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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5987_Библиотеки_им_академика_М_И_Перельмана.pdf
202
Pharmaceutical Chemistry of Natural Products
HCO
3
HCO
3
HCO
3
HCO
3
HCO
3
HCO
3
HCO
3
HCO
3
HCO
3
HCO
3
HC
[CH]
58
CH
2
OCH
3
OCH
3
OCH
3
OCH
3
OCH
3
OCH
3
OCH
3
OCH
3
OCH
3
OCH
3
N
CH
2
CH
2
[CH]
47
CH
2
Emetine
2 HEM
CH
2
N
HC
3
CH
2
[CH]
47
CH
2
(i) 2H
2
(ii) HEM
(MeN)⫺
3
Me N
2
CH
2
CH
N
CH
2
HC
3
[CH]
47
(i) H
(ii) HEM
2
HC
[CH]
47
CH
2
(CH ) NCH
32 2
HEM
(MeN)⫺
3
VI
HN
The compound VI obtained by complete exhaustive methylation is ozonolysed to yield
6-ethyl veratraldehyde and an unsaturated aldehyde which upon further ozonolysis yields
methyl ethyl ketone. This indicates that the component C
5
H
8
of Hofmann degraded product
of emetine contains grouping of the type shown below.
Alkaloids
203
C
C
HC
3
CH
25
O
3
O
C
HC
3
CH
25
Hence, the complete structure of the degraded product may be depicted as below.
HCO
3
HCO
3
HC C
CH
2
HC
3
CH
25
OCH
3
OCH
3
VI
HCO
3
HCO
3
NH
CH
3
CH⭈CH CH
23
CH
HC
2
CH
2
HCO
3
HCO
3
NH
VII
9. If we go backwards from compound VI to emetine, one can depict full carbon skeleton of
emetine as VII. Now the only problem that remains is to settle the third valency of one
of the nitrogen so as to make it 3°. For this, there are three possibilities to give the three
different structures for emetine.
HCO
3
HCO
3
HCO
3
HCO
3
CH
25
N
CH
2
NH
VIII
HCO
3
HCO
3
HCO
3
HCO
3
N
CH
3
CH
3
CH
2
NH
IX
HCO
3
HCO
3
HCO
3
HCO
3
N
CH
3
CH
25
CH
2
NH
X
10. Robinson on biogenetic considerations proposed the correct structure for emetine as VIII.
Furthermore, as emetine is found to have only one C-alkyl group, structures IX and X are
discarded.
204
Pharmaceutical Chemistry of Natural Products
11. Synthesis: The above proposed structure is proved by the synthesis.
HCO
3
HCO
3
N
HC
3
HCl
HCO
3
HCO
3
CH C H⭈
25
C
2
H
N
⫹
CO
(i) Resolution by ( )-camphor-10-sulphonic
acid in ethyl acetate
⫺
(ii) ( )-form taken
(iii) Ph P CH.COOC H
(Wittig reagent)
⫺
⫺
325
HCO
3
HCO
3
H
N
H
CH
25
H /Catalyst
2
HCO
3
HCO
3
H
N
H
H
CH
25
CH COOC H
225
⭈
(i) Hydrolysis
(ii) SOCl
2
(iii) Homoveratrylamine
⫹H
⫹
⫺H
⫺
HCO
3
HCO
3
H
N
O
H
CH
25
HCO
3
HCO
3
CH
25
N
CH
2
OC
NH
HCO
3
HCO
3
HCO
3
HCO
3
CH
25
CH
2
N
NH
POCl as in (i) method
3
Isoemetine
(Stereoisomer of emetine)
Catalytic reduction
o-Methylpsychotrine
(i) Alkali ( NCl HCl)⫺⫺
(ii) NaOCl (NH NCl)⫺
Emetine
CH NMe
22
CH C H⭈
25
CO
HC
3
CH COOC H⭈
25
HCO
3
⫹
HCO
3
⫹
Alkaloids
205
Phenylethylamine Alkaloids
Ephedrine
CHCHCH
3
123
OH NHCH
3
Ephedrine is a sympathomimetic amine, obtained from the genus Ephedra, along with fi ve other
alkaloids, namely pseudoephedrine, methylephedrine, methylpseudoephedrine, norephedrine and
norpseudoephedrine. Ephedrine is the most important one among them and has two asymmetric
carbon atoms and four optical isomers. The erythro racemate is called ephedrine.
Mode of action: The principal mechanism of its action relies on its indirect stimulation of the
adrenergic receptor system, which is a part of the sympathetic nervous system, by increasing
the activity of noradrenaline at the postsynaptic α- (mediates through IP
3
/DAG) and β-receptors
(mediated through cyclic adenosine monophosphate). It is a pressor agent and produces increase
in heart rate, vasoconstriction, bronchodilation and mydriasis in eye.
Properties and uses: Occurs as a waxy solid and as crystals and has a characteristic pronounced
odour. It is soluble in alcohol, water and organic solvents. It has both α- and β-adrenergic agonist
activity, metabolized by catechol-O-methyltransferase. It is used in a variety of conditions such as
allergic disorder, cold, hypotension conditions and narcolepsy. Also, it is occasionally used to treat
enuresis to dilate the pupil.
Structural elucidation
The structure of ephedrine is established as follows:
1. Molecular formula: The molecular formula of ephedrine is found to be C
10
H
15
NO.
2. Presence of one 2° N: Results from the usual standard tests reveal that ephedrine possess
2° amino group.
3. Presence of –OH group: On benzoylation, it forms dibenzoyl derivative. The oxygen
atom is present as hydroxyl group which is benzoylated and the other benzoyl group is
introduced at the NH group.
4. Nature of the skeleton: Ephedrine yields benzoic acid upon oxidation, which indicates
that ephedrine is a monosubstituted benzene.
5. Nature of the side chain: When heated with hydrochloric acid, ephedrine yields
methylamine and propiophenone.
CHNO
10 15
HCl
CH NH
32
⫹
C H COCH CH
65 2 3
6. Structure of ephedrine: From this reaction, the following two structures are suggested
for ephedrine.
C H CHOHCH CH NHCH
65 2 2 3
I
CHCH CH
65 3
CH
NHCH
3
II
OH
206
Pharmaceutical Chemistry of Natural Products
Ephedrine hydrochloride on heating undergoes hydramine fi ssion to form
propiophenone, phenylacetone and methylamine. Hydramine fi ssion is characteristic of
the compounds having
C
6
H
5
—CHOH—CH—NHR
group, and hence ephedrine must be of
structure II.
C H CHOH CHCH
65 3
⭈
HCl
NHCH
3
C H COCH CH
65 2 3
Ephedrine
⫹
CH NH
32
⫹
C H CH COCH
65 2 3
Propiophenone Methylamine Phenylacetone
7. The above structure for ephedrine is confi rmed by Hofmann exhaustive methylation to
afford sym-1,2-methylphenylethylene oxide.
C H CHOH CHCH
65 3
⭈
NHCH
3
(i) MeI
(ii) AgOH
C H CHOH CHCH
65 3
⭈
(i) Heat
(HO)⫺
2
C H CH-CHCH
65 3
⫹
NMe OH
3
⫺
O
⫹
Me N
3
Ephedrine sym-Methylphenylethylene oxide
8. Synthesis: The structure proposed is further confi rmed by its synthesis and optical
isomerism.
CHCOCOCH
65 3
⭈⭈
⫹
NH CH
23
CH OH
3
CHCOCCH
65 3
⭈⭈
NCH
3
H –Pt
2
C H CHOHCH CH
65 3
⭈
NHCH
3
( )-Ephedrine⫹
The racemic ephedrine is resolved into optically active ephedrine by means of mandelic acid.
Optical isomerism in ephedrine: As ephedrine has two dissimilar asymmetric carbon
atoms (marked by asterisk), four optically active isomers, i.e. two enantiomeric pairs are possible
and are known as (+) and (–) ephedrines and (+) and (–) pseudoephedrines.
Only (–) ephedrine and (+) pseudoephedrine occur in nature.
(±) Pseudo or ψ ephedrine has also been synthesized.
CH
3
C
C
CH
65
H
HOH
NHCH
3
( )-Ephedrine⫺
CH
3
C
C
CH
65
H CHN
3
H
( )-Ephedrine⫹
HO H
CH
3
C
C
CH
65
H CHN
3
H
( )- -Ephedrine⫺⌿
HOH
CH
3
C
C
CH
65
H NHCH
3
( )- -Ephedrine⫺⌿
HO H
Enantiomers Enantiomers
Diastereomers
M.P. 38
[ ] 6.3°␣⫽⫾
D
M.P. 118
[ ] 512°␣⫽⫾
D
Alkaloids
207
Indole Alkaloids
Ergotamine
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CONH
17
N.CH
3
N
H
1’
2’
3’
4’
5’
6’
7’
8’
9’
10’
11’
12’
CHCH
265
CH
CO
N
H
C
O
HOH
H
N
C
OH
O
CH
3
Ergotamine is an alkaloid isolated from ergot or Secale cornutum, product of a fi lamentous fungus
Claviceps purpurea which grows parasitically on rye and other grasses and cereals. As ergot is having
pharmacological action on the uterus and on the vasomotor centre, it has been used in medicine.
Among the alkaloids isolated from ‘ergot’ the important alkaloids are ergotamine, ergotaminine,
ergosine and ergosinine.
Mode of action: The antimigraine effect is due to constriction of the intracranial extra cerebral
blood vessels through the 5-HT
1B
receptor and by inhibition of trigeminal neurotransmission by
5-HT
1D
receptors. Ergotamine also has effects on the dopamine and norepinephrine receptors. It is
its action on the D
2
dopamine and 5-HT
1A
receptors that can cause some side effects. It produces
carotid A–V shunt channels and reduces neurogenic infl ammation and leakage of plasma into
dura mater occurs due to perivascular afferent nerves.
Properties and uses: It possesses structural similarity to several neurotransmitters such as serotonin,
dopamine and epinephrine and binds to several receptors acting as an agonist and has biological
activity as a vasoconstrictor. It is used medicinally for treatment of acute migraine attacks (sometimes
in combination with caffeine) and to induce child birth and prevent postpartum haemorrhage.
Structural elucidation
The structure of ergotamine is established as follows:
1. Molecular formula: The molecular formula of ergotamine is found to be C
33
H
35
N
5
O
5
.
2. Hydrolysis: Ergotamine on alkaline hydrolysis yields D-lysergic acid as one of the
principal products along with α-hydroxyalanine (isolated as pyruvic acid), D-proline and
L-phenylalanine.
CHNO
335553
CHNO
16 16 2 2
Hydrolysis
Ergotamine
Lysergic acid
⫹
HC
3
C COOH
NH
2
OH
␣-Hydroxyalanine
⫹
CHHC
652
CH COOH
NH
2
Phenylalanine
⫹
N
H
COOH
d-Proline
The complete structure of ergotamine can thus be studied under two heads.
1. Structure of lysergic acid
2. Structure of nonlysergic acid moiety
208
Pharmaceutical Chemistry of Natural Products
Structure of lysergic acid (molecular formula: C
16
H
16
N
2
O
2
)
Results from the usual tests reveal that lysergic acid contains a –COOH group, 2° N, 3° N and
an olefi nic double bond.
Fusion of the dihydro derivative of lysergic acid with KOH affords 3,4-dimethylindole,
1-methyl-5-aminonaphthalene and methylamine.
Dihydrolysergic acid
KOH
HN
3,4-Dimethylindole
1-Methyl-5-amino-naphthalene
Methylamine
CHNO
16 18 2 2
CH
3
CH
3
⫹
NH
2
CH
3
CH NH
32
⫹
The following conclusions have been drawn from this reaction:
In lysergic acid an indole and naphthalene nucleus is present.
The formation of methylamine and 3,4-dimethylindole reveals that the N atom of 1-methyl-5-
aminonaphthalene is not its own but belongs to the indole nucleus of the lysergic acid, which
contains only two N atoms (in the above reaction one N atom is eliminated as methylamine
and the other N is eliminated in the form of 3,4-dimethylindole).
Oxidation of lysergic acid with HNO
3
affords a tricarboxylic acid which on distillation with
soda lime gives quinoline, indicating that lysergic acid also possesses a quinoline nucleus,
probably reduced.
The formation of 3,4-dimethyl indole, 1-methyl-5-aminonaphthalene and quinoline
derivative indicates that lysergic acid must be possessing the following type of structure in order
to explain the formation of various above mentioned cyclic products.
8
7
NCH
3
6
5
4
3
21
HN
9
10
11
12
13
14
15
+ COOH group and
one double bond
Tetracyclic structure of lysergic acid
The additional double bond of lysergic and isolysergic acids may be present in conjugation with
the indole system, i.e. either between C-9 and C-10 or between C-5 and C-10. This is inferred
by comparing the UV spectra of lysergic and isolysergic acids with that dihydrolysergic acid.
Lysergic acid behaves like a β-amino acid, which is inferred from the following reaction:
heating dihydrolysergic acid yields a neutral substance I which has one mole of water less
than the dihydrolysergic acid. The neutral compound I has easily reducible double bond and
Alkaloids
209
also answer for Keller reaction (blue colour with concentrated H
2
SO
4
and glacial acetic acid
containing a trace of iron chloride). This indicates that the position of the –COOH group in
lysergic acid is at C-8. All these reactions can be thus explained as described here.
COOH CH
2
O
N
CH
3
I
COOH
NHCH
3
NCH
3
8
7
6
5
10
9
-Amino acid
(only one ring is shown)
D
Lactonization
When lysergic acid is heated, the newly formed double bond in compound I is found to be
in conjugation with the already present double bond (indicated by UV spectrum) and hence in
lysergic acid the double bond must be between C-9 and C-10.
All the reactions can be explained as follows:
+
1-Methyl-5-amino-naphthalene Methylamine
HN
COOH
Lysergic acid
KOH
HN
3,4-Dimethylindole
NCH
3
CH
3
CH
3
CH
3
NH
3
CH NH
32
⫹
HN
COOH
Lysergic acid
(O)
HOOC
HOOC
COOH
N
Tricarboxylic acid
Quinoline
Lime
NCH
3
COO
⫺
NCH
⫹
3
It must be noted from the formula of the carboxylic acid that although it is a tetracarboxylic
acid, it is known as tricarboxylic acid; actually the fourth acidic group is masked by the positively
charged 4° N atom.
210
Pharmaceutical Chemistry of Natural Products
The above structure of lysergic acid has been confi rmed by its synthesis.
HOOC
CHOCN
65
⭈
(i) SOCl
2
(ii) AlCl
3
(iii) H O
2
N-Benzoyl-3-(Beta-carboxyethyl)
dihydroindole
Internal Friedel–
Crafts acylation
CHOCN
65
⭈
O
O
Br
2
CHOCN
65
⭈
Br
2
HC
2
CH
2
OO
C
HC
3
CH NHCH
23
HC
2
CH
2
OO
C
HC
3
CH
2
CHOCN
65
⭈
O
NCH
3
(Hydrolysis of ethylene ketal
and benzoyl group)
Acid
O
C
CH
2
HC
3
NCH
3
O
HN
HN
O
(i) (CH CO) O
(ii) NaBH
32
4
NCH
3
H COC N
3
⭈
OH
NCH
3
(i) SOCl
(ii) NaCN
(iii) HCl
2
Dehydrogenation
HN
COOH
NCH
3
COOH
NCH
3
HN
( )-Lysergic acid⫾
CH ONa
3
Alkaloids
211
Structure of nonlysergic acid moiety
The hydrolysis products of ergotamine to lysergic acid, D-proline, phenylalanine and pyruvic
acid infer that the alkaloid contains peptide bonds; which on hydrolysis afford amino acids.
As there is no free keto group found in the alkaloid, α-keto acids like pyruvic acid is not
present but
D-proline and phenylalanine are found to be present as such in the alkaloid.
Moreover, the fact that keto acids are not present as such in the ergot alkaloids came from the
following observation.
Me HC—C—COOH
2
OH
NH
2
Hydrolysis
(–NH )
3
Me HC—C—COOH
2
×
O
dimethylpyruvic acid
(actual product)
␣-Hydroxyisovaleric acid
(expected product)
Me HC—CH
2
×
OH
COOH
On hydrolysis dihydroergocristine affords dimethylpyruvic acid (or α-keto acids) which
decomposes to the corresponding keto acid, and an equivalent ammonia upon hydrolysis. It
means the pyruvic acid must be present as hydroxyalanine in ergotamine.
H N—C—OH
2
CH
3
COOH
KOH
Hydroxyalanine
H
C—C + N
3
H
3
O
COOH
Pyruvic acid
The different points which led to the accepted structure are given below:
The various amino acids are present in the form of a cyclic structure as the nonlysergic acid
moiety contains neither a free carboxyl group nor a basic amino group.
Lysergic acid amide (ergine), instead of lysergic acid, is obtained from mild alkaline hydrolysis;
an acid–amide linkage is present between lysergic acid carboxyl and the α-hydroxy-α-amino
acid moiety.
Dihydrolysergic acid hydrazide and propionyl- L-phenylalanyl-L-proline are obtained when
dihydroergotamine is treated with hydrazine (the keto acid component is reduced by hydrazine
to the corresponding fatty acid).
Dihydrolysergic acid hydrazide and pyruvoyl- L-phenylalanyl-L-proline is obtained on mild
hydrolysis of dihydroergotamine with one equivalent of alkali in alcohol.
The products of the above two reactions indicate the following sequence of the amino acids
in the nonlysergic acid moiety.
Pyruvic acid–phenylalanine–proline
The products of these two reactions always contain a considerable quantity a diketopiperazine,
i.e. phenylalanine–proline lactam indicating that in the alkaloid phenylalanine and proline
units are linked with each other in a way to form a six-membered ring along with a fi ve-
membered ring. Similar products, i.e. compounds having six-membered as well as fi ve-
membered rings, were also formed by reduction with LiAIH
4
and thermal cleavage.