2. The Chemistry of Pyrrolizidine Alkaloids.
Most medicinal plants discussed in this review article contain PAs of the ester type the basic components of which, called necines, are derived from bicyclic amino alcohols which, in turn, are derived from 1-hydroxypyrrolizidine. The necine can either be saturated or possess a double bond in the 1,2-position (ring B, Fig. 1).
Moreover, they may additionally bear one or two hydroxy groups at C-2, C-6 or C-7 resulting in the formation of stereoisomers. Dashed and thickened (wedges) lines denote a- and b-orientations of bonds, respectively; a meaning orientation away from the observer, b toward the observer. With a few exceptions the bases of most alkaloids belong to the C-8 a series . Figure 2 compiles the necines of the alkaloids found in the medicinal plants discussed in this article.
A special role plays otonecine because it is not a genuine bicyclic five-membered ring system but an N-methylated azacyclooctan-4-one system. It may act as a pyrrolizidine ring system due to transannular interactions. The binding between the N atom and the CO group is widered to such an extent that the indicated resonance structures result. The PAs derived from these structures constitute a subgroup of the otonecine alkaloids (OPAs). The corresponding esterification of necines containing a double bond in the 1,2-position results in the formation of the toxic alkaloids (Fig. 1).
The acids with which the necines are esterified are called necic acids. Apart from acetic acid they possess 5 to 10 C atoms and differ from each other in their structure. They include mono- and dicarboxylic acids with branched carbon chains which are based on simple structural constituents. They bear as substituents hydroxy, methoxy, epoxy, carboxy, acetoxy or other alkoxy groups besides methoxy substituent. Thus numerous structural, stereo- and diastereoisomers may be derived. In Figs. 3-6 are listed the most important mono- and dicarboxylic acids that have been detected in alkaloids so far.
The esterification possibilities are exemplified by several alkaloids. Necines containing one hydroxy group can be esterified with one monocarboxylic acid only as shown in Fig. 7 for amabiline. Necines bearing two hydroxy groups such as 7,9-necinediols can be esterified with a monocarboxylic acid either in the 7- or 9-position as demonstrated by 7-angeloyl respectively 9-angeloylretronecine.
Echimidine is an example of a twofold esterification. With dicarboxylic acids a double esterification takes place exclusively leading to the formation of alkaloids with 11- to 14-membered ring systems. The most widely known PAs are the 11-membered monocrotaline, the 12-membered alkaloids senecionine and senkirkine, the 13-membered doronenine, and the 14-membered parsonsine.
Fig. 3: The most important monocarboxylic acids occurring in PAs
Fig. 4: The most important dicarboxylic acids used for the construction of 11-membered macrocyclic PAs
Fig. 5: The most important dicarboxylic acids used for the construction of 12-membered macrocyclic PAs
Through combination of necines with necic acids an unimaginably large number of alkaloids may be theoretically obtained. In nature ca. 350 alkaloids were found so far and their structures elucidated.
With the exception of about 30 known otonecine alkaloids, which cannot form N-oxides, together with the N-oxides of the other alkaloids more than 640 alkaloids are known [24-29].
|R = Cl||Doronine||54|
Fig. 8: Structures of pyrrolizidine alkaloids detected in medicinal plants
Medicinal plants in Europe containing pyrrolizidine alkaloids was written by Prof. Dr. E. Röder and published in the journal "Pharmazie" 50 (1995), pages 83-98.