Quinolizidine Alkaloids

2.4.2 Quinolizidine Alkaloids


The quinolizidine alkaloids comprise of lupinine, lupanine and sparteine which are responsible for the toxic properties are characterized by a quinolizidine skeleton. The bi-heterocyclic nucleus is closely related to the ornithine-derived pyrrolizidine system, but is believed to be formed from two molecules of lysine.

Lysine Pyarrolizidine Quinolizidine
The aforesaid three alkaloids shall now be discussed individually in the pages that follows:

A. Lupinine

Synonyms l-Lupinine; (–)-Lupinine.
Biological Source The naturally occurring l-form is obtained from the seeds and herb of Lupinus luteus L. and other Lupinus species belonging to the natural order Lequminoseae; and also found in Anabasis aphylla L. (Chenopodiaceae).
Chemical Structure

Lupinine
[1R-trans]-Octahydro-2H-quinolizidine-1-methanol (C10H19NO).
Isolation The isolation of lupinine from the seeds and herb of Lupinus lutens may be affected by the method evolved by Couch* (1934).
Characteristic Features
1. Lupinine is obtained as stout orthorhombic prisms from acetone having mp 68.5-69.2°C.
2. Its physical parameters are: bp4 160-164°C; bp755 269-270°C; [α]D26 -25.9o (C = 3 in water) ; [α]D28 -21o (C = 9.5 in ethanol);
3. It is soluble in water, ethanol, ether and chloroform.
4. It is a strong base.
Identification Tests
1. l-Form Lupinine Hydrochloride Derivative (C10H20ClNO): Its orthorhombic prisms have mp 208-213°C, and [α]D –14°.
2. dl-Form Lupinine: The crystals obtained from acetone have mp 58.5-59.5°C.

B. Lupanine

Biological Source It is obtained from the herb of Genista tinctoria L. (Fabaceae) (Dyer’s Broom).
Chemical Structure

Lupanine
(7α, 7aα, 14α, 14aβ)-Dodecahydro-7, 14-methano-2H, 11H-dipyridiol [1, 2-a: 1’, 2’-e] diazocin-11-one; (C15H24N2O].
Isolation The racemic and optical isomers of lupanine have been duly isolated from various species of Lupinus (Fabaceae/Leguminosae) as stated below:
(±)-Lupanine—from white lupins;
d-Lupanine—from blue lupins;
l-Lupanine—from the natural racemic form;
Characteristic Features The physical parameters of the above three forms of lupanine are given below:
dl-Lupanine: It is obtained as orthorhombic prisms obtained from acetone having mp 98-99°C; bp1.0 185-195°C; It is soluble in ethanol, ether, chloroform and water; and insoluble in petroleum ether.
d-Lupanine (Synonym: 2-Oxosparteine): It is obtained as syrup crystallizing difficultly in hygroscopic needles having mp 40-44°C; bp3 190-193°C; nD24 1.5444; [α]D25  +84o (C = 4.8 in ethanol). It is found to be freely soluble in water, ethanol, ether and chloroform.
l-Lupanine (Synonym: Hydrorhombinine): It is a viscous liquid having bp1.0 186-188°C; [α]D - 61o in acetone.
Identification Test Lupanine forms the corresponding lupanine hydrochloride dihydrate (C15H24N2O.HCl.2H2O) which is obtained as rhombic crystals from water having mp 127°C (dry).
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* Couch, J.F., J. Am. Chem. Soc., 56, 2434 (1934).

C. Sparteine

Synonyms l-Sparteine; Lupinidine.
Biological Sources It is obtained from yellow and black lupin beans Lupinus luteus L., and Lupinus niger Hort.; and also found in Cytisus scoparius (L.) Link. (Fabaceae) (Scotch Broom); Anagyris foetida L., belonging to natural order Leguminosae. Besides, it is also obtained from the roots of Aconitum napellus L. (Ranunculaceae) (Aconite, Monkshood, Blue Rocket); from the herbs of Chelidonium majus L. (Papaveraceae) (Celandine, Great Celandine, Nipplewort); from leaves of Peumus boldus Molina (Monimiaceae) (Boldo).
Chemical Structure

Sparteine
[7S-(7α, 7aα, 14α, 14a β]-Dodecahydro-7, 14-methano-2H, 6H-dipyrido [1, 2-a: 1’, 2’-e] [1, 5] diazocine, (C15H26N2).
Isolation It is isolated from yellow and black lupin beans by the method put forward by Clemo* (1949).
Characteristic Features
1. It is a viscous oily liquid having bp8 173°C.
2. It is volatile with steam.
3. Its physical parameters are: [α ]D21  -16.4o (C = 10 in absolute ethanol); nD20 1.5312; d420 1.020; pK1 at 20°C : 2.24; pK2:9.46; pH of 0.01 molar solution is 11.6.
4. Solubility profile: It is freely soluble in ethanol, ether and chloroform; and 1 g dissolves in 325 ml of water.
Identification Test
Sparteine Sulphate Pentahydrate (C15H26N2.H2SO4.5H2O): (Synonyms: Depasan;
Tocosamine) It is obtained as columnar crystals which loses water of crystallization at 100°C turning brown and ultimately gets decomposed at 136°C. The pH of a 0.05 molar solution is 3.3. It is practically insoluble in ether and chloroform, and 1 g dissolves in 1.1 ml of water, 3 ml of ethanol.
Uses
1. It is used mostly as an oxytocic.
2. It is employed as a cardiac depresant, cathartic, diuretic and for stimulating uterine contractions.
3. Sparteine is used occasionally as a quinidine substitute in stubborn cases of atrial fibrillation.
Biosynthesis of Lupinine, Lupanine and Sparteine Experimental evidence reveals lysine to be incorporated into lupinine via cadaverine; however, the intermediate related to homospermidine is excluded. It has been observed that ∆1-piperideine happens to be an important intermediate after
cadaverine. Thus, the proposed pathway given below suggests coupling of two such molecules. In fact, the two tautomers of ∆1-piperideine, as N-analogues of corresponding carbonyl compounds, are in a position to couple by an aldol-type mechanism. In reality, this coupling takes place in solution at physiological pHs, although the stereospecific coupling as shown in the proposed pathway shall evidently require the participation of suitable enzymes. After coupling, the imine system gets hydrolyzed, the resulting primary amine function undergoes oxidation, and ultimately the formation of the quinolizidine nucleus is accomplished by Schiff base formation. Thus, lupinine is then synthesized by two further reductive steps. Hence, the pathway to sparteine and lupanine eventually requires participation of another molecule of cadaverine or ∆1-piperideine.

Biosynthesis of Lupinine, Lupanine and Sparteine
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* Clemo et al. J. Chem. Soc. 6.63, (1949)

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