Quinolizidine alkaloids

The third structural group of alkaloids, from the same a, are quinolizidine alkaloids (QAs). It is a large group of compounds with very different abilities7'16'40'119'213'215'218'219'220'228'229'230'231'232'233'234'235'236'237'238 The structural development of quinolizidine alkaloids is presented in Figure 54. The a (l-lysine) provides the basic components of the quinolizidine nucleus and skeleton. The ^ is cadaverine and is synthesized in the same way as piperidine alkaloids (by the activity of PLP). The transformation from ^ to ^ also occurs through the activity of diamine oxidase (DO). The ^ is A1-piperideine, which develops by the Schiff base formation, the aldol-type reaction between enamine and iminium, the hydrolysis of imine to aldehyde, oxidative deamination and, again, the Schiff base formation. During this stage, the quinolizidine nucleus is formed. From ^ as a subway product the (—)-lupinine is synthesized, which is a two-cycle quino-lizidine alkaloid. The first A is therefore a two-cycle quinolizidine alkaloid32, although in previous studies four-ring quinolizidine alkaloids have been said to form first216 217 218 220. The main way that the product will be formed is by the step reaction of the Schiff base formation, for which the molecule of the ^ or the ^ is again needed. The four-cycle quinolizidine skeleton is formed in this stage by the molecule coupling with cationed nitrogen in the x (second obligatory intermedia), which is simply two transformed molecules of the ^ with cationed nitrogen. In reality, this x is two molecules of (—)-lupinine connected together in an opposite molecule order with H atom reduction. This strongly suggests that there is also an alternative way for four-cycle quinolizidine alkaloids synthesis from (—)-lupinine.

The x is transformed in two directions: (—)-sparteine and (+)-lupanine, the two basic quinolizidine alkaloids which occur in nature and which have an important role in the ecosystem. The (—)-sparteine is transformed by the cleavage of the C4 unit to (+)-cytisine, a three-cycle quinolizidine alkaloid with a pyridon nucleus, and from this step to the other pyridon quinolizidine alkaloids (P' P1). The (+)-lupanine converts to the lupanine derivatives, angustifoline, a-isolupanine and 13a-hydroxylupanine (P) (Figure 54).

Bicyclic quinolizidine alkaloids

Bicyclic quinolizidine alkaloids have the simplest chemical structure, based only on the quinolizidine nucleus7. Typical representatives of this type of alkaloids are lupinine, epilupinine, and lusitanine7'239'240. Lusitanine is an alkaloid derived from Genista lusitanica L.241, Lupinus excubitus and Lupinus holosericeus242. In their absolute configurations, the melting-point of Lusitanine is 184-186 °C, of dihydro 96-100 °C and of epidyhydrolusitanine 140-144 °C241. Lupinine and epilupinine are typical bicyclic quinolizidine alkaloids in lupines, especially in co2h "nh2 "nh2


Alkaloid Chemistry

Cadaverine iSBF1


Cadaverine iSBF1

Alkaloid Lupinine

N 11 P Angustifoline o-isolupanine


Figure 54. Structural development of quinolizidine alkaloids.

N 11 P Angustifoline o-isolupanine


Figure 54. Structural development of quinolizidine alkaloids.

Lupinus luteus L., Lupinus hispanicus L., Lupinus hirsutus L. They have also been found in Anabasis aphyla. In absolute configuration, lupinine is in its (—)-form, which is non-stable thermally, and is easily epimerized to epilupinine, whichis a stable (+)- form of lupinine240 241. The melting point of (—)-lupinine is 70-71 °C, of mixed (+ and —)-lupinine 63-64 °C, and of (+)-lupinine (synthetic)

167-1680C. Lupinine and epilupinine contain esters, which have been found in

L.luteus seedlings7'240'241.

Tricyclic quinolizidine alkaloids

Tricyclic quinolizidine alkaloids occur in lupines. Angustifoline, with its derivatives and albine, are examples of this structural group of alkaloids. Angustifoline is identical with jamaicensine, an alkaloid isolated from Ormosia jamaicensis. Angustifoline is a compound which has been found in L. angustifolius L., L. polyphyllus Lindl. and Lupinus albus L.243. Angustifoline is in the (—)-form in absolute configuration, with a melting point of 79-80 0C241. From L. albus L. and from viable seeds of Lupinus termis L. (+)-angustifoline as a diasrereoisomer of (—)-angustifoline has been isolated by Wysocka and Przybyl244'245 in the Alkaloid Chemistry Laboratory in Poland. Other derivatives of angustifoline are dihy-droangustifoline, with a melting point of 82-83 0C241, and isoangustifoline, with a melting point of 96-97 0C120 234. Albine has been found in L. albus246 and structurally reinvestigated by Wysocka and Brukwicki247'248, Wysocka et al.249'250, Wysocka and Przybyl245.

Tetracyclic quinolizidine alkaloids

Tetracyclic quinolizidine alkaloids can be divided into two types, both according to chemical structure and, especially, biological activity. These are tetracyclic alkaloids, which contain a quinolizidine nucleus, and others with a pyridone nucleus. Here, the first type of alkaloids (with a quinolizidine nucleus) will be discussed. The second type will be considered in the next sub-chapter as pyridone alkaloids.

Sparteine is one of the basic, and probably most important, tetracyclic alkaloids with a quinolizidine nucleus. In absolute configuration, sparteine occurs as (—)-sparteine, which is lupinidine. Lupinidine, with a melting point of 1810C, occurs in all lupine species, although in different concentrations. In L. luteus sparteine (lupinidine) is a major alkaloid, and consequently this yellow lupine has been described as a "typical" sparteine species. However, sparteine is also found in Lupinus mutabilis251, L. polyphyllus120'121'234 and Genista tinctoria252. (+)-Sparteine has been detected in Lupinus pussilus, Cytisus caucasicus and many other plants253'254. Most recently this alkaloid was discoverd in Hovea linearis255, Maackia amurensis256, Termopsis mongolica251, Lygos raetam258 and in L. albus259. The melting point of (+)-sparteine is 173-174 0C, and it is also known as pachycarpine241. Sparteine is also familiar in the form of (±)-sparteine. Its melting point is 2310C. According to the literature, this alkaloid form does not occur in the lupin species241.

Lupinus sericeus contains (—)-7-hydroxy-^-isosparteine and 10, 17-dioxo-^-isosparteine, which are also sparteines: tetracyclic quinolizidine alkaloids with a quinolizidine nucleus. Moreover, other alkaloids from this group include epi-aphylline and aphylline, alkaloids from L. latifolius, and (—)-lindenianine, an alkaloid from Lupinus lindenianus and Lupinus verbasciformis240'260. Nuttalline

(4^-hydroxy-2-oxosparteine) is a tetracyclic quinolizidine alkaloid from Lupi-nus nuttalli240. An alkaloid, sparteine can be converted to a-isosparteine or ^-isosparteine, which occurs particulary in Cytisophyllum sessilifolium243'252'261. In contrast to aphylline, 17-oxosparteine is known to be synthesized only under energetic conditions243.

One of the most important tetracyclic quinolizidine alkaloids with a quinolizidine nucleus is lupanine, which is in fact 2-oxo-11a-sparteine. In absolute configuration, lupanine is (+)-lupanine with a molecular weight of 248 and melting point of 127 0C7'241. Lupanine occurs in L. polyphyllus, L. albus and L. angustifolius and is, like sparteine, probably found in all lupine species in different concentrations, from main compounds to mere traces. Lupanine is the main alkaloid in the seeds of Lupinus rotundiflorus, Lupinus exaltatus and Lupinus mexicanus. It has been discovered in considerable amounts in Lupinus mon-tanus and Lupinus madrensis, but only traces were noted in Lupinus elegans119. Moreover, lupanine occurs in Cytisus scoparius and Leontice eversmannii241.

The (—)-lupanine is hydrorhombinine and has been isolated from L. pussilus and Lupinus macouni as well as other species, such as Baptisia versicolor and Podalyria calyptrata. The melting point of (-)-lupanine is 190 °C241. In such species as L. albus and L. termis lupanine occurs as (±)-lupanine with melting points of 127-128 °C and 250-2520C241. In L. polyphyllus Lindl., L. angustifolius L. and L. albus L., 17-oxolupanine has also been detected243'245'252. Hydroxylupa-nine and their esters occur in Lupinus bicolor, Lupinus densiflorus, L. latifolius, Lupinus polycarpus, Lupinus ruber, Lupinus burkei251, L. rotundiflorus, L. mon-tanus, L. exaltatus, L. mexicanus, L. madrensis119 and L. polyphyllus120'121'234.

Pyridone alkaloids

This group of alkaloids has a pyridone nucleus and generally takes the tetracyclic or tricyclic form. The a for pyridone alkaloids is L-lysine, while the ^ ^ and x are the same as for other quinolizidine alkaloids. Quinolizidine alkaloids containing the pyridone nucleus are the P from the (-)-sparteine by cleavage of the C4 unit32. The first quinolizidine alkaloid with the pyridone nucleus is tricyclic cytisine, which converts to four cyclic alkaloids. In this synthesis the anagyrine, the most poisonous quinolizidine alkaloid with a pyridone nucleus, has its own synthesis pathway.

Anagyrine has a molecular weight of 244 and a melting point of 264 0C. It only takes a (±)-form241. This alkaloid occurs in L. latifolius260, Lupinus arboreus, Lupinus caudatus, L. densiflorus, L. sericeus, Lupinus argen-teus, Lupinus leucophyllus242. Anagyrine was found in neither bitter nor sweet L. polyphyllus Lindl., which grows in Finland120'121'234.

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