Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, June 7, 2010
Douglass F. Taber
University of Delaware

The Magnus Synthesis of ()-Codeine

Although there have been many synthetic approaches to morphine and its methyl ether codeine (3), the pentacyclic structure of these Papaver alkaloids continues to intrigue organic chemists. Philip Magnus of the University of Texas devised (J. Am. Chem. Soc. 2009, 131, 16045. DOI: 10.1021/ja9085534) an elegant route to 3 based on the conversion of 1 to 2 by way of an intramolecular Michael addition.

The starting point for the synthesis was the commercial bromoaldehyde 4. Coupling with 5 delivered the substituted biphenyl 6, that was carried on to the mixed bromo acetal 8. On exposure to fluoride ion, 8 was desilylated, and the intermediate phenoxide cyclized with impressive facility to give 1. Exposure of 1 to nitromethane delivered the tetracyclic 2. This reaction apparently was initiated by Henry addition of the nitromethane to the aldehyde. The intramolecular Michael addition of the intermediate Henry adduct then proceeded to give the desired cis diastereomer of the newly formed ring. Finally, loss of water gave 2.

Conjugate reduction of the nitroalkene 2 led to 9 with remarkable diastereocontrol. Exposure of 9 to LiAlH4 converted the nitro group to the amine, and the enone to the allylic alcohol. On exposure to acid, the hemiacetal was hydrolyzed. The liberated aldehyde underwent reductive amination with the free amine, while at the same time ionic cyclization closed the ether ring. N-Acylation completed the conversion to 10.

The ether 10 had previously been converted to codeine, and then, in a single demethylation step, to morphine. In that synthesis, the alkene of 10 was directly epoxidized. The resulting “up” epoxide reacted only sluggishly with phenylselenide anion, and the relative configuration of the resulting allylic alcohol had to be inverted by oxidation followed by reduction. In the current synthesis, exposure of the alkene 10 to dibromohydantoin under aqueous conditions, to form the bromohydrin, effected concomitant arene bromination, to give, after base treatment, the “down” epoxide 12. Phenylselenide opening of the epoxide was then facile, and the product allylic alcohol had the correct relative configuration for codeine and morphine. The extra Br was of no consequence, as it was removed by the final LiAlH4 reduction.

Except for the stereogenic center of the acetal, the dienone 1 is prochiral. This raises the exciting possibility that it may be possible to set the absolute configuration of codeine and thus of morphine by asymmetric catalysis of the Henry reaction of 1.

D. F. Taber, Org. Chem. Highlights 2010, June 7.