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SYNTHESIS OF RESERPINE (1958)
Reserpine, a constituent of the Indian snakeroot Rauwolfia
serpentina (Sarpgandha), is an alkaloid with curative properties for
the treatment of hypertension, as well as nervous and mental
disorders.
Reserpine was isolated in 1952 and yielded to structural
elucidation in 1955 (Schlittler and co-workers) and to total synthesis
in 1958 (Woodward et al.).
methyl-11,17- -dimethoxy-18β-[(3,4,5-trimethoxybenzoyl)
oxy]-3β,20- -yohimban-16β-carboxylate](https://image.slidesharecdn.com/alkaloids-240329102230-b5f5eb09/85/alkaloids-General-methods-of-structural-elucidation-of-Alkaloids-Structural-Elucidation-and-synthesis-33-320.jpg)
alkaloids -General methods of structural elucidation of Alkaloids. Structural Elucidation and synthesis
- 1. 2/27/2019 1 1 Alkaloids General methods of structural elucidation of Alkaloids. Structural Elucidation and synthesis of Papaverine, Quinine and Morphine. Stereoselective synthesis of Reserpine. Biosynthesis of Alkaloids. Sem II, Paper III, Unit II…… 2 NATURAL PRODUCTS CHEMISTRY NATURAL PRODUCTS CHEMISTRY Definition : Definition : “That branch of chemistry which deals with the isolation, identification, structure elucidation, and study of the chemical characteristics of chemical substances produced by living organisms”
- 2. 2/27/2019 2 4 Problems with Synthetic Drugs Problems with Synthetic Drugs • Potency • Cost • Side effects • Requires close supervision of clinician • Resistance • Unavailability (Sometimes) • Stability…. 5 Source of Natural Products Source of Natural Products •Plants •Microorganisms •Bacteria, fungus •Marine organisms •Animal products Plant research is at the forefront to find an effective, safe pharmacological treatment of diseases. WHO estimates 65-80% of world population use traditional medicine & 80 % of these involves plant extracts.
- 3. 2/27/2019 3 Primary metabolites (needful for the cell survival and present in all living system, plants and animals) •Carbohydrates •Lipids •Proteins •Organic acids •Vitamins •Chlorophylls Secondary metabolites (synthesized from primary metabolites; they are not needful for the cell survival, but contribute to the survival of the whole organism) •Glycosides •Phenolic compounds •Terpenoids •Alkaloids Metabolites ALKALOIDS Alkaloids are naturally-occurring organic compounds containing nitrogen moiety, and are usually heterocyclic in nature. They are nitrogen based organic compounds, with nitrogen enclosed in an heterocyclic ring. The alkyl amines are referred to as proalkaloids. Characteristics of alkaloids (1)They are basic in nature due to the presence of nitrogen in their ring. (2) They have complex structures. (3) They have bitter principles. (4) They are mostly obtained from plant materials. (5) They have high pharmacological and physiological activities. Examples of alkaloids are:
- 4. 2/27/2019 4 Quinine is an antipyretic alkaloid. Its molecular formular is C20H24N2O2. Functional groups present in quinine are: methoxyl – OCH3, hydroxyl –OH, tertiary amine group, etc. Other examples of alkaloids are: morphine, cocaine, heroine, etc. Most are highly narcotic in nature. (1)Quinine — an antimalarial drug isolated from a plant called Cinchonia officialis R = R' = H Morphine alkaloid R =H, R' = CH3 Codeine R = R' = COCH3 Heroine Morphine is highly narcotic, analgesic and is isolated from the plant Papavera omniferous Morphine is an opium alkaloid. Nicotine is another example of alkaloid
- 5. 2/27/2019 5 Cocaine - - Cocaine is obtained from coca leaves, - Cocaine is the first local anaesthetic ever discovered by man, - Cocaine is highly narcotic and stimulates the central nervous system i.e. CNS depressant, - Cocaine can lead to psychiatric problem when taken in high dose or when addicted to it. Cocaine Caffeine is an alkaloid obtained from coffee, tea. It is also a strong stimulant which can increase alertness, thereby causing insomnia when the body gets addicted.
- 6. 2/27/2019 6 Structures of the various classification based on chemical structures are illustrated below Extraction method for Alkaloids The extraction procedure often used in the isolation of alkaloid is summarized in the table below.
- 7. 2/27/2019 7 19 Alkaloid as Natural Products •Largest class of secondary metabolites, >6500 compounds known •Contains N, most compounds are basic (alkaline) •Often highly toxic •Found in certain higher plants •Little is known regarding why alkaloids are produced •Biosynthesis from amino acids 20 Many of these substances have marked physiological effects, a fact discovered by many ancient people long before organic chemistry developed. Like, alkaloid quinine, a chief constituent of bark of Cinchona, has been used as effective antimalarial since 1639. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants and animals and are part of the group of natural products (also called secondary metabolites).
- 8. 2/27/2019 8 21 The boundary between alkaloids and other nitrogen-containing natural compounds is unclear. Compounds like amino acid, peptides, proteins, nucleotides, nucleic acid, amines and antibiotics are usually not called alkaloids. Natural compounds containing nitrogen in the exocyclic position (mescaline, serotonin, dopamine, etc.) are usually attributed to amines rather than alkaloids. Some authors, however, consider alkaloids a special case of amines. 22 Effects of alkaloids on humans •High biological activity •Produce varying degrees of physiological and psychological responses - largely by interfering with neurotransmitters –others interfere with membrane transport, protein synthesis or other processes •In large doses - highly toxic - fatal •In small doses, many have therapeutic value –muscle relaxants, tranquilizers, pain killers, mind altering drugs, chemotherapy
- 9. 2/27/2019 9 23 Psychoactive alkaloids (affecting mental process) • Although only a small percent are psychoactive, these get much focus • Affect the central nervous system - often by influencing neurotransmitters • Categories of psychoactive compounds – Stimulants – Hallucinogens – Depressants • May also be narcotic (addictive) 24 Psychoactive alkaloids Stimulants Hallucinogens Depressants Cocaine Tropane alkaloids Morphine Ephedrine Mescaline Codeine Caffeine Psilocybin Heroin Ergot alkaloids (LSD)
- 10. 2/27/2019 10 26 27 Tests for Alkaloids – Most alkaloids are precipitated from neutral or slightly acidic solution by – Mayer's reagent (potassiomercuric iodide solution) Cream coloured precipitate. – Dragendorff's reagent (solution of potassium bismuth iodide) orange coloured precipitate. – Wagner’s reagent (iodine in potassium iodide) red-brown precipitate – Hagers reagent (picric acid) yellow precipitate
- 11. 2/27/2019 11 28 Physical & Chemical Properties of Alkaloids MW: 100 – 900 Most bases which do not contain Oxygen are liquid at room temperature (nicotine), while those that do are solids. In rare cases they are coloured. Most solid bases rotate the plane of polarized light, have high melting points. Normally are not soluble in water (occasionally slightly soluble). Soluble in non polar or slightly polar organic solvents. 29 The basicity of alkaloids depends on the availability of the lone pair of electrons on the N atoms: Electron donating groups enhance basicity, while e- withdrawing groups decrease it. Because some alkaloids have a carbonyl group on the amide, they can also be neutral (colchicine & piperine). NHCOCH3 O OCH3 Colchicine H3CO H3CO
- 12. 2/27/2019 12 32 MOST ALKALOIDS ARE DERIVED FROM -AMINO ACIDS NH2 NH2 COOH ornithine N H N H NH2 COOH NH2 lysine NH2 COOH R R = H phenylalanine R = OH tyrosine NH2 R and N R R' N R and R = H, CH3 R’ = H, alkyl N NH2 COOH H N R H tryptophan SOME OF THE MAJOR RELATIONSHIPS ARE SHOWN BELOW Pyrrolidene Indole Pipiridene 33 Ex: FORMATION OF ISOQUINOLINE ALKALOIDS NH2 COOH O H NH2 O H NH2 O H O H O C H CH3 .. N O H O CH3 H H H .. .. + N O H O CH3 H H H H .. + Enz-B: O H O H N CH3 H O O N CH3 CH3 CH3 CH3 Methylations could also have taken place before step three. 1 2 3 4 5 6,7,8 Acetaldehyde CH3CHO is a readily available metabolic intermediate imine formation Mannich reaction and aromatic substitution decarboxylation hydroxylation methylation Tyrosine ##
- 13. 2/27/2019 13 34 Mechanism – Imine formation 42 Biogenesis of Alkaloids • Alkaloids are produced in plants by basic substances and reactions well-known in organic chemistry. • Biosynthetic origin cannot be discussed in general terms for all alkaloids, instead it has to be covered separately for each of the major groups of alkaloids. • True alkaloids are based on an amino acid (pre-cursor). • Only a few amino acids form the pre-cursors for all alkaloids: ornithine, lysine, phenylalanine, tyrosine, tryptophan, histidine and anthranilic acid.
- 14. 2/27/2019 14 43 Alkaloid formation may require the involvement of only one molecule of amino acid, or 2 molecules of the same AA, or less commonly, 2 molecules of different AA or else several molecules of the same AA. The formation starts with the creation of a Schiff base or a Mannich reaction. When the alkaloid has additional C-atoms, these play important roles in other metabolic pathways. 46 Alkaloids are often divided into the following major groups: "True alkaloids", which contain Nitrogen in the heterocycle and originate from amino acids. Their characteristic examples are atropine, nicotine and morphine. This group also includes some alkaloids which beside nitrogen heterocycle contain terpene (e.g. evonine) or peptide fragments (e.g. ergotamine) as well as it also includes piperidine alkaloids coniine and coniceine although they do not originate from amino acids.
- 15. 2/27/2019 15 47 "Protoalkaloids", which contain nitrogen and also originate from amino acids but does not have heterocyclic ring. Examples include mescaline, adrenaline and ephedrine. Polyamine alkaloids – derivatives of putrescine, spermidine and spermine. Peptide and cyclopeptide alkaloids. 48 Pseudalkaloids – alkaloid-like compounds which do not originate from amino acids. This group includes, terpene-like and steroid-like alkaloids, as well as purine-like alkaloids such as caffeine, theobromine and theophylline. Some authors classify ephedrine and cathinone as pseudoalkaloids. Those originate from the amino acid phenylalanine, but acquire their nitrogen atom not from the amino acid but through transamination. Some alkaloids do not have the carbon skeleton characteristic of their group. So, galantamine and homoaporphines do not contain isoquimoline fragment, but are generally attributed to isoquinoline alkaloids.
- 16. 2/27/2019 16 78 Ergotism is the effect of long-term ergot poisoning, traditionally due to the ingestion of the alkaloids produced by the Claviceps purpurea fungus which infects rye and other cereals, and more recently by the action of a number of ergoline-based drugs. It is also known as ergotoxicosis, ergot poisoning and Saint Anthony's Fire. Causes The toxic ergoline derivatives are found in ergot-based drugs (such as methylergometrine, ergotamine or, previously, ergotoxine). Historically, eating grain products contaminated with the fungus Clavicep purpurea also caused ergotism. Finally, the alkaloids can also pass through lactation from mother to child, causing ergotism in infants. ERGOT POISONING…………… 79 Q: How and when did the Salem witchcraft epidemic begin? A: The epidemic that led to the Salem Witch Trials began in a town called Danvers, at the time known as Salem Village in colonial America. Sometime early in 1692, several children in the Samuel Parris household had convulsions and hallucinations. At first they accused Tituba, a Caribbean serving woman, of being a witch. Soon more cases of convulsions and accused witches spread throughout the county, and an epidemic began. Q: What are the connections between ergot and Salem witch- hunting? A: Ergot is a toxic fungus that affects rye; the toxin causes tingling in the fingers, hallucinations and convulsions—all symptoms that appeared in those who accused others of being witches. Ergot thrives in wet summers followed by cold summers, conditions that were present in Salem during January and February of 1692. ERGOT POISONING……………
- 17. 2/27/2019 17 80 Fungal Pathogens on Food • Ergot poisoning – Fungus (Claviceps spp.) growing on Rye or Wheat or other grasses; humans eat the flour – Ascomycete fungus; makes a hard black elongated structure – Grain containing more than 0.3% ergot is prohibited from sale – Over 40 alkaloids present; related to lysergic acid – Symptoms include irritable digestive tract, loss of balance, convulsions, drowsiness ERGOT POISONING…………… 95 GENERAL METHODS OF STRUCTURE DETERMINATION OF ALKALOIDS • In structure determination of alkaloids, a variety of general chemical methods and more recently physical methods are employed. • In general, elemental composition is obtained from combustion analysis and after determination of molecular weight, molecular formula is calculated. The measurement of optical rotation indicates the presence of optical activity. • METHODS: – A. Chemical Methods – B. Degradation of Alkaloids – C. Physical Methods
- 18. 2/27/2019 18 96 CHEMICAL METHODS • The alkaloids mostly contains one or more oxygen atoms, which may be present as hydroxyl, methoxy, methylenedioxy, carbonyl, carbonyl ester, lactone, amide, lactam, epoxide groups or ether linkage. • i) Hydroxyl group Molecule contains hydroxyl group or -NH group then the number of these groups can be estimated by acetylation or Zerewitinoff's method. • Acetylation's method R-OH + CH3-CO-Cl → R-OCO-CH3 R-NH-R1 + CH3-CO-Cl → R-N(COCH3)-R1 • Zerewitinoff's method R-OH + MeMgI → R-OMgI + CH4 R-NH-R' + MeMgI → R-N(MgI)-R' + CH4 • If hydroxyl group is present it may be Alcoholic or Phenolic. Phenolic compounds are soluble in sodium hydroxide and are reprecipitated by carbon dioxide and give colouration with ferric chloride while alcoholic does not respond to these tests . 97 CHEMICAL METHODS Contd…… • ii) Carbonyl group Ascertained by usual reactions with hydroxylamine, semicarbazide or 2,4- dinitrophenyldrazine. The carbonyl group may be present as an aldehyde or a ketone. This distinction can be made from Tollen's reagent and silver mirror. • iii) Carboxyl group Dissolved in bicarbonate or ammonia and reprecipitation with carbon dioxide indicates the presence of carboxyl group. The formation of ester on treatment with alcohol in the presence of dehydrating agent. • iv) Methoxy group Use Zeisel’s method, which is similar to the Herzig-Meyer method
- 19. 2/27/2019 19 98 CHEMICAL METHODS Contd…….. • v) Methylenedioxy group (-O-CH2-O-) On heating with hydrochloric or sulfuric acid yields formaldehyde. • vi) Amide, lactam, ester, lactone groups Be detected and estimated through acid or alkaline hydrolysis. • vii) Epoxide and ether linkage Be cleaved by the addition of hydrogen bromide or hydroiodic acid. • viii) Tertiary methyl group Estimated by Kuhn-Roth oxidation (K2Cr2O7/H2SO4) to acetic acid, which is distilled off and titrated against standard base. -C-Me + K2Cr2O7/H2SO4 → CH3COOH • ix) Nature of nitrogen The acetylation or benzoylation can distinguish tertiary amine from secondary amine, the former being inert whereas the latter gives acetate or benzoate derivative. This distinction can also be done by treatment with HNO2 or methyl iodide or oxidation with 30% hydrogen peroxide. 99 CHEMICAL METHODS Contd……….. • ix) Nature of nitrogen The presence of N-methyl group is often detected by distillation of amine with sodalime or estimated by the treatment with hydroiodic acid at 150- 300 and conversion of methyl iodide produced to silver iodide as mentioned for estimation of methoxy groups. • Secondary amine • >N-H + HNO2 → >N-NO+H2O • >NH + CH3I → >N-Me + HI • Tertiary amine • >N + CH3I → >N+ -Me I- • >N + H2O2 → >N+-O-+ H2O • N-Methyl group • >N -Me + CaO → CH3NH2 • >N -Me + HI → N-H + MeI AgI AgNO3
- 20. 2/27/2019 20 100 DEGRADATION OF ALKALOIDS The following methods are used to find out structural fragments of alkaloid molecules: i. Hofmann exhaustive methylation. ii. Emde's degradation. iii. von Braun's method. iv. Hydrolysis. v. Alkali fusion. vi. Dehydrogenation. 101 DEGRADATION OF ALKALOIDS Now we discuss the mainly used methods of Hofmann degradation and Emde's degradation. i. Hofmann exhaustive methylation •It consists in opening of the heterocyclic ring with elimination of ‘N’ to give a carbon fraction. •In this method, the alkaloid is first hydrogenated (if it is unsaturated) and then converted into quaternary methyl ammonium hydroxide, which on heating loses a molecule of water. •The hydroxyl group is eliminated from tetra methyl ammonium hydroxide and the hydrogen atom from the position with respect to the ‘N’ atom resulting in ring opening at the “N’ atom on the same side from which the hydrogen was eliminated. •The process is repeated on the formed product till the ‘N’ is eliminated & an unsaturated hydrocarbon is left which isomerizes to a conjugated diene
- 21. 2/27/2019 21 102 103 DEGRADATION OF ALKALOIDS •ii. Emde's degradation The alkaloid is converted to quaternary ammonium salt by refluxing with alkyl halide and the resulting salt is subjected to reductive cleavage by the treatment with sodium amalgam in alkanol or sodium in liquid ammonia or by catalytic hydrogenation. Tetrahydroquinoline and tetrahydroisoquinoline quarternary salts undergo Emde's degradation.
- 22. 2/27/2019 22 104 N Isoquinoline Na EtOH NH tetrahydro isoquinoline 1. MeI 2. AgOH NMe2OH -H2O CH2NMe2 MeI CH2NMe3I Na-Hg aq. EtOH CH3 + Me3N O-methyl styrene A The intermediate 'A' can not be degraded by Hoffmann's method as it has no hydrogen but it can be degraded by Emde's method. 105 N Quinoline Na EtOH N tetrahydroquinoline H 1. MeI 2. AgOH N Me2OH MeI N Me2I Na-Hg Emde's Degradation N Me2 -Dimethylamino propylbenzene Hoffmann's degradation N Me + MeOH tetrahydro-N-methyl quinoline In case of tetrahydroquinoline, though it contains a hydrogen, the Hoffmann's degradation fails. The ring may however be opened by Emde's degradation-
- 23. 2/27/2019 23 106 PHYSICAL METHODS Recently physical methods are used, in conjunction with chemical reactions to elucidate structure of alkaloids and it is possible to determine a structure in a matter of days given a few milligrams(or less) of a pure compound. • Infrared spectrum：Gives information about many functional groups • Ultraviolet spectra：Used to indicate the nature of unsaturation or aromatic rings • NMR spectroscopy：More versatile for detecting many function groups, the nature of protons, carbons, heterocyclic rings etc • Mass spectra：The fragmentation gives the information about molecular weight and degradation of the skeleton. • Single crystal X-ray analysis :Offers means for determining or confirming stereochemistry as well as distinguishing between alternate structures that appear to fit well for a particular alkaloid. • optical rotatory dispersion or circular dichroism: Further support for the stereochemistry QUININE 107
- 33. 2/27/2019 33 126 127 SYNTHESIS OF RESERPINE (1958) Reserpine, a constituent of the Indian snakeroot Rauwolfia serpentina (Sarpgandha), is an alkaloid with curative properties for the treatment of hypertension, as well as nervous and mental disorders. Reserpine was isolated in 1952 and yielded to structural elucidation in 1955 (Schlittler and co-workers) and to total synthesis in 1958 (Woodward et al.). methyl-11,17- -dimethoxy-18β-[(3,4,5-trimethoxybenzoyl) oxy]-3β,20- -yohimban-16β-carboxylate
- 34. 2/27/2019 34 128 •Reserpine consisted of three parts: the indole (the AB unit), the trimethoxybenzene system, and the highly substituted E-ring cyclohexane. 129 * * *
- 35. 2/27/2019 35 130 MPV (Meerwein Pondorff Valery Reduction) vs OPP (Oppenauer oxidation) * *