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BIOSYNTHESIS OF BIOSYNTHESIS OF OPIUM ALKALOIDS. tyrosine DOPA dopamine norlaudanosoline thebaine codeine morphine papaverine * * * * * * * * 14 C-Tyrosine.

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Presentation on theme: "BIOSYNTHESIS OF BIOSYNTHESIS OF OPIUM ALKALOIDS. tyrosine DOPA dopamine norlaudanosoline thebaine codeine morphine papaverine * * * * * * * * 14 C-Tyrosine."— Presentation transcript:

1 BIOSYNTHESIS OF BIOSYNTHESIS OF OPIUM ALKALOIDS

2 tyrosine DOPA dopamine norlaudanosoline thebaine codeine morphine papaverine * * * * * * * * 14 C-Tyrosine fed to opium poppy seedlings (in all poppies) PLP SAM FAD Mannich + Arom. Subst. hydroxylase O2O2 Two labels are incorporated into papaverine and norlaudanosoline, implying that two tyrosines are used. If labeled DOPA is fed only one label is found.

3 thebaine codeine morphine This order was established by growing the poppies in a greenhouse with 14 CO 2 and watching the order of appearance and buildup of the the radioactivity 14 CO 2 FEEDING EXPERIMENT norlaudanosoline At first the rate of incorporation is greater for thebaine than for codeine or morphine. After several days, the rate of incorporation into morphine is greatest. This indicates that thebaine is formed first, and that codeine and morphine follow in order. The same result is obtained with carbon-14 labeled tyrosine. Also, labeled thebaine is converted to both codeine and morphine, but not the other way around. Finally, codeine is demethylated to morphine; the reverse is not observed.

4 norlaudanosoline * * laudanosine * * papaverine * * laudanosoline * * (-)-reticulene * * redrawn (folded) on the next slide ….. SAM FAD SAM In a separate set of experiments, it can be shown that the methyl groups originate from methionine ( 14 C labeled CH 3 ) and hence SAM. Norlaudanosoline is incorporated into papaverine and thebaine at a higher rate than tyrosine - it’s closer.

5 (-)-reticulene (5 labels) * *. thebaine * *. (all labels intact !) MULTIPLE LABELS not an easy synthesis ! When multiple labels survive intact it is a good indication that the incorporation study is a very valid one!

6 (-)-reticulene (5 labels) * *. * *... * *. coupling [O] salutaridine OXIDATIVE COUPLING * *. enolization

7 (+)-salutaridine ORIGINAL HYPOTHESIS (ALA PUMMERERS KETONE) * *. * *. Michael addition NADPH * *. H+ THEBAINE -H 2 O IT MISLEAD THEM

8 REVISION OF ROUTE TO THEBAINE * *. salutaridinol (+)-salutaridine * *. NADPH allylic displacement * *. THEBAINE Labeled salutaridine is incorporated at a high rate into thebaine, codeine and morphine. Labeled salutaridinol (both -OH epimers) is also incorporated at a high rate.

9 thebaine + H 2 O- H 2 O neopinone codeinone hemiketal codeinemorphine NADPH isomerization of double bond demethylation THE FINAL INTERCONVERSIONS Labeled neopinone is converted to codeine in the plant.

10 (+)-reticulene * *. (-)-reticulene * *. ANOTHER REVISION 1,2-dihydroreticulene * *. + (-)-reticulene * *. (+)-Reticulene appears to be formed first, and than converted to (-)-reticulene through the 1,2-dihydroreticulene intermediate. (-)-Reticulene is incorporated with the tritium label intact. (+)-Reticulene loses the label. TRITIUM SURVIVES TRITIUM IS LOST

11 WHAT WAS NOT SHOWN Remember, each of the labeled compounds had to be synthesized with high specificity. Each of the destination compounds had to be specifically degraded to find the position of the label. At times the percentage incorporation was important to know - this requires painstaking work. Most times, fortunately, it is sufficient just to know where the label ended up. All of these plants had to be grown and tended to. Manipulation of radioactive waste was a major problem ( 14 C has a half-life of 5730 years) it doesn’t go away if spilled. Dilution compounds had to isolated or synthesized.

12 Much of this work was done by Sir Alan Rushton Battersby (b. 1925) and his co-workers. Manchester College, England Ph.D. Dundee (1959) Reader at Bristol, Liverpool and Cambridge A.R. Battersby and B.J.T. Harper, “Biogenesis of Morphine”, Chemistry and Industry 1958, 364. A.R. Battersby, R. Binks, D.J.Le Count, “Biosynthesis of Morphine”, Proceedings of the Chemical Society, 1960, 287. OPTIONAL READING

13 ASSIGNMENTS Read: Hesse Alkaloids - Nature’s Cure or Curse, Wiley-VCH (2000) “Alkaloid Biogenesis in Papaver Somniferum”, pp Two of the degradation procedures will be found here in Figures 8.16 (C9) and 8.17 (C16). You will already be familiar with some of this chemistry as we learned it in the discussion of the structure proof of morphine.


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