Assignment on

Source, stereochemistry, medicinal values and structural elucidation of Morphine

Submitted to: Mr. Ashwinee Shrestha, Department of Pharmacy School of Science Kathmandu University

Submitted by: Amik Tuladhar, Roll-18 M. Pharm. 1st Year 2nd Semester (Batch 2010)

Submission date: 18.09.2011

Source, stereochemistry, medicinal values and structural elucidation of Morphine

Source of morphine Morphine is the most abundant alkaloid found in opium, the dried sap (latex) derived from shallowly slicing the unripe seedpods of the opium, or common and/or edible, poppy, Papaver somniferum. Morphine was the first active principle purified from a plant source and is one of at least 50 alkaloids of several different types present in opium, Poppy Straw Concentrate, and other poppy derivatives. Morphine is generally 8 to 17 percent of the dry weight of opium, although specially-bred cultivars reach 26 percent or produce little morphine at all, under 1 percent, perhaps down to 0.04 percent. The latter varieties, including the 'Przemko' and 'Norman' cultivars of the opium poppy, are used to produce two other alkaloids, thebaine and oripavine, which are used in the manufacture of semi-synthetic and synthetic opioids like oxycodone and etorphine and some other types of drugs. P. bracteatum does not contain morphine or codeine, or other narcotic phenanthrene-type, alkaloids. This species is rather a source of thebaine. Occurrence of morphine in otherpapaverales and papaveraceae, as well as in some species of hops and mulberry trees has not been confirmed. Morphine is produced most predominantly early in the life cycle of the plant. Past the optimum point for extraction, various processes in the plant produce codeine, thebaine, and in some cases negligible amounts of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydrothebaine and hydrocodone (these compounds are rather synthesized from thebaine and oripavine). Morphine and its derivatives are classified as narcotic analgesics, they being strongly hypnotic. Their use tends to habit formation. Codeine and its salts are narcotic, analgesics and antitussive. Codeine is considerably less toxic and involves much less danger from habit formation. Morphine is the most important of the opium alkaloids. It was first isolated from opium by Serturner in 1816 and elucidation of its structure became the goal of many researchers. Morphine has hydrophenanthrene skeleton with fused N-methyl-piperidine ring and contains a phenolic and an alcoholic hydroxyl groups. A formula proposed by Gulland and Robinson in 1925 was secure in all respects except the position of anchoring ethanamine- bridge extending from C-9. Finally, a total synthesis of morphine was done by Gates in 1952, and established that the chain is indeed linked at C-13.Heroin is prepared by acetylation of morphine.

Here, 4.34 is the structure of morphine. Its acetylation leads to the formation of Heroin. Stereochemistry of morphine

Fig: Structure of Morphine The morphine is named after the Greek god of sleep, Morpheus. It is a constituent of opium. Its structure was the subject of several investigations which ultimately led to its formulation as shown in the figure above. It can be seen that there are five chiral centers in this structure, at positions 5, 6,9,13 and 14. The most convincing experimental evidence with regard to the relative configurations at C5 and C6 was generated by Rapoport and co-workers by selectively burning out the benzene ring. The starting material was dihydrocodeine, (codeine, which is the monomethyl ether of morphine is also a constituent of opium), which was subjected to ozonolysis. This ozonide was worked up and subsequently reduced with lithium aluminium hydride (LAH) to obtain a tetrahydroxy compound (2.1.4) which behaved as a 1,2-diol. Since the gross structure of dihydrocodeine was already known, the structure of this tetraol could be figured out as shown below:

Thus, it could be considered as a cyclohexane 1,2-diol derivative. That the two hydroxyls in this part of the molecule were cis to each other was indicated by the facile reaction of the compound with lead tetraacetate. On the other hand, the corresponding tetrahydroxy compound (2.1.6) obtained from dihydroisocodeine (2.1.5) by an identical series of reactions was found to be three times less reactive towards lead tetraacetate. Therefore, in dihydrocodeine, the C5-oxygen bridge and the C6 hydroxyl should be cis to each other. At this point, it would perhaps be useful to recall the differences in rates of reaction between cis and trans cyclohexane 1,2-diols. The cis compound is also known to react faster with acetone and to increase the conductivity of boric acid to a larger extent. However, reactions of 1,2-diols with lead tetraacetate and periodic acid are more amenable to quantitative analysis.

Relating the configurational centers at C6 and C13, which are not adjacent but close enough, was not as straight forward as relating C5 and C6. Dihydroisocodeine (2.1.5), on Hoffmann exhaustive methylation, followed by catalytic hydrogenation and a second Hoffmann reaction, yielded, as expected, an unsaturated, nitrogen-free compound (2.1.7) which underwent a facile acid-catalyzed rearrangement to give a cyclic ether (2.1.8). For the formation of such ether, the hydroxyl at position C6 and the newly formed vinyl group at C13 in the end-product should be on the same side of the ring.

On the other hand, in agreement with this logic, the corresponding nitrogen-free, unsaturated compound (2.1.9) similarly obtained from dihydrocodeine was not affected by acids; it failed to give any cyclic ether. Therefore, in codeine, the C6 hydroxyl and the C13-C15 bond should be trans to each other as they are on the same side in isocodeine.

The chiral centers C9 and C13 could be readily related to each other. The C13-C15 bond and the C9-N bond should be on the same side of the middle ring as they are an integral part of the bridged

bicyclic system which could only be cis fused. Perhaps the most difficult part of the chemical approach towards delineating the stereochemistry of morphine and its derivatives was to devise a suitable strategy to relate C13 and C14. Medicinal values of Morphine Morphine was used to relieve pain and diarrhea experienced by the soldiers living in deplorable conditions while at war. The medicinal use of morphine remains an integral, but strictly regulated, part of clinical medicine. Morphine is commonly used in hospitals for the management of postoperative and chronic pain. Structural elucidation of Morphine The presence of a hydrophenanthrene ring system was suggested in 1881 by the isolation of phenanthrene as a product of zinc dust distillation of morphine. The location of the three oxygen functions was established by degradation leading to phenanthrene derivative oxygenated at 3,4,5 positions as shown in figure below.

Morphine on heating with hydrochloric acid gave apomorphine. This reaction is shown below:

The 1914 Harrison Narcotics Tax Act in the United States made possession of morphine a criminal act. Forensic scientists exploit a group characteristic property of morphine and its related compounds: a peculiar reaction with Mecke's (or Lafon's) reagent. The reagent consists of selenious acid (H2SeO3) in concentrated sulfuric acid (H2SO4). If morphine and the reagent react, the following colors appear: green, then quickly a greenish blue, changing to blue, next slowly to bluish green with a yellow-brown edge, then finally olivaceous green. This is one of a variety of color tests that are used. Most, however, are presumptive tests, meaning that they suggest the presence of opiates but don't absolutely prove it. Final confirmation is obtained through instrumentation, either gas chromatography-mass-spectrometry or by Fourier Transform Infrared Spectroscopy. NMR has also been used to identify heroin.

References
1. http://en.wikipedia.org/wiki/Morphine 2. http://media.wiley.com/product_data/excerpt/4X/35273144/352731444X.pdf elucidation) Sivakumar, Pg. 258
4. Chemistry of natural products: a unified approach By N. R. Krishnaswamy, Pg. 49 5. Morphine By Gregory D. Busse, D. J. Triggle, Pg. 19

(structural

3. Chemistry of natural products By Sujata V. Bhat, Bhimsen A. Nagasampagi, Meenakshi

6. http://www.emsb.qc.ca/laurenhill/science/morphine.html