Methyl-coniine

Figure 2.2 Three piperidine alkaloid teratogens from Conium maculatum (poison-hemlock) (a) coniine, (b) y-coniceine, and (c) A-methyl coniine, with accompanying LD50 as determined in a mouse bioassay.

Pharmacologically, the properties of all three alkaloids are very similar, except y-coniceine is more stimulatory to autonomic ganglia and VV-methyl coniine has a greater blocking effect (Fodor and Colasanti, 1985). 

Anders als bei der katalytischen Hydrierung wird bei der Reduktion von N-substituierten Carbamidsiiure-alkylestern mit Lithium-alanat die N-Alkoxycarbonyl-Gruppe nicht ab-gespalten, sondern zur Methyl-Gruppe reduziert. So erhalt man z.B. bei der Reduktion von ( + )-l-Methoxycarbonyl-2-propyl-piperidin mit Lithium-alanat in siedendem Ether ( + )-l-Methyl-2-propyl-piperidin [( + )-N-Methyl-coniin 64%]3. 

Conium maculatum (hemlock) contains the poisonons piperidine alkaloid, coniine, and related alkaloids, N-methyl-coniine, conhydrine, pseudoconhydrine, and gamma-coniceine. It has well-established teratogenic activity in certain animal species. 

Coniine (piperidine alkaloid), N-methyl coniine, conhydrine, /l-coniceine, and pseudconhydrine are the toxins identified. Coniine has a number of pharmacological activities resembling nicotine. It is capable of producing stimulation followed by depression of autonomic ganglia. 

CoNiuM. y-Coniceine is the principal alkaloid in young plants of Conium macviatum L., especially in the leaves. It is still the chief constituent of leaves in two-year plants, but coniine dominates in the flowers and fruits. During ripening coniceine disappears and JV -methyl-coniine is predominant (261, 356). 

Coniine—Conicine—Cicutine——125—is obtained from Con ium maculatum, in which it is accompamed hy two other alkaloids, methyl coniine, C H, N(CH,), and conhydrine, C,H NO—the former a volatile liquid, the second a crystalline solid. 

Comum Fruit, Hemlock poison hemlock spotted hemlock poison parsley spotted cowbane, Full-grown, but unripe, carefully dried fruit of Conium maculatum L., Um-belUferae. Habit. Europe, Asia, naturalized in U.S. Constit. 0.5 15% coniine, conhydrine, pseudoconhydrine, methyl-coniine, ethylpi peri dine, comic acid, volatile and fixed oil. Has antispasmodic activity. 

N-methyl-d-coniine, C9H19N, has been found in Conium maculatum (110) it is obtained by treating the hydrochloride of the higher boiling fraction of crude coniine with sodium nitrite to remove the coniine as the insoluble nitroso compound. The base is an oil, b.p. 173-174°, d 0.8318, [ ] D + 81.33°, which forms a hydrochloride, m.p. 188-189°, an aurichlo-ride, m.p. 79°, and a chloroplatinate, m.p. 158-160°. It is identical with iV-methyl-d-coniine prepared by methylation of d-coniine with potassium methyl sulfate (167). Von Braun (112) recommends separating V-methyl-coniine from the secondary bases by benzoylation of the latter, v. Braun s base, however, had a low optical rotation and was eventually shown to contain a little ZV-methyl-Z-coniine (168). 

Phytochemistry The roots contain up to 0.042 % total alkaloids, with the stems up to 0.065 % and leaves up to 0.1 %. The fruits contain up to 1 % total alkaloids, but sometimes unripe fruits contain up to 2 % (with 50 % of it being coniine). Other alkaloids include conhydrine, pseudoconhydrine, y-coniceine, and methyl-coniine. The above parts also contain essential oils (mainly terpenes), vitamin C, carotene, and caflfeic acid. Quercetin and kaempferol have been isolated from the flowers (Khalmatov 1964 Lopez et al. 1999). 

A number of other syntheses of coniine have been effected, of which that of Diels and Alder is of special interest. The initial adduct of pyridine and methyl acetylenedicarboxylate, viz., tetraraethylquinolizine-1 2 3 4-tetracarboxylate (IX) on oxidation with dilute nitric acid is converted into methyl indolizinetricarboxylate (X). This, on hydrolysis and decarboxylation, furnishes indolizine, the octahydro-derivative (XI) of which, also known as octahydropyrrocoline, is converted by the cyanogen bromide method (as applied by Winterfeld and Holschneider to lupinane, p. 123) successively into the broraocyanoamide (XII), cyanoaraide (XIII) and dZ-coniine (XIV). A synthesis of the alkaloid, starting from indolizine (pyrrocoline) is described by Ochiai and Tsuda. ... 

Hess and Eichel have shown that d-coniine with formaldehyde and formic acid yields an active A -methyl-d-coniine, and that methylZso-pelletierine hydrazone (see p. 57) yields ZV-methyl-dZ-coniine when heated with sodium ethoxide at 150-70°. 

We now consider 7V-methyl-2-(3-pyridyl)pyrrolidine (7), also known as the alkaloid nicotine. Parallelling our discussion of coniine, we find in Kharasch and Domalski the nearly century-old enthalpy of formation for the liquid of 39 kJmol-1. Is this value plausible With (liquid, tert/R, R1, R2) necessary to transform a tertiary amine into the corresponding hydrocarbon24, we would conclude that the enthalpy of formation of liquid l-methyl-2-(3-pyridyl)cyclopentane (8, R = 3-Py) is ca —50 kJmol-1. To estimate the last datum in another way, we assume that equation 10 is essentially thermoneutral. 

In the first series (see Scheme 2) lythrine (1) was transformed to 7V-methyl-piperidine (44). The optical rotation was —31° in 43 and + 31° in the corresponding derivative of vertine. The plain positive ORD curve of the O-methyl derivative of the latter compound corresponded to those of D-(-h)-coniine and D-(-f-)-2-methylpiperidine. 

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. 

A simpler way to restrict the conformation of an enolate is to coniine it in aheterocycle and an important group of chiral enolates come from various derivatives of amino acids. The hrst successful such compounds were Schollkopf s bislactim ethers 41 derived from the diketopiperazines 40 formed when an amino acid such as alanine 39 condenses with itself.4 Treatment of 41 with butyl lithium creates a lithium enolate on one position in the ring the methyl group in the other position keeps the chirality intact. Alkylation occurs selectively on the opposite side to the remaining methyl group 42 and hydrolysis releases a new tertiary amino acid 43 and one of the original alanines. 

The vapor which it gives ofif at ordinary temperatures forms a white cloud when it comes in contact with a glass rod moistened with HCl, as does NH,. It forms salts which crystallize with difficulty. Cl and Br combine with it to form crystallizable compounds I in alcoholic solution forms a brown precipitate in alcoholic solutions of coniine, which is soluble without color in an excess. Oxidizing agents attack it with production of butyric acid (see below). The iodides of ethyl and methyl combine with it to form iodides of ethyl and methjl-conium. It has been obtained synthetically by first allowing butyric aldehyde and an alcoholic solution of ammonia to remain some months in contact at 30 (86 F ), when dibutyimldine is formed. 

Oxidation of coniine with chromic acid produces butyric acid (115, 124), while dehydrogenation of the alkaloid with silver acetate converts it to abase, conyrine (125), which is also obtained from coniine hydrochloride by distillation with zinc dust (126). Conyrine, CgHnN, is a colorless, fluorescent oil, b.p. 166-168°, which forms a chloroplatinate and an aurichloride it can be converted back to coniine by reduction with hydriodic acid, it behaves on methylation like a pyridine base, and further, it gives rise on oxidation to a-pyridinecarboxylic acid. Therefore, conyrine is a 2-propylpyridine (XCIV) while coniine is a 2-propylpiperidine (XCV) (126), in which the side chain is normal since conyrine is not identical with 2-isopropylpyridine (127). 

An ingenious synthesis of coniine has been obtained by an adaptation of the Diels-Alder type of reaction thus the reaction of pyridine with methyl acetylene dicarboxylate in ether gives rise to methyl quinolizine-1 2 3 4-tetracarboxylate (CII), m.p. 187-188°, and this, on oxidation either... 

N-Methyl-Uconiine, C9H19N, was first isolated from C. maculatum by Ahrens (169) who obtained it from a residue left from the manufacture of d-coniine. It is separated from coniine by fractional crystallization of the hydrobromides, coniine hydrobromide being the less soluble of the two. The coniine which is thus separated is a mixture of d- and dZ-coniine. iV-Methyl-Z-coniine is a colorless oil, b.p. 175-176°, < 0.8349, [a]D — 81.92°. It forms a hydrochloride, colorless leaflets, m.p. 189-190°, a hydriodide, m.p. 147°, a chloroplatinate, orange crystals, m.p. 153-154°, an aurichloride, m.p. 77-78°, a mercurichloride, B HCl 3HgCU, m.p. 152-153°, and a picrate, m.p. 121-122°. 

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