Alkaloids coniine

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). 

The simple piperidine alkaloid coniine from poison hemlock is not derived from lysine, but originates by an animation process and is discussed on page 381. 

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

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. 

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. 

Solenopsis ants produce piperidine alkaloids which resemble the plant alkaloid coniine. These alkaloids are strong deterrents and inhibit several cellular processes, such as electron transport chains (Table IV) 28,494). Many insects indicate the content of toxic natural products by warning colors (aposematism) or by the production of malodorous pyrazines 4,17,231,494). 

The majority of alkaloids have been found to be derived from amino acids, such as tyrosine, phenylalanine, anthranilic acid, tryptophan/tryptamine, ornithine/arginine, lysine, histidine and nicotinic acid (Fig. 2.1). However, alkaloids maybe derived from other precursors such as purines in case of caffeine, terpenoids, which become aminated after the main skeleton has been synthesized i.e. aconitine or the steroidal alkaloids, are found in the Solanaceae and Liliaceae. Alkaloids may also be formed from acetate-derived polyketides, where the amino nitrogen is introduced as in the hemlock alkaloid, coniine. 

This would favour hypothesis II in Fig. 7.15. Even animals share some of the proteins (TDC, ODC, TyrDC, STS and CR). These observations indicate that the proteins very likely evolved in prokaryotes and were transferred into eucaryotes via either protobacteria (Fig. 7.18) or cyanobacteria, the progenitors of mitochondria or chloroplasts, respectively. A number of SM (e.g. many terpenoids, QAs, the piperidine alkaloid coniine) are produced completely or partly in chloroplasts and/or mitochondria (see Chapter 1). The corresponding genes are mostly nuclear today. It is tempting to speculate that these localizations are indirect indicators of a former bacterial origin of the corresponding pathways. The introduction of bacterial genomes into eukaryotes was... 

This method was recently used in the synthesis of different natural products, like the ladybug defence alkaloid harmonine, a- and p-amino acetals and acids (eq 14), and both enantiomers of the hemlock alkaloid coniine, utilizing the nucleophilic 1,2-addition of organolithium and -lanthanoid reagents to SAMP/RAMP hydrazones. 

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. 

Pinidine and Coniine.—Pinidine (8) and the hemlock alkaloid coniine (9) are unusual among simple piperidine alkaloids in being derived exclusively from acetate units. The combination is in each case a simple linear one and proceeds either via polyketide intermediates or, arguably in the case of coniine, via the fatty acid (10). Strong evidence from tracer and enzyme studies points to (11) as an intermediate... 

FOOLS PARSLEY Aethusa cynapium, L., Family Apiaceae, is a European weed. The whole plant is poisonous due to the occurrence of very low content of the alkaloid coniine, a cicutoxin-like substance and essential oil. There have been lethal poisonings among humans and cattle. Symptoms of poisoning are stomach-ache, increased production of saliva, vomiting, diarrhoea, headache and blurred vision. 

The pinidine isolated after feeding [l- C]acetate to P. jeffreyi was degraded to reveal essentially all the activity located at the four positions expected of a linear combination of five acetate units (Scheme 1). On the other hand, a tow incorporation of [2- " C]-DL-lysine was obtained, which partial degradation showed was not specific to the piperidine ring of the alkaloid. The incorporation found was rationalised as being the result of catabolism of the lysine to acetate. Thus, the biosynthetic pathway to pinidine is similar to that of the hemlock alkaloid coniine. 

Adulteration Conii maculali fructus (alkaloid coniin) Aethusae cynap. fructus... 

Although structurally very similar to pelletierine (16) the hemlock alkaloid coniine (17) is notably of quite different origins, arising as it does from acetate in a fairly well understood pathway. 

The a-propyl-piperidine prepared in this way differed from coniine in being inactive. By the crystallization of the tartrate of the base two optically active forms were obtained the dextrorotatory form proved to be identical with the natural alkaloid. Coniine is a colorless liquid which boils at 167° it possesses a penetrating odor and is poisonous. 

A possible way to avoid intermediate stable isoquinolines like 33 and 35 is reductive amination of the more reactive carbonyl function of A (representing 31 or 32), [which is biochemically plausible, e.g., with pyridoxylamine (36)], leading directly to the dihydroisoquinolines B, which then might very easily be further oxidized to isoquinolines C or reduced to tetrahydroisoquinolines D (see Scheme 4). This possible pathway closely resembles the known 39, 39a) biosynthesis of the hemlock alkaloid coniine (39), where reductive amination of the more reactive carbonyl function of the diketo precursor 37 leads to the cyclic imine y-coniceine (38), which is further reduced to 39 (see Scheme 5). 

One of the oldest recorded incidents of the deliberate use of a toxic plant concerns the simple alkaloid coniine. Based on the writings of Plato in the Phaedo, it is known that the Greek philosopher Socrates (470-399 BC) died by taking an extract of C. maculatum.Thc main toxic component of C. maculatum is coniine (Chapter 15.1), whose basic skeleton is derived from a polyketide precursor. 

Biological Activity of Tropane Alkaloids Distribution of Tropane Alkaloids Piperidine Alkaloids Alkaloids from Piper Species Piperine Alkaloids Involving Condensation with Acetate/Malonate Sedum Alkaloids Lobelia Alkaloids Lycopodium Alkaloids Piperidine Alkaloids in Insects Polyketide-Derived Alkaloids Coniine... 

Although the alkaloids coniine (48) and y-coniceine (51) bear a structural resemblance to the piperidine alkaloids, these compounds are derived from a polyketide pathway (Fig. 29.17). Lysine is a poor precursor, and early attempts to show incorporation of this compound resulted in failure. Acetate is a much better precursor. Coniine is a highly toxic alkaloid and is one of the toxic components of poison hemlock (Conium maculatum, Apiaceae) (Cutler, 1992). Otherwise, alkaloids are very uncommon in the Apiaceae. Coniine does occur in several other plants, for example, Sarracenia (Sarracenia). y-Coniceine is found in several species of Aloe (Liliaceae) (Dring et al., 1984). Coniine is toxic to the aquatic plant Lemna (Wink, 1993). The LDioo p.o. in the... 

Scheme 69 Intramolecular azsi-Michael reaction (IMAMR) for the syntheses of the hemlock alkaloids (+)-coniine (105), (+)-sedamine (304), and (+)-allosedamine (305) 288)...

Carbohydrates are inexpensive and renewable natural products which contain numerous functional groups and chiral centers. Utilizing their pronounced complexing abilities and their content of chiral information, carbohydrates are applied as chiral auxiliaries in Diels-Alder and aza-Diels-Alder reactions. The method involves the use of Lewis acid catalysts with different complexing properties. Thus, dienes of low reactivity can be transformed to their cycloadducts with high asymmetric induction. The use of N-glycosyl imines as the dienophiles offers stereoselective access to enantiomerically pure piperidine derivatives, e.g. the alkaloids coniin and anabasin. 

The assigment of the absolute configuration of the products 20 is achieved by conversion of the n-propyl derivative 20f to the alkaloid coniin. To this end, the C=C double bond of 20f is reduced with L-selectride (34). The resulting piperidi-none is converted to its dithiolane derivative which subsequently is subjected to desulfurization with Raney nickel to deliver the N-galactosyl coniin 21. The final release of the enantiomerically pure alkaloid 22 from the carbohydrate template is achieved by treatment of 21 with HCI/methanol (31). 

The biological activities of the poison hemlock (Conium maculatum) are due to the content of piperidine alkaloids — coniine (2-propylpiperidine), y-coniceine (2n-propyl-ly-piperidine), conhydrine (2-(l- hydroxypropyl)-piperi-dine), A/-methylc(Miiine (1-methyl-2- propylpiperidine), pseudoconhydrine ((5-hydroxypropyl)-piperidine), conhydrinone ((l-oxo-propyl)-piperidine), W-methylpseudoconhydrine (5-hydroxy-l-methyl-2-propyl-piperidine), and 2-methylpiperidine. The poismiing effect of hemlock supplements by the presence of poly-p-keto acid (2,5,7-tri-oxo-octanoic acid), quercetin, kaempferol, and glycoside dioxymid [4, 12,13, 20, 52, 85, 87]. 

Mitich W (1998) Poison-hemlock (Conium maculatum L.). Weed Technol 12 194—197 Moody CJ, Lightfoot AP, Gallagher PT (1997) Asymmetric synthesis of 2-substituted piperidines. Synthesis of the alkaloids (—)-coniine and ( )-pseudoconhydrine. J Org Chem 62 746-748... 

The application of the same reaction principle (eq. 14) to the analogous butyraldimine 31 opens up a highly stereoselective synthesis of the alkaloid coniin. 

Bases are less common in foods than acids because of their bitter taste. A Sour Patch Kid coated with a base would never sell. Our aversion to the taste of bases is probably an adaptation to protect us against alkaloids, organic bases foimd in plants (see the Chemistry and Health box in Section 14.9). Alkaloids are often poisonous—the active component of hemlock, for example, is the alkaloid coniine—and their bitter taste warns us against eating tirem. Nonetheless, some foods, such as coffee, contain small amounts of base (caffeine is a base). Many people enjoy the bitterness, but only after acquiring the taste over time. 

Simple examples of piperidine alkaloids are iV-methylpelletierine 6.19) and the hemlock alkaloid, coniine 6.14). In these bases the structural relationship is manifestly close. This relationship is similarly apparent between anabasine 6.20) and anatabine 6.7) which are, moreover, found in the same plant. It is however, clear, from biosynthetic experiments, that whilst the piperidine rings of iV-methylpelletierine 6.19) and anabasine 6.20) derive from the amino acid lysine 6.17) those of coniine 6.14) and, most surprisingly, anatabine 6.7) have quite different origins. It is proved that anatabine 6.7) is formed from two molecules of nicotinic acid 6.4) [4] (the labelling results, and a suggested pathway, is illustrated in Scheme 6.4). Only the pyridine ring of anabasine derives from... 

Figure 6.32. Interconversion of the hemlock alkaloids coniine and y-coniceine the pathway of N-methylconiine formation (Roberts, 1971,1974,1975). Courtesy of the author and Pergamon Press, Ltd., copyright 1971, 1974, 1975. (Dietrich and Martin, 1969). Courtesy of the authors and the journal.

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