Anatabine

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 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).] 

The formation of a/S-dipyridyl in Nicotiana species occurs from anatabine (34) during drying of the plants prior to isolation of alkaloids.  

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Anabasine, CmHj Na N-Methylanabasine, CuHigNj woNicoteine, CjoHiaNa Anatabine, C10H1.N,... 

Comparison of these results indicates identity of the two substances isolated independently by Orekhov and Ehrenstein, but Spiith and Kesztler have suggested that Pictet s nicoteine and Ehrenstein s base, consisted of impure Z-anatabine (p. 46). In this connection it may be noted that Ehrenstein s base was laevorotatory in acid solution, whereas Salts of anabasine are dextrorotatory. These authors have themselves isolated Z-anabasine from tobacco. The identity of synthetic 2-(3 -Pyridyl)piperidine with dZ-anabasine seems to have been definitely established. Anabasis aphylla is the source of the anabasine raanufac-... 

A similar oxazolidine-based strategy was employed in the syntheses of R-(+)-anatabine (84) and (+)-benzomorphan (85), utilizing Zincke-derived salts 80 and 81, respectively (Scheme 8.4.26). In these cases, borohydride reduction, followed by cyclization, led to oxazolidines 82 and 83 as substrates for organometallic addition and subsequent elaboration to the natural products... 

Precursors and Formation. Tobaccos used for commercial products in the U.S.A, contain between 0,5 and 2,7% alkaloids. Nicotine constitutes 85-95% of the total alkaloids (14,26,27). Important minor alkaloids are nornicotine, anatabine, anabasine, cotinine and N -formylnornicotine (Figure 6), Several of these alkaloids are secondary and tertiary amines and, as such, amenable to N-nitrosation. The N-nitrosated alkaloids identified to date in tobacco and tobacco smoke include N -nitrosonornico-tine (NNN), 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) and N -nitrosoanatabine (NAT Figure 7). In model experiments, nitrosation of nicotine also yielded 4-(methylnitrosamino)-4-(3-pyridyl)butanal (NNA 28). 

In studies of smoking cessation, anatabine is recommended as nicotine replacement therapies will lead to the presence of nicotine and cotinine without any tobacco exposure... 

The primary alkaloid in tobacco is nicotine, but tobacco also contains small amounts of minor alkaloids such as anabasine, anatabine, myosmine, and others. The minor alkaloids are absorbed systemically and can be measured in the urine of smokers and users of smokeless tobacco (Jacob et al. 1999). The measurement of minor alkaloids is a way to quantitate tobacco use when a person is also taking in pure nicotine from a nicotine medication or a nontobacco nicotine delivery system. This method has been used to assess tobacco abstinence in clinical trials of smoking cessation with treatment by nicotine medications (Jacob et al. 2002). 

Jacob P, 3rd, Hatsukami D, Severson H, Hall S, Yu L, Benowitz NL (2002) Anabasine and anatabine as biomarkers for tobacco use during nicotine replacement therapy. Cancer Epidemiol Biomarkers Prev 11(12) 1668-1673... 

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... 

Diagram of anatabine, anabasine and ricinine synthesis pathway 86... 

NT437 Leete, E., and S. A. Slattery. Incorporation of (2- C) nicotinic acid into the tobacco alkaloids. Biosynthesis of anatabine and alpha, beta-dipyridyl. J Am Chem Soc 1976 98 6326. 

Although discussion of the chemistry and biochemistry of pyridylpiperi-dines, bipiperidines, and related reduced bipyridines is outside the scope of a review on bipyridines, it is necessary for the understanding of subsequent sections of this review to record the structures of reduced 2,3 -bipyridines that occur naturally. Several compounds of this type are important alkaloids isolated from several plant species, notably. Anabasis, Duboisia, Mackinlaya, Marsdenia, Nicotiana, and Priesteya. Anabasine (also known as neonicotinel has structure 12 (R = H), and is insecticidal. The closely related structures 1-methylanabasine (12 R = anatabine (13 R = its... 

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]. 

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... 

The evidence for dioscorine biosynthesis is consistent likewise with the intermediacy of (4) (see Scheme 1). The sequences of saturation and condensation leading to dioscorine, and also anatabine, cannot yet be specified, but are clearly well worth exploring. Of interest too, in the case of dioscorine, is the way in which the branched acetate chain originates (stepwise introduction of acetoacetate units in the course of the biosynthesis of the alkaloid ). 

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.)... 

Anabasine (3-(2-piperidinyl)-pyridine) from Mcotiana and Duboisia species (Solanaceae) is an nACh-R agonist used to discourage tobacco smoking as is the JV-methylated tricyclic piperidine (—)-lobeline from Lobelia species (Campanulaceae). Lobeline-related compounds from Lobelia species include the bicyclic jV methyltetrahydropyridines isolobinine and lobinine and the tricyclic jV-methylpiperidines lobelanine and lobelanidine. Anabasine-related compounds include anatabine (2-(3-pyridyl)-l,2,3,6-tetrahydropyridine) from M tabacum and (+)-ammodendrine (jV-acetyltetrahydroanabasine) from Ammodendron and Sophora species (Fabaceae). 

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