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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5987_Библиотеки_им_академика_М_И_Перельмана.pdf
212
Pharmaceutical Chemistry of Natural Products
Thus the peptide or nonlysergic acid portion of the ergotamine may be described as follows:
O
N
O
HN
CHCH
265
Hence, the nonlysergic acid moiety of dihydroergotamine may be written as mentioned
below which explains the various reactions.
RCONH
2
C
C
⫹
CH
3
O
O
O
N
C
N
CHCH
265
O
OH
⫺
COOH
CO
CH
3
⫹
O
O
CHCH
265
HN
N
Dihydrolysergic acid
amide
Pyruvylphenylalanylproline
200°–220 or mild hydrolysis
with one mole of ammonia
°
Pyruvic acid Phenylalanylproline
ROCHNC⭈⭈⭈
CH
3
C
O
O
C
N
OH
CHCH
265
N
O
NaOH
RCOOH
⫹
CO
COOH
CH
3
HOOC
⫹
N
H
⫹
NH
3
⫹
HN
2
CHCOOH
CHCH
265
PhenylalanineProlineDihydrolysergic acid amide
(where R lysergic acid portion)⫽
Lysergic acid Pyruvic acid
CH
3
CH NH CH R⭈
2
⭈
HC
2
N
N
CHCH
265
(H)
RH C HN
2
⭈
⫹
CH
⫹
HN
CHCH
265
N
CH OH
2
CH
3
Alkaloids
213
Therefore the complete structure for ergotamine can be written as mentioned here.
CONH
NCH⭈
3
N
H
OH
H
C
O
CH R
2
O
H
O
OH
C
N
H
CH
R”
C
O
H
OH
N
General structure of ergot alkaloids
1. Ergotamine: R= H R′′ = CH
2
C
6
H
5
2. Ergosine: R= H R′′ = CH
2
CHMe
2
3. Ergocristine: R= CH
3
R′′ = CH
2
C
6
H
5
The three isomeric alkaloids having isolysergic acid are ergotaminine, ergosinine and
ergocristinine.
These alkaloids have all other fragments same as the fi rst above-mentioned series.
Isolysergic acid is the diastereomer of lysergic acid at C-8. The two acids and of course their
corresponding alkaloids are interconvertible in the following way:
COOHH
N
CH
3
HN
OH
C OH
N
CH
3
HN
Lysergic acid Isolysergic acid
HN
HOOC H
N
CH
3
214
Pharmaceutical Chemistry of Natural Products
Synthesis: Finally, the above proposed structure for ergotamine is confi rmed by its
synthesis.
C H OOC
25
C H
CH
3
OC H
25
CO
Methylmalonic acid diethyl ester
(i) Br
(ii) C H CH ONa
2
65 2
C H OOC
25
C OCHCH
265
CH
3
OC H
25
CO
(i) Partial hydrolysis
(ii) SOCl
2
C H OOC
25
C OCHCH
265
CH
3
ClCO
CHCH
265
HN
O
N
O
Pyridine
CHCH
265
N
N
O
O
CH
3
C
OCHCH
265
C H OOC
25
O
C H OOC
25
C OH
C
O
CH
3
N
N
CHCH
265
O
O
(H)
C H OOC
25
C
CH
3
C
O
O
N
OH
N
CHCH
265
O
Lysergic acid chloride
hydrochloride in chloroform
in presence of -butylaminet
Ergotamine
HCl H N⭈
2
CH
3
C
C
O
O
OH
N
N
O
CHCH
265
NaOH (—COOC H COONa)
25
—
(i)
(ii)
Oxalyl chloride ( COONa COCl)——
(iii)
NaN ( COCl CON )
33
——
(iv)
C H CH OH ( CON NHCOOCHCH)
65 2 3 265
——
Pd–H ( NHCOOCH C H NH )
22652
——
(v)
(vi)
HCl ( NH NH Cl)
22
——
Reserpine
Reserpine is the most important alkaloid obtained from Rauwolfi a species. The snake like roots of
rauwolfi a is used for controlling hypertension, epilepsy, insomnia, fever, cholera, dizziness and
headache. Phytochemical investigation of about 60 various Rauwolfi a species led to the isolation of
nearly 50–70 alkaloids, known as rauwolfi a alkaloids.
Alkaloids
215
Mode of action: Reserpine blocks the ability of aminergic transmitter vesicles to take up and
store biogenic amines, probably by interfering with an uptake mechanism that depends on Mg
2+
and adenosine triphosphate. This effect occurs throughout the body, resulting in depletion of
norepinephrine, dopamine and serotonin in both central and peripheral neurons. Action of
reserpine on adrenergic vesicles appears irreversible; trace amounts of the drug remain bound
to vesicular membranes for many days. Although high doses of reserpine in animals can reduce
catecholamine stores to zero, lower doses cause inhibition of neurotransmission that is roughly
proportionate to the degree of amine depletion. Depletion of peripheral amines probably accounts
for much of the benefi cial antihypertensive effect. Reserpine readily enters the brain, and depletion
of cerebral amine stores causes sedation, mental depression and Parkinsonian symptoms.
Properties and uses: At lower doses used for treatment of mild hypertension, reserpine lowers
blood pressure by a combination of decreased cardiac output and decreased peripheral vascular
resistance. High doses of reserpine characteristically produce sedation, lassitude, nightmares and
severe mental depression; occasionally, these occur even in patients receiving low doses. Reserpine
produces extrapyramidal effects resembling Parkinson’s disease due to dopamine depletion in the
corpus striatum.
Structural elucidation
The structure of reserpine is established as follows:
1. Molecular formula: The molecular formula of reserpine is found to be C
33
H
40
N
2
O
9
.
2. Presence of fi ve methoxy groups: By Zeisel’s test it was found to possess fi ve –OCH
3
groups
3. Nature of N atoms: Both the nitrogen atoms found to present in ring. It undergoes
acetylation reveals the presence of an –NH group or OH group. Results from the usual
standard test reveal that no OH group is present, and hence the acetylation is due to the
presence of –NH group. It has been further confi rmed by the IR spectral data, which reveals
the presence of an indole nucleus. Second nitrogen atom must exist as 3°, as reserpine
forms methiodide readily with methyl iodide.
4. Hydrolysis: Reserpine upon alkaline hydrolysis gives methanol, 3,4,5-trimethoxybenzoic
acid and reserpic acid (A) with the composition of C
22
H
28
N
2
O
5
.
9
87
6
5
4
N
10
11
HCO
3
12
13
1
N
H
2
3
14
15
21
20
19
18
16
H COOC
3
OCH
3
17
OCO×
OCH
3
OCH
3
OCH
3
216
Pharmaceutical Chemistry of Natural Products
COOH
OMeMeO
OMe
C H N O + 2H O
33 40 2 9 2
NaOH
+ CH OH + C H N O
3222825
Reserpic acidReserpine
3,4,5-Trimethoxy benzoic acid
(CHO)
10 12 5
Reserpine has no –COOH or –OH group. The formation of two –COOH groups (one in
3,4,5-trimthoxybenzoic acid and the other in reserpic acid) and two alcoholic groups (one
in CH
3
OH and the other in reserpic acid) in the hydrolysis products indicates that reserpine
is a diester. This is confi rmed by the reduction of reserpine with LiAlH
4
to reserpic alcohol,
C
22
H
30
N
2
O
4
and 3,4,5-trimethoxybenzyl alcohol.
5. Structure of reserpic acid (C
22
H
28
N
2
O
5
):
(a) Presence of two –OCH
3
, one –COOH, one 2° alcoholic –OH, one 2° N atom and one 3°
N atom: By the usual standard tests, reserpic acid is found to possess two –OCH
3
, one
–COOH, one 2° alcoholic –OH, one 2° N atom and one 3° N atom.
(b) Oxidation of reserpic acid: Reserpic acid yields 4-methoxy-N-oxalyl anthranilic acid
as one of the products on oxidation with KMnO
4
, confi rming the presence of indole
nucleus (which was suggested in point 3).
CHNO
22 28 2 5
KMnO
4
Oxidation
COOH
NHCMeO
O
COOH
COOH
OHHOOC
KOH
Fusion
OHHOOC
O
OC
Gamma Lactone
(c) Fusion with KOH: Reserpic acid on fusion with KOH gives 5-hydroxyisophthalic acid.
One of the acidic groups of isophthalic acid must be the acidic group of reserpic acid
itself, the hydroxyl and carboxyl groups in reserpic acid are meta to each other. It
is confi rmed by the formation of γ-lactone upon heating reserpic acid with acetic
anhydride.
(d) Dehydrogenation: Methyl reserpate upon selenium dehydrogenation yields yobyrine of
the composition C
19
H
16
N
2
as one of the principal products. Hence, the carbon framework
of reserpic acid and thus reserpine can be established by knowing the structure of the
yobyrine.
Alkaloids
217
6. Structure of the yobyrine (C
19
H
16
N
2
):
(a) The compound yobyrine yields 3-ethylindole and isoquinoline on zinc dust
distillation.
(b) Yobyrine affords phthalic acid on permanganate oxidation and o-toluic acid on chromic
acid oxidation.
(c) Yobyrine condenses with aldehydes suggesting the presence of a pyridine ring with a
–CH
2
substituent adjacent to N.
CH
3
COOH
O-Toluic acid
CrO
3
CHN
19 16 2
Yobyrine
Zn dust
KMnO
4
COOH
COOH
Phthalic acid
CH
25
N
H
3-Ethylindole Isoquinoline
N
⫹
From the above facts, the structure of yobyrine has been postulated as follows:
N
N
H
CH
3
Yobyrine
The above proposed structure of yobyrine is confi rmed by the synthesis.
N
H
NH
2
COCl
CH
3
⫹
N
H
OC
NH
CH
3
POCl
3
218
Pharmaceutical Chemistry of Natural Products
CH
3
N
N
H
⫺2H
CH
3
N
N
H
Yobyrine
The formation of yobyrine from reserpic acid indicates that the reserpic acid is having the
following type of carbon skeleton.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
N
H
N
(d) From point 5(b) we know that one of the methoxy groups is in the m-position to the
–NH group of indole, i.e. on C-11.
Presence of the –COOH group at C-16 is revealed by the dehydrogenation of reserpic
acid with selenium to 11-hydroxy-16-methylyobyrine (during dehydrogenation
–COOH group is converted into –CH
3
).
CHNO
22 28 2 5
Reserpic acid
Dehydrogenation
Se
HO
N
H
N
CH
3
HC
3
11-Hydroxy-16-methylyobyrine
From point 5(c) we know that –COOH and OH groups are meta to each other, and
therefore the OH group in reserpic acid must be present on C-18.
Alkaloids
219
7. Reserpic acid: The second –OCH
3
group has been assigned position C-17 for purely
biogenetic reasons and thus the complete structure for reserpic acid can be written as
follows:
N
H
N
OH
OCH
3
HOOC
HCO
3
Reserpic acid
8. On the basis of the above structure of reserpic acid, reserpine (a diester of reserpic acid)
structure is assigned as follows:
HCO
3
N
H
HOOC
OCH
3
OH
N
Reserpic acid
COOH
HCO
3
HCO
3
HCO
3
CH OH
3
⫹⫹
HCO
3
N
H
N
H COOC
3
OCH
3
OCO⭈
OCH
3
OCH
3
OCH
3
Reserpine
220
Pharmaceutical Chemistry of Natural Products
9. Synthesis: The above structure of reserpine has been proved by its synthesis from quinone.
O
O
⫹
CH
HC
COOH
HC
2
CH
Diels–Alder
Reaction
O
O
H
COOH
H
NaBH
4
Reduction of less
hindered ketonic
group
OH
O
COOH
CHCOH
65 3
O
OH
O
COOH
Ac O–AcONa
2
O
O
CO
O
Aluminium
isopropoxide
O
O
CO
OH
⫺HO
2
O
O
CO
CH O
3
Na
CH O
3
H
O
O
CO
OCH
3
NBS–H
2
SO
4
O
O
CO
OCH
3
HO
Br
CrO
3
CH COO
3
H
O
O
CO
OCH
3
O
Br
ZN–CH
3
COOH
O
OH
COOH
OCH
3
(i) CH N
22
(ii) AcO Pyridine
2
–
(iii) OsO –H O
42
O
OAc
COOCH
3
OCH
3
OH
HO
Quinone
Alkaloids
221
HCO
3
H
OCH
3
N
N
H
H
H
OAc
H
3
COOC
(i) POC1
3
(ii) NaBH
4
(i) Resolve
(ii) NaOH
(iii) HCl
(iv) DCC
(i) HIO
4
(ii) CH
2
N
2
OHC
OAc
OCH
3
COOCH
3
HC
3
COO
6-Methoxytryptamine
N
NH
2
H
HCO
3
OCH
3
OAc
N
N
H
H
3
COOC
COOCH
3
CH
HCO
3
NaBH
4
OCH
3
OAc
N
HN
H
H
3
COOC
COOCH
3
HCO
3
Not isolated
⫺CH
3
OH
OCH
3
OAc
N
H
H
3
COOC
HCO
3
N
O