Alkaloids Case Study Essay

Alkaloids store corpuscleic upshot 18 the intimately diverse group of subsidiary metabolites and e genuinelywhere 5000 starts atomic number 18 cognize. They argon closely unremarkably encountered in the coif kingdom, un slight re commitatives conduct been separate from close to both(prenominal) another(prenominal)wisewise orders of organisms ranging from fungus kingdom to mammals. For long time, there has been interest in their pharmacologic activities, and for a long time selected workings returns ( drive obtain awaying alkaloids) cave in been employ as poisons for hunting, murder, euthanasia, a euphoriants, psychedelics, and stimulants (e.g. morphia and cocain) or as medicines (e.g. ephedrine). umpteen of our modern drugs immediately contain the resembling compound or unreal analogues, and the pharmacological and hepatotoxicological properties of these compounds be consequently of great interest and importance.Al intimately devil centuries admit elapsed since Serturner uncaring the prototypal constitutive(a) base clearly recognised as such(prenominal), a crystal channel substance that he obtained from the opium poppy, Papaver somniferum, and c totallyed morphia. The tell a set forth alkaloid is employ to the members of a class of intrinsic products of basic nature, and is derived from the name vegetable alkali for the first time use to these substances. They all owe their basic nature to an amino group northward. It is more than difficult than at first might be conjectural to define the term alkaloid. The work was coined in 1818 by Meissner and implies a compound inter transposeable to an alkali, referring to the basic properties of this class of substance. Meyers Konversations- Lexikon of 1896 states, Alkaloids ( mark off bases) materialise propertyally in plants and atomic number 18 ofttimes rarified by their remarkable physiologic activity. They contain iodin C, hydrogen and atomic number 7 and i n most cases oxygen as strong in gayy cases they resemble the alkalis. modern font dictionary definitions notwithstanding differ in minor details from those of the older untechnical lit successionture.A definition collectable to Pelletier in 1982 includes cyclic atomic number 7- containing molecules which be true secondary metabolites (i.e. of limited deceaserence and produced by alimentation organisms. Simple acyclic first derivatives of ammonia and easy amines ar thus excluded, and the additional requirement, that the nitrogen atom must have a negative oxidation state, excludes nitro and nitroso compounds.As for other natural products, no uni institute schema of nomenclature has so far been devised for alkaloids. In most cases the name of the alkaloid has been derived from the plant name. Thus, papaverine was called after the Papaver species from which it was isolated. The label cocain (from Erythoxylum coca) and atropine (from genus Atropa belladonna) atomic num ber 18 other examples. condescendlytimes several alkaloids be obtained from the same plant, and the names devised for them will depend on the ecstasy of the natural products chemist who isolated them.Alkaloids as a class have discount organic chemists bulge push throughly on reckon of their physiological litigate on the sensual organism, and partly on account of the obscure structural and synthetical puzzles that they pose. The alchemy of the alkaloids is further a branch of the wide chemistry of nitrogenous heterocyclic compounds, besides the orders by which the organises of individual bases be deduced from degradative evidence and substantiate by total discount ar typical of the methods applied for these purposes whole athletic field the chemistry of natural products are demonstrative of the general fundamental principles of organic chemistry. morphological fountsAlkaloids are usually classified check to the amino venomouss (or their derivatives) from which they arise. Thus, the most of the essence(predicate) classes are derived from the fontline Amino corrosives* Ornithine and Lysine* Aromatic amino red-hot phenylalanine and tyrosine* Tryptophan and a moiety of mevalonoid originAlso a number of compounds are in any case derived from* Anthranilic acid* Nicotinic acidThis classification however, fails to include the alkaloids derived from a polyketide or a terpenoid, with the incorporation of a nitrogen atom, ultimately from ammonia. Examples are Conine and batrachotoxin which are often kn experience as pseudoalkaloids. Other compounds cover by Pelletiers definition excessively exist. Examples are the antibiotic cycloserine, mitomycin C, cull toxin muscimol and the purine alkaloids such as caffein.There is a nonher(prenominal) classification of the alkaloids according to the location of the nitrogen atom in certain structural features1. Heterocyclic alkaloids2. Alkaloids with exocyclic nitrogen and aliphatic amines3. P utrescine, spermidine and spermine alkaloids4. Peptide alkaloids5. Terpene and steroidal alkaloidsClassifying the whole rake of alkaloids according to this establishment result in them world dividing them up unequally as the great absolute studyity fall into the heterocyclis group and the smallest group is the putrescine, spermidine and spermine alkaloids. positionOf the more than 5000 alkaloids kn take in, most occur in flowering plants, although the distri yetion is far from uniform. Thus, although 40% of all plant families have at least single species containing alkaloids, when the 10000 plant genera are readed, just now about 9% of these have been shown to produce alkaloids.Increasing verse of alkaloids have been isolated from animals, insects, and microorganisms. Although mammalian alkaloids are rare, two examples are (-)-castoramine (a) from the Canadian stovepipe and muscopyridine (b) from the musk deer.Both compound have a role in communication as territorial marke r substances.Insects produce a variety of structural types which include the 2,6- dialkylpiperidines of the fire ant (c), the tricyclic N-oxides of the ladybird (d) and the quinazolines of the European milliped (e).Tese compounds are spendd for defence.During the decision 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 spate aggregations of such organisms, and food drunkenness when he toxic alkaloids are passed on the food chain to humanness. The Japanese puffer fish is naughtyly look upond as a culinary delicacy, but it is gaga because its liver and ovaries contain the super toxic tetrodotoxin.Fungi likewise produce alkaloids, and these too, preface 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 Mi ddle Ages by the contamination of rye bread. Some of these were neurotoxic whilst others ca apply vasocontriction.During the last 40 years most of these non plant alkaloids have been isolated and their expressions elucidated. The inlet of modern chromatographic and spectroscopic techniques facilitated this. isolationWork 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 albumenthorn be entitled to generic rank. There are few plants which produce a genius alkaloid so the main problem is the insulation 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 idler thus be extracted into acid re solvent apply aqueous hydrochloric, tartaric, or cit ric acids. Neutral alkaloids such as colchicines or piperine, which are in fact amides, last out in the organic phase, whilst most other alkaloids are isolated after basification and origin into ethyl acetate.Steam distillation grass be apply also be employ with low molecular saddle alkaloids but almost invariably sudsequent nuance of the crude alkaloid mixtures is effected by chromatography employ silica or alumina, and hence recrystallisation of the partly purified compounds from solvent corpses like aqueous ethanol, wood spirit/chloroform, or methanol/acet mavin.Structure clearingClassical eraThe classical era for structural studies on alkaloids was the 19th speed of light, though this could be extended to the 1930s (advent of roentgenogram crystallography) or blush to the 1970s (advent of high gear resolution NMR facilities and modern methods of mass spectroscopy. dickens 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 study spry agent 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 mental price reduction is as followsStandard showed that the nitrogen atom was fully substituted, and that the phenolic hydroxyl was redeem 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 link as codeine absent one. It was demonstrate that a cut back phenanthrene with a two-carbon bridge containing a tertiary nitrogen atom (with methyl radical group as on substituent) was present, and the construction 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 gener ally a natural product but arises finished racemisation of (-)-hyoscyamine (see (a) beneath) 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 because through subtraction found the structure of tropic acidExhaustive degradation of tropine, carried out by Willstlter between 1985 and 1901, provided evidence for the cyclic structure of tropine.The most widely used process in degradative studies of alaloids is arrant(a) methylation, known as Hofmann degradeation. . This involves the pyrolysis of a four more or less ammonium ion hydroxide to form and olefin an a tertiary baseTo ensure the consummate 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 expecte d to give 1,4-dienes, the alkaline conditions of the chemical reception whitethorn 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 suffer about ring fission of cyclic amines, Emde degradation, invoving catalytic step-down of a quaternary salt by sodium dental amalgam or sodium in fluidness ammonia, may be applied. For example, attempted Hofmann degradation of N-methyltetrahydroquinoline methoxide results in regeneration of the parent base, plot of land Emde reduction with sodium amalgam affords the ring-opened amine.Alkaloids containing diphenyl diethyl ether linkages, for example, bis-benzylisoquinoline, are cleaved into two fragments by reduction with sodium in placid ammonia. For example, the structure of the alkaloid dauricine was established by reductive sectionalization of O-methyl-dauricine.Modern eraDuring the last 30 years, structure elucidation has benn facilitated by the use of mass spectroscopy, and 1H and 13C NMR techniques. It is now feasible to determine the structure in eld 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, overtone or total synthesis bum be attempted.BiosynthesisIt 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 belike biosynthetic pathways. This was sometimes successful as for example, the suggested pathway to the isoquinoline alkaloid is as follows It is possible to split 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 lysinePyrrolidine alkaloids hygrine, cocaine, tropinone, hyoscyamine etcPiperidine alkaoids piperine, (-)-lobeline etcQuinolizidine alkaloids sparteine, cytosine, (-)-lupinine etcPyridine alkaloids nicotine, anabasine, anatabine etcAlkaloids derived from phenylalanine and tyrosineMonocyclic compounds hordenine etcTetrahydroisoquinoline alkaloids morphine, codeine, thebaine, noscapine (narcotine), papaverine, heroin etcAlkaloids derived from tryptophanSimple indole derivatives psilocybin, dimethyltryptamine, physostigmine etc interlacing indole derivatives harmaline, echinulin, ergonovine etcNo class of course occurring organic substances shows such an enormous range of structures as the alkaloids with over 5000 kno wn. It would be insufferable to discuss each one of these deep down the time limit. Therefore, this project is concerned with the following alkaloidsmorphia ( including codeine and heroin), cocaine, Nicotine and caffein (including theophylline).These alkaloids are present in enormous quantities in the gentleman and seem appropriate to be discussed due to the current interest in their set up particularly when used illegally. They are some of the most well known alkaloids.morphia (Codeine and Heroin)When the unripe seed capsules of the opium poppy, Papaver somniferum, is reduce or pricked, a viscous liquid is exuded. After the exudates dries and darkens with exposure to air, a operose but still partly mortifying mass is obtained. This is opium, which has been used for many a(prenominal) centuries by some for medicinal purposes. Opium is important as a disquietkilling drug in its own right, but is also the source of other analgesic drugs such as morphine and heroin. Mankind h ad 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 rest period of pain. Thomas Sydenham, the 17th Century pioneer of English medicine wrote, Among the remedies which it has felicitous Almighty God to give to man to relieve its sufferings, none is so universal joint 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.morphia is a naturally occurring substance and is the major constituent of opium, constituting about 10% (sometimes up to 20%) of its angle.Morphine was first isolated in 1805 by Friedrich Sertrner. However, its basic structure was not correctly determined until long hundred years by and by. 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 atomic number 50 cause death by respiratory failure. Its analgesic properties are cogitate to the ability of the molecule to fit into and full stop a specific sit on a nerve cell. This eliminates the action of the pain receptorCocaineCocaine is obtained from coca leaves (Erythryloxum coca) and has the formula C17H23O4N and a molecular lading of 303.39. The anaesthetic properties of cocaine were first recognised by Koller in 1882, but it has now been largely replaced in the clinic by synthetic analogues due to its widespread abuse as a narcotic. It is, however, still much used as a s timulant by Andean Indians. After chewing the leaves, they are easily fatigued and can go on for long periods without food.Cocaine is shipped and interchange in the form of the water-soluble hydrochloride salt, which may be ingested through the nasal passages by snorting orally and intravenously. There are severe physical and psychological side effects of the drug, such as wizardry seizures, respiratory collapse, rawness attack, paranoia, and depression.Cocaine may be hydrolysed by acids or alkalis to methyl alcohol, benzoic acid, and (-)-ecgonine, C9H15O3 N only partial hydrolysis, to benzoyl- (-)-ecgonine, C16 H19O4 N, and methyl alcohol when the alkaloid is boiled with water.Cocaine can be regarded as being derived from ornithine. Willsttter worked on a tortuous synthesis (of about 20 travel) of tropinone between 1900 and 1903, but in 1917 Robinson reported his one-pot synthesis and also provided what was probably the first example of a formal retrosynthetic analysis. He stat ed By imaginary hydrolysis at the points indicated by the stud lines, the substance may be solved into succinaldehyde, methylamine and propanone.The yield of this reaction was slimy but Schpf and Lehmann reported optimised conditions (buffered solution at pH5 and 25C) which allowed 85% yield. A variety of mechanisms are possible and the one shown below envisages a reaction between the enol form of acetone dicarboxylate and the condensation product from succinaldehyde and methylamine.Willsttter made his own contributions based on this type of chemistry, and realised simple synthesis of tropinone in 1921 and a synthesis of cocaine in 1923. The synthesis of cocaine is as followsA Robinson- type reaction yielded the expected azabicyclo structure but with a fortuitous axial stereochemistry for the carbomethoxyl group. Racemic cocaine was formed after separation of the diastereoisomeric products on the reduction of the ketone and benzoylation of the mixture of alcohols.An important e xpression of Robinsons passageway is that it represented the first biomimetic synthesis of an alkaloid. He provided inspiration for others to consider possible biosynthetic pathways, before planning their synthetic routes to alkaloids.NicotineNicotine, present in desiccated baccy plant leaves of the plant nicotiana tabacum in 2-8% concentration, is the active ingredient in cigarettes and other tobacco products. The reason tobacco is used by so many nation is because it contains this powerful drug nicotine. When tobacco is smoked, nicotine is absorbed by the lungs and quickly moves into the bloodstream, where it is circulated throughout the brain. only of this happens very rapidly. In fact, nicotine reaches the brain within 8 seconds after someone inhales tobacco smoke. Nicotine can also enter the blood stream through the mucous membranes that line the mouth or nose, or even through the skin. Smoking and chewing tobacco have been connected to oculus and lung sickness and can cer, mainly a result of the presence of carcinogens, carbon monoxide and other toxins.Nicotine affects the entire body. Nicotine acts instantaneously on the heart to change heart rate and blood pressure. It also acts on the nerves that control respiration to change breathing patterns. In high concentration, nicotine is deadly. In fact, one drop of purified nicotine on the clapper will kill a person. Its so lethal that it has been used as a pesticide for centuries.So why do people smoke? The mode of action of nicotine is complex. Ingestion of the molecule may contract or calm the user and it may affect his or her mood, appetite, and cognition.There appears to be little doubt that nicotine is an habit-forming drug, and the turn about how to regulate its availability is ongoing.Nicotine is part of the pyridine alkaloids and is the chief alkaloid of tobacco.It can therefore be classed as a tobacco alkaloid. Nicotine has the experimental formula C10 H14 N2, a molecular weight of 16 2.26 and was first observed by Vanquelin in 1809 and isolated 19 years later by Posselt and Reimann. Its structure is as followsIt is a colourless liquid with a simmering point of 246.1-246.2C and is miscible in all proportions with water below 60 and higher up 210. It is less soluble between these temperatures.When oxidate with chromic acid it yields an amino acid, C6H5O2N, which may be decarboxylated to pyridinecarboxylic acid. Nicotine is therefore a 3-substituted pyridine and that the substituent is a saturated group containing five carbon atoms and one nitrogen atom. The alkaloid forms a sheer addition compound with zinc chloride, and when this is het up(p) with lime pyridine, pyrrole and methylamine are obtained, suggesting that the structure be as above (1). This was supported by the degradation of the alkaloid to N-methylproline (1) to (5) (below), the oxidation of dibromocotinine (6) to nicotinc acid, malonic acid and methylamine (6) to (7). Also, by the reductive hydro lysis of bromocotinine to methylamine and the dihydroxy-acid (8).The structure of nicotine was finally sustain by synthesis. Three syntheses of nicotine have been recorded.The first was based on the discovery that N-acetylpyrrole is modify by heat to C-acetylpyrrole shown to be ?-acetylpyrrole.Pictet and Crepieux applied this reaction to N- pyridylpyrrole (3) (below) obtained by the reaction of -aminopyridine1 with mucic acid (2).The compound 31- pyridyl-2-pyrrole (4) was formed. An attempt to methylate the pyrrole nitrogen by heating the yard derivative with yielded (5) (methiodide of 31- pyridyl-N-methyl-2-pyrrole). distillation of this with calcium oxide gave nicotyrine (6). Selective hydrogenation of the pyrrole nucleus with a palladium-carbon catalyst reborn nicotyrine (6) to nicotine with about a 25% yield.PICTETS SYNTHESISPictets classical synthesis involves two steps at high temperatures, one of which is a rearrangement. It cannot therefore be regarded as unambiguous.Ho wever, a second synthesis by Spth and Bretschneider involves no rearrangement at high temperature and are thus structurally specific.SPATHS SYNTHESIS(1) (Above) was converted into (2) via electrolytic reduction, which on intervention with potassium and methyl sulphate gave (3) (N-methylpyrrolidone). Ethyl nicotinate was then condensed with (3) in the presence of sodium ethanoate and the resulting -pyridyl-1- -(N1 methyl-?1- pyrrolidonyl) ketone (4) was hydrolysed with fuming hydrochloric acid at 130. The derived amino ketone (5) was reduced with zinc and sodium hydroxide to the similar alcohol (6), which was converted to nicotine on treatment with hydrogen iodide and potassium hydroxide.A ternion synthesis of nicotine by Craig was also carried outCRAIGS SYNTHESISNicotinonitrile (1) (above) was reacted with ?- ethoxypropylmagnesium bromide. The product of the reaction (2) (3-pyridyl-?-ethoxypropylketone) formed an oxime (3), which was reduced to an amino derivative (4). On heati ng to 150-155 with 48% hydrobromic acid this was converted to nornicotine (5), which in turn was methylated to nicotine.The pyridine ring in nicotine is derived from nicotine acid, which itself is derived from aspartic acid and glyceraldehyde-3- phosphateThe remaining steps en route to nicotine are shown belowCaffeineThe purine system occurs widely in nature. Two purines, ampere and guanine, are constituents of the nucleic acids adenine is a character of coenzymes I and II, of flavin adenine dinucleotide and of adenosine with 3 distinguished compounds caffeine, theophylline and theobromine. They are physiologically active constituents of deep brown, hot chocolate, and tea. The compounds have different biochemical effects, and are present in different ratios in different plant sources. These compounds are very similar and differ only by the presence of methyl groups in two positions of chemical structure as shown belowThey are easily oxidised to uric acid and other methyluric aci ds, which are also similar in chemical stucture. caffein 1,3,7- trimethylxanthineSOURCES Coffee, tea, cola nuts, mate, guarana effect Stimulant of the central nervous system, cardiac muscle and respiratory system, diuretic, delays fatigue.THEOPHYLLINE 1,3 dimethylxanthineSOURCES TeaEFFECTS cardiac stimulant, smooth muscle relaxant, diuretic, vasodilator.THEOBROMINE 3,7- dimethylxanthineSOURCES Principle alkaloid of the cocoa bean (1.5-3%), cola nuts and tea.EFFECTS Diuretic, smooth muscle relaxant, cardiac stimulant, vasodilator.theophylline has a stronger effect on heart and breathing than caffeine. For this reason it is the drug of excerption in home remedies for treating asthma, bronchitis and emphysema. Theophylline found in medicine is made from extracts from coffee or tea. Theobromine is weaker than caffeine and theophylline has one tenth of the stimulating effect.When isolated in pure form, caffeine is a white crystalline powder that tastes very bitter. Recreatio nally, it is used to provide a boost in energy or a cutaneous senses of heightened alterness. Its often used to dumbfound awake longer. Caffeine inhibits the action of an enzyme, phosphodiesterase, whose affair it is to inactive a molecule called cyclic adenosine monophosphate (AMP). Cyclic -AMP is involved in the governing body of glucose in the bloodstream. Deactivation of phosphodiesterase by caffeine frees cyclic AMP to do its job, more glucose appears, and we feel more energetic.Caffeine is an addictive drug. Among its many actions it operates using the same mechanisms that amphetamines, cocaine and heroin use to stimulate the brain. Caffeines effects are milder but it is manipulating the same channels and that it is one of the things that give caffeine its addictive qualities. It is one of the most widely used drugs. More than 90% of the population Britain consume it everyday and its long effects are of current interest.Purines are usually synthesised by Traubes method i n which a 4, 5 diaminopyrimidine is tempered with formic acid or, better, sodium dithioformate.4, 5- diaminopyrimidines are themselves obtained from 4- aminopyrimidines by nitrosation followed by reduction or via diazonium coupling of activated methylene compounds followed by cyclisation and reduction. Two examples are as followsuric acid (an 8-Hydroxypurine) are made using ethyl chloroformate in place of formic acidUric acid is then the starting material for other purines synopsisThe term alkaloid refers to any Nitrogen containing compound extracted from plants, although the word is used loosely and some compounds of non-plant origin are also unremarkably known as alkaloids. The name is derived from their characteristic basic properties (alkali-like), which are induced by the lone-pair of electrons on nitrogen. The basic nature of the alkaloids, in conjunction with their particular three-dimensional architecture, gives rise to often-potent physiological activities, e.g. the narco tics morphine and heroin.The laboratory synthesis of an alkaloid can be a challenging problem. The goal nowadays is not only to synthesise the natural product, but also to do so from simple molecules by a short luxe pathway. such(prenominal) syntheses have practical importance because many alkaloids are desirable drugs. Large amounts of these alkaloids are often difficult to obtain from natural sources. A simple synthesis can provide an alternative supply of such a drug.The 19th century was the boot for structural studies on the alkaloids and the 20th century was notable for the large number of elegant syntheses that have been accomplished. Virtually all of the major alkaloids have now been synthesised.