Lupanine pathway

The lupinine, lupanine, sparteine and cytisine synthesis pathway... 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

This pathway clearly proves that the first quinolizidine alkaloid to be synthesized is (—) lupinine (two cycling alkaloids) and subsequently both (+)-lupanine and (-)-sparteine. This is a new approach to the synthesis of this type of alkaloids because in the older literature just four cycling alkaloids (lupanine and sparteine) were mentioned as the first synthesized molecules . In the cadaverine conversion, the participation of diamine oxidase is more reliable than the oxosparteine synthase mentioned by some older studies °. 

Figure 51. Diagram of the lupinine, sparteine, lupanine and cytisine synthesis pathway. Abbreviations PLP = coenzyme pyridoxal phosphate C = cleavage of C4 unit.

The pathway to sparteine and lupanine undoubtedly requires participation of another molecule of cadaverine or A piperideine. Experimental data are not clear-cut and Figure 6.25 merely indicates how incorporation of a further piperidine ring might be envisaged. Loss of one or other of the outermost rings and oxidation to a pyridone system offers a potential route to cytisine. 

Essentially only lupanine (27) is accumulated in cell suspension cultures of Lupinus polyphyllus,29,30 Sarothamnus scoparius,29 and Baptista australis,29,31 whereas the intact plants accumulate other alkaloids. It is reasonable to assume that the cultures will accumulate alkaloids early rather than late in a biosynthetic pathway. Thus lupanine (27) is identified as a likely intermediate in the biosynthesis of the other alkaloids of these plants. In the case of B. australis, these alkaloids are of the pyridone type, e.g. anagyrine (28) and cytisine (29).31 Earlier results with... 

Alkaloid metabolism in lupine was proved by Wink and Hartmann to be associated with chloroplasts (34). A series of enzymes involved in the biosynthesis of lupine alkaloids were localized in chloroplasts isolated from leaves of Lupinus polyphylls and seedlings of L. albus by differential centrifugation. They proposed a pathway for the biosynthesis of lupanine via conversion of exogenous 17-oxosparteine to lupanine with intact chloroplasts. The biosynthetic pathway of lupinine was also studied by Wink and Hartmann (35). Two enzymes involved in the biosynthesis of alkaloids, namely, lysine decarboxylase and 17-oxosparteine synthetase, were found in the chloroplast stoma. The activities of the two enzymes were as low as one-thousandth that of diaminopimelate decarboxylase, an enzyme involved in the biosynthetic pathway from lysine to diaminopimelate. It was suggested that these differences are not caused by substrate availability (e,g., lysine concentration) as a critical factor in the synthesis of alkaloids. Feedback inhibition would play a major role in the regulation of amino acid biosynthesis but not in the control of alkaloid formation. 

The most common group of alkaloids possessing a quinolizidine nucleus is that of the lupine alkaloids which can simply be classified as bicyclic (lupinine/epilupinine type), tricyclic (cytisine type) or tetracyclic, (sparteine/lupanine or matrine type). Fig. (23). This grouping is made according to structure complexity and without considering biosynthesis, as the detailed biosynthetic pathways are still not completely understood. 

The conversion of lupanine into camoensidine may represent a biosynthetic pathway, and cleavage of the C-16 C-17 bond of a tetracyclic quinolizidine [cf. mamanine (3)] followed by carbon-carbon cyclization could lead to tetracyclic derivatives containing terminal piperidine rings. New alkaloids of this type have been obtained recently. Aloperine was first isolated from Sophora alopercuroides over forty years ago, and structure (12) has now been assigned to the alkaloid on the basis of spectral studies. Allylaloperine (13) is a constituent of the same species. Nitraramine (14) and 7V-hydroxynitraramine (15) from Nitraria schoberi are... 

The lupin alkaloids sparteine (98) and lupanine (99) are both derived from lysine, and it is possible on the basis of past work that either one may be a precursor of the other.63 However, recent work suggests that they are derived by divergent pathways.64... 

We propose the biosynthetic pathway of the carbon framework of matrine as shown in Fig. 4. This scheme also indicates the pathway for the formation of sparteine and lupanine. The former part of this scheme was proposed by Wink et al. [63], with minor modification by Leete [64], from the in vitro experiments using isolated chloroplasts of leaves of Lupinus. They postulated the presence of 17-oxosparteine as the first key intermediate for the formation of lupanine and sparteine [63]. However, this hypothesis involving 17-oxosparteine synthase was not confirmed by the tracer experiments using and independently conducted by the groups of Spenser [65, 66] and Robins [67]. They, in turn, hypothesized the pathway involving the diiminium cation (73) as the tetracyclic intermediate [68, 69]. The postulation of the presence of this reactive intermediate is consistent with the results of isotope incorporation into lupanine and sparteine. The biosynthetic scheme of matrine can be also drawn by involving the electronically equivalent diiminium cation (76) preceded by additional 1,3-hydride shift or imine-enamine isomerization (74 75). All these reactions take... 

Lupinine, lupanine, sparteine, and cytisine synthesis pathway 129... 

The biosynthetic pathway of sparteine 115 and lupanine 116 starts from lysine 117, which was converted into the cadaverine 118 by the lysine decarboxylase (LCD). Three units of cadaverine are used to form the quinolizidine skeleton. 

Figure 7.32 Early proposed biosynthetic pathway of sparteine and lupanine.

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