The Alkaloids of Hemlock

Of the alkaloids belonging to this group, neither conhydrine nor pseudoconhydrine had ever been synthesized. Syntheses of both have now been published, together with further work concerning 8-coniceine. 

The structure of conhydrine, i.e., l-(a-piperidyl)-propan-l-ol, has been deduced from a study of the Hofmann degradation of the base (33). It has now been fully confirmed by synthesis of the optically active base. a-Pyridylethyl ketone in hydrochloric acid solution is hydrogenated catalyticaUy in the presence of platinum and gives rise to a product which, after distillation in vaevx), consists of a mixture of both racemates of a-piperidylethylcarbinol, m.p. 87-90°. Fractional crystallization in ether yields the high-melting racemate, m.p. 100°. The two optically active enantiomorphs of this racemate are obtained by resolution with d- and Z-dinitrodiphenic acid. The dextrorotatory form, m.p. 121°, [oJ -flO.O in absolute ethanol, is identical with conhydrine (34). 

Pseudoconhydrine was assigned the structure of 5-hydroxy-2- -propyl-piperidine in 1935 (35). Many years later, it was synthesized simultaneously in three different laboratories. In one synthesis 

2-chloro-5-nitropyridine is condensed with sodiomalonic ester, and the resulting diethyl 5-nitro-2-pyridinemalonate is successively converted to 2-propyl-5-nitropyridine, the corresponding 5-amino compound, and 5-hydroxy compound. This last substance is reduced to 2-propyl- 

5-hydroxypiperidine, which is resolved with d-dinitrodiphenic acid (36). The same authors also obtained 2-propyl-5-aminopyridine from 

A color test utilizing isatin for piperidine and pyrrolidine alkaloids containing the structural unit — NH—CH2—CH2— has been described (53). Coniine and conhydrine give a positive test but pseudoconhydrine, which lacks the above feature, does not. The Conium alkaloids have been separated by gas-liquid chromatography (54). 

A new s3rnthesis of coniine has been reported (55). 2-Cyanopyridine with ethyl magnesium bromide gave 2-propionylpyridine which was transformed to coniine by Wolff-Kishner reduction followed by catalytic hydrogenation. Clemmensen reduction of the 2-propionylp5rridine gave 

It has been shown (64) that rearrangement of 2-ri-propylpyridine N-osxAe with acetic anhydride followed by hydrolysis yields 2-(l -hydroxypropyl)pyridine as well as a small amount of 5-hydroxy-2-propylpyridine. Reduction of the former gives conhydrine, while reduction of the latter gives pseudoconhydrine. 

Two new syntheses of -coniceine (L) have been reported. In one 74), l-methyl-2-pyrrolidone and 4-methoxybutylmagnesium bromide yield the dihydropyrrole LI which is reduced to the pyrrolidine, converted to the bromo compound, cyclized, and the resulting methobromide thermally decomposed to give S-coniceine (L). 

In the other synthesis 75), the Leuckart reaction on y-ketosuberic acid gave 3-(6-oxopiperidyl)propionic acid which on heating yielded LII. Lithium aluminum hydride reduction of LII gave S-coniceine (L). 

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This author discussed the nature of the poison taken by Socrates and concluded that it was a mixture of the alkaloids of hemlock and opium. 

Coniine, CgHiyN, the alkaloid of hemlock, is of interest on account of the fact that it was the first natural alkaloid synthesized. Its preparation was effected by condensing a-pic-oline with aldehyde and reducing the resulting product by means of sodium and alcohol —... 

Of the total alkaloids of hemlock isolated by the method of Chemnitius and fractionally distilled, the portion boiling up to 190° contains most of the coniine, -y-coniceine and A -methylconiine, the eonhydrine and... 

Conine is also of especial interest because it is the first natural alkaloid to have been made synthetically. In 1886 Ladenburg prepared it from a//>/fa-picoline which is alpha-m hy pyridine. By condensing this with acetaldehyde he obtained alpha-dXLy pyridine and by reduction this yielded the corresponding saturated compound, viz., alpha-yroyyl piperidine. This proved to be inactive conine and from it the dextro and levo isomers were obtained. The dextro conine thus prepared is identical with the natural alkaloid of hemlock. The reactions are as follows ... 

An ingenious application was in the asymmetric synthesis of coniine15 114, the alkaloid in hemlock by which Socrates met his death. The sultam amide 111 incorporates a protected ketone so that acidic hydrolysis forms the cyclic nitrone 112 by capture of that ketone. Reduction and base-catalysed cleavage of the amide gives coniine 114. 

C. maculatum and its disappearance coincided with the appearance of alkaloids. This suggested a possible role for (4) in the biosynthesis of hemlock alkaloids. In addition, attention was drawn to the structural similarity of (4) to various piperidine and pyridine alkaloids, not least of which is nicotine also the ease of amination of pyrones and the conversion of gentiopicrin (5) into gentianine (6). ... 

The four main alkaloids are coniine, y-coniceine, iV-methylconiine, and conhydrine. Conhydrine occurs in the smallest proportions and has the weakest pharmacological action [3,4,19,20, 31,67, 85, 87]. The most distinctive action of the three other hemlock alkaloids plus nicotine is their ability, provided the dose is small, to inhibit the crossed extensor reflex and the so-called knee-jerk by an action potential in the spinal cord. Since neurons in the spinal cord may both be inhibited and activated by the action of hemlock, the mechanisms involved are a bit complicated. If the alkaloids initially stimulate inhibitory neurons rather than blocking excitatory ones, the antagonistic relationship of the two substances may be explained. There is evidence that its central synapse is controlled by polysynaptic inhibitory pathways, although the patellar reflex is monosynaptic [3, 19, 67]. It is possible that the C. maculatum piperidine alkaloids may act upon the mechanism that regulates the amniotic liquid, adding to the production of malformations. Finally, lack of fetal movement, whatever its origin, can also cause limb malformations. 

Coniine (12), impHcated by Plato in the death of Socrates, is the major toxic constituent of Conium maculatum L. (poison hemlock) and, as pointed out eadier, was apparendy the first alkaloid to be synthesized. For years it was thought that coniine was derived from lysine (24), as were many of its obvious relatives containing reduced piperidine nuclei and a side chain, eg, peUetierine (46). However, it is now known (99) that coniine is derived from a polyketooctanoic acid [7028-40-2] (138), CgH QO, or some other similar straight chain analogue. 

The common hemlock, Conium maculatum, contain five alkaloids. Power and Tutin found a similar mixture in fool s parsley, and a volatile alkaloid resembling coniine i.s stated to occur in certain aroids. According to Svagr, water hemlock Cicuta virosa) owes its poisonous properties to toxin and not to cicutine, a name sometimes used as a synonym for coniine. The toxic properties of hemlock juice have been known ftom very early times thus it was the chief ingredient in the poison administered to criminals by the Greeks. The leaves and the unripe fruits are the parts used in medicine. The following are the names and formulae of the alkaloids —... 

Caffeine occurs in tea leaves, coffee beans, and cola nuts. Morphine is obtained from unripe opium poppy seed pods. Coniine, extracted from hemlock, is the alkaloid that killed Socrates. Fie was sentenced to death because of unconventional teaching methods teacher evaluations had teeth in them in ancient Greece. 

The profound physiological effects of alkaloids have been known for centuries. For example, Socrates was put to death with an extract of hemlock, which contains a poisonous alkaloid, coniine. Other alkaloids have long been valued for their beneficial medical effects. Examples include morphine (a painkiller), quinine (used to treat malaria), and atropine (used to treat Parkinson s disease and in eye drops that dilate the pupils). 

Piperidine alkaloids such as coniine and (—)-coniceine are very poisonous. They occur in hemlock (Conium maculatum L.), known as a very toxic plant. One of the characteristics of these piperidine alkaloids is smell. Moreover, they are neurotoxins which have acute effects such as chronic toxicity. 

Heterocycles which are not biosynthesized in humans, but which are natural products produced by other life forms, are very important in the history of drug design. This is particularly true of alkaloids containing a piperidine ring. These include coniine (8.87, extracted from poison hemlock, Conium maculatum, a member of the Umbelliferae carrot family), atropine (from Atropa belladonna and other genera of the Solanaceae plant family the plant was called belladonna [ beautiful woman ] since it was used by... 

Coniine Coniine or (5 )-2-propylpiperidine, molecular formula CgHnN, is a poisonous alkaloid found in the hemlock poison and the yellow pitcher plant (Sarracenia flava). Coniine contributes to the foul smell of hemlock. It is a neurotoxin, causes respiratory paralysis and is toxic to all classes of livestock and humans. In 399 BC, Socrates was put to death hy this poison. 

The solanaceae alkaloids and other other sources of antimuscarinics affect the CNS. They can produce hallucinations in addition to their effects on the peripheral nervous system. Witchcraft of the Middle Ages produced mixtures of plants - deadly nightshade, monkshood, and hemlock among them - as "flying ointments". The combined toxins disturbed the rhythm of the heart and led to delirium which could create a sensation of rising and falling, that is, flying. 

Several cyclic imines were reduced with phenylsilane as a reducing agent in the presence of the chiral titanocene catalyst 11 followed by a workup process to give the corresponding cyclic amines in excellent ee [26]. The hydrosilylation of 2-propyl-3,4,5,6-tetrahydropyridine with (R)-ll (substrate Ti=100 l) in THF at room temperature was completed in about 6 h (Scheme 14) [29]. The reaction mixture was treated with an acid and then with an aqueous base to afford (S)-coniine, the poisonous hemlock alkaloid, in 99% ee. 

The alkaloid coniine has been isolated from hemlock and purified. Its molecular formula is C8H17N. Treatment of coniine with excess methyl iodide, followed by silver oxide and heating, gives the pure (S)-enantiomer of A,A-dimethyloct-7-ene-4-amine. Propose a complete stmcture for coniine, and show how this reaction gives the observed product. 

By the end of this chapter we hope you will be able to recognize some basic classes of natural products and know a bit about their chemistry. We will meet alkaloids such as coniine, the molecule in hemlock that killed Socrates, and terpenes such as thujone, which was probably the toxin in absinthe that killed the nineteenth-century artists in Paris. 

Alkaloids are widespread in plants and include some very well-known poisons (notably coniine and strychnine), hallucinogens (morphine, cocaine and muscimol) and other potentially lethal compounds that are nevertheless used in medical practice (e.g. atropine, codeine, colchicine and morphine). As indicated by the preliminary snap-shot above, alkaloids typically have names ending in -ine and which are often related to the plant source or properties. Thus, morphine was named after Morpheus (the God of sleep) and coniine derives from Conium maculatum (hemlock), the plant used in the judicial murder of Socrates (399 BC). Various chemical tests for alkaloids are used as preliminary indicators of alkaloid presence in crude plant extracts. Finally, it should be noted that alkaloids can also exist as jVoxides of the alkaloid base. 

Socrates death by ingesting hemlock, 399 bc Socrates was charged with religious heresy and corrupting the morals of local youth. The active chemical used was the alkaloid coniine, which, when ingested, causes paralysis, convulsions, and potentially death. 

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