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2. The Chemistry of Pyrrolizidine Alkaloids.

2.1. Necines

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 [23]. Figure 2 compiles the necines of the alkaloids found in the medicinal plants discussed in this article.

Fig. 1: Structure of necines
Fig. 1: Structure of necines

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).

Fig. 1: Structure of necines
Fig. 2: Necines occurring in the PAs of medicinal plants

2.2. Necic acids

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.

2-C-acids: Acetic acid (Ac)
Me-CO2H
5-C-acids:
Fig. 3, 5-C-acids
R1 R2 R3
H Me Me Senecioic acid (Sen)
Me Me H Tiglic acid (Tig)
Me H Me Angelic acid (Ang)
Ch2OH H Me Sarracinic acid (Sar)
7-C-acids:
Fig. 3, 7-C-acids
R1 R2 R3
H H OH (-)-Viridifloric acid
H OH h (+)-Trachelanthic acid
OH OH H Echimidinic acid
OH OMe H Lasiocarpic acid
7-C-acids:
Fig. 3, 7-C-acids
R1 R2
H OH (-)-Trachelanthic acid
OH H (+)-Viridifloric acid

Fig. 3: The most important monocarboxylic acids occurring in PAs

8-C-acids:
Fig. 4, 8-C-acids
R1 R2
OH OH Monocrotalic acid
H OH Crotaleschenic acid
10-C-acids:
Fig. 4, 10-C-acids
R1 R2
H H Incanic acid
H OH Trichodesmic acid
OH OH Globiferic acid

Fig. 4: The most important dicarboxylic acids used for the construction of 11-membered macrocyclic PAs

10-C-acids:
Fig. 5, 10-C-acids
R1 R2 R3 R4
Me H H H Senecinic acid
H Me H H Integerrinecic acid
H H Me H Senecivernic acid
Me H H OH Isatinecic acid
H Me H OH Retronecic acid
10-C-acids:
Fig. 5, 10-C-acids
R1 R2 R3
Me H H Seneciphyllic acid
H Me H Spartioidinic acid
Me H OH Riddelliic acid
10-C-acids:
Fig. 5, 10-C-acids
Erucifolinecic acid
10-C-acids:
Fig. 5, 10-C-acids
Petasinecic acid

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].

Fig. 8: Structures of pyrrolizidine alkaloids detected in medicinal plants:

Acetic acid (Ac)
Fig. 8, Acetic acid
R = H Laburnine 1
R =Ac Acetyllaburnine 2
Thesinine Thesinine 3
Dihydroxytriangularine
R1 R2 R3 R4 R5
H OH H OH H Intermedine 4
OH H H OH H Lycopsamine 5
H OH H OAc H 7-Acetylintermedine 6
OH H H OAc H 7-Acetyllycopsamine 7
OH H OH OAc H Uplandicine 8
OH H H OAng H Symlandine 9
OH H H OSen H Symviridine 10
H OH H OTig H Myoscorpine 11
OH H H OTig H Symphytine 12
H OH OH OAng H Echimidine 13
H OTig H OH H Anadoline 14
OTig H H Off H Scorpioidine 15
OTig H H OAc H 7-Acetylscorpioidine 16
Off H H H H Amabiline 17
H OH H H H Supinine 18
OH H OH H OAng Heliosupine 19
OAc H OH H OAng 12-Acetylheliosupine 20
H OMe OH H OAng Lasiocarpine 21
H OH H H OH Rinderine 22
OH H H H OH Echinatine 23
H OMe H H OH Heliotrine 24
Fig. 8, part Dihydroxytriangularine 25
Fig. 8, part
R = H Lithosenine 26
R =Ac 12-Acetyllithosenine 27
Fig. 8, part
R1 R2
OH OH Indicine 28
OAc OH 12-Acetylindicine 29
OH OAng Echiumine 30
Fig. 8, part Farfugine 31
Fig. 8, part
R1 R2 R3
OH OAng H 7-Angeloylretronecine 32
OAng OH H 9-Angeloylretronecine 33
OH OSen H 7-Senecioylretronecine 34
OSar OAng H Triangularine 35
OH H OAng 7-Angeloylheliotridine 36
Fig. 8, part
R1 R2 R3
OSen OH H Fuchsisenecionine 37
OSar OAng H Sarracine 38
Fig. 8, part
R1 R2 R3 R4 R5 R6
H H CH3 H CH3 CH3 Senecivernine 39
CH3 H H H CH3 CH3 Senecionine 40
H CH3 H H CH3 CH3 Integerrimine 41
CH3 H H H CH3 CH2OH Retrosine 42
H CH3 H H CH3 CH2OH Usaramine 43
H CH2OH H H CH3 CH3 21-Hydroxyintegerrimine 44
CH3 H H —CH2— CH3 Seneciphylline 45
H CH3 H —CH2— CH3 Spartioidine 46
CH3 H H —CH2— CH2OH Riddelline 47
Fig. 8, part
R1 R2
CH3 H Platyphylline 48
H CH3 Neoplatyphylline 49
Fig. 8, part Retroisosenine 50
Fig. 8, part Nemorensine 51
Fig. 8, part Senkirkine 52
Fig. 8, part
R=OH Floridanine 53
R = Cl Doronine 54
Fig. 8, part
R = H Otosenine 55
R =Ac Florosenine 56
Fig. 8, part
R = H Petasitenine 57
R =Ac Neopetasitenine 58
Fig. 8, part
R=OH Jacoline 59
R = Cl Jaconine 60
Fig. 8, part
R1 R2
H CH3 Jacobine 61
—CH2— Jacozine 62
Fig. 8, part
R1 R2 R3
CH3 H CH2OH Z-Erucifoline 63
H CH3 CH2OH E-Erucifoline 64
CH3 H CH2OAc 13-Acetylerucifoline 65
Fig. 8, part Doronenine 66
Fig. 8, part Bulgarsenine 67
Fig. 8, part
R1 R2 R3 R4
H CO2Me OH Me Isotussilagine 68
CO2Me H Me OH Isotussilaginine 69
H CO2Me Me OH Tussilagine 70
CO2Me H OH Me Tussilaginine 71

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.



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