Codeine biomimetic synthesis

A commercially profitable biomimetic synthesis of morphinane alkaloids will require the conversion of reticuline into salutaridine in sufficient yield (Scheme 14) (see Section III,D) and the conversion of salutaridine into thebaine, codeine, and morphine. 

White JD, Caravatti G, Kline TB, Edstrom E, Rice KC, Brossi A (1983) Biomimetic total synthesis of (—)-codeine. Tetrahedron 39 2393-2397... 

Initial investigations in opiate total synthesis at NIH focused on the biomimetic route, shown above and recently studied extensively by Szantay et al. (1983) and Schwartz and Zoda (1981) in which a reticuline derivative (11) is oxidatively cyclized to a salutaridine derivative (12) which would be convertible to thebaine and hence to codeine and morphine. Traditionally, this approach has been complicated by control of the product distribution ratio and the tendency of the desired morphinandienones to undergo secondary transformations. An effective synthesis of reticuline derivatives (Rice and Brossi 1980) was developed as a prerequisite to this approach at NIH, and a simple synthesis of racemic and chiral pavinans and isopavinans (Rice et al. 1980) resulted from these studies, but attempts at development of an oxidative cyclization which would be useful for large scale synthesis were unsuccessful. 

White JD, Caravatti G, Kline TB, Edstrom E, Rice KC, Brossi A (1983) Biomimetic total synthesis of (-)-codeine.Tetrahedron 39 2393-2397 Windholz M (1984) The Merck Index, 10th edn. Merck, Rahway NJ, no 6728 Wright CRA (1874) On the action of organic adds and their anhydrides on the natural alkaloids Part I. J Chem Soc 27 1031-1043... 

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