During the last three decades Marine organisms have been investigated. Amongst the alkaloids are the exceedingly complex Saxitoxin (f) produced by a red coloured dinoflagellate. The ‘red tides’ contain mass aggregations of such organisms, and food poisoning when he toxic alkaloids are passed along the food chain to man. The Japanese puffer fish is highly valued as a culinary delicacy, but it is hazardous because its liver and ovaries contain the highly toxic tetrodotoxin.
Fungi also produce alkaloids, and these too, present potential hazards as food contaminants. The ergot alkaloids, for example, Chanoclavine (g) produced by the fungus Claviceps purpurea, were a frequent soure of misery and death during the Middle Ages through the contamination of rye bread. Some of these were neurotoxic whilst others caused vasocontriction. During the last 40 years most of these non plant alkaloids have been isolated and their structures elucidated.
The introduction of modern chromatographic and spectroscopic techniques facilitated this. Isolation Work on the constitution of alkaloids is often prefaced by the problem of their isolation from plant material or from residues after commercially important constituents have been removed. The isolation of each alkaloid is an individual problem there are a variety of procedures which may be entitled to generic rank. There are few plants which produce a single alkaloid so the main problem is the separation of mixtures.
Many alkaloids are basic and occur as salts of 2-hydroxybutane-1, 4-dioic acid (malic acid), or of 1,3,4,5-tetrahydroxycyclohexane (quinic acid). They can thus be extracted into acid solution using aqueous hydrochloric, tartaric, or citric acids. Neutral alkaloids such as colchicines or piperine, which are in fact amides, remain in the organic phase, whilst most other alkaloids are isolated after basification and extraction into ethyl acetate.
Steam distillation can be used also be used with low molecular weight alkaloids; but almost invariably sudsequent purification of the crude alkaloid mixtures is effected by chromatography using silica or alumina, and then recrystallisation of the partially purified compounds from solvent systems like aqueous ethanol, methanol/chloroform, or methanol/acetone. Structure elucidation Classical era:
The classical era for structural studies on alkaloids was the 19th Century, though this could be extended to the 1930’s (advent of x-ray crystallography) or even to the 1970’s (advent of high resolution NMR facilities and modern methods of mass spectroscopy. Two case histories will be discussed, those of morphine and atropine. Opium has been used by man for thousands of years, so it is not suprising that the major active ingedient, morphine, was the first alkaloid to be isolated in pure state (by Serturner in 1805). It was not until 1923 that Sir Robert Robinson established the stucture of morphine.
Chemical evidence for the structure is as follows: Standard showed that the nitrogen atom was fully substituted, and that the phenolic hydroxyl was present as it gave a positive FeCl3 test. Two hydoxyls were present as a diacetate and dibenzoate could be formed. Both compounds contained one olefinic double bond as codeine absorbed one. It was found that a reduced phenanthrene with a two-carbon bridge containing a tertiary nitrogen atom (with methyl as on substituent) was present, and the structure of morphine and codeine were first proposed in 1923 and 1925 respectively by Robinson and Gulland.
Synthesis of morphine was carried out in 1956 by Gates. Atropine on the other hand, is not generally a natural product but arises through racemisation of (-)-hyoscyamine (see (a) below) and purification, and is thus ( )-hyoscyamine. (-)-hyoscyamine is the most common tropane alkaloid. In 1833 atropine was isolated from Atropa belladonna. Hydrolysis with warm barium hydroxide solution produced racemic tropic acid and tropine. Degradative studies and then through synthesis found the structure of tropic acid: Exhaustive degradation of tropine, carried out by Willsti??
lter between 1985 and 1901, provided evidence for the bicyclic structure of tropine. The most widely used process in degradative studies of alaloids is exhaustive methylation, known as Hofmann degradeation. . This involves the pyrolysis of a quaternary ammonium hydroxide to form and olefin an a tertiary base: To ensure the complete removal of the nitrogen atom when it constitutes part of a ring, two degrdations must be carried out. When exhaustive methylation of of cyclic compounds might be expected to give 1,4-dienes, the alkaline conditions of the reaction may result in the migration of one of the double bonds to give a 1,3-diene.
For example, the exhaustive methylation of N-methylpiperidine gives 1,3-pentadiene (piperylene) and not 1,4-pentadiene. The diene is then easily hydrogenated to form a saturated hydrocarbon. If Hofmann degradation fails to bring about ring fission of cyclic amines, Emde degradation, invoving catalytic reduction of a quaternary salt by sodium amalgam or sodium in liquid ammonia, may be applied. For example, attempted Hofmann degradation of N-methyltetrahydroquinoline methoxide results in regeneration of the parent base, while Emde reduction with sodium amalgam affords the ring-opened amine.
Alkaloids containing diphenyl ether linkages, for example, bis-benzylisoquinoline, are cleaved into two fragments by reduction with sodium in liquid ammonia. For example, the structure of the alkaloid dauricine was established by reductive cleavage of O-methyl-dauricine. Modern era: During the last 30 years, structure elucidation has benn facilitated by the use of mass spectroscopy, and 1H and 13C NMR techniques. It is now possible to determine the structure in days with a few milligrams or less of pure compound.
It took 118 years to determine the structure of morphine. The mass spectrum data for morphine is highly informative and is shown below and would have helped enormously years ago. Once the structure of an alkaloid is known, partial or total synthesis can be attempted. Biosynthesis It is possible to determine the amino acid from which an alkaloid is derived just by looking at the structure. Before availability of radio-isotopes 14C and tritium, and more recently the stable isotopes 13C and 15N it was only possible to speculate about the likely biosynthetic pathways.
This was sometimes successful as for example, the suggested pathway to the isoquinoline alkaloid is as follows: It is possible to divide the biosynthesis of the alkaloids into two categories according to whether products are obtained from the amino acids ornithine and lysine, or the aromatic amino acids phenylalanine, tyrosine, tryptophan. Alkaloids derived from ornithine and lysine: Pyrrolidine alkaloids – hygrine, cocaine, tropinone, hyoscyamine etc Piperidine alkaoids – piperine, (-)-lobeline etc
Quinolizidine alkaloids – sparteine, cytosine, (-)-lupinine etc Pyridine alkaloids – nicotine, anabasine, anatabine etc Alkaloids derived from phenylalanine and tyrosine: Monocyclic compounds – hordenine etc Tetrahydroisoquinoline alkaloids – morphine, codeine, thebaine, noscapine (narcotine), papaverine, heroin etc Alkaloids derived from tryptophan: Simple indole derivatives: psilocybin, dimethyltryptamine, physostigmine etc Complex indole derivatives : harmaline, echinulin, ergonovine etc
No class of naturally occurring organic substances shows such an enormous range of structures as the alkaloids with over 5000 known. It would be impossible to discuss each one of these within the time limit. Therefore, this project is concerned with the following alkaloids: Morphine ( including codeine and heroin), Cocaine, Nicotine and Caffeine (including theophylline). These alkaloids are present in enormous quantities in the world and seem appropriate to be discussed due to the current interest in their effects particularly when used illegally.
They are some of the most well known alkaloids. Morphine (Codeine and Heroin) When the unripe seed capsules of the opium poppy, Papaver somniferum, is cut or pricked, a viscous liquid is exuded. After the exudates dries and darkens with exposure to air, a hard but still partly sticky mass is obtained. This is opium, which has been used for many centuries by some for medicinal purposes. Opium is important as a painkilling drug in its own right, but is also the source of other analgesic drugs such as morphine and heroin.
Mankind had discovered the use of opium by the time of the earliest written records. In fact, the first recorded use of opium as a painkiller was around 6000 years ago by the Sumerians, and the Babylonian and Egyptian writings contain many references to the value of opium preparations for the relief of pain. Thomas Sydenham, the 17th Century pioneer of English medicine wrote, “Among the remedies which it has pleased Almighty God to give to man to relieve its sufferings, none is so universal and so efficacious as opium”.
Nowadays, although opium is no longer regareded as a universal analgesic, it is still a very important source of morphine. The pharmacologically active constituents of opium have been employed in medicine for many thousand of years. During the 19th century these constituents were isolated as pure chemical entities. Morphine is a naturally occurring substance and is the major constituent of opium, constituting about 10% (sometimes up to 20%) of its weight. Morphine was first isolated in 1805 by Friedrich Serti?? rner.
However, its basic structure was not correctly determined until 120 years later. Morphine provides symptomatic relief of moderately severe to severe pain. Morphine acts as an anesthetic without decreasing consciousness, and it is one of the most powerful analgesics known. However, it also suppresses the repiratory system, and high doses can cause death by respiratory failure. Its analgesic properties are related to the ability of the molecule to fit into and block a specific sit on a nerve cell. This eliminates the action of the pain receptor.