MORPHINE

1. Part Three Structure Proof MORPHINE

2. NOW THAT WE KNOW THE STRUCTURE OF METHYLMORPHENOL WE CAN BEGIN TO FORMULATE THE STRUCTURE OF CODEINE codeine 1 2 3 Hofmanns these groups are in one of these two rings 1 2 3 . . loses nitrogen, oxygen and two carbons -CH2-CH2- N CH3 methylmorphenol OH Codeine H

3. MORPHINE HERE IS THE CORRECT STRUCTURE The location of the double bond was also difficult to establish. There was a great deal of difficulty in locating the third oxygen.

4. A LITTLE BIT ABOUT THEBAINE Thebaine was used in the studies to locate the third oxygen. Morphine: C17H19NO3 Codeine : C18H21NO3 Thebaine Differs from codeine by having: C19H21NO3 a) one extra double bond b) the alcoholic -OH as a methoxyl group PtO2 2 H2 1) CH3I, NaOH PhNMe3+ OH- Dihydromorphine dimethyl ether 2) PtO2, 1 H2 Codeine Morphine These conversions imply that thebaine has the same skeleton as morphine and codeine, and an extra double bond. Also implied are two methoxy groups, and no OH.

5. CONVERSION OF THEBAINE TO CODEINONE KETONE 1N H2SO4 Thebaine Codeinone 7% yield C19H21NO3 C18H19NO3 This implies that there is an enol ether in thebaine. H+ + MeOH H2O H2O hydrolysis of enol ether keto enol enol ether - : : + equilibrium resonance

6. THEBAINE PART STRUCTURE Thebaine has two double bonds, one an enol (methyl) ether that hydrolyzes to a ketone. CH2CH2- We know from methylmorphenol work that morphine, codeine and thebaine all have this skeleton.

7. ACETOLYSIS The position of the third oxygen was proven by doing “acetolysis” of all three compounds (morphine, codeine, thebaine) and also codeinone. NaOAc, HOAc Ac2O D Acetolysis involves heating the compounds with a mixture of sodium acetate (NaOAc), a base, acetic acid (HOAc), and acetic anhydride (Ac2O), an acetylating compound. All OH groups are acetylated and, if they are not attached to an aromatic ring, an elimination reaction forms a double bond (acetate is a good leaving group) . After protonation, OH groups may be eliminatated as water. Ethers which have at least one aliphatic group are cleaved. Dehydrations, eliminations and enolizations cause rings to become aromatic. Morphine, codeine and tebaine all form aromatic rings with this procedure.

8. EXAMPLE ACETOLYSIS acetylate OAC- .. .. + -H2O AcO- + + open ether, lose bridge, aromatize, acetylate OH

9. ACETOLYSIS RESULTS These were all synthesized by the Pschorr method. CH3I NaOH acetolysis morphine morphine methiodide codeine coedeine methiodide codeinone codeinone methiodide thebaine thebaine methiodide These results establish the position of the third oxygen atom.

10. HYDROXYCODEINONE K2Cr2O7 codeine hydroxycodeine -20oC dil H2SO4 CH3I NaOH A new OH group was introduced, position unknown. acetolysis I- hydroxycodeine methiodide + Ac2O, HOAc NaOAc D 1) Ag2O 2) D H2SO4 CrO3 << a ketone >> this result means the nitrogen bridge must also be a C9 or C10 loses one -OAc group - must be at C9 or C10 (see next slide) << an anthraquinone >>

11. EXPLANATION OF THE KETONE RESULT 1) We know the new OH went into position C9 or C10 in hydroxycodeine. 2) The nitrogen bridge must also be at C9 or C10 KEEP IN MIND: C9-N C9-N C10-OH C9-OH + + + + + + BOTH ARE KETONES The same two ketones would be obtained if N were at C10.

12. ULTRAVIOLET SPECTROSCOPY COMES INTO PLAY + + C10 C=O C9 C=O BOTH ARE KETONES This ketone can be ruled out by the ultraviolet spectrum. The oxygen had to be at carbon 9. lmax =245 (6500) lmax =286 (1100) vs. lmax =278 (20) conjugated ketone unconjugated ketone

13. A RETURN TO THE a and b-CODEIMETHINES codeine methiodide + codeine double bond must be here (it cannot be in the enolic position) 1) CH3I x 2) Ag2O 3) D All arguments lead to the same conclusion. We’ll go through them all in detail. styrene chromophore extended chromophore 250o lmax= 275 (10000) lmax= 355 (10000) lmax= 310 (7000) b-codeimethine a-codeimethine The other end of the chain containing N must attach here otherwise a naphthalene ring would be expected. . Second double bond moves into conjugation BLOCKED

14. . . This would block rearrangement of a-codeimethine to b-codeimethine. These would not block the rearrangement to a naphthalene system (which does not happen).

15. + + HO- OH- .. first Hofmann codeine methiodide a-codeimethine second Hofmann fragmentation THE ABNORMAL HOFMANN DEGRADATION .. OH- aromatization - H2O methylmorphenol

16. SOME DIFFICULTIES ALONG THE WAY REARRANGEMENTS

17. REARRANGEMENTS Morphine, codeine and thebaine are star performing acrobats ! One of the things that drew organic chemists to natural products was the challenging and interesting chemistry that they found. EXAMPLE concentrated HCl Morphine Apomorphine - H2O C17H19NO3 C17H17NO2 This looks like a simple dehydration of morphine. Many hours of work were spent on apomorphine on the assumption that it had the same ring structure as morphine with only a loss of water. Eventually the structure of apomorphine was proved to be the structure shown to the right. All the work on apomorphine had no bearing on the stucture of morphine and was, in fact, misleading!

18. REARRANGEMENTS dilute HCl boil 2 min. thebaine thebenine dilute HCl Another puzzler! codeinone

19. REARRANGEMENTS PhMgBr ether thebaine Bizarre, eh ?

20. PHARMACOLOGY

21. ENKEPHALINS From larger peptide structures found in the brain called endorphins. Bind to a pain-reducing receptor in the brain. Leu-enkephalin Tyr-Gly-Gly-Phe-Leu morphine The enkephalins are rapidly degraded in the body and are therefore not good for drug use. Met-enkephalin Tyr-Gly-Gly-Phe-Met

22. SYNTHETIC OPIUM ANALGESIC DRUGS morphine dextromethorphan (levomethorphan) phenazocine naloxone oxycodone naltrexone pentazocine (with cyclopropyl)

23. SYNTHETIC OPIUM ANALGESIC DRUGS meperidine (demerol) (pethidine) morphine fentanyl methadone

24. ASSIGNMENTS Read: Hesse Alkaloids - Nature’s Cure or Curse, Wiley-VCH (2000) 5.6 “Morphines”, pp 272-277 Discusses the effect of stereochemistry on analgesic activity.