Acetate-Derived Alkaloids

2.1.1 Acetate-Derived Alkaloids


Socrates was made to drink the decoction of the Hemlock plant and died soonafter. Thus, the poison present in it is really too dangerous for herbal administration by the uninitiated. The Hemlock plant is comprised of several potent alkaloids, such as: coniine, γ-coniceine, conhydrine, N-methyl conine and pseudoconhydrine. These alkaloids shall now be discussed as under:
A. Coniine
Synonyms Cicutine, Conicine.
Biological Sources It is obtained from the unripe, fully grown dried fruits of Conium maculatum
L. (Umbelliferae).
It also occurs in the plant Aethusa cynapium L. (Apiaceae) (Fool’s Parsley); Cicuta maculata L.
(Apiaceae) (Water Hemlock).
Chemical Structure

Coniine
(S)-2-Propylpiperidine. It occurs naturally as the (S)-(+)- isomer.
Isolation Coniine may be isolated by adopting the various following steps, namely:
(i) The powdered unripe, fully grown dried fruits of hemlock are mixed with a dilute solution of KOH and then subjected to stream distillation. The distillate is collected and neutrallized carefully with dilute HCl and evaporated to dryness preferably under vacuum.
(ii) The residue obtained as stated in (i) above is extracted with alcohol, filtered and the alcohol evaporated to dryness under vacuum. The alcohol helps in extracting the alkaloidal salts that are dissolved in water; it is then rendered alkaline either with diluted KOH solution or with dilute NH4OH and finally extracted with ether successively.
(iii) The ether from the combined ethereal layer is evaporated completely, when an oily liquid consisting of the free bases remains in the residue.
(iv) Finally, the residue is subjected to fractional distillation in a current of H2-gas when the alkaloids could be broadly separated and a mixture containing coniine and γ-coniceine shall pars over as the first fraction at 171-172°C. These two alkaloids are consequently made to their corresponding hydrochloride salts, evaporated to dryness and extracted with acetone.
Thus, coniine hydrochloride would be separated as an insoluble product, while the γ –coniceine may be recovered by evaporating acetone under vacuum.
Note: Coniine enjoys the unique distinction of being the First Alkaloid produced synthetically.
Characteristic Features
(i) It is a colourless alkaline liquid.
(ii) It darkens and polymerizes on being exposed to air and light.
(iii) It has a mousy odour.
(iv) Its physical parameters are as follows: mp ~ – 2°C; bp 166-166.5°C; bp20 65-66°C. d420 0. 844-0.848; - nD23 1.4505; α D25 +8.40C (c = 4.0 in CHCl3); α D23 +14.60(heat) pKa = 3.1.
(v) It is steam volatile.
(viSolubility: 1 ml dissolves in 90 ml of water, less soluble in hot water. The base dissolves in about 25% water at room temperature. It is found to be soluble in alcohol, ether, acetone, benzene, amyl alcohol, and slightly soluble in chloroform.
Identification Tests
(i) It readily forms the corresponding hydrobromide (C8H17N.HBr), obtained as prisms, mp 211°C, 1 g dissolves in 2 ml water, 3 ml alcohol, and soluble freely in ether and chloroform.
(ii) Its hydrochloride (C8H17N . HCl) forms rhomboids, mp 221°C, freely soluble in water, alcohol and chloroform.
(iii) It gives a red colouration with sodium nitroprusside slowly, which on addition of acetaldehyde changes to violet or blue.
Caution It exhibits potential symptoms of over exposure as: weakness, drowsiness, parasthesias, ataxia, nausea, excessive salivation, and bradycardia followed by tachycardia.*
Uses Externally, the coniine salts are used as ointments and infrequently employed for their local analgesic action in the symptomatic relief of pruritis, hemorrhoids and fissures.
B. γ-Coniceine
Biological Source It is obtained from the seeds of Conium maculatum L. (Umbelliferae).
Chemical Structure

gama-Coniceine
2, 3, 4, 5-Tetrahydro-6-propylpyridine.
Characteristic Features
(i) It is a colourless liquid alkaloid.
(ii) It possesses a distinct mousy odour.
(iii) It is steam volatile.
(iv) Its physical parameters are: bp 171°C; d415 0.8753; nD16 1.4661.
(v) It is slightly soluble in water, but freely soluble in ethanol, chloroform and ether.
Identification Test
(i -Coniceine when subjected to reduction, it gives rise to a racemic mixture of dl-coniine.
(ii) It forms γ-coniceine hydrochloride (C8H15N.HCl) which gives hygroscopic crystals from ether mp 143°C.
C. Conhydrine
Biological Source It is obtained from the seeds of Conium maculatum L. (Umbelliferae).
Chemical Structure

Conhydrine
[R-(R*, S*)-a-Ethyl-2-piperidine methanol.
Characteristic Features
(i) The crystals obtained from ether has mp 121°C, bp 226°C and [α]+ 10°C.
(ii) It is slightly soluble in water, but easily soluble in ethanol, ether and chloroform.
D. N-Methylconiine
Biological Source It is same as for (C) above.
Chemical Structure

N-Methylconiine
1-Methyl-2-propylpiperidine.
Isolation The d-form is stated to occur in Hemlock in small quantities, while the l-form may be isolated from residues left in the preparation of coniine by crystallization of the hydrobromides.
Characteristic Features The physical characteristic features of dld- and l-forms are given below:

Characteristic Features The physical characteristic features of dl, d- and l-forms
E. Pseudoconhydrine
Biological Source Its biological source is same as for (A) through (D) above.
Chemical Structure

Pseudoconhydrine
(3S-trans)-6-Propyl-3-piperidinol.
Characteristic Features
(i) It gives hygroscopic needles from absolute ether.
(ii) Its mp stands at 106°C, whereas its monohydrate, scales, gives mp 60°C from moist ether.
(iii) Its physical parameters are: bp 236°C ;[α]D20 +110 (c = 10 in alcohol); pK (18°C): 3.70
(iv) It is soluble in water and
Identification Tests It readily forms the hydrochloride salt (C8H17NO.HCl) as the crystals from ethanol having mp 213ºC.
Biosynthesis of γ-Coniceine and Coniine A fatty acid precursor octanoic acid (capric acid) is employed, which is subsequently transformed into the ketoaldehyde through successive oxidation and reduction steps. The resulting ketoaldehyde acts as a substrate for a transamination reaction, the amino moiety is derived from L-alanine. The ultimate transformation lead to the formation of imine giving the heterocyclic ring present in g-coniceine, and then reduction the coniine as shown below:

Biosynthesis of g-Coniceine and Coniine

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