Nicotinic acid-derived alkaloids

Alkaloids derived from nicotinic acid contain a pyridine nucleus. Nicotinic acid itself is synthesized from L-tryptophan via A-formylkynurenine, L-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid. 

The other alkaloids derived from nicotinic acid, with pyridine nucleus such as arecoline, arecaidine and guvacoline, are tetrahydronicotinic acid (guvacine) derivatives. 

L-lysine furnishes alkaloids with at least four different nuclei. It is a protein amino acid, one of the most important alkaloid precursors. L-lysine-derived 

---

Nicotinic acid Nicotinic acid-derived alkaloids True alkaloids Pyridine alkaloids Sesquiterpene pyridine alkaloids... 

GroB, D. Nicotinic acid derived alkaloids. In Biochemistry of Alkaloids (K. Mothes, H. R. 

Lefebvre, C.L. Ergot of Paspalum Phytopathology (1939) 29 365-367 Lehrfeld, J. Burkman, AM. Gearien, J.E. Synthesis of 6-Substi-tuted Nicotinic Acid Derivatives as Analogs of Ergot Alkaloids Journal of Medicinal Chemistry (1964) 7 150-154... 

It is interesting that anatabine was not derived from lysine, but nicotinic acid. (This alkaloid is characteristic for Nicotiana plants but was also detected in Lobelia inflata) (Fig. 11.21), [1]. 

Tobacco Alkaloids. The relatively small number of alkaloids derived from nicotinic acid (27) (the tobacco alkaloids) are obtained from plants of significant commercial value and have been extensively studied. They are distinguished from the bases derived from ornithine (23) and, in particular, lysine (24), since the six-membered aromatic substituted pyridine nucleus common to these bases apparendy is not derived from (24). 

Tobacco use is primarily due to psychopharmacological effects of nicotine (Henningfleld et al. 2006). Nicotine is a tobacco alkaloid, a basic substance that contains a cychc nitrogenous nucleus. In Nicotiana plants, most alkaloids are 3-pyridyl derivatives In cured leaf of Maryland Robinson Medium Broadleaf, 24 pyridine derivatives were identified, including nicotine, nomicotine, anabasine, oxynicotine, myosmine, 3-acetylpyridine, 2,3 -dipyridyl, iticotinamide, anatabine, nicotinic acid, and unidentified pyridine alkaloids of derivatives thereof (Tso 1990). Nicotine is the principal alkaloid in commercial tobacco (this was confirmed in 34 out of 65 Nicotiana species) nomicotine, rather than nicotine, appears to be the main alkaloid in 19 out of 65 species and anabasine is the third most important. In addition to the above-mentioned principal and minor alkaloids, the presence of many trace amounts of new alkaloids or their derivatives were frequently reported, including, for example, 2.4 -dipyridyl, 4,4 -dipyridyl, N -formylanabasine, A -formylanatabine, N -acetylanatabine, N -hexanoyl-nomicotine, N -octanoyl-nomicotine, T-(6-hydroxyoctanoyl) nomicotine, and l -(7-hydroxyoctanoyl) nor-nicotine. 

Figure 29. The nucleus of alkaloids derived from nicotinic acid.

The tobacco alkaloids, especially nicotine, are derived from nicotinic acid (see page 311) but also contain a pyrrolidine ring system derived from ornithine as a portion of their structure. 

This allows an aldol-type reaction with the A-methylpyrrolinium cation, and finally dehydrogenation of the dihydropyridine ring back to a pyridine gives nicotine. Nornicotine is derived by oxidative demethylation of nicotine. Anaba-sine is produced from nicotinic acid and lysine via the A1 -piperidinium cation in an essentially analogous manner (Figure 6.32). A subtle anomaly has been exposed in that a further Nicotiana alkaloid anatabine appears to be derived by... 

Nicotinic acid undoubtedly provides the basic skeleton for some other alkaloids. Ricinine (Figure 6.35) is a 2-pyridone structure and contains a nitrile grouping, probably formed by dehydration of a nicotinamide derivative. This alkaloid is a toxic constituent of castor oil seeds (Ricinus communis Euphorbiaceae), though the toxicity of the seeds results mainly from the polypeptide ricin (see page 434). Arecoline (Figure 6.36) is found in Betel nuts (Areca catechu Palmae/Arecaceae) and is a tetrahydronicotinic acid derivative. Betel nuts are chewed in India and Asia for the stimulant effect of arecoline. 

The Rutaceae oxazoles are evidently derived from /V-nicotinoyl-p-(p-hydroxy)-phenylethylamide (51), with the exception of balsoxin (25) and texamine (26) in which the nicotinoyl moiety is replaced by benzoyl. The condensation of these tyramine and nicotinic acid residues does not represent any major departure from the standard routes of alkaloid biosynthesis in the Rutaceae, for it has long been recognized that the alkaloids of this family are all derived from either phenylalanine (52), tyrosine, (53), or anthranilic acid (54) (22), the latter being the acknowledged precursor to nicotinic acid in most organisms (23). The formation of the putative oxazole precursor 51 or its equivalent therefore constitutes a convergence of the two predominant modes of alkaloid biosynthesis in the family. 

GROSS, D., Alkaloids derived from nicotinic acid, in Biochemistry of Alkaloids, (K. Mothes, H.-R. Schiitte and M. Luckner, eds.), VCH, Weinheim. 1085, pp. 163-187. 

The rather similar alkaloids anabasine and anatabine come from different biosynthetic pathways. Labelling experiments outlined below show the origin of one carbon atom from lysine and others from nicotinic acid. Suggest detailed pathways. (Hint. Nicotinic acid and the intermediate yoi have been using in Problem 3 in the biosynthesis of the piperidine alkaloid are both electrophilic at position 2. You also need an intermediate derived from nicotinic acid which is nucleophilic at position 3. The biosynthesis involves reduction.)... 

---