Morphines synthesis

Suggest a synthesis of alkene (1>, needed for a morphine synthesis. ... 

Morphine Morphine, 4,5-epoxy-17-methymorphin-7-ene-3,6-diol (3.1.19), is the oldest and most weU-known analgesic. It is made from opium— the dried, milky sap of unripe opium poppy bulbs, whose analgesic properties have been known for over 3000 years. This plant also contains a large number of other alkaloids that are subdivided into groups of phenanthrenes and benzyhsoquinoline. However, ways of making synthetic morphine have also been proposed. One of the proposed, exquisite, multi-phase methods of morphine synthesis is described below. 

Hudlicky, T., Butora, G., Fearnley, S.F., Gum, A.G., Stabile, M.R. A historical perspective of morphine synthesis, in Studies in natural products chemistry, edited by Atta-ur-Rahman, 1996, Elsevier, Amsterdam, 43-116. 

The isolation of the cDNAs encoding the enzymes involved in diverse isoquinoline alkaloid formation in plants and microorganisms allowed the first metabolic engineering routes to be developed and paved the way for new ways of future production of isoquinoline alkaloids. For instance, transgenic opium poppy plants were created in which codeinone reductase was suppressed by RNAi, resulting in the substitution of morphine synthesis with the non-narcotic precursor reticuline [110]. In a similar approach, RNAi suppression or overexpression of salutaridinol 1-0-acetyltransferase in opium poppy led to accumulation of salutaridine or increase of morphine, codeine and thebaine content [111], suppression of the BBE led to accumulation of berberine in California poppy cells [112],... 

A later report of the total synthesis of ( -methylpallidinine (106) involved construction of the morphinan nucleus by addition of diazomethane to an iminium salt. The requisite iminium salt 104 was synthesized from the ketone 103 as shown in Scheme 20. When the iminium salt 104 was treated with diazomethane, the morphinan 105 was directly formed in 30% yield along with the aziridinium ion. In Evans s morphine synthesis, a morphinan product was produced directly in 30% yield from reaction of diazomethane... 

Hudlicky, T., Boros, C. H., Boros, E. E. A model study directed towards a practical enantioselective total synthesis of (-)-morphine. Synthesis t992, 174-178. 

A different approach to the problem of morphine synthesis was made by Ghosh and Robinson [41], who built up the hydrogenated-phenan-threne nucleus from a /3-tetralone by the now familiar addition of a Mannich base mothiodide. The tetralono [oxxxv, R = Cl] was con-... 

Hudlicky T, Butora G, Feamley SP, Gum AG, Stabile MR (1996) A historical perspective of morphine synthesis. In Atta-ur-Rahman (ed) Natural products chemistry, vol 18. Elsevier, Amsterdam, p 45... 

New aspects of the Ireland and related Claisen rearrangements (syntheses and transformations of lactones and lactams, morphine synthesis) 02T2905. 

On closer comparison of these successful routes, several distinct styles are apparent. The early approaches of Gates and Ginsburg are truly "synthetic", effectively working blindfolded due to their reliance upon knowledge gained solely from the extensive, but essentially crude, degradative structural studies in fact, as a result, morphine synthesis has probably offered as much to phenanthrene, and in turn to steroid chemistry, as to actual production of the alkaloid itself ... 

The authors are grateful to Mallinckrodt Speciality Chemicals for support of the research work regarding their own approaches to morphine. We thank Kenner Rice (NIH) for reading the manuscript and for providing information connected to the use of morphine and derivatives and Professor David R. Dalton of Temple University for sharing with us a copy of a recent dissertation. Scott Richardson of Mallinckrodt Specialty Chemicals is acknowledged for sharing with us a review of morphine synthesis. 

I. List of Dissertation Titles Concerning Morphine Synthesis... 

A study directed at the total synthesis of (-)-codeine and (-)- morphine synthesis via a novel asymmetric intramolecular Diels-Alder reaction Costanzo, Michael John... 

The relative stabilities of substituted cis- and trans-l,2,3,4,4a,9,10,10a-octahydrophenanthrenes, including configurational corrections in the Elad-Ginsburg morphine synthesis... 

Structure related to morphine. Synthesis of. alpha.-2-N-heptyl-2 -hydroxy-5,9-dimethyl-6,7-benzomorphan from 3,4-lutidine. II... 

Scheme 7. Morphine synthesis via aryl radical cyclization...

These issues have been addressed in detail in many previous reviews [18,21-26]. Since our update on morphine synthesis was published 5 years ago in Synlett [18], several new approaches have appeared in the literature. This review summarizes the recent accomplishments and also provides for an update in methods used to approach some of the semisynthetic opiates. 

Novak BH, Hudlicky T, Reed JW, Mulzer J, Trauner D (2000) Morphine synthesis and biosynthesis - an update. Curr Org Chem 4 343-362... 

When the Beckmann reaction was performed with mesylated oxime intermediate 113, lactam 112, from the Beckmann rearrangement, was obtained as the sole product tScheme 5.261. thus shutting down the Beckmann fragmentation pathway.This reaction is similar to what White and coworkers observed during their morphine synthesis. Beckmann reaction of an intermediate brosylated oxime in acetic acid provided the desired lactam, whereas the reaction of the corresponding oxime under acidic conditions did not yield any lactam... 

Fig. 9.17 Steps in mammalian morphine synthesis [905, 906], P450 3A4 and 3A5 eatalyze the 0 -demethylation of thebaine with 3A5 being 10-fold more aetive than P450 3 A4 [906]. The mierosomal oxidation of oripavine is very slow and is eonsidered not to eontribute. The eonversion of eodeinone to eodeine is eatalyzed by a reduetase. (Adapted with kind permission from Springer Seienee + Business Media [149])...

P450 has also been demonstrated to play important roles in the biosynthesis of endogenous morphine in mammals, catalyzing both (1) the cyclizations of (7 )-reticuline to salutaridine [905] and (2) the elusive 0 -demethylation of thebaine involved in the latter stages of morphine synthesis [906] (Fig. 9.17). With this, a minimal scheme can be proposed with P450 enzymes capable of all oxidative steps in the pathway. 

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