Evolution of the Morphinan Synthesis Daniel Lednicwl University of Missouri-Columbia, Columbia, MO 65211 One of the earliest and longest lasting targets for medicinal chemists has been the relief of pain. Most of the central analgetics, though quite effective, present a serious drawback in that thev often lead to addiction. A considerable amount of effort has thus been devoted toward attempts to oroduce structural analoeues. Moruhinans such as levallor&an. I, and benzomorpians surhas pentazocine, 2, which are essentiallv ahbreviawd versions of morphine and are but single ~e~reskntatives of very large seriesof analogues, do show reduced addiction potential. The key reaction to the preparation of these structures is the Grewe carbocation cyclization.
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The original central analgetic agent, morphine, 3, was first isolated from opium, the dried sap from the seed pod of Papauer somniferum, in pure crystalline form by Serturner as early as 1803. Structural proposals by Robinson (I) and by Schopf (2) followed 120 years later, after organic chemistry had developed sufficiently to tackle complex molecules. Grewe's research led to the first synthesis for the morphine skeleton and also provided the first generalized entry to simplified analogues of morphine. It is fitting that Rudolf Grewe received his training in the natural products laboratory of Windaus at Gottingen. His initial work actually involved heterocyclic rather than alicyclic chemistry and led to a paper, with Windaus, (3) on the structural determination of the newly purified "antineuritic" vitamin (4), a substance known today as thiamine or vitamin B. The structural analysis that identifies the isoquinoline and phenanthrene moieties present in morphine appeared in the first of a small series of papers on the synthesis of this alkaloid. The synthetic plan was made explicit by the running title for the series: "Syntheses in the Phenanthrene Series". The initial approach involved preparation of some intermediate such as 4 containing groups at the 4a and 9 positions that could he used later to construct the additional isoquinoline ring required for morphine (5). Earlier work
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Prewnt address: DS(LC8, National Cancer Institute, EPN. Suite 831, Bslhesda. MD 20892.
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from other laboratories had shown that angularly substituted hvdroohenanthrenes could be obtained by proper choice of s&ting materials; treatment of phenethil cyclohexanol, 5, with strong acid, for example, gives the phenanthrene 6 (6),while 7 leads to the alternate methylated product 8 (7). (That earlier work was also directed at the total synthesis of natural products containing angular substitution-the steroids.) Grewe shortly published two additional communications in which he reported on the preparation of compounds such as 8 that had the required substitution pattern (8,9).
The only available instrumental method for organic structural determination a t that time was ultraviolet spectroscopy. Infrared spectroscopy had not yet adapted to instrumentation. The routine method for structural assignment of these cyclization products involved treatment ivith a dehydrogenation catalyst such as platinum or palladium. It had been established empirically that angularly substituted products would lose the alkyl groups to give phenanthrene proper; nuclearly alkylated products would give the corresponding alkylphenanthrenes. All these publications appeared under Grewe's name as sole author; as a junior member of a well-established department he no doubt had to carry out all the laboratory work that appeared in print under his name. This, and the fact that Germany had by then entered a major war, prohably accounts for the fact that the solution to the morphinan problem did not appear until 1943. In a stepwise exploration of his original strategy, he applied the cyclizationreaction to the cyclohexanol9. The major product, as determined by its dehydrogenation to 12, disappointingly consisted of 10 rather than the hoped-for angularly alkylated product 11,which would have provided a nitrogen atom in the position required for a morphine-like structure (10). This is in marked contrast to findings with the methyl analogue 7 or the ally1 comnound 13 (10). This can be rationalized in resent-day k&hy assuming that the initially formed ca;bocation in anv of these cvclizations needs to underao a 1.2 hydride shift prior to ring &sure. That leading to logives greater separation between the charge on carbon and that on the protonated side chain amino Goup in the intermediate to 11.
enaminelike double bond a t the 2 position (pyridine numbering) can be reduced selectively to leave the tetrasuhstituted olefin 29. Treatment with strong acid leads to the morphinan 31, via the intermediacy of carbocation 30. Only a single product is possible in this case, neglecting a theoretically possible spiroannulated compound (12).
Repetition of the experiment that led to the dialkylated product 8 starting with the ally1 derivative 15 surprisingly led to a product, 20, that contained the carhocyclic equivalent of the morphine ring system (11). Grewe reasoned that the initial reaction in this case involved formation of a hydronaphthalene system such as 18, which includes a new .carhocyclic ring. This was then postulated to undergo further cyclization to the bridged system. In today's terms, carbocation 16, from loss of a hydroxyl from 15, would undergo a 1,2 hydride shift to form 17; electrophilic attack on the ally1 double bond will lead to 18. The intermediate 18 then rearranges to the favored tertiary carbocation 19; electrophilic attack on the aromatic ring leads to the observed hicyclic product 20. Grewe highlighted the significance of the work by concluding the written account of a talk announcing the synthesis with the note, ..this preparation will allow access to numerous morphine type structures which may show special pharmacological properties." This optimism was no doubt prompted by the observation that "This synthetic base possesses good analgetic properties; its pain killing properties are of the same magnitude as those of natural morphine" (13). . . The first total synthesis of a derivative of a naturally occurring morohinan started bv oreoaration of odahvdroisoquinolhe 32 by suitable &dikcation of the dar~ier scheme. Treatment of this intermediate with strong acid gave the cyclization product 34 in which the ether ortho to the phenanthrene ring fortuitously demethylated under the reaction conditions. The levorotatory isomer ohtained by resolution proved identical to a sample of the same product ohtained in several steps from dihydrothehainone, a minor constituent of opium (14). Practical consequences from this work appeared in very short order with the synthesis of the analgetic agent racemorphan, 37, by chemists at Hoffman LaRoche (15). In practice, the compound is marketed as an analgetic drug as its levorotatow isomer. levorohanol. The dextrorotarv isomer, which is used separately,is inactive as an andgetic; it is familiar to all as a part of cold remedies as the antitussive agent dextromorphan. The subsequent finding that compounds that lacked yet one more ring as in 2 retained eood activity led to a second wave of research. The Grewe cycrization again provided the key reaction. This culminated in the preparation of the benzomorphan, pentazocine, 2 (16), an analgetic that shows reduced addiction potential (17).
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The seemingly serendipitous discovery that the bridging ring can be incorporated in prefabricated form in the cyclization reaction may have provided inspiration for the s h t h e sis in its fmal form. The three-year delay in the publication of this work was, in all probability, due to the massive disruption of life in Germany at the end of World War 2. Working now with a collaborator, Alhert Mondon. Grewe first developed a route to an octah;droquinoline designed as a heterocyclic analogue of the postulated reaction intermediate 18. The synthesis star& with the relatively routine construction of the fused pyridinium salt 27. Though Grim a d reaeents will not add to imines., thev do so readilv ~~-~~~~~ " to -the far m&e electrophilic ternary iminium salts such as 27; addition of henzylmagnesium chloride to 27 leads to 2% the
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Literature Clted 1. G d h d , J. M.;Robinson, R. Mem. R a c . Monch. tif.Phi1.Sac. 1)25,69,79-86 2. Sehopf, C.Ann. 1327,452,211-267. 3. Windaus,A.: Twhesche, R.: Gmare,R.Z.phwiol. C k m . 19U.118.27-32. 4. Glewe,R.Nofurmken. 1936.2.1.657462. 5. Gcewe. R . C k m . B w . 19J9.72,426432. :
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14. Greae, R.;Mondon.A.; Nolte. E. Ann. 1949.5M, 161-198. G-ner, k Helo. Chirn.Acto 1949,32,821-929. 15. Schnidu. 0.: 16. Archer, S.; Albertaon. N. F.; Harris, L. S.; Piersen, k K.: Bird, J. G. J Mad. Chem. 19U,7,12Fl21. 17. For detailed aemunrs ofthi m r k w Burger,A,: Anolgofies: Academic New Ywk, 1965. Johoson,M. R.;Milne, G. M. InBurger8MediciwIChernO*t~.4~th.; Waf, M. E.: Ed.: Wiiey: New York, 1981; Part nI, Chapter 52. Lednieer, D. la Centrol Awlgefic8; Ledni~er.D.; Ed.; Wiiey: New York, 1982: Chapter(.
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