparation and reactions of 4-O-methylsalutaridine methoperchborate. Monatsschr Chem 102:775–780CrossRefGoogle Scholar
  33. Hellerbach J, Schnider O, Besendorf H, Pellmont B (1966) In: Synthetic analgesics, part II(A). Morphinans, organic chemistry, vol VIII. Pergamon Press, New York, pp 1–112Google Scholar
  34. Henecka H (1953a) Neue Synthesen in der Morphinanreihe. Ann Chem 583:110–129Google Scholar
  35. Henecka H (1953b) Neue Synthesen in der Morphinanreihe. Liebigs Ann 583:110–128CrossRefGoogle Scholar
  36. Hindley NC (1961) Hoffmann-La Roche, Br Pat 832025Google Scholar
  37. Hite GJ (1981) In: Foye WO (ed) Principles in medicinal chemistry. Lea and Febiger, Philadelphia, pp 261–302Google Scholar
  38. Hori M, Katoaoka T, Shimizu H, Imaf E, Suzuki Y, Kawamura N, Fujimura H, No Zak M, Niwa M (1983) Agonist-antagonist properties of 5,7-ethano-4,5,5a,6,7,1lb-hexahydro-2,6,7-trimethyl-1H-benzo(g)homoquinolin-9-ol and 4,6-ethano-3,4,4a,5,6,10b-hexahydro-2,5,6-trimethylbenzo(f)quinolin-8ol. Chem Pharm Bull 31:2520–2522PubMedGoogle Scholar
  39. Hsu FL, Jacobson AE, Rice KC, Brossi A (1979) Partial synthesis of 3-deoxydihydromorphine from (-)11-hydroxy-6-keto N-methylmophinan. Heterocycles 13:259–261CrossRefGoogle Scholar
  40. Hsu FL, Rice KC, Brossi A (1982) Total synthesis of (±)-3-deoxy-7,8-dihydromorphine, (±)4methoxy N-methylmorphinan-6one and 2,4-dioxygenated (±)-congeners. Helv Chim Acta 65: 1576–1589CrossRefGoogle Scholar
  41. Lijima I, Rice KC, Brossi A (1977) The oxidation of thebaine with m-chloroperbenzoic acid. Studies in the (+)-morphinan Ser 3. Helv Chim Acta 60:2135–2137CrossRefGoogle Scholar
  42. Lijima I, Minamikawa J, Jacobson AE, Brossi A, Rice KC (1978a) Studies in the (+)-morphinan series. 5, Synthesis and biological properties of (+)-naloxone. J Med Chem 21:398–400CrossRefGoogle Scholar
  43. lijima I, Minamikawa J, Rice KC, Jacobson AE, Brossi A (1978b) Studies in the (+)-morphinan, Ser 4: A markedly improved synthesis of (+)-morphine. J Org Chem 43:1462–1463CrossRefGoogle Scholar
  44. Jacobson AE (1978) In: Barnett G, Trsic M, Willette R (eds) Quasar, Res Monogr 22. Natl Inst Drug Abuse, pp 129–145Google Scholar
  45. Jacobson AE, Rice KC, Reden J, Lupinacci L, Brossi A, Streaty RA, Klee W (1979) Paradoxical effects of N-cyanoalkyl substituents upon the activities of several classes of opioids. J Med Chem 22:328–331PubMedCrossRefGoogle Scholar
  46. Jacobson AE, Schmidhammer H, Hsu FL, Rozwadowska MD, Atwell L, Aceto MD, Harris LS, Katz JL, Woods JH, Medzirhadsky F (1981) Structure-activity relationships of oxygenated morphinans III: an exploration of the effect of the aromatic oxygen and 6-keto group on antinociceptive activity; receptor affinity; and narcotic antagonism. NIDA Res Monogr 41: 86–92Google Scholar
  47. Jacquet YF, Klee WA, Rice KC, Lijima I, Minimikawa J (1977) Stereospecific and nonstereospecific effects of (+)- and (-)-morphine: evidence for a new class of receptors? Science 198: 842–845PubMedCrossRefGoogle Scholar
  48. Kalvoda J, Buchschacher P, Jeger O (1955) Über die absolute Konfiguration des Morphins and verwandter Alkaloide. Helv Chim Acta 38:1847–1856CrossRefGoogle Scholar
  49. Kerekes P, Chang CS, Brossi A (1984) in preparationGoogle Scholar
  50. Kobylecki RJ, Lane AC, Smith CFC, Wakelin LPG, Cruse WBT, Egert E, Kennard O (1982) N-methylnalorphine: Definition of N-allyl conformation for antagonist at the opiate receptor. J Mec Chem 25:1278–1280CrossRefGoogle Scholar
  51. Leimgruber W (1972) Hoffmann-La Roche, Nutley, USA Pat 3624429Google Scholar
  52. Lie TS et al. (1978a) Chemistry of opium alkaloids, part XI. Synthesis of racemic and chiral codeine and morphine via the dihydrothebainones. Red Tray Chim Pays-Bas Belg 98:419–420CrossRefGoogle Scholar
  53. Lie TS et al. (1978b) Chemistry of opium alkaloids, part X, Synthesis of racemic and optically active codeine and morphine via the N-formylnordihydrothebainones. Recl Tray Chim Pays-Bas Belg 97:127–130Google Scholar
  54. Maeda R, Ohsugi E (1968) Synthesis of racemic 3-methoxy-6oxo-N-methylmorphinan. Chem Pharm Bull (Tokyo) 16:897–908Google Scholar
  55. Manmade A, Marshall JL, Minns RA, Dalzell H, Razdan RK (1982) Total synthesis of (±)-3deoxy-7,8dihydromorphine. J Org Chem 47:1717–1721CrossRefGoogle Scholar
  56. Mannering GJ, Schanker LS (1958) Metabolic fate of levo-3-hydroxy-N-allylmorphinan (Levallorphan). J Pharmacol Exp Ther 124:296–304PubMedGoogle Scholar
  57. Merz H, Langbain A, Stockhaus K, Walther G, Wick H (1974) Narcotic antagonism. In: Braude MC, Harris LS, May EL, Smith JP, Villareal JE (eds) Advances in psychopharmacology, vol VIII. Raven Press, New York, pp 91–107Google Scholar
  58. Minamikawa J, Brossi A (1978) Studies in the (+)-morphinan, Ser IV. Dimers of natural (-) and unnatural (+)-sinomenine. Heterocycles 10:79–84CrossRefGoogle Scholar
  59. Mohacsi E (1983) Hoffmann-La Roche. Nutley, USA Pat 4374139Google Scholar
  60. Mohacsi E, Leimgruber W, Baruth H (1979) Problems of drug dependence. Proc 41st Ann Sci Meet 77Google Scholar
  61. Mohacsi E, Leimgruber W, Baruth H (1982) Synthesis and pharmacology of metabolically stable tert-butyl ethers of morphine and levorphanol. J Med Chem 25:1264–1266PubMedCrossRefGoogle Scholar
  62. Monkovic I, Conway TT, Wong H, Perron YG, Pachter IJ, Belleau B (1973) Total synthesis and pharmacological activities of N-substituted 3,14-dihydroxymorphinans 1. J Am Chem Soc 95:7910–7912PubMedCrossRefGoogle Scholar
  63. Monkovic I, Wong H, Belleau B, Pachter IJ, Perron YG (1975a) Synthetic morphinans and hasubanans IV; Total synthesis of 3,14-dihydroxyisomorphinans; 3-methoxy-,08,14-morphinans; and 9,a-hydroxy-3-methoxyhasubanan. Can J Chem 53:2515–2523CrossRefGoogle Scholar
  64. Monkovic I, Wong H, Pircio AW, Perron YG, Pachter IJ, Belleau B (1975b) Oxilorphan and butorphanol (L-17-cyclobutylmethyl-3,14-dihydroxymorphinan); Potent narcotic antagonists and nonaddicting analgesics in the 3,14-dihydroxymorphinan, Ser 5. Can J Chem 53:3094–3102CrossRefGoogle Scholar
  65. Okuda S, Yamaguchi S, Kawazoe T, Tsuda K (1964) Studies on morphine alkaloids. I. Nuclear magnetic resonance spectral studies on morphine alkaloids (I). Chem Pharm Bull 12(1): 104–112PubMedGoogle Scholar
  66. Olieman C, Nagelhout Ph, Groot AD de, Maat L, Beyerman HC (1980) Chemistry of opium alkaloids, part XIV. Synthesis of racemic 3.hydroxy-N-methyl-6-oxomorphinan. Recl Tray Chim Pays-Bas Belg 99:353–355CrossRefGoogle Scholar
  67. Pert CB, Snyder SH (1974) Opiate receptor of agonists and antagonists affected differentially by sodium. Mol Pharmacol 10:868–879Google Scholar
  68. Pert CB, Pasternak G, Snyder SH (1973) Opiate agonists and antagonists discriminated by receptor binding in brain. Science 182:1359–1361PubMedCrossRefGoogle Scholar
  69. Polazzi JO, Schut RN, Kotick MP, Howes JH, Osgood PF, Razdan RK, Villareal JE (1980) Analgesic narcotic antagonist 2. 8-alkymorphinan-6-ones. J Med Chem 23:174–179PubMedCrossRefGoogle Scholar
  70. Rahman MF, Brossi A (1977) Preparation and analgesic activity of some 3,4-disubstituted N-methylmorphinans of the (-) series. Heterocycles 6:881–885CrossRefGoogle Scholar
  71. Rapoport H, Levine JB (1953) Stereochemical studies in the morphine series. The relative configuration at carbon thirteen and fourteen. J Am Chem Soc 75:5329–5334CrossRefGoogle Scholar
  72. Rapoport H, Masamune S (1955) The stereochemistry of 10-hydroxycodeine derivatives. J Am Chem Soc 77:4330–4335CrossRefGoogle Scholar
  73. Razdan RK, SISA (1981) USA Pat 4272540Google Scholar
  74. Razdan RK, Portlock DE, Dalzell HC, Malmberg C (1978) Synthesis of Adihydrothebainone. J Org Chem 43:3604–3606CrossRefGoogle Scholar
  75. Reden J, Reich MF, Rice KC, Jacobson AE, Brossi A (1979) Deoxymorphines: Role of the phenolic hydroxyl in antinociception and opiate receptor interactions. J Med Chem 22: 256–259PubMedCrossRefGoogle Scholar
  76. Rice KC (1980) Synthetic opium alkaloids and derivatives. A short total synthesis of (±)-dihydrothebainone, (±)-dihydrocodeinone and (±)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine and congeners. J Org Chem 45:3135–3137CrossRefGoogle Scholar
  77. Rice KC (1983a) A practical total synthesis of natural and unnatural codeine, morphine, thebaine, their opium-derived congeners and antagonists. Proc Jpn Pharm Soc XX:64–66Google Scholar
  78. Rice KC, Jacobson AE, Burke TR Jr, Bajwa BS (1983) Irreversible ligands with high selectivity toward 8 or (l opiate receptors. Science 220:314–316PubMedCrossRefGoogle Scholar
  79. Robinson R, Sugasawa S (1933) Preliminary synthetic experiments in the morphine group, Part V. Completion of the synthesis of a laudanosoline dimethyl ether related to sinomenine. J Chem Soc 280–281 and references thereinGoogle Scholar
  80. Rozwadowska MD, Hsu FL, Jacobson AE, Rice KC, Brossi A (1980) 4-Hydroxy-N-formylmorphinan-6-one; a versatile intermediate for the synthesis of 3-deoxyopioids. Can J Chem 58:1855–1859CrossRefGoogle Scholar
  81. Sawa YK, Maeda S (1964) Elimination of the 4-hydroxyl group of the alkaloids related to morphine I. Tetrahedron 20:2247–2253CrossRefGoogle Scholar
  82. Sawa YK, Tada H (1968) Elimination of the 4-hydroxyl group of the alkaloids related to morphine-XI. Synthesis of (-)-14-hydroxy-3-methoxy-N-methylmorphinan derivatives. Tetrahedron 24:61–85Google Scholar
  83. Sawa YK, Tsuji N, Maeda S (1961) Elimination of the 4-hydroxyl group of the alkaloids related to morphine. I. Tetrahedron 15:144–153CrossRefGoogle Scholar
  84. Schmidhammer H, Brossi A (1982) Synthesis of (-)- and (+)-2-hydroxy-6-keto-N-methylmorphinans, their 0-methyl ethers and 2-deoxy congeners. Can J Chem 60:3055–3060CrossRefGoogle Scholar
  85. Schmidhammer H, Brossi A (1983) Synthesis of (-)-1-hydroxy-N-methylmorphinan-6-one and its 0-methyl ether from (-)4-hydroxy-N-formylmorphinan-6–0ne. J Org Chem 48:1469–1471CrossRefGoogle Scholar
  86. Schmidhammer H, Jacobson AE, Atwell L, Brossi A (1981) Structure-activity relationship of oxygenated morphinans V. Narcotic agonist and antagonist activity in the 14-hydroxymorphinan series, preliminary communication. Helv Chim Acta 64:2540–2543CrossRefGoogle Scholar
  87. Schmidhammer H, Jacobson AE, Brossi A (1982) Morphinans and 6-ketomorphinans unsubstituted in the aromatic ring; high analgesic activity of (-)-6-keto-N-methylmorphinan, IV. Heterocycles 17:391–394CrossRefGoogle Scholar
  88. Schmidhammer H, Brossi A, Flippen-Anderson JL, Gilardi R (1983a) Apomorphinans from isoquinolines: Grewe cyclization of 1-(2-hydroxybenzyl)-N-methyloctahydroisoquinoline and its O-methyl ether. Helv Chim Acta 66:2437–2442CrossRefGoogle Scholar
  89. Schmidhammer H, Jacobson AE, Brossi A (1983b) Chemical and biological study of aromatic oxygenated 6-ketomorphinans. Med Res Rev 3:1–19CrossRefGoogle Scholar
  90. Schmidhammer H, Aeppli L, Atwell L, Fritsch F, Hoick M, Jacobson AE, Nebuchla M, Sperk G (1984) J Med Chem (in press)Google Scholar
  91. Schnider O, Grüssner A (1951) Oxy-morphinane (3. Mitteilung). Optisch aktive 3-Oxymorphinane. Helv Chim Acta 34:2211–2217CrossRefGoogle Scholar
  92. Schnider O, Hellerbach J (1950) Synthese von Morphinanen (2. Mitteilung). Helv Chim Acta 33:1437–1448CrossRefGoogle Scholar
  93. Schöpf C, Thierfelder K (1939) Synthetische Versuche in der Benzylisochinolin-Reihe III Laudanosolin-3,7dimethyläther ans Laudanosin. Liebigs Ann 537:143–156CrossRefGoogle Scholar
  94. Schöpf C, Winterhalder L (1927) Die Konstitution der Morphiumalkaloide. Liebigs Ann 452: 232–267Google Scholar
  95. Schwartz MA, Mami IS (1975) A biogenetically patterned synthesis of the morphine alkaloids. J Am Chem Soc 97:1239–1240PubMedCrossRefGoogle Scholar
  96. Seki I, Takagi H, Kobayashi S (1964) Pharmacological studies on morphine derivatives III. On the chemical structure-activity relationships of 14-hydroxymorphine derivatives. J Pharm Soc Jpn 84:280–289Google Scholar
  97. Simon LD, Simon FR, Mohacsi E, Berger L, Simon EJ (1981) Effect of the position of the phenolic group in morphinans on their affinity for opiate receptor binding. Life Sci 28:2769–2772PubMedCrossRefGoogle Scholar
  98. SISA (1983) Cambridge, US Pat 4370333Google Scholar
  99. Stork G (1952) The reduction of thebaine. J Am Chem Soc 74:767–773CrossRefGoogle Scholar
  100. Szntay C, Bârczai-Beke M, Péchy P, Blask6 G, Dörnyei G (1982) Studies aimed at the synthesis of morphine. 3. Synthesis of (±)-salutaridine via phenolic oxidative coupling of (±)-reticuline. J Org Chem 47:594–596CrossRefGoogle Scholar
  101. Vane FM, Ellis DH, Rao J, Blount JF, Mohacsi E, Szuna A, Kamm JJ (1978) Metabolism of the enantiomers of 2-hydroxy-N-cyclopropylmethylmorphinan in dog and man. Biomed Mass Spectrom 5:498–507PubMedCrossRefGoogle Scholar
  102. Vecchietti V, Casagrande C, Gerrari G (1976) Ocobotrine and 14-episinomenine, new trans-morphinane alkaloids of Ocotea brachybotra.Tetrahedron Lett:1631–1633Google Scholar
  103. Weller DD, Rapoport H (1976) A practical synthesis of codeine from dihydrothebainone. J Med Chem 19:1171–1175PubMedCrossRefGoogle Scholar
  104. White JD, Caravatti G, Kline TB, Edstrom E, Rice KC, Brossi A (1983) Biomimetic total synthesis of (-)-codeine. Tetrahedron 39:2393–2397CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1985

Authors and Affiliations

  • A. Brossi
    • 1
  1. 1.Section of Medicinal Chemistry, Laboratory of Chemistry, National Institute of Arthritis, Diabetes, Digestive and Kidney DiseasesNational Institute of HealthBethesdaUSA

Personalised recommendations