Alkaloids other precursors

Other precursors of alkaloids form intermedia as acids (e.g., capric acid in the coniine pathway, 26-hydroxycholesterol in the solasodine pathway and piperidine in the jervine pathway). Moreover, in the case of purine as an alkaloid precursor, the intermedia is inosine monophosphate (IMP). 

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 majority of alkaloids have been found to be derived from amino acids, such as tyrosine, phenylalanine, anthranilic acid, tryptophan/tryptamine, ornithine/arginine, lysine, histidine and nicotinic acid (Fig. 2.1). However, alkaloids maybe derived from other precursors such as purines in case of caffeine, terpenoids, which become aminated after the main skeleton has been synthesized i.e. aconitine or the steroidal alkaloids, are found in the Solanaceae and Liliaceae. Alkaloids may also be formed from acetate-derived polyketides, where the amino nitrogen is introduced as in the hemlock alkaloid, coniine. 

As both lysine and ACpiperideine lead to unequal labelling of C-2 and C-6 in anabasine, and the biosynthetic sequence must be lysine— A -piperideine (11)— anabasine (14), any other precursors for (14) after lysine must be un-symmetrical in nature. Thus cadaverine, although incorporated into anabasine, cannot be a true precursor for the alkaloid. Two other groups of workers have also cast doubt on the role of cadaverine in alkaloid biosynthesis, and it is worth remembering in general that even if a proposed precursor is specifically incorporated it may not lie on the normal pathway to a particular alkaloid. Rather, it may merely test the adaptability of the plant in the face of an unusual substrate. 

The presence of some enamine, at equilibrium, is demonstrated by the conversion of piperideine into a dimer, indeed, the ability of these two systems to serve as both imines and enamines in such condensations is at the basis of their roles in alkaloid biosynthesis. Formed in nature by the oxidative deamination and decarboxylation of ornithine and lysine, they become incorporated into alkaloid structures by condensation with other precursor units. Hygrine is a simple example in which the pyrroline has condensed with ace-toacetate, or its equivalent. 

The Monarch butterfly Danaus plexippus) was found to sequester and store pyrrolizidine alkaloids when fed on homogenized leaves of Senecio vulgaris. It is thought that the presence of these alkaloids in the butterfly may contribute towards its defence mechanism, by making it unpalatable to potential predators. Unlike many other danaids, the Monarch is not dependent on pyrrolizidine alkaloids as precursors of its sex pheromones. 

It has been observed that labeled strictosidine [3] geis-soschizine [4] (80,85,86) stemmadenine [7] (86,87) and tabersonine [7b,9] (86-88) were all incorporated into both catharanthine [8] and vindoline [10] in Catharanthus roseus plants, indicating that these are the main precursors in the biosynthetic pathway to the Aspidosperma-lboga alkaloids. Other intermediates such as geissoschizine oxindole [5], preakuammicine [6] have been detected 28-40 hours after germination of c. roseus seeds (85,87,89) provided strong evidence for the formation of catharanthine [8] and vindoline [10] as presented in schemes I and ll. 

Fodor, G. B. Alkaloids derived from histidine and other precursors. In Encyclopedia of Plant Physiology, New Series, Vol. 8, Secondary Plant Products (E. A. Bell, B. V. Charlwood, eds.), pp. 160-166. Springer, Berlin-Heidelberg-New York 1980... 

Application of NMR spectroscopy to heterocyclic chemistry has developed very rapidly during the past 15 years, and the technique is now used almost as routinely as H NMR spectroscopy. There are four main areas of application of interest to the heterocyclic chemist (i) elucidation of structure, where the method can be particularly valuable for complex natural products such as alkaloids and carbohydrate antibiotics (ii) stereochemical studies, especially conformational analysis of saturated heterocyclic systems (iii) the correlation of various theoretical aspects of structure and electronic distribution with chemical shifts, coupling constants and other NMR derived parameters and (iv) the unravelling of biosynthetic pathways to natural products, where, in contrast to related studies with " C-labelled precursors, stepwise degradation of the secondary metabolite is usually unnecessary. 

The pseudobenzylisoquinoline alkaloids are fairly widespread in nature, being found among members of Berberidaceae, Annonaceae, Fumariaceae, and Ranunculaceae. The biogenesis of the pseudobenzylisoquinoline alkaloids assumes their formation from protoberberinium salts by C-8—C-8a bond scission in a Baeyer-Villiger-type oxidative rearrangement to produce the enamides of type 73 and 74. These amides may be further biotransformed either to rugosinone (76) type alkaloids by hydrolytic N-deformylation followed by oxidation or to ledecorine (75) by enzymatic reduction. These transformations were corroborated by in vitro studies (80-82). It is suggested that enamide seco alkaloids may be precursors of aporphine alkaloids (80), on one hand, and of cularine alkaloids (77), on the other. 

Secoiridoids are complex phenols produced from the secondary metabolism of terpenes as precursors of several indole alkaloids (Soler-Rivas and others 2000). They are characterized by the presence of elenolic acid, in its glucosidic or aglyconic form, in their molecular structure. Oleuropein, the best-known secoiridoid, is a heterosidic ester of elenolic acid and 3,4- dihydroxyphenylethanol containing a molecule of glucose, the hydrolysis of which yields elenolic acid and hydroxytyrosol (Soler-Rivas and others 2000). 

With a morphine biosynthetic gene in hand, we believed we could begin to address the question why only P. somniferum produces morphine, while other Papaver species such as P. rhoeas, P. orientale, and P. bracteatum do not. Unexpectedly, we found that the codeinone reductase transcript was present to some degree in all four species investigated. A review of the literature revealed no alkaloids reported in P. rhoeas for which codeinone reductase should participate in the synthesis. Similarly, P. orientale accumulates the alternate morphine biosynthetic precursor oripavine, but codeinone reductase is not involved in the biosynthesis of oripavine, acting instead after this alkaloid along the biosynthetic pathway to morphine.22 P. bracteatum produces the morphine precursor thebaine as a major alkaloid. As for oripavine in P. orientale, codeinone reductase would act in P. bracteatum after thebaine formation on the pathway to morphine. It appears, therefore, that the reason that P. rhoeas, P. orientale, and P. bracteatum do not produce morphine is not related to the absence of the transcript of the morphine biosynthesis-specific gene codeinone reductase. The expression of codeinone reductase may simply be an evolutionary remnant in these species. 

Microbial transformations of ellipticine (15) and 9-methoxyellipticine (16) were reported by Chien and Rosazza (143, 144). Of 211 cultures screened for their abilities to transform 9-methoxyellipticine (16), several, including Botrytis alii (NRRL 2502), Cunninghamella echinulata (NRRL 1386), C. echinulata (NRRL 3655), and Penicillium brevi-compactum (ATCC 10418), achieved O-demethylation of 16 in good yield (Scheme 9). P. brevi-compactum was used to prepare 9-hydroxyellipticine (22) from the methoxylated precursor, and 150 mg of product was obtained from 400 mg of starting material (37% yield). The structure of the metabolite was confirmed by direct comparison with authentic 9-hydroxyellipticine (143). O-Demethylation is a common microbial metabolic transformation with 16 and many other alkaloids (143). Meunier et al. have also demonstrated that peroxidases catalyze the O-demethylation reaction with 9-methoxyellipticine (145). 

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