Two review articles in the Bulletin [vol. II, no. 2, pp. 8-20 (1950), and vol. III, no. 2, pp. 12-31 (1951)] have attempted to describe the main lines of the chemical research that led in 1925 to the generally-accepted structural formula for morphine (formula XII on the accompanying chart) and it has been tried (on pages 19-24 of the second article) to give a brief résumé of the chemical reactions which have resulted in total syntheses of two different chemical compounds, each of which has been found identical with a transformation product of codeine. Those syntheses had given convincing support to the correctness of formula XII for morphine but final proof by total synthesis had not yet been provided.
Author: Ulrich Weiss
Pages: 34 to 35
Creation Date: 1952/01/01
Two review articles in the Bulletin [vol. II, no. 2, pp. 8-20 (1950), and vol. III, no. 2, pp. 12-31 (1951)] have attempted to describe the main lines of the chemical research that led in 1925 to the generally-accepted structural formula for morphine (formula XII on the accompanying chart) and it has been tried (on pages 19-24 of the second article) to give a brief résumé of the chemical reactions which have resulted in total syntheses of two different chemical compounds, each of which has been found identical with a transformation product of codeine. Those syntheses had given convincing support to the correctness of formula XII for morphine but final proof by total synthesis had not yet been provided.
It is therefore of the greatest importance that Gates and Tschudi, continuing their earlier synthetic work,[1] have succeeded in performing a total synthesis of morphine. This synthesis is outlined in a short communication in the issue of 20 February 1952, of the Journal of the American Chemical Society (vol. 74, page 1109). We feel that the magnitude of this scientific achievement warrants a brief exposé of the sequence of chemical reactions followed, which is represented in the accompanying chart.
This involved series of reactions constitutes a transformation of the synthetic compound I, described earlier,[1] into morphine, and furnishes unequivocal proof for the formula XII for morphine. The lengthy history of the structural elucidation of this base can therefore be considered to have reached the long expected satisfactory conclusion.
Brief comment on some of the chemistry of this synthesis may seem in order. It will be recalled (cf. the Bulletin, vol. III, no. 2, p. 24) that Gates and Tschudi[1] had been able to convert compound I in several steps into the racemate of II, which had been proved by infra-red spectroscopy to have the same chemical constitution as Β-dihydrodesoxycodeine, a compound derived from the natural alkaloid in a way which led to inversion of the configuration at carbon atom 14. This "unnatural" configuration is indicated by the prefix Β.
The synthetic racemate of II has now been resolved into the optical antipodes, of which the d-form has served as starting material for the subsequent steps, most of which will be clear from the chart. In every step, the intermediates obtained were compared with previously known transformation products of codeine, or with derivatives of the natural alkaloid prepared for this purpose (compounds VI, IX, X); identity was established in every case.
The following individual steps may require comment:
V-VI: Compound V must have been brominated in the 1- and 7- positions, contrary to earlier experience in the codeine-series,[2] where bromination first in I, then in 5 has been generally observed. In the reaction V-VI, HBr must have been eliminated subsequently under the influence of the 2,4-dinitrophenylhydrazine, establishing the desired double bond between C 7 and C 8, a type of reaction much utilized in recent work on steroids. In the present case, however, the configuration at C 14 has changed simultaneously from the "unnatural" B- type to the one normally present in codeine-derivatives, no doubt through transient shift of the double bond into the 8,14-position. Such shifts have been postulated earlier.[3]
VIII-IX: This reaction is analogous to the one just discussed, except for the closure of the oxygen bridge, which is generally observed on bromination of codeinederivatives in the 5-position and subsequent action of base.[2]
XI-XII: The demethylation of codeine to morphine with pyridine-HC1 has recently been described for the first time by Rapoport, Lovell and Tolbert.[4] This reaction permits the transformation of the synthetic codeine into morphine itself.
Several of the reactions of this synthesis proceed with low yields or result in mixtures (II-IV, VIII-IX, IX-X); even without this fact, the large number of steps required would seem to make any practical utilization of this synthesis quite unlikely, which of course does not in any way diminish its scientific importance.
1 Gates and Tschudi, Journ. Amer. Chem Soc 72, 4839 (1950).
002p0002 Cf., e g, Schoepf et al, Ann. 483, 157 (1930), 492, 213 (1932); Small et al, Journ Amer Chem Soc 58, 1457 (1936)
003p0003 Cf Small, Chemistry of the Opium Alkaloids (1932), p. 248.
004p0004 Rapoport, Lovell and Tolbert, Journ. Amer Chem Soc. 73, 5900 (1951)
