Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5467_Библиотеки_им_академика_М_И_Перельмана.pdf
222
Pharmaceutical Chemistry of Natural Products
HCO
3
H
OCH
3
OC
O
N
N
H
H
H
Isoreserpic acid lactone
(i) Isomerization
(ii) CH OH
3
(iii) CIOC
OCH
3
OCH
3
OCH
3
HCO
3
H
OCH
3
O.CO
N
N
H
H
H
3
COOC
OCH
3
OCH
3
OCH
3
Reserpine
Strychnine
N
O
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
O
Alkaloids
223
Strychnine is an indole alkaloid obtained from the seeds and bark of Strychnos nux-vomica, which is
always accompanied by another alkaloid brucine. Strychnine is distinguished from brucine by its
reactivity with nitric acid readily with the formation of intense red colour due to oxidation. It is
optically active and levorotatory in nature.
Mode of action: The CNS is controlled by excitatory neurotransmitters (glutamate, aspartate and
biogenic amines which may act as modulatory neurotransmitter) and inhibitory neurotransmitter
(gamma-aminobutyric acid and glycine). Excitatory neurotransmitter release causes fi ring of
neurons and inhibitory release causes inhibition of fi ring rate of neurons. Strychnine blocks the
inhibitory neurotransmitter receptor and diminishes the effi cacy of interneuron synaptic inhibition
mediated by the amino acid glycine. As a consequence, an unrestrained spread of nerve impulse
is produced in the spinal cord which develops convulsions.
Properties and uses: At lower doses, it stimulates the CNS and vasomotor centres. In very
lower doses it is used as an antidote for (IV) barbiturate. Larger doses of strychnine produce
convulsions.
Structural elucidation
The structure of strychnine is established as follows:
1. Molecular formula: The molecular formula of strychnine is found to be C
21
H
22
N
2
O
2
.
2. Presence of 3° N atom: Strychnine is found to contain 3° N (strong monoacid tertiary
base) and does not have –NCH
3
group, revealing that the nitrogen is present as —N
|
—.
3. Presence of amide system: The second N is found to be nonbasic and present as an
amide system, as strychnine upon warming with KOH solution gives strychnic acid having
a secondary amino and carboxyl group. This change can be represented as below.
N C
O
N N O
ONOH
—NH
KOH
⫹
NMe I
2
⫺
2MeI
COOR
COOH
COONa
⫹
ROH
NaOH
4. Nature of oxygen: One of the O’s is accounted as amide and the second O atom is found
to be present as cyclic ether. The oxygen atom of the cyclic ether is eliminated by reducing
strychnine with hydriodic acid and red phosphorus to form desoxystrychnine. However,
during this change oxygen atom of the amide linkage is not eliminated (confi rmed by the
alkaline hydrolysis of desoxystrychnine to desoxystrychnic acid).
5. Reduction of strychnine: Strychnine gives dihydrostrychnine upon catalytic
hydrogenation, while on electrolytic reduction it gives strychnidine, which on catalytic
reduction gives dihydrostrychnidine.
224
Pharmaceutical Chemistry of Natural Products
Dihydrostrychnidine Strychnidine Strychnine Dihydrostrychnine
CHNO
21 26 2
CHNO
21 24 2
CHNO
21 22 2 2
CHNO
21 24 2 2
Pd–H
2
Pd H
2
–
E.R.
These reactions represent the reduction of double bond and/or ketonic group.
6. Presence of —N—C—CH
2
— group:
O
Strychnine and its derivative (except strychnidine)
condense with benzaldehyde to form benzylidene derivative, which shows that the
strychnine is having a reactive methylene group (–CH
2
–CO–) and hence strychnine must
possess the —N—C—CH
2
—
O
type of grouping.
7. Oxidation of strychnine: Upon oxidation with concentrated HNO
3
, strychnine gives din-
itrostrychol carboxylic acid (having an acidic group) which upon decarboxylation forms
dinitrostrychol. The dinitrostrychol is still having an acidic group and can be converted
into dinitroisatin via the amine. Also, dinitrostrychol carboxylic acid upon degradation by
Curtius method yields dinitroisatin.
ON
2
NO
2
O
N
H
O
Dinitroisatin
Dinitrostrychol
⫺CO
2
Dinitrostrychol carboxylic acid
Degradation by Curtius method
Strychnine
Conc. HNO
3
Hence, dinitrostrychol and dinitrostrychol carboxylic acid may be assigned structures I
and II, respectively.
ON
2
NO
2
COOH
N
H
ON
2
NO
2
COOH
N
H
COOH
III
Alkaloids
225
The above postulated structures have been confi rmed by the synthesis.
NO
2
CHO
OCH
3
ON
2
Hippuric acid
CHC
65
N.CH COOH
2
OH
NO
2
C
OCH
3
ON
2
CC
N
C
O
O
CH
56
CH
56
OH
NH
3
ON
2
NO
2
CONH
2
N
H
ON
2
NO
2
COOH
N
H
Dinitrostrychol
H
The formation of dinitrostrychol carboxylic acid upon oxidation of strychnine indicates
the following points.
(a) Presence of indole nucleus in it.
(b) The two –COOH groups of dinitrostrychol carboxylic acid represent the remnants of
the rest of the molecule.
8. Presence of carbazole nucleus in strychnine: The presence of –N–CO– group is
confi rmed by the formation of a deep purple colour when strychnine heated with 80%
H
2
SO
4
/K
2
Cr
2
O
7
(Otto reaction). Further, the deep blue purple colour obtained is most closely
matched by that given by certain hydrogenated carbazoles, indicating that the strychnine
contains the carbazole nucleus.
On the basis of above observations, the partial structure of strychnine can be depicted
as mentioned below.
N
H
Carbazole
CH
2
N
CO
Strychnine on distillation with lime yields carbazole and indole, which confi rms the
presence of carbazole nucleus in strychnine.
9. A saturated nonbasic keto-monocarboxylic acid called strychninonic acid with the molecular
formula of C
21
H
20
O
6
N
2
is obtained upon oxidation of strychnine with KMnO
4
in acetone.
226
Pharmaceutical Chemistry of Natural Products
Strychninonic acid is nonbasic, and both the N atoms must be present as –N–CO
groups, which is proved by the hydrolysis of the keto acid with two molecules of water to
a tricarboxylic acid (C
12
H
24
N
2
O
8
).
Strychninonic acid on reduction with sodium amalgam gives strychninolic acid, which
undergoes acetylation and does not respond to carbonyl reagents, which shows that during
the reduction, –CO– group of strychninonic acid is reduced to –CHOH group.
When strychninolic acid is allowed to stand in contact with normal aqueous NaOH
for several hours, strychninolone (having both the amide groups) and glycolic acid are
produced by the cleavage of ethereal linkage. Further strychninolone is found to exist in
two isomeric forms (differ in the position of double bond), namely α and β.
Strychninonic acid
( CO, COOH)⫺⫺
Na/Hg
Strychninolic acid
( CHOH, COOH)⫺⫺
NaOH
⫺⫺CH OH COOH
2
Strychninolone
(No COOH group and exist in 2 forms)⫺
The formation of glycolic and two isomeric strychninolone from strychninolic acid can
be explained if the latter has following type of grouping:
CH
2
CH
CH
2
CH COOH
2
O
NaOH
CH
CH
CH
2
⫹
CH
2
CH
CH
⫹
CH
2
OH.COOH
Strychninolic acid ␣-Strychninolone -Glycolic acid
Strychninolone α and β yield malonic and oxalic acids, respectively, on oxidation,
indicating the following systems in the two isomers.
N
OC
CH
C
H
2
Strychninolone-␣
[O]
N
OC
O
CH
2
COOH
HO
2
N
H
O
⫹
COOH.CH
2
.COOH
N
OC
CH
C
H
Strychninolone-
[O]
N
OC
COOH
COOH
HO
2
N
H
COOH
⫹
COOH
COOH
Alkaloids
227
By knowing the structures of strychninolones α and β and on the basis of the point 9,
the part structure of strychninolic acid may be postulated as below.
N
OCH COOH
2
OC
10. From point 9 we know that the acidic group in strychninolic acid is coming from the
double bond of the alkaloid, and hence the latter compound’s part of the structure can be
proposed as follows:
N
OCH . C
2
C
O
C
11. Position of the basic N-atom in strychnine: Strychnine on distillation with lime gives
β-collidine and tryptamine, in addition to that of carbazole and indole.
N
CH CH
23
CH
3
H
N
CH CH
222
NH
-Collidine
Tryptamine
From the formation of β-collidine, the presence of a 3,4-disubstituted pyridine ring is
confi rmed. As the amide type of nitrogen is present in an indole nucleus (see point 2), the
tertiary basic nitrogen atom of strychnine must be present in the reduced pyridine nucleus.
Furthermore, the formation of tryptamine reveals that the rest of the two carbon atoms
are linked to β-position of the indole nucleus. From all the above facts, the structure of
strychnine can be postulated as mentioned below, which will explain all the aforementioned
reactions.
228
Pharmaceutical Chemistry of Natural Products
CH
CH
CH
O
CH
2
CH
2
N
N
H
2
C
O
Strychnine
KMno
4
(CH)CO
32
C
O
CO
CH
2
N
N
H
2
C
O
CH
2
O
COOH
Strychninonic acid
(Reduction)
Na–Hg
CH
O
CO
CH
2
N
N
H
2
C
O
CH
2
OH
COOH
NaOH
CH
CO
CH
2
N
N
H
2
C
O
OH
⫹
CH
CO
CH
2
N
N
H
2
C
O
OH
⫹
CH
2
OH
COOH
␣-Strychninolone -Strychninolone
Oxidation Oxidation
Alkaloids
229
CH
CO
CH
2
N
N
H
2
C
O
OH
CH
2
COOH
O
CH
CO
CH
2
N
N
H
2
C
O
OH
COOH
COOH
Hydrolysis Hydrolysis
CH
CO
CH
2
N
N
H
2
C
OH
H
O
COOH
CH
2
COOH
⫹
Malonic acid
CH
CO
CH
2
N
N
H
2
C
OH
H
COOH
⫹
COOH
COOH
Oxalic acid
12. Synthesis: The above proposed structure of strychnine is confi rmed by the synthesis.
NHNH
2
CH
3
OC
OCH
3
OCH
3
Phenylhydrazine
3,4-Dimethoxy acetophenone
⫹
Fischer indole
synthesis
N
H
OCH
3
OCH
3
HCHO NH(CH )
(Mannich reaction)
⫹
32
N
H
OCH
3
OCH
3
CH N(CH
322
)
(i) CH I
(ii) NaCN
(iii) LiA1H
3
4
N
H
OCH
3
OCH
3
CH NH
222
CH
CHO.COOC H
25
230
Pharmaceutical Chemistry of Natural Products
N
O
COOCH
3
N.COCH
3
SCH Ph
2
N
O
COOCH
3
N.COCH
3
Raney nickel
H
2
N
H
OCH
3
OCH
3
CH
2
CH
2
N
CH.COOC H
25
p-Tosyl chloride
Pyridine
N
OCH
3
OCH
3
N.TOS
COOC H
25
NaBH
4
N
Ac
OCH
3
OCH
3
N.TOS
COOC H
25
N
H
OCH
3
OCH
3
N.TOS
COOC H
25
Ac
2
O
O
2
N
Ac
COOCH
3
N.TOS
COOC H
25
COOCH
3
CH
3
OH–HCl
N
O
COOCH
3
N.TOS
COOC H
25
(i) Hydrolysis
(ii) Esterification
(iii) Acetylation
N
O
COOCH
3
N.COCH
3
COOC H
25
CH
3
ONa
N
O
COOCH
3
N.COCH
3
OH
PhCH
2
SNa
Alkaloids
231
(i) H
2
(ii) cis form treated with KOH
N.COCH
3
N
CH
3
OCOCH
3
(i) Resolve
(ii) (-) form treated Ac O–pyridine
2
Allylic rearrangement
N
H
COOH
N.COCH
3
O
H
Racemic trans acid
COCH
3
N
NH
SeO –C H OH
225
N
O
N
(i) Na–NH
3
(ii) CH CH⬅
(iii) H Pd
2
–
N
HC
N
HO
LiA1H
4
N
HC
CH
2
HO
N
KOH–C H OH
25
N
O
N
Strychnine Isostrychnine
Acid
N
HC
CH
2
OH
N
O
O
O
O
O
O
O
O
Dihydrostrychnine
O
CH
2