2.6.2 Tropane Alkaloids
Tropane is a bicyclic compound obtained by the condensation of one mole each of pyrrolidine and piperidine as shown below.
Tropane is regarded as the principle base of a plethora of alkaloids obtained from various members of the natural order, viz., Solanaceae, Erythroxylaceae, Convolvulaceae, and Dioscoreaceae. It essentially consists of a 7-carbon bicyclic ring with a N-atom strategically bridged between C-1 and C-5 and providing a C7N unit. It is, however, pertinent to mention here that the tropane base contains two chiral centres (i.e., asymmetric C-atoms), namely: C-1 and C-5, but surprisingly it does not exhibit any optical activity (an exception) by virtue of the fact that intramolecular compensation prevails. It happens to be a meso-compound. A few important members belonging to the tropane alkaloids are, namely: atropine, cocaine, cinnamoyl cocaine, ecgonine and hyoscyamine. These alkaloids shall now be treated individually in the sections that follows:
A. Atropine
Synonyms Tropine tropate; dl-Hyoscyamine; dl-Tropyl Tropate; Tropic acid ester with Tropine.
Biological Sources It is obtained from the roots and leaves of Atropa belladona Linn. (Solanaceae) (Belladona); and the seeds and leaves of Datura stramonium Linn. (Syn.: Datura tatula Linn.) (Solanaceae) (Jimson Weed, Thorn Apple, Stramonium), besides other species of Solanaceae, such as: D. metel Linn.; D. innoxia Mill., D. alba Nees.; and D. fastuosa Linn.
Chemical Structure
1α H, 5α H-Tropan-3α-ol (±)-tropate (ester); (C17H23NO3).
Characteristic Features
1. Atropine is obtained as long orthorhombic prisms from acetone having mp 114-116°C.
2. It usually sublimes in high vacuum at 93-110°C.
3. It has a dissociation constant pK 4.35; and the pH of a 0.0015 molar solution is 10.0.
4. Solubility: 1 g dissolves in 455 ml water; 90 ml water at 80°C; 2 ml ethanol; 1.2 ml ethanol at 60°C; 27 ml glycerol; 25 ml ether, 1 ml chloroform; and in benzene.
Identification Tests It forms various types of salts, namely:
1. Atropine Hydrochloride (C17H23NO3.CH3NO3): The granular crystals have mp 165°C. It is soluble in water and ethanol. The pH of 0.05 molar solution is 5.8.
2. Atropine Methyl Bromide (C17H23NO3.CH3Br) (Tropin): Its crystals have mp 222-223°C. It is soluble in 1 part of water, slightly soluble in ethanol, and practically insoluble in ether and chloroform.
3. Atropine Methylnitrate (C17H23NO3.CH3NO3) (Methylatropine nitrate, Eumydrin, Metropine, Harvatrate, Metanite, Ekomine): Its crystals have mp 163°C. It is found to be freely soluble in water or ethanol; and very slightly soluble in chloroform and ether.
4. Atropine Sulphate Monohydrate [(C17H23NO3)2.H2SO4.H2O] (Atropisol): It is obtained as either crystals or powder with mp 190-194°C. It is inactive optically. It has a very bitter taste. It shows pH ~ 5.4. Its bitterness is threshold 1:10,000. It is found to be incompatible with a host of substances, such as, tannin, alkalies, salts of gold and mercury, borax, bromides, iodides, benzoates and vegetable decoctions or infusions.
Its solubility profile is: 1 g dissolves in 0.4 ml water; in 5 ml cold and 2.5 ml boiling ethanol; in 2.5 ml glycerol; 420 ml chloroform and 3000 ml ether.
Uses
1. It is used in preanaesthetic medication.
2. It is employed as an anticholinergic agent.
3. It is also used as a mydriatic.
4. It is employed as an antidote in opium and chloral hydrate poisoning.
5. It is frequently employed to minimize spasm in cases of intestinal gripping caused due to strong purgatives.
6. It also find its applications to reduce such secretions as: saliva, sweat, and gastric juice.
B. Cocaine
Synonyms 2β-Carbomethoxy-3β-benzoxytropane; l-Cocaine; β-Cocaine; Benzoylmethylecgonine; Ecgonine methyl ester benzoate.
Biological Sources It is obtained from the leaves of Erythroxylon coca Lam. and other species of Erythroxylon, (Erythroxylaceae); and leaves of Erythroxylon truxillense Rusby (Erythroxylaceae).
Chemical Structure
[IR-(exo, exo]-3-(Benzoyloxy)-8-methyl-8-azabicyclol [3, 2, 1] octane-2-carboxylic acid methyl ester; (C17H21NO4).
Isolation Cocaine is extracted from the plant by digestion either with sodium carbonate solution or with lime water and by subsequent solvent extraction using petroleum ether (bp 160-180°C; or 200-220°C). The combined petroleum ether extract is shaken up with dilute HCl. The solution of hydrochloride thus obtained is concentrated carefully in a thin-film evaporator. In case, the leaves are rich in cocaine content, as in the Peruvian coca leaves, a major portion of cocaine gets separated as crystals.
Characteristic Features
1. Cocaine is obtained as the monoclinic tablets from ethanol having mp 98°C.
2. It usually becomes volatile above 90°C; however, the resulting sublimate is not crystalline in nature.
3. Its physical parameters are as follows; bp0.1, 187-188°C; [α]D18 -350 (50% ethanol); [α]D20 -160 (C = 4 in chloroform); pKa (15°C) 8.61 and pKb (15°C) 5.59.
4. Solubility Profile: 1 g of cocaine dissolves in 600 ml of water; 270 ml of water at 80°C; 6.5 ml of ethanol; 0.7 ml of chloroform; 3.5 ml of ether; 12 ml of turpentine; 12 ml of pure olive oil; and 30-50 ml of liquid petrolatum. It is also soluble in acetone, carbon disulphide and ethyl acetate.
Identification Tests
1. Cocaine Permanganate: The addition of a drop of saturated solution of KMnO4 to a solution of cocaine prepared in a saturated solution of alum gives rise to a violet crystalline precipitate due to the formation of cocaine permanganate. It clearly shows characteristic violet aggregates of plates when examined under the microscope.
2. Cocaine Hydrochloride (C17H21NO4.HCl) (Cocaine Muriate): It is obtained as granules, crystals, or powder. It has a slightly bitter taste and usually numbs lips and tongue. Its physical characteristics are: mp ~ 195°C; [α]D – 72° (C = 2 in aqueous solution); 1 g dissolves in 0.4 ml of water; 3.2 ml cold and 2 ml hot alcohol; 12.5 ml chloroform. It is also soluble in glycerol and acetone; and insoluble in ether or oils.
3. Cocaine Nitrate Dihydrate (C17H22N2O7.2H2O): Its crystals have mp 58-63°C. It is freely soluble in water or ethanol; and slightly soluble in ether.
4. Cocaine Sulphate (C17H21NO4.H2SO4): It is obtained as white, crystalline or granular powder, which is soluble in ethanol and water.
Uses
1. It is used as a local anaesthetic as it causes numbness.
2. Its main action is a CNS-stimulant and, therefore, categorized as ‘narcotic drugs’. It is a highly habit-forming drug.
C. Cinnamoyl Cocaine
Synonyms Ecgonine Methyl Ester; Cinnamoylcocaine; Cinnamoyl-methylecgonine; Ecgonine Cinnamate Methyl Ester.
Biological Source It is obtained from the leaves of Erythroxylon coca Lann. (Erythroxylaceae), particularly from the Javanese leaves.
Chemical Structure
[1R-(exo, exo)]-8-Methyl-3-[(1-oxo-3-phenyl-2-propenyl)oxy]-8-azabicyclol [3, 2, 1] octane-2-carboxylic acid methyl ester; (C19H23NO4).
Isolation Instead of the Peruvian leaves the Java leaves of E. coca are treated in the same manner and fashion as described under cocaine earlier (section ‘B’). It has been observed that the mixed hydrochlorides mostly comprise of cinnamoyl cocaine which gets separated as fine needles.
Characteristic Features
1. It is obtained as fine needles having mp 121°C.
2. Its specific optical rotation is [α]D – 4.7° (chloroform).
3. It is freely soluble in ether, ethanol and chloroform; and almost insoluble in water.
Identification Tests
1. It reduces an acidic solution of KMnO4 in cold i.e., at ambient temperature, which helps to detect the presence of this alkaloid in an admixture with cocaine.
2. It undergoes hydrolysis when warmed with HCl to yield l-ecgonine, cinnamic acid and methanol.
D. Ecgonine
Biological Source It is also obtained from the leaves of Erythroxylum coca Lam. (Erythroxylaceae) (Coca) as its l-form.
Chemical Structure
[1R-(exo, exo)]-3-Hydroxy-8-methyl-8-azabicyclol [3, 2, 1] octane-2-carboxylic acid; (C9H15NO3). It is the principal part of the cocaine molecule.
Isolation Ecgonine may be obtained by the hydrolysis of cocaine as given below:
Cocaine -------Hydrolysis----à Ecgonine + Benzoic acid + Methanol
Characteristic Features
1. The l-form ecgonine monohydrate is obtained as triboluminescent, monoclinic prisms from ethanol having mp 198°C (anhydrous substance gets decomposed at 205°C).
2. Its specific optical rotation [α ]D15 -450 (C = 5); dissociation constants are: pKa 11.11, and pKb 11.22.
3. Solubility Profile: 1 g dissolves in 5 ml water, 67 ml ethanol, 20 ml ethanol, 75 ml ethyl acetate; sparingly soluble in ether, acetone, benzene, chloroform and petroleum ether.
Identification Tests
1. Ecgonine Hydrochloride (C9H15NO3.HCl): It is obtained as the triclinic plates obtained from water having mp 246°C; [α]D15 -590 (C = 10); soluble in water and slightly in ethanol.
2. dl-Ecgonine Trihydrate: It is obtained as plates from 90% ethanol having mp 93-118°C (anhydrous substance gets decomposed at 212°C).
Uses It is mostly used as a topical anaesthetic.
E. Hyoscyamine
Synonyms l-Tropine Tropate; Daturine; Duboisine; l-Hyoscyamine; Cystospaz; Levsin; l-Tropic acid ester with Tropine; 3α-Tropanyl S-(–)-Tropate.
Biological Sources It is obtained from the roots and leaves of Atropa bella-dona L. (Solanaceae) (0.21%) (Thorn Apple); fruits, roots and leaves of Datura metel L. (Solanaceae) (Unmatal, Metel, Hindu Datura); leaves and seeds of Datura stramonium L. (Solanaceae) (Jimson Weed, Thorn Apple, Stramonium); root bark of Duboisia myoporoides R. Br. (Solanaceae) (Pituri, Corkwood Tree); young plants of Hyoscyamus niger L. (Solanaceae) (Henbane, Henblain Jusquaime); seeds of Lactuca virosa L. (Asteraceae) (Bitter Lettuce, Wild Lettuce); and the herb Mandragora officinarum L. (Solanaceae) (Mandrake, Loveapple).
Chemical Structure
1αH, 5αH-Tropan-3α-ol (–)-tropate (ester); (C17H23NO3).
Isolation Hyoscyamine may be isolated from the Belladona leaves by adopting the following steps sequentially:
1. The finely powdered and sieved Belladona leaves is extracted with 95% (v/v) ethanol in a Soxhlet Apparatus till no more alkaloids come out from the marc. The ethanolic extract is concentrated to a syrupy residue under vaccuo and subsequently treated with dilute HCl. The resinous matter is separated by filtration and the resulting solution is further purified by shaking out with petroleum ether (40-60°C) several times.
2. The purified acidic solution thus obtained is made alkaline with ammonia solution (dilute) carefully and extracted with chloroform successively. The combined chloroform layer is once again shaken with dilute HCl, and the acidic solution made alkaline with dilute ammonia solution and extracted with chloroform successively.
3. The combined chloroform layer is removed by distillation under reduced pressure. The crude alkaloids thus obtained is neutralized with oxalic acid. The oxalates of atropine and hyoscyamine may be separated by fractional crystallization from acetone and ether wherein the hyoscyamine oxalate being more soluble gets separated as the second crop.
Characteristic Features
1. Hyoscyamine is obtained as silky tetragonal needles from evaporating ethanol having mp 108.5°C.
2. The physical parameters are: [α]D20 -210 (ethanol); and dissociation constant K at 19° is 1.9 ×10–12.
3. Solubility Profile: 1 g dissolves in 281 ml water (pH 9.5), 69 ml ether, 150 ml benzene, and 1ml chloroform. It is freely soluble in dilute mineral acids and ethanol.
Identification Tests The various identification tests for hyoscyamine are, namely:
1. Gerrard Reaction: Hyoscyamine (and also atropine) responds to the Gerrard Reaction wherein about 5-10 mg of it reacts with mereuric chloride solution (2% w/v) in 50% ethanol to give rise to an instant red colouration without warming.
2. Schaer’s Reagent: A few mg of hyoscyamine when made to react with a few drops of the Schaer’s Reagent i.e., 1 volume of 30% H2O2 mixed with 10 volumes of concentrated sulphuric acid, produces a distinct green colouration.
3. Vitali-Morin Colour Reaction: A few mg of hyoscyamine (and also atropine) is treated with about 0.2 ml of fuming HNO3, evaporated to dryness on the water-bath. To the residue is then added 0.5 ml of a 3% (w/v) solution of KOH in methanol, it gives a bright purple colouration, that changes to red and finally fades to colourless.
Note: (a) The 3% solution of KOH must be freshly prepared.
(b) The reaction is very sensitive i.e., upto 0.0001 mg of any of the alkaloids viz., strychnine, apomorphine, veratrine, physostigmine etc. give a positive test.
4. para-Dimethylaminobenzaldehyde Reagent: [Prepared by dissolving 2 g of
p-Dimethylaminobenzaldehyde in 6 g of H2SO4 to which 0.4 ml of water is added previously]. Add to 5-10 mg of hyoscyamine in an evaporating dish 2-3 drops of this reagent and heat on a boiling water-bath for several minutes. A distinct red colouration is produced that ultimately gets changed to permanent cherry red upon cooling.
5. Hyoscyamine Hydrobromide (C17H23NO3.HBr): It is obtained as deliquescent crystals having mp 152°C; very soluble in water; 1 g dissolves in 3 ml ethanol; 1.2 ml chloroform and 2260 ml ether.
6. Hyoscyamine Hydrochloride (C17H23NO3.HCl): The crystals have mp 149-151°C; and freely soluble in water and ethanol.
7. Hyoscyamine Methyl Bromide (C17H23NO3.CH3Br) (N-Methylhyo-scyaminium bromide): The crystals have mp 210-212°C; and freely soluble in water, dilute ethanol; and slightly soluble in absolute ethanol.
8. Hyoscyamine Sulphate Dihydrate [(C17H23NO3)2.H2SO4.2H2O] (Egacene, Peptard, Egazil Duretter): It is obtained as needles from ethanol having mp 206°C (when dry); [α]D15 -290 (C = 2); pH 5.3 (1 in 100); 1 g dissolves in 0.5 ml water and about 5.0 ml ethanol; and very slightly soluble in ether and chloroform.
Uses
1. It is mostly employed as an anticholinergic drug.
2. It exerts relaxation of bronchial and intestinal smooth museles (i.e., antispasmodic action).
3. It also inhibits contraction of the iris muscle of the eye to produce mydriasis.
4. It decreases significantly decreases the sweat gland and salivary gland secretions.
Biosynthesis of Hygrine, Cuscohygrine, Cocaine, Cinnamoyl Ecgonine (Methylecgonine) and Hyoscyamine The pyrrolidine ring system, present in hygrine and cuscohygrine, is formed initially as a ∆1-pyrrolinium cation. The extra C-atoms required for hygrine formation are derived from acetate via acetyl-CoA; and the sequence appears to involve stepwise addition of two acetyl-CoA units as shown below:
These two steps may be explained as under:
(a) The enolate anion from acetyl-CoA serves as nucleophile for the pyrrolinium ion in a Mannichlike reaction, that may give rise to products having either R or S stereochemistry.
(b) An addition is caused by virtue of a Claisen condensation which essentially extends the sidechain, and the product is 2-substituted pyrrolidine, thereby retaining the thioester moiety of the second acetyl-CoA.
It has been observed that Hygrine and most of the naturally occurring tropane alkaloids is devoid of this specific C-atom, which is subsequently eliminated by suitable decarboxylation hydrolysis reactions. Interestingly, the genesis of the bicyclic structure of the tropane skeleton existing in either cocaine or hyoscyamine is accomplished due to the repeatation of the Mannich-like reaction stated above. These reactions are summarized in the description given under.
