Pyrrolidine and Tropane Alkaloids

The extra carbon atoms required for hygrine formation are derived from acetate via acetyl-CoA, 

2-substituted pyrrolidine, retaining the thioester group of the second acetyl-CoA. Hygrine and most of the natural tropane alkaloids lack this particular carbon atom, which is lost by suitable hydrolysis/decarboxylation reactions. The bicyclic structure of the tropane skeleton in hyoscyamine and cocaine is achieved by a repeat of the Mannich-like reaction just observed. This requires an oxidation step to generate a new A pyrrolinium cation, and removal of a proton a to the carbonyl. The intramolecular Mannich reaction on the R enantiomer accompanied by decarboxylation 

The tropane alkaloids (—)-hyoscyamine and (—)-hyoscine are among the most important of the natural alkaloids used in medicine. They are found in a variety of solanaceous plants, including Atropa belladonna (deadly nightshade), Datura stramonium (thornapple) and other Datura species, Hyoscyamus niger (henbane), and Duboisia species. These alkaloids 

The third species of Duboisia, D. hopwoodi, contains little tropane alkaloid content, but produces mainly nicotine and related alkaloids, e.g. nornicotine (see page 313). Leaves of this plant were chewed by aborigines for their stimulating effects. 

Tropane alkaloids, principally hyoscyamine and hyoscine, are also found in two other medicinal plants, scopolia and mandrake, but these plants find little current use. Scopolia (Scopolia carniolica Solanaceae) resembles belladonna in appearance, though it is considerably smaller. Both root and leaf materials have been employed medicinally. The European mandrake (Mandragora officinarum Solanaceae) has a complex history as a hypnotic, a general panacea, and an aphrodisiac. Its collection has been surrounded by much folklore and superstition, in that pulling it from the ground was said to drive its collector mad due to the unearthly shrieks emitted. The roots are frequently forked and are loosely likened to a man or woman. Despite the Doctrine of Signatures, which teaches that the appearance of an object indicates its special properties, from a pharmacological point of view, this plant would be much more efficient as a pain-reliever than as an aphrodisiac. 

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L-metilionine to -adenosylmethionine. In this process a positively charged sulphur is produced and facilitates the nucleophilic reaction. By the activity of diamine oxidase, the A -methyl-A -pyrrolinium cation is formed and after that the first alkaloid, hygrine. From hygrine, by way of acetyl CoA, hydrolysis and intramolecular Mannich reactions, other pyrrolidine and tropane alkaloids are synthesized cuscohygrine, hyoscyamine or tropinone, tropine and cocaine. The Mannich reaction involves the combination of an amine, an aldehyde or a ketone with a nucleophilic carbon. This reaction is typical in alkaloid synthesis, and can be written as follows ... 

Table 3.2 Occurrence of frequent types of pyrrolidine and tropane alkaloids as well as nicotine in the Convolvulaceae proved by isolation or GC/MS analysis. Classification according to Fig. 2.3 (continued)... 

Nicotine is also accumulated in considerable proportions in other Nicotiana species and in a few species of some other solanaceous genera, e.g., Duboisia (for details see below). Moreover, it was detected in extremely small amounts in species of several other genera of this family. Furthermore, it is also a common minor component in the Convolvulaceae beside pyrrolidine and tropane alkaloids (for details see below). 

The first committed biosynthetic step toward pyrrolidine and tropane alkaloids involves N-methylation of putrescine to furnish A-methylputrescine (21) by SAM-dependent putrescine A-methyltransferase (EC 2.1.1.53) (Scheme 11.4) [9, 19, 20]. Oxidative deamination by A-methylputrescine oxidase (EC 1.4.3.21) affords 4-methylaminobutanal (22), which spontaneously cyclizes to furnish the corresponding A-methyl-A -pyrrolinium cation (23) via intramolecular Schiff-base formation. Although no enzymes have been identified catalyzing the subsequent biosynthetic steps, from... 

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. 

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