Pyrrolidine ring of nicotine

Nicotine.—The pyrrolidine ring of nicotine (6) derives from ornithine (1), label from, e.g., C-2 appearing equally spread over C-2 and C-5. This symmetrical incorporation of the precursor amino-acid is accounted for by the intermediacy of the symmetrical diamine putrescine (4), which is supported by other evidence too.1,2 The symmetrical incorporation of ornithine into nicotine (6) and into nornicotine (7) has been confirmed by the results4 of experiments with [2,3-13C2]ornithine [as (1)], thus reinforcing earlier 14C and 13C results (cf. Vol. 8, p. 5 Vol. 10, p. 14). Equal labelling of C-2, C-3 and of C-4, C-5 was observed. 

Synthetic compounds (54) representing structures in which each of the bonds of the pyrrolidine ring of nicotine is cleaved, one by one, produced a series of "seconicotines" (102). 

Contraction of the pyrrolidine ring of nicotine to an azetidine, as with MPA (11), has little effect on affinity (Abood et al., 1987), whereas increasing the size of the pyrrolidine ring to a piperidine ring reduces receptor affinity. This can be seen in comparing, for example, nomico-... 

Hecht et al. (1563, 1565) suggested that nicotine was the precursor of NNK and 4-(iV-methylnitrosamino)-4-(3-pyridinyl)-l-butanal in tobacco via opening of the pyrrolidine ring of nicotine. 

Leete, E., E.G. Gros, and T.J. Gilbertson Biosynthesis of the pyrrolidine ring of nicotine Feeding experiments with V-15-labelled omithine-2-C14 Tetrahedron Lett. (1964) 587-592. 

Nicotine.—A wealth of experimental work has led to confusion rather than clarity about the biosynthesis of the pyrrolidine ring of nicotine (60). Tracer and enzymic evidence seems to favour a pathway involving at least one symmetrical intermediate (putrescine), illustrated in Scheme 5, although others are possible. 

There is an alternative way of viewing the above results, however. It could be that the biosynthetic pathway to the pyrrolidine ring of nicotine is similar (in part) to the route to the piperidine alkaloids. Part of the model suggested for the biosynthesis of the piperidine nucleus from lysine (see above) could be easily adapted to account for the C02 and nornicotine results, that is variable/in-complete equilibration of bound putrescine (arising by enzyme-mediated decarboxylation of ornithine) with unbound material. L-Ornithine decarboxylase (EC 4.1.1.17, L-ornithine carboxy-lyase) occurs widely in higher plants and like L-lysine decarboxylase requires pyridoxal phosphate as a co-factor. ... 

Pyrrolidine Alkaloids.—and tracer feeding results are in conflict for the biosynthesis of the pyrrolidine ring of nicotine. On the one hand ° [2- C]lysine afforded nicotine (138) with equal labelling of C-2 and C-3, whereas on the other the alkaloid obtained after exposing Nicotiana glutinosa plants to C02 was found to be more heavily labelled at C-4 and C-5 than C-2 and C-3 other workers have found uniform labelling of the pyrrolidine ring after application of... 

In contradiction to the scheme shown is the finding (137) that the source of the nitrogen of the pyrrolidine ring of nicotine is the S-amino group of ornithine, not the a-amino group as required above. No nitrogen from ornithine-2-440-(x-i5N was incorporated by a sterile root culture of N. tabacum ornithine-2-i40- -i5iJ resulted in a specific incorporation of... 

The formation of nicotinic acid—or, more precisely, of quinolinic acid—via two different pathways is an example of biochemical convergence, Now to the biosynthesis of the pyrrolidine ring of nicotine and nornicotine. Ornithine comes into play here. It furnishes the pyrrolidine component by the route already outlined, and this is then combined with nicotinic acid to give nicotine (Fig. 124). It is not known with certainty at what stage the methyl group is introduced. Very probably ornithine or putrescine is methylated and the methylated precursor is then icorporated into nicotine. Nicotine can be converted into nornicotine by demethyla-tion. 

NicotioHa Species.—Some progress is being made in isolating the enzymes responsible for the biosynthesis of nicotine. The immediate precursor of the pyrrolidine ring of nicotine is the 1-methyl-l-pyrrolinium salt (42). - This is formed from putresdne [(38), the decarboxylation product of ornithine] by the route illustrated in Scheme 9. A putrescine-JV-methyltransferase was... 

These results completely validate the previous work on the Incorporation of ornithine into the pyrrolidine ring of nicotine and nornlcotine, namely that the ornithine is Incorporated via a symmetrical intermediate, presumably putresclne. It also demonstrates that precursors labelled with contiguous atoms are especially useful for investigating blos3mthetlc pathways, since satellites which arise from such precursors in the n.m.r. can be detected at high dilutions[Pg.175]

---