Pyrrolidine alkaloids biosynthesis

A key stage in the biosynthesis of piperidine alkaloids is reached with the formation of A -piperideine. For the elaboration of diverse alkaloids, this intermediate undergoes condensation with a variety of nucleophiles, commonly a /3-keto-acid. (A similar situation is found for pyrrolidine alkaloid biosynthesis see, e.g., Scheme l).1,2 Existing evidence on Lythraceae alkaloid biosynthesis, taken up again below, indicated that condensation occurred in this case between A piperideine (17) and acetoacetic acid to give pelletierine (26), further elaboration yielding alkaloids like (22). In the event, however, labelled pelletierine was found not to be a precursor for (22) or (23).8 Negative evidence is always difficult to interpret, but is here made persuasive by the fact that other precursors that were fed concurrently were incorporated. Conclusive support for these results depended on others outlined below. 

The imine salt is perfectly placed for an intramolecular electrophilic aromatic substitution by the electron-rich dihydroxyphenyl ring. This closes the isoquinoline ring in a Mannich-like process (Chapter 27) with the phenol replacing the enol in the pyrrolidine alkaloid biosynthesis. 

This closes the isoquinoline ring in a Mannich-like process with the phenol replacing the enol in the pyrrolidine alkaloid biosynthesis. 

Simple Pyrrolidine Alkaloids.—It is well established that ornithine (1) is a key precursor in the biosynthesis of pyrrolidine alkaloids. Notably, the amino-acid (1) is utilized for the biosynthesis of nicotine (5) via the symmetrical intermediate putrescine (3), whereas the biosynthesis of tropane alkaloids, e.g. scopolamine (6), avoids any symmetrical intermediate1,2 (cf. Vol. 11. p. 1). 

The first step is the Claisen ester condensation of two molecules of acetyl CoA, one acting as an enol and the other as an electrophilic acylating agent to give acetoacetyl CoA. We saw the same reaction in the biosynthesis of the pyrrolidine alkaloids earlier in this chapter. 

Tropane and Pyrrolidine Alkaloids.— The biosynthesis of cuscohygrine (29) has been examined in Scopolia lurida and Atropa belladonna. Both [l- C]acetate and [2- C]acetate were specifically incorporated into cuscohygrine in the latter plant. Degradation revealed a labelling pattern in the C3 chain [see (29)], consistent with an origin from acetoacetate. 

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... 

The Strecker degradation of ornithine proceeds analogously, but the intermediate 4-aminobutanal forms by cychsation the final product, 1-pyrroHne (Figure 2.59). This reaction is important for the development of the characteristic aroma of bread crust (see Section 8.2.12.4.1), the aroma of other cereal products, certain fragrant rice varieties (such as Basmati rice) and in the biosynthesis of pyrrolidine alkaloids in plants (see Section 10.3.2.1.1). It was proposed that pyrrolidine and l-pyrrohne also result upon Strecker-type reaction of proline by a-dicarbonyl compounds. 

After subsequent Claisen condensation with a second equivalent acetyl-CoA, 4-(l-methyl-pyrrolidin-2-yl)-3-oxobu-tanoyl-CoA 25a/b is formed, the link between pyrrolidine and tropane alkaloid biosynthesis. From this intermediate, characteristic pyrrolidine alkaloids, such as hygrine (26) and cuscohygrine (27), two alkaloids commonly found in coca leaves [9], are formed either directly by hydrolysis and subsequent decarboxylation (for 26) or via an additional Mannich reaction with the aforementioned IV-methyl-A -pyrrolinium cation (23) followed by hydrolysis and decarboxylation (27). 

The corresponding A -piperideinium cation (41), probably the universal intermediate in piperidine, quinolizidine, and lycopodium alkaloid biosynthesis, is susceptible to nucleophilic attack much like its V-methyl-A -pyrrolinium cation counterpart in pyrrolidine and tropane alkaloid biosynthesis. Moreover, A -piperideine (40) might be reduced to piperidine (42), which now in turn might serve as nucleophilic species. For example, condensation of piperidine (42) with piperoyl-CoA catalyzed by piperidine V-piperoyltransferase (EC 2.3.1.145) yields piperine (43), the main alkaloid found in black pepper where it is responsible for the characteristic pungent taste. 

Putrescine, apart from being a precursor of the higher PAs spermidine and spermine, is also a precursor in the biosynthesis of the pyrrolidine alkaloids... 

For several years it was assumed that the putrescine, which forms a part of nicotine and other pyrrolidine alkaloids, arises through the action of ODC (Mizusaki et a/., 1973) and, in fact, pyrrolidine alkaloids have been classified as ornithine-derived compounds (Leete, 1980). In contrast, our investigations with tobacco callus tissue have shown that (1) changes in the ADC activity parallel changes in alkaloid levels, while changes in ODC activity do not (2) DFMA effectively inhibits the biosynthesis of nicotine and nomicotine, while DFMO is less effective and (3) the flow of from uniformly labeled arginine... 

In the case of QAs it has been demonstrated that the decarboxylation of lysine to cadaverine is the first step of their biosynthesis (see review in Wink, 1985). In contrast with the pyrrolidine alkaloids, which are mainly synthesized in the roots, the biosynthesis of QAs occurs in the aerial parts. The enzyme of QA formation (LE)C) was demonstrated in leaves of Lupinus polyphyllus (Wink and Hartmann, 1981) and subsequently localized in the stroma of chloroplasts (Wink and Hartmann, 1982). In QA alkaloid-bearing cultures of Heimia sali-cifolia, LEXT activity was found to be positively correlated with chlorophyll levels (Pelosi et al, 1986). It appears that QAs act not only in nitrogen storage, nitrogen transport, and chemical defense (Wink, 1985), but also in the regulation of polypeptide biosynthesis (Twardowski et al, 1982). 

Brevicolline.—The /3-carboline part of the plant alkaloid brevicolline (114) has been shown to derive from tryptophan (94) and pyruvic acid.37 Putrescine (4) and related compounds provide the pyrrolidine ring.38 A key intermediate in brevicolline biosynthesis is likely to be (113), derived by oxidative decarboxylation of (111), which in turn is formed through the condensation of (94) with pyruvic acid condensation of (113) and (112) (formed from putrescine) would lead to (114). This has been supported by successfully mimicking the biogenetic sequence, starting with the chemical oxidative decarboxylation of (111).39... 

The biosynthesis of alkaloids containing a pyrrolidine ring such as hyoscyamine (18) and hygrine (19) is similar to the biosynthesis of those with a piperidine... 

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. ... 

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