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Chapter 4 Pyrrolizidine Alkaloids
29
11.1.
PYRROLIZIDINE, PYRIDINE, P I P E R I D I N E AND QUINOLIZIOINE ALKALOIDS
Chapter 4 PYRROLIZIDINE ALKALOIDS
....... ....................
................................... ...................................
4.1. P y r r o l i z i d i n e a l k a l o i d s 4.2.
References
29
32
4.1 PYRROLIZIDINE ALKALOIDS I n a systematic study on gas chromatography o f p y r r o l i r i d i n e a l k a l o i d s , Chalmers e t a l .
1
emphasized the importance o f using a s i l a n i z e d a l l - g l a s s system and w e l l deactivated support m a t e r i a l t o reduce t h e p o s s i b i l i t i e s o f adsorption and decomposition d u r i n g gas chromatography. On a 6 ft. long s i l a n i z e d glass column packed w i t h 4 % SE-30 on GasChrom P, t h e none s t e r a l k a l o i d s could be gas chromatographed a t 14OoC, and the e s t e r s w i t h monocarboxylic acids and the macrocyclic d i e s t e r a l k a l o i d s a t 205OC. The s t r u c t u r e s o f some p y r r o l i z i d i n e a l k a l o i d s are given i n Figure 4.1. FIGURE 4 . 1
PY RROLIZIDINE ALKALOIDS I = l-Methoxymethyl-1,2-dehydropyrrolizidine, t r i n e , I V = monocrotaline, V = senecionine
I 1 = i t s 7phydroxy d e r i v a t i v e , 111 = h e l i o -
4’
RmcH20cH3 11’
3‘
2’
CH2OCOC-CH-CH3 Hb
H3C
OH
I I CH3-CH-C-C-CH3 I I I CO H O
I
OpJCH2
m
CO
>o
hCH3
CH3 O H 7’
6’
CH3-CH=C-
5’
I
C’
CM2-
13‘
12’
CH-C-CH3
co
I co
O m C H 2 -
O
I
I
P
1’
30
The retention times o f the non-ester alkaloids and derivatives are listed in Table 4.1 and those o f the esters with monocarboxylic acids in Table 4.2. In Table 4.3 the retention times of the macrocyclic diesters are given. TABLE 4.1 RETENTION TIMES, tR, OF NON-ESTER PYRROLIZIDINE ALKALOIDS AND DERIVATIVES ON A 4 % SE-30 PACKED COLUMN ON GAS CHROM P AT 14OoC1
A1 kaloid
B.p.('C/mm)
1-Methylenepyrrolizidine Heliotridane (lp-methyl-8wpyrrolizidine Anhydroplatynecine 7p-Hydroxy-1-methyl ene-8a-pyrrolzidi ne Desoxyretronecine (7~-hydroxy-1-methyl1 ,2-dehydro-8a-pyrrol izidi ne) 7p-Hydroxy-1-methylene-8p-pyrrolizidine Retronecanol (7D-hydroxy-lp-rnethy1-8a-
pyrrol i zidi ne) Hydroxyhel iotridane (7a-hydroxy-lp-methylb-pyrrolizidine) 7a-Hydroxy-l-methyl-1,2-dehydro-8a-pyrrolizidine 1-Methoxymethy 1 1 ,Z-dehydr o - b - pyrro1 i zi d i ne 1-Methoxymethyl- 1,2-epoxypyrroli z i di ne Isoretronal ( lp-hydroxymethyl-8a-pyrrol i zidi ne) Supinidi ne (l-hydroxymethyl-l,2-dehydro-8apyrrolizidine) 1- Hydroxymethy 1 - 1 ,2-epoxy-8a-pyrro1 i z i di ne
-
7p-Hydroxy-l-methoxymethyl-l,2-dehydro-8a-
pyrrol izidine
7p-Acetoxy-l-methox)rmethyl-1,2-dehydro-b-
M.p.(OC)
t.(min)
41/0.1
35-36
1.6 i.8 2.4 3.3
62/0.03
79-80 34-36
3.4 4.4
98-98.5
4.5
92/0.5 61.5-62.5 114/3.5 67-68 loo/10 53/0.1 115-16/1.5 39-40
4.5 4.5 5.4 6.4 7.4
115/150
---. 194/750
1691760 .--
140/30
90/0.1 80/0.04
29-30
7710.4
36-38
7.4
8.3
9.0 15.0
pyrrol izidine Retronecine (7p-hydroxy-1hydroxymethyl-1,2dehydro-8a-pyrrolizidine)
He1 iotri dine ( 7a-hydroxy-1-hydroxymethyl-1 ,2dehydro-8a-pyrrolizidine) Platynecine (7p-hydroxy-lp-hydroxymethyl8a-pyrrolizidine
117-118
15.0
117-118
15.0
148-148.5
15.0
TABLE 4.2 RETENTION TIMES OF PYRROLIZIDINE ESTERS WITH MONO CARBOXYLIC ACIDS ON A 4 % SE-30 PACKED COLUMN ON GAS CHROM P AT 2O5OC1 Alkaloid 7-Angelylretronecine 7-Angelylheliotridine Heleurine Supinine Heliotrine Indicine Retronecine trachelanthate Retronecine viridiflorate Rinderine Echi nat i ne Europine Sarracine
M.p. (OC) 76-77 116-117 67-68 148-149 128 97-98 100-101 109-110 (N-oxide 171) 45-46
tR(min) 4.2 4.8
8.0 8.8
12.4 14.3 14.3 14.3 15.6 15.6 18.2 29.1
31 TABLE 4.2 (continued) A1 k a l o i d
-
Echi umine Lasi ocarpi ne Echimi d i ne Heliosupine L a t i f o l ine
M. p. (OC)
tR(min)
99-100 96.5-97 ( p i i r a t e 142-143) ( p i c r a t e 103-106) 102-103
35.6 46.4 47.6 50.6 55.0
TABLE 4.3 RETENTION TIMES OF MACROCYCLIC DIESTER ALKALOIDS ON A 4 % SE-30 PACKED COLUMN ON GAS CHROM P
AT 2O5OC1 A1 kal o i d Retusine Fulvine Crispatine Monocrotaline Senecionine Seneci phyl 1ine Platyphyl 1i n e Integerrimine Spectabi 1 i n e Senk ir k ine Jacobine Scel e r a t i n e Jacoz ine Jacol i n e Rosmari nine Jaconine Ret r o r s ine R i ddel 1iine Retusamine Otoseni ne Grantianine
M . P . [OC)
174-175 213.5-214 137-138 202-203 245 217 129 172.5 185.5-186 198 228 178 228 221 209 147 219-220 198 174.5 22 1 209-209.5
t,(mi
n1
13:9 15.5 15.6 19.5 20.6 21.1 24.0 24.3 27.2 31.6 34.0 34.6 35.5 36.6 37.1 40.4 40.7 41.9 50.3 51.0 57.0
Stengl e t a1.2 c a r r i e d o u t an i n v e s t i g a t i o n o f the l i v e r t o x i c p y r r o l i z i d i n e a l k a l o i d s i n Symphytum o f f i c i n a l e by means o f gas chromatography. The a l k a l o i d m i x t u r e was e x t r a c t e d i n a Soxhlet apparatus w i t h methanol, the e x t r a c t p u r i f i e d by repeated a c i d i c aqueous and a1 k a l i n e organic s o l v e n t e x t r a c t i o n and column chromatography on F l o r i s i l . A f t e r d e r i v a t i z a t i o n w i t h n - b u t y l b o r o n i c a c i d and N,N-bis(trimethylsily1)trifluoroacetamide were gas chromatographed on a 1.8 m by 2 rnrn I . D .
the a l k a l o i d s
glass column packed w i t h 4 % SE-30 on Vara-
p o r t (80-100 mesh). F i v e a l k a l o i d s , lycopsamine, intermedine, acetyllycopsamine,
acetyl-
intermedine and symphytine were i d e n t i f i e d and t h e i r amounts q u a n t i t a t i v e l y determined. The gas chromatographic separation o f the a l k a l o i d d e r i v a t i v e s i s shown i n Table 4.4.
References p. 32
32
TABLE 4.4 RETENTION TIMES
OF
2
Si'hfPHYTrhV OFFICINALE ALKALOIDS
a f t e r d e r i v a t i z a t i o n w i t h n-butylboronic a c i d and N,N-bis(trimetylsily),)trifluo&oacetamide on a packed column w i t h 4 X SE-30 and temperature programming from 200 C t o 300 C
tR (set)
tR(rel)
7 79 Symphyti ne Acetyl 1ycopsami ne 576 Acetyl i n termedi ne 598 Lycopsamine 545 Intenedine 56 2 I n t . standard (Cholesterol TMS)1116
0.698 0.516 0.536 Oi489 0.504 1.000
TABLE 4.5 EXPERIMENTAL CONDITIONS USED FOR GAS CHROMATOGRAPHY
OF PYRROLIZIOINE ALKALOIDS
Col umn
S o l i d support
Stat.phase %
Temperature
glass, 6 f t x 6 mn I . D .
Gas Chrom P
SE-30
4
glass, 1.8 m x 2 mn I.D.
Varaport
SE-30
4
14OoC non e s t e r a l k . 205'C e s t e r a l k . 200-300°C p r .
Comp.Prep.
Abbreviations: a l k = a l k a l o i d ( s ) , p r = (temperature) programming 4.2 REFERENCES
1 A.H. Chalmers. C.C.J. Culvenor and L.W. Smith, J. Chromatogr., 20 (1965) 270. 2 P. Stengl, W. Wiedenfeld and E. Rider, Dtsch. Apoth.-ztg., 122 (1982) 851.
Ref.
1 2
11.1.
PYRROLIZIDINE, PYRIDINE, P I P E R I D I N E AND QUINOLIZIOINE ALKALOIDS
Chapter 4 PYRROLIZIDINE ALKALOIDS
....... ....................
................................... ...................................
4.1. P y r r o l i z i d i n e a l k a l o i d s 4.2.
References
29
32
4.1 PYRROLIZIDINE ALKALOIDS I n a systematic study on gas chromatography o f p y r r o l i r i d i n e a l k a l o i d s , Chalmers e t a l .
1
emphasized the importance o f using a s i l a n i z e d a l l - g l a s s system and w e l l deactivated support m a t e r i a l t o reduce t h e p o s s i b i l i t i e s o f adsorption and decomposition d u r i n g gas chromatography. On a 6 ft. long s i l a n i z e d glass column packed w i t h 4 % SE-30 on GasChrom P, t h e none s t e r a l k a l o i d s could be gas chromatographed a t 14OoC, and the e s t e r s w i t h monocarboxylic acids and the macrocyclic d i e s t e r a l k a l o i d s a t 205OC. The s t r u c t u r e s o f some p y r r o l i z i d i n e a l k a l o i d s are given i n Figure 4.1. FIGURE 4 . 1
PY RROLIZIDINE ALKALOIDS I = l-Methoxymethyl-1,2-dehydropyrrolizidine, t r i n e , I V = monocrotaline, V = senecionine
I 1 = i t s 7phydroxy d e r i v a t i v e , 111 = h e l i o -
4’
RmcH20cH3 11’
3‘
2’
CH2OCOC-CH-CH3 Hb
H3C
OH
I I CH3-CH-C-C-CH3 I I I CO H O
I
OpJCH2
m
CO
>o
hCH3
CH3 O H 7’
6’
CH3-CH=C-
5’
I
C’
CM2-
13‘
12’
CH-C-CH3
co
I co
O m C H 2 -
O
I
I
P
1’
30
The retention times o f the non-ester alkaloids and derivatives are listed in Table 4.1 and those o f the esters with monocarboxylic acids in Table 4.2. In Table 4.3 the retention times of the macrocyclic diesters are given. TABLE 4.1 RETENTION TIMES, tR, OF NON-ESTER PYRROLIZIDINE ALKALOIDS AND DERIVATIVES ON A 4 % SE-30 PACKED COLUMN ON GAS CHROM P AT 14OoC1
A1 kaloid
B.p.('C/mm)
1-Methylenepyrrolizidine Heliotridane (lp-methyl-8wpyrrolizidine Anhydroplatynecine 7p-Hydroxy-1-methyl ene-8a-pyrrolzidi ne Desoxyretronecine (7~-hydroxy-1-methyl1 ,2-dehydro-8a-pyrrol izidi ne) 7p-Hydroxy-1-methylene-8p-pyrrolizidine Retronecanol (7D-hydroxy-lp-rnethy1-8a-
pyrrol i zidi ne) Hydroxyhel iotridane (7a-hydroxy-lp-methylb-pyrrolizidine) 7a-Hydroxy-l-methyl-1,2-dehydro-8a-pyrrolizidine 1-Methoxymethy 1 1 ,Z-dehydr o - b - pyrro1 i zi d i ne 1-Methoxymethyl- 1,2-epoxypyrroli z i di ne Isoretronal ( lp-hydroxymethyl-8a-pyrrol i zidi ne) Supinidi ne (l-hydroxymethyl-l,2-dehydro-8apyrrolizidine) 1- Hydroxymethy 1 - 1 ,2-epoxy-8a-pyrro1 i z i di ne
-
7p-Hydroxy-l-methoxymethyl-l,2-dehydro-8a-
pyrrol izidine
7p-Acetoxy-l-methox)rmethyl-1,2-dehydro-b-
M.p.(OC)
t.(min)
41/0.1
35-36
1.6 i.8 2.4 3.3
62/0.03
79-80 34-36
3.4 4.4
98-98.5
4.5
92/0.5 61.5-62.5 114/3.5 67-68 loo/10 53/0.1 115-16/1.5 39-40
4.5 4.5 5.4 6.4 7.4
115/150
---. 194/750
1691760 .--
140/30
90/0.1 80/0.04
29-30
7710.4
36-38
7.4
8.3
9.0 15.0
pyrrol izidine Retronecine (7p-hydroxy-1hydroxymethyl-1,2dehydro-8a-pyrrolizidine)
He1 iotri dine ( 7a-hydroxy-1-hydroxymethyl-1 ,2dehydro-8a-pyrrolizidine) Platynecine (7p-hydroxy-lp-hydroxymethyl8a-pyrrolizidine
117-118
15.0
117-118
15.0
148-148.5
15.0
TABLE 4.2 RETENTION TIMES OF PYRROLIZIDINE ESTERS WITH MONO CARBOXYLIC ACIDS ON A 4 % SE-30 PACKED COLUMN ON GAS CHROM P AT 2O5OC1 Alkaloid 7-Angelylretronecine 7-Angelylheliotridine Heleurine Supinine Heliotrine Indicine Retronecine trachelanthate Retronecine viridiflorate Rinderine Echi nat i ne Europine Sarracine
M.p. (OC) 76-77 116-117 67-68 148-149 128 97-98 100-101 109-110 (N-oxide 171) 45-46
tR(min) 4.2 4.8
8.0 8.8
12.4 14.3 14.3 14.3 15.6 15.6 18.2 29.1
31 TABLE 4.2 (continued) A1 k a l o i d
-
Echi umine Lasi ocarpi ne Echimi d i ne Heliosupine L a t i f o l ine
M. p. (OC)
tR(min)
99-100 96.5-97 ( p i i r a t e 142-143) ( p i c r a t e 103-106) 102-103
35.6 46.4 47.6 50.6 55.0
TABLE 4.3 RETENTION TIMES OF MACROCYCLIC DIESTER ALKALOIDS ON A 4 % SE-30 PACKED COLUMN ON GAS CHROM P
AT 2O5OC1 A1 kal o i d Retusine Fulvine Crispatine Monocrotaline Senecionine Seneci phyl 1ine Platyphyl 1i n e Integerrimine Spectabi 1 i n e Senk ir k ine Jacobine Scel e r a t i n e Jacoz ine Jacol i n e Rosmari nine Jaconine Ret r o r s ine R i ddel 1iine Retusamine Otoseni ne Grantianine
M . P . [OC)
174-175 213.5-214 137-138 202-203 245 217 129 172.5 185.5-186 198 228 178 228 221 209 147 219-220 198 174.5 22 1 209-209.5
t,(mi
n1
13:9 15.5 15.6 19.5 20.6 21.1 24.0 24.3 27.2 31.6 34.0 34.6 35.5 36.6 37.1 40.4 40.7 41.9 50.3 51.0 57.0
Stengl e t a1.2 c a r r i e d o u t an i n v e s t i g a t i o n o f the l i v e r t o x i c p y r r o l i z i d i n e a l k a l o i d s i n Symphytum o f f i c i n a l e by means o f gas chromatography. The a l k a l o i d m i x t u r e was e x t r a c t e d i n a Soxhlet apparatus w i t h methanol, the e x t r a c t p u r i f i e d by repeated a c i d i c aqueous and a1 k a l i n e organic s o l v e n t e x t r a c t i o n and column chromatography on F l o r i s i l . A f t e r d e r i v a t i z a t i o n w i t h n - b u t y l b o r o n i c a c i d and N,N-bis(trimethylsily1)trifluoroacetamide were gas chromatographed on a 1.8 m by 2 rnrn I . D .
the a l k a l o i d s
glass column packed w i t h 4 % SE-30 on Vara-
p o r t (80-100 mesh). F i v e a l k a l o i d s , lycopsamine, intermedine, acetyllycopsamine,
acetyl-
intermedine and symphytine were i d e n t i f i e d and t h e i r amounts q u a n t i t a t i v e l y determined. The gas chromatographic separation o f the a l k a l o i d d e r i v a t i v e s i s shown i n Table 4.4.
References p. 32
32
TABLE 4.4 RETENTION TIMES
OF
2
Si'hfPHYTrhV OFFICINALE ALKALOIDS
a f t e r d e r i v a t i z a t i o n w i t h n-butylboronic a c i d and N,N-bis(trimetylsily),)trifluo&oacetamide on a packed column w i t h 4 X SE-30 and temperature programming from 200 C t o 300 C
tR (set)
tR(rel)
7 79 Symphyti ne Acetyl 1ycopsami ne 576 Acetyl i n termedi ne 598 Lycopsamine 545 Intenedine 56 2 I n t . standard (Cholesterol TMS)1116
0.698 0.516 0.536 Oi489 0.504 1.000
TABLE 4.5 EXPERIMENTAL CONDITIONS USED FOR GAS CHROMATOGRAPHY
OF PYRROLIZIOINE ALKALOIDS
Col umn
S o l i d support
Stat.phase %
Temperature
glass, 6 f t x 6 mn I . D .
Gas Chrom P
SE-30
4
glass, 1.8 m x 2 mn I.D.
Varaport
SE-30
4
14OoC non e s t e r a l k . 205'C e s t e r a l k . 200-300°C p r .
Comp.Prep.
Abbreviations: a l k = a l k a l o i d ( s ) , p r = (temperature) programming 4.2 REFERENCES
1 A.H. Chalmers. C.C.J. Culvenor and L.W. Smith, J. Chromatogr., 20 (1965) 270. 2 P. Stengl, W. Wiedenfeld and E. Rider, Dtsch. Apoth.-ztg., 122 (1982) 851.
Ref.
1 2