Nicotinic acid anabasine

Figure 9.4 The biosynthesis of nicotine from ornithine and nicotinic acid. Anabasine,...

Tobacco and its alkaloids have long ceased to have any therapeutic importance, but their extensive use as insecticides and the demand for nicotine for the manufacture of nicotinic acid have stimulated interest in processes of extraction and methods of estimation. On the latter subject there is a voluminous literature, of which critical resumes have been published by various authors.Recent work on this subject has been specially concerned with (1) the development of miero- and semi-miero-methods suitable for estimating nieotine in tobacco smoke and the distribution of nieotine on sprayed garden produce, in treated soils and in tobaeeo leaves,(2) the study of conditions necessary to ensure satisfactory results in using particular processes, " and (3) methods of separation and estimation of nicotine, nomicotine and anabasine in mixtures of these bases. ) In the United States and in Russia considerable interest is being shown in the cultivation of types of tobacco rich in nicotine, in finding new industrial uses for tobacco and its alkaloids, and in possible by-products from tobacco plants such as citric and malic acids, i " Surveys of information on tobacco alkaloids have been published by Jackson, i Marion and Spath and Kuffner. ... 

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. 

Nicotinic acid (Figure 29) provides alkaloids with the pyridine nucleus in the synthesizing process. This nucleus appears in such alkaloids as anabasine, anatabine, nicotine, nornicotine, ricine and arecoline. Moreover, many alkaloids... 

Labeling by deuterium or carbon-13 always leads to unequivocal signal identification of specific carbon atoms [600, 602, 640], After the administration of [5,6-14C-13C2]nicotinic acid to Nicotiana tabacum and N. glauca labeled anabasine anatabine, nicotine and nomicotine could be isolated. The satellites at the resonances of the labeled natural products helped to complete the signal assignments of the 13C NMR spectra of these alkaloids [602]. 

In these experiments radioactive a,/3-bipyridyl (8) was isolated and it appears from degradation studies that both rings of the alkaloid arise from nicotinic acid, so (8) can arise from anatabine (6) but not from anabasine (7), in which only one ring originates from nicotinic acid. 

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.)... 

The labelling and the hints given in the problem suggest an outline biosynthesis in which two molecules of nicotinic acid, one made nucleophilic by reduction, combine to give anatabine whilst the iminium salt we made in the last problem is attacked by the same nucleophilic derivative of nicotinic acid to give anabasine. 

Simple pyridine, pyrazine, and pyrrolo derivatives have been described from many different types of arthropods. Nicotine (177), nicotinamide, nicotinic acid, 2-pyrrolidone, N-methylpyrrolididone (178), 8-hydroxyquinoline (179), and 2-isobutyl-3-methoxypyrazine (180) have been detected in the defensive secretion and blood of larvae of the moth Lymantria dispar The nicotine isomer anabasine (181) and its congener anabaseine (182) have been identified as venom components in several ant species,whereas... 

The alkaloids anabasine (86) and sedamine (87) are typical representatives of one such alkaloid family past results suggest that they are both formed by condensation of a suitable nucleophile with a unit of A piperideine (85) derived from lysine (Scheme 15). The nucleophile is possibly benzoylacetic acid for sedamine49 and has been shown to be derived from nicotinic acid for anabasine.50 The origin of the different side-chains will be discussed in detail later under the individual alkaloids. For the moment this account will focus on the pattern of incorporation of lysine and will try to correlate the results from different systems. 

A new photometric determination of volatile bases in tobacco and tobacco smoke in terms of nicotine, which compares quantitatively with mass spectral and g.c. methods, has been developed.27 A colorimetric method for the estimation of nicotine alkaloids in tobacco by reaction with cyanogen bromide and 4,4 -di-aminostilbene-2,2 -disulphonic acid has also been reported.28 Dilute sulphuric acid extraction of nicotine and anabasine from autopsy tissue appears to be a more efficient method than extraction with acidified ethanol, aqueous oxalic acid, and steam distillation.29 Thin-layer chromatography has been effective in the analysis of nicotine and other alkaloids and drugs.30 Two reports on the isolation of anabasine from anabasine-lupinine mixtures have appeared.31 The P a values of some nicotine-type compounds have been determined.32... 

Anabasine (3-pyridyl-2-piperidine) appears to be the sole constituent of N. glauca R. Grah., and this plant has been used for the study of the biogenesis of the alkaloid. Anabasine isolated from N. glauca cultured in hydroponic solution containing lysine-2-C hydrochloride is radioactive (53). The alkaloid when oxidized with nitric acid gives nicotinic acid which by decarboxylation yields pyridine and carbon dioxide isolated as barium carbonate. Whereas the activity of anabasine is... 

Nicotinic acid (6) is well established as a precursor of the pyridine ring of nicotine and is also a precursor of this moiety in anabasine.[6- C]Nieotinic acid, as might therefore be expected, gave radioactive anatabine, but surprisingly the activity was divided equally between C-6 and C-6 ([carhoxy- C]nicotinic acid failed to label any of the alkaloids significantly). It follows that nicotinic acid (6) is the source for both rings of anatabine and the equal distribution of label indicates that the two units from which the alkaloid is formed are closely related, if not identical. 

The formation of a monobenzoyl derivative and a mononitroso derivative, b.p. 176°/4 mm., [a]u — 155° (no solvent) shows that anabasine is a secondary-tertiary diacidic base. This conclusion is substantiated by the formation of an A-methylanabasine, b.p. 268°, when the base is heated with formaldehyde and formic acid (420). With potassium permanganate anabasine is oxidized to nicotinic acid whereas dehydrogenation either with silver acetate or with zinc dust causes the loss of six hydrogen atoms and the formation of 3, 2-dipyridyl, b.p. 293-294° (picrate, m.p. 151-152°)(423). These experiments support structure CLXXIV previously applied to anabasine (399), a formulation that is confirmed by the following experiments. When A-benzoylanabasine methiodide is oxidized with potassium ferricyanide, the 7V-benzoyl derivative of the corresponding pyridone,... 

It has been established that nicotinic acid is the precursor of the pyridine ring in anabasine 140) and that carbons 2 and 3 are derived from the methylene carbons of succinate 127). It has also been shown that glycerol serves as a precursor for C-4, C-5, and C-6 119). Lysine serves as the precursor of the piperidine ring of anabasine 140, 141), C-2 of lysine becoming C-2 of anabasine. Tracer experiments with lysine-2- labeled with on the a- or e-nitrogen indicate that the piperidine nitrogen is derived from the e-amino group 142). The mechanism by which nicotinic acid is incorporated into nicotine must involve C-6 since nicotinic acid-G- H was incorporated with loss of the label, whereas nicotinic acid-2-3H was incorporated with retention of the label 140). A... 

The biosynthesis of nicotine and anabasine can reasonably proceed via (30), which will be electrophilic towards (31) and (3), which are intermediates for the other parts of the alkaloids, subsequent aromatization leading to loss of tritium. Coupling of two molecules of (30), decarboxylation, and aromatization would give anatabine, with 50% retention of tritium observed the stereochemistry of (30) follows from that determined in anatabine (34). [Direct coupling of two molecules of (30) makes use of the higher electrophilicity associated with this molecule cf. fatty acid biosynthesis), and so is preferred to the suggested coupling with two molecules of (35).]... 

Physiology biosynthesis Like the tropane alkaloids, T. a. are formed in the roots and transported to the aboveground parts for storage by the plant s phloem system. In some sorts of tobacco plants a part of the nicotine is demethylated to nomicotine during transport to the shoot. Nomicotine and anabasine are often the main alkaloids in the so-called nicotine-poor tobacco plant types. The T. a. are formed biogenetically from nicotinic acid, made available via the pyridine nucleotide cycle (see nicotinamide), and a pyrrolidine or piperidine building block (figure). In the case of nicotine, like for the tropane alkaloids, Al-methylpyr-roline is an intermediate, in the biosynthesis of anabasine the intermediate is a piperidine derived from the amino acid lysine (see piperidine alkaloids). 

Pyridine alkaloids are compounds with a pyridine nucleus and a pyrrolidine or piperidine unit. The pyrrolidine ring appears in nicotine and the piperidine ring in anabasine. Typical alkaloids from this group are nomicotine and anatabine. The a of pyridine alkaloids is nicotinic acid, the p is dihydro-nicotinic acid, the q> is 1,2-dihydropyridine (Figure 2.41). The A is nicotine and its P is nomicotine. ... 

The use of HPLC for separation of tobacco alkaloids has been limited to few studies (Court 1986). Saunders and Blume (1981) developed a procedure for analyses of nicotine, nornicotine, anabasine, and anatabine in tobacco. This method utilized a pBondapak Cig reversed-phase column. The mobile phase of 40% methanol containing 0.2% phosphoric acid was adjusted to pH 7.25 with triethylamine. Retention times with 0.5ml/min flow rates were 23 min for nicotine, 13.9min for anatabine, 12.2min for anabasine, and ll.Omin for nornicotine. This method is capable of analyzing samples containing 40-50 ng of alkaloid, and quantitative results were reliable. The column was stable for 800-1000 injections before it showed appreciable degradation in separation but was still capable of separating nicotine and nornicotine. 

Nicotine and anabasine are considered to be alkaloids derived firom nicotinic acid (pyridine-3-carboxylic acid).These alkaloids can be also classified as derived from ornithine and lysine, respectively. Therefore, these alkaloids are described in Chapter 10.1 (as alkaloids derived from nicotinic acid), in Chapter 3.1 (alkaloids derived from ornithine and arginine), and in Chapter 4.3 (alkaloids derived from lysine). However, such exceptions are relatively rare if the classification of alkaloids is conducted based on their biosynthetic origin. 

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