Pyrroloindole Alkaloids

2.8.5 Pyrroloindole Alkaloids

The indole nucleus has two C-atoms in the heterocyclic portion, viz., C-2 and C-3. Interestingly, both C-2 and C-3 may be regarded as nucleophilic in character. However, it has been established beyond any reasonable doubt that the reactions essentially involving C-2 appear to be the most common in alkaloid biosynthesis.

It is, however, pertinent to mention here that the nucleophic character of C-3 has been duly exploited thereby generating the almost rare pyrroloindole nucleus as given below:

pyrroloindole nucleus
Physostigmine is a typical example of this specific category of alkaloid which shall now be discussed in details as under:


Synonyms Eserine; Cogmine;
Biological Sources It is obtained from the seeds of Physostigma venenosum Balf. (Fabaceae) (Calabar Bean, Ordeal Bean) yielding not less than 0.15% of the total alkaloids of physostigma.
Chemical Structure

Physostigmine Synonyms Eserine; Cogmine
(3aS-cis)-1, 2, 3, 3α, 8, 8α-Hexahydro-1, 3α, 8-trimethylpyrrolol [2, 3-b] indol-5-ol methylcarbamate (ester); (C15H21N3O2).
Isolation Physostigmine may be isolated by adopting the following two steps, namely:
Step I: The seeds are dried, powdered, sieved and extracted by continuous percolation with hot ethanol (95%) and the solvent is subsequently removed by distillation under vacuo. Water is added to the residue and the floating fatty layer is separated The lower aqueous layer is subjected to alkalinization with sodium carbonate and the liberated alkaloid is then extracted with ether successively.
Step II: The combined ethereal extract is then concentrated to a small volume and washed with 5% (w/v) sulphuric acid repeatedly unless and until the washings give a positive acidic reaction to litmus paper. To this aqueous acidic solution (containing the alkaloids as sulphates) is added an excess of a saturated solution of sodium salicylate when the physostigmine salicylate separates out as a crystalline product. The physostigmine may be recovered from the resulting salt by treating it with sodium carbonate followed by an immediate extraction with ether successively. The ether is evaporated in a Rotary Thin-Film Evaporator and the desired physostigmine is collected as prisms or clusters.
* Schwyzer, Die Fabrikation Pharmazeutischer and Chemisch-Technischer Produkte (Berlin, 1931) p 338.
However, physostigmine may also be isolated by the methods described by Schwyzer* and Cheminitius.*
Characteristic Features
1. It is obtained as orthorhombic sphenoidal prisms or clusters of leaflets from ether or benzene having mp 105-106°C. It is also available as an unstable, low melting form mp 86-87°C.
2. Its specific optical rotations are: [α]17D - 76° (C = 1.3 in chloroform); and [α]25D - 120° (benzene).
3. It has two dissociation constants: pKa1 6.12, and pKa2 12.24.
4. Solubility ProfileIt is slightly soluble in water; soluble in ethanol, benzene, chloroform and oils.
Identification Tests Physostigmine may be identified either by specific colour tests or by preparing their derivatives as stated below:
(aColour Tests: These are as follows:
1. Physostigmine or its salts, a few mg, when warmed with 1 ml of strong ammonia solution it gives rise to a yellowish-red colouration. On further evaporation to dryness on a steam-bath, a bluish residue (eserine blue) is obtained that is soluble in ethanol forming a blue solution.
2. Both solid and solutions of physostigmine eventually turn red on being exposed to heat, light and air; and also on contact with traces of metals. This colour change indicates hydrolysis to eseroline and oxidation to rubreserine.
3. Physostigmine gives an instant blue colouration when treated with potassium ferricyanide [K3Fe(CN)6] and a few drops of FeCl3 solution (1% w/v).
4. Physostigmine produces a deep-yellow colouration on being heated with 0.5-1 ml of KOH solution (1% w/v).
Note: (a) This is a very sensitive test and can detect it upto 10 mcg level.
(b) Under controlled experimental parameters the intensity of the yellow colour produced may be measured spectrophotometrically at 470 nm and can serve as an assay method.
5. When a small quantity of physostigmine is heated in a porcelain basin on a steam both with a drop or two of fuming HNO3, a yellow solution is obtained. The resulting solution on evaporation to dryness forms a green residue due to the formation of chloreserine, which is readily soluble in ethanol to give a green solution.
6. Physostigmine when treated with a solution of phosphomolybdic acid and ammonium meta vanadate in H2SO4 it gives rise to an emerald green colour.
(bDerivatives: Major derivatives of physostigmine are:
1. Physostigmine Salicylate (C22H27N3O5) (Antilirium): It is obtained as acicular crystals having mp 185-187°C. It has uvmax (methanol: 239, 252, 303 nm (log ε 4.09, 4.04, 3.78). 1g dissolves in 75 ml water at 25°C. The pH 0.5% (w/v) aqueous solution is 5.8. It is soluble in 16 ml ethanol; 5 ml of boiling ethanol; 6 ml of chloroform; and 250 ml of ether.
2. Physostigmine Sulphate [(C15H21N3O2)2.H2SO4]: It is mostly obtained as deliquescent scales having mp 140°C (after drying at 100°C). 1g dissolves in 0.4 ml ethanol, 4 ml water, 1200 ml
ether. The pH of 0.05 M aqueous solution is 4.7. The solutions of the sulphate salt are more
prone to change colour than those of the corresponding salt of the salicylate.
3. Physostigmine Sulphite [(C15H21N3O2)2.H2SO3]: The white powder is found to be freely soluble in ethanol and water. The aqueous solution is observed to remain colourless for a long duration.
1. It possesses a cholinergic (anticholinesterase) and miotic activities.
2. It was used earlier to treat myasthenia gravis; but now it is more frequently used for the eye.
3. It is employed as an antidote for reversing CNS and cardiovascular (viz., arrythmia and tachycardia) effects of excessive dosages with tricyclic antidepressants.
4. It helps in the contraction of the ciliary muscle of eye, and a decrease in the intraocular pressure produced by an increased out-flow of the aqueous humor.
5. Physostigmine is employed frequently in ophthalmology to treat glaucoma.
Biosynthesis of Physostigmine The various steps involved in the biosynthesis of physostigmine are as follows.
1. Tryptamine undergoes C-methylation at C-3 of the indole nucleus due to its nucleophilic character.
2. Formation of the ‘third pyrrole’ ring takes place by virtue of the nucleophilic attack of the primary amine function on to the iminium ion.
3. Further substitution on the phenyl ring leads to the formation of physostigmine.
The above three steps are summarized as given below:

Biosynthesis of Physostigmine
* Chemnitius, J. Prabt. Chem116, 59 (1927).

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