Piperidine alkaloids anabasine

The well-known piperidine alkaloid anabasine, found in Anabasis aphylla L. (Chenopodiaceae) and Nicotiana glauca Graeb. (Solanaceae), is thought to be synthesized in plants through dimerization of A1-piperideine (followed by oxidation).243 A terpyridine nicotelline (173) was found in tobacco leaf,244andits structure was proved by synthesis.245... 

The chiral boron complex prepared in situ from chiral binaphthol and B(OPh)3 is utilized for the asymmetric aza-Diels-Alder reaction of Danishefsky s diene and imines [67] (Eq. 8A.43). Although the asymmetric reaction of prochiral imine affords products with up to 90% ee, the double asymmetric induction with chiral imine by using oc-benzylamine as a chiral auxiliary has achieved almost complete diastereoselectivity for both aliphatic and aromatic aldimines. This method has been successfully applied to the efficient asymmetric synthesis of anabasine and coniine of piperidine alkaloides. 

Lysine.—Lysine is a common precursor of piperidine alkaloids. Of the two enantiomers of this amino-acid, the L-isomer is the more direct precursor, in plants, for piperidine alkaloids, e.g. anabasine, whereas D-lysine is more directly implicated in the biosynthesis of pipecolic acid (24)1,2,23 (cf Vol. 7, p. 7). It has now been shown that a pathway exists in the plant Nicotiana glauca,24 and also in the micro-organism Neurospora crassa2S which transforms D-lysine into L-lysine by way of L-pipecolic acid (24). 

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.)... 

Nicotine and related pyridine alkaloids (A) Ammodendrine (A) anabasine (A) arborine (AA) boldine and other aporphine alkaloids (AA) berberine and related protoberberine alkaloids C-toxiferine (AA) coniine and related piperidine alkaloids (A) cytisine, lupanine, and other quinolizidine alkaloids (A) tubocurarine (AA) codeine (A) erysodine and related Erythrina alkaloids (AA) histrionicotoxin (AA) lobeline (A) methyllycaconitine (AA) pseudopelletierine (A)... 

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... 

The Early Stages of Alkaloid Biosynthesis. — It is well established that L-lysine (13) is incorporated into some piperidine alkaloids by way of a symmetrical intermediate it is accepted that this symmetrical intermediate is cadaverine (17), which is also an alkaloid precursor. Lysine, however, is incorporated into other alkaloids, e.g. anabasine (12) (Section 1.5) and sedamine (18), without the intervention of any symmetrical intermediate. Cadaverine (17), although able to act as an alkaloid precursor. 

Piperidine Alkaloids.—There is now a wealth of detail on the incorporation of lysine into the piperidine nucleus of alkaloids such as sedamine (20), anabasine... 

C12H20N2O, Mr 208.30, mp. 43-46°C, [a]o +15° (C2H5OH) racemate, mp. 50- 60 °C. A. is a piperidine alkaloid, occurring together with quinolizidine alkaloids in many Fabaceae genera (e.g., Ammodendron, Baptisia, Cytisus, Lupinus). Its Structure is closely related to that of anabasine. 

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). 

Also obtained from tobacco are the alkaloids (-)-anabasine and (-)-anatabine and related derivatives. (-)-Anabasine is biosynthesized by combining nicotinic acid and a piperidine ring derived from lysine. 

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... 

The pathways deduced for coniine 6.14) and pinidine 6.15) on the one hand, and anatabine 6.7) and dioscorine 6.8) on the other, are exceptional. That deduced for iV-methylpelletierine 6.19) can be considered much more typical of piperidine alkaloids because the piperidine ring originates from lysine 6.17). Two other alkaloids, anabasine 6.20) and sedamine 6.21) have similar origins and much of the evidence for the three alkaloids is interlocking so they are best discussed together. 

Secondary alicyclic amines, such as pyrrolidine and piperidine, have many properties typical of the corresponding aliphatic amines. Metabolic oxidation at secondary alicyclic nitrogens results in the formation of hydroxylamines, which may then undergo enzymic or non-enzymic conversion to nitrones, and in some cases to nitroxide radicals. For example, the 2-substituted piperidino derivative (- )-anabasine (1), a tobacco alkaloid, is metabolized initially to a hydroxylamine (2) and then to the nitrone (3), when incubated with liver and... 

N-Methylpelletierine.— Labelling of 7V-methylpelietierine (13) by [6- C]-dl-lysine in Sedum sarmentosum has been shown to be confined to C-6 and thus the piperidine ring of this alkaloid, like anabasine (14), is derived from lysine by way of unsymmetrical intermediates, and cadaverine cannot be a true precursor. In confirmation of the role of this amino-acid, [4,5- H2,6- C]-DL-lysine was incorporated into iV-methylpelletierine without alteration of the ratio. 

The diastereoselective hetero-Diels Alder reaction of imines leads to enantiomerically pure 2-substituted piperidines, important synthons for the synthesis of nitrogen-containing natural products. 2,3,4,6-Tetra-0-pivaloyl-/ -D-galactopyranosylimines 1, easily synthesized from the respective 1-galactosamine. react with isoprene (2a), 2,3-dimethyl-l,3-butadiene (2b) and ( )-l-methoxy-3-trimethylsiloxy-l,3-butadiene (4) under zinc chloride etherate catalysis71. Adducts 3 are obtained with moderate to good diastereoselectivities, while adduct 5 is produced with a diastereomeric ratio of greater than 95 5. Adduct 5 can then be converted into the alkaloid (S)-anabasin. 

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