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_5987_Библиотеки_им_академика_М_И_Перельмана.pdf
392
Pharmaceutical Chemistry of Natural Products
5. Synthesis: The above proposed structure for menthone and menthol is proved by the
syntheses. The (±) menthol obtained is resolved by using phthalic acid.
OH
O
OH
H –Ni
2
CrO
3
m-Cresol
3-Methylcyclohexanone
(COOCH)/Na
252
O
O
COOC H
25
Heat
⫺CO
COOC H
25
O
(i) C H ONa
(ii) (CH ) CHI
25
32
COOC H
25
O
(i) C H ONa
(ii) H
25
⫹
COOH
COOH
Calcium salt
Heat
O
H over
copper chromite
2
OH
2-Isopropyl-5-
methylpimelic acid
Menthone
( ) Menthol⫾
Pulegone
It was the fi rst terpenoid to have the structure established, and hence, it helped in establishing
the structure of many other terpenoids. Pulegone is an optically active liquid and is obtained from
buchu leaves (various species of Barosma; Family: Rutaceae).
Pulegone or
5-Methyl-2-(propan-2-ylidene)cyclohexanone
O
Terpenoids
393
Carvone
O
Carvone
Carvone is obtained mainly from caraway (Carum carvi Linn; Family: Umbelliferae). It is also
obtained from dill. Carvone occurs as racemic and in optically active form. It is used as an aromatic,
a stimulant and a carminative.
Structural elucidation
1. Molecular formula: The molecular formula of carvone is found to be C
10
H
14
O.
2. Presence of two double bonds: By the usual standard chemical reactions, carvone is
found to contain two double bonds.
3. Presence of ␣,-unsaturated carbonyl system: By the usual standard chemical
reactions, carvone is found to contain a ketonic group. The UV absorption spectrum shows
λ
max
235 nm, indicating the presence of an α,β-unsaturated carbonyl system.
4. Presence of ketone: The oxygen atom in carvone is found to be present as ketone.
5. Presence of monocyclic skeleton: From the above observations it is understood that the
fully saturated hydrocarbon of carvone will have C
10
H
20
, which corresponds to the general
formula C
n
H
2n
and hence, carvone must be monocyclic.
6. Presence of p-menthane skeleton: Carvone gives carvacrol (2-methyl-5-isopropyl
phenol) upon heating with phosphoric acid, which reveals the presence of p-menthane
skeleton with ketonic group at position 2 in carvone.
Carvacrol
OH
HPO
34
C
O
C
C
C
C
C
C
C
C
C
Carvone
7. Position of two double bonds: Now the only problem is to assign the position of the two
double bonds in the p-menthane structure having a keto group at C-2. This is established
by its close relation to limonene, namely limonene nitrosochloride which upon treatment
with ethanolic potash forms the same oxime as obtained from the carvone with NH
2
OH.
394
Pharmaceutical Chemistry of Natural Products
NOCl
Isomerization
CHOH
25
KOH
Cl
NOH
NH OH
2
H
⫹
Limonene
Cl
NO
Limonene
nitrosochloride
NOH
Carvoxime
O
Carvone
The formation of the same oxime for limonene and carvone reveals that like limonene,
in carvone also one of the double bonds must be between C
8
and C
9
and the other double
bond must be between C
1
and C
6
because at C
2
the ketonic group is already present.
To establish the position of the two double bonds in carvone, it is degraded as follows:
Carvone
Dihydrocarveol
(one double bond and
2° alcoholic group)
Trihydroxy compound
Ketonic alcohol
Hydroxy acid
CI
10
CII
10
C III
10
CIV
9
Na/C H OH
25
+4H
1% Alkaline
KMnO
4
CrO
3
CH COOH
3
NaOBr
Br /H O
22
190°C
CV
8
COOH
OH
CH
3
3-Hydroxy-4-methyl benzoic acid
The above reactions led to the following conclusions:
(a) Reduction of (I) to (II) reveals that ketonic group and one of the double bonds of the
carvone are reduced during this reduction.
(b) The conversion of (II) to (III) indicates that the hydroxylation occurred in carvone.
(c) Oxidation of (III) to (IV) represents the oxidation of the glycolic linkage of the trihydroxy
compounds.
(d) The oxidation of the ketone (IV) to (V) with one less carbon atom indicates that the
former must be a methyl ketone which clearly indicates that the compound (I) contains
isopropenyl group, i.e. a double bond is in between C
8
and C
9
.
(e) The formation of 3-hydroxy-4-methyl benzoic acid reveals that the double bond
oxidized in the above degradation must be present in the side chain which is oxidized
to acidic group. So the structure of carvone is proposed as (I) or (Ia).
Terpenoids
395
1
2
3
4
5
6
O
O
II
a
Carvone
*
Now because carvone is optically active, structure (I) having an asymmetric carbon
atom at C
4
is correct and therefore structure (Ia) which is devoid of any chiral carbon atom
is eliminated.
O
OH
OH
OH
OH
OH
COOH
COOH
OH
OH
O
Carvone, I
Dihydrocarveol, II
Trihydroxy compound, III
3-Hydroxy-4-
methyl benzoic acid, VI
Hydroxy acid, V Ketonic alcohol, IV
Na/C H OH
25
1% Alk. KMnO
4
CrO
CH COOH
3
3
NaOBr
Br /H O
22
190°C
The structure (I) for carvone explains its degradation reactions as above.
If the double bond is in between the positions 4 and 8 instead of between 8 and 9, then
structure (I) for carvone would have given 3-hydroxy-4-methyl cyclohexanone along with
the loss of three carbon atoms in the form of acetone and no compound corresponding to
(V) and (VI) would have been obtained.
396
Pharmaceutical Chemistry of Natural Products
⫺(CH)CO
32
O
I
a
OH
II
a
OH
OH
OH
III
a
O
OH
IV
a
OH
OH
VI
a
Evidence for the double bond at position 6: The presence of double bond in carvone at
position 6 is proved by its oxidative degradation to isopropyl succinic acid and pyruvic acid,
according to following steps via carvotanacetone.
Carvone
Carvone hydrobromide
Carvotanacetone
Isopropyl succinic acid
Pyruvic acid
⫹
HBr
Zn dust
CH OH
( Br, +H)
3
⫺
KMnO
4
I VII VIII
The above series of reactions leads to following conclusions:
(a) Conversion of (I) to (VIII) via (VII) involves saturation of one of the two double
bonds.
(b) Formation of pyruvic acid (CH
3
CO–COOH) indicates that in carvotanacetone the
carbon atom having double bond is also having a methyl group.
(c) This series of reactions can be written very well by taking (I) as the structure of
carvone.
HBr
O
Carvone
Br
O
Carvone hydrobromide
O
Carvotanacetone
COOH
COOH
Isopropyl succinic acid
O
COOH
Pyruvic acid
Zn dust
CH COOH
( Br, +H)
3
⫺
KMnO
4
⫹
I VII VIII
The above structure for carvone also explains the formation of 3-isopropyl glutaric acid
and acetic acid on oxidation of carvotanacetone with permanganate.
Terpenoids
397
KMnO
4
COOH COOH
⫹
COOH
CH
3
Carvotanacetone
3-Isopropyl glutaric acid
VIII
O
8. Synthesis: The above structure of carvone is confi rmed by synthesis.
NOCl
OH
Cl
NO
OH
Isomerization
Cl
NOH
OH
C H ONa
25
⫺HCl
NOH
OH
HSO
24
O
Carvone
␣-Terpineol
Ionones
Three isomeric ionones are existing (α, β and γ), but only α and β are important and occur in the
essential oil of Boronia megastigma and in costus oil. The α-isomer is optically active, exists in (+),
(–) and (±) forms, while the β-isomer is optically inactive. The dihydro-γ-ionone has been isolated
from ambergris. In nature β-ionone predominates, but in large-scale preparations both β- and
α-ionones are obtained. β-Isomer of ionones is used in the preparation of vitamin A
1
.
Structural elucidation
1. Molecular formula: Molecular formula of ionones is found to be C
13
H
20
O.
2. Presence of two double bonds and ketone: By the usual standard chemical reactions,
ionones are found to contain two double bonds and a ketonic group.
3. Structure of ionones: The structure of ionones is established by KMnO
4
oxidation.
(a) Oxidation of β-ionone gives a mixture of geronic acid (I), 2,2-dimethyl adipic acid (II)
and 2,2-dimethyl succinic acid (III).
398
Pharmaceutical Chemistry of Natural Products
(b) The oxidation of α-ionone gives a mixture of isogeronic acid (IV), 3,3-dimethyl adipic
acid (V) and 2,2-dimethyl glutaric acid (VI).
On the basis of the above reactions, the structure of α- and β-ionone is proposed as
follows:
-Ionone
␣-Ionone
O
O
COOH
O
COOH
COOH
COOH
COOH
⫹⫹
I II III
IV V VI
COOH
O
COOH
COOH
COOH
COOH
⫹⫹
The above structures of α- and β-isomers are supported by their UV absorption spectra
(β-ionone has extended conjugation).
Ionone Observed Calculated
α
228.5 nm
277 nm
β
296 nm 299 nm
4. Synthesis: The above structure of ionones is confi rmed by synthesis.
CHO
H
O
Acetone
⫹
Ba(OH)
2
H
O
-Ionone
Citral
⫹
H
⫹
O
O
O
O
⫹
⫹
⫺H
⫹
-Ionone
␣-Ionone
Terpenoids
399
Bicyclic Monoterpenoids
These terpenoids contain two rings in their structure and these bicyclic monoterpenoids can be
classifi ed into three categories according to the size of the second ring, the fi rst ring is a six-
membered ring in each class. Some of the important compounds are described below:
␣-Pinene
α-Pinene is an optically active bicyclic monoterpenoid: the (+) form is present in American,
German and Russian oil of turpentine and the (–) form is present in French turpentine oil. The
inactive or racemic form is obtained by the action of aniline on active pinene nitrosochloride. The
most widely distributed among all the terpenoids is α-pinene obtained from Pinus roxburghii or
Pinus palustris or from other species of pinus, belonging to family Pinaceae. Turpentine oil mainly
contains α-pinene (20–30%), β-pinene (5–10%), camphene, β-phellandrene, delta-3-carene and
limonene. About 40 terpenes are reported in turpentine oil. It is a counterirritant, weak antiseptic
and expectorant. It is also used in the treatment of chronic bronchitis.
Structural elucidation
1. Molecular formula: The molecular formula of α-pinene is found to be C
10
H
16
.
2. Presence of one double bond: By the usual standard chemical reactions, α-pinene is
found to contain one double bond.
C H NOCl
10
16
␣-Pinene
nitrosochloride
NOCl
␣-Pinene
CH
10
16
CHBr
10
16 2
Br
2
␣-Pinene dibromide
3. Bicyclic nature of ␣-pinene: The molecular formula of α-pinene’s saturated hydrocarbon
is C
10
H
18
which corresponds to the molecular formula of bicyclic compounds (C
n
H
2n–2
).
Hence, α-pinene must be a bicyclic compound.
4. Presence of six-membered ring: Upon reaction of α-pinene with alcoholic sulphuric
acid α-terpineol is obtained, which is having well-known structure.
␣-Terpineol
(CHO)
10
16
OH
CH
10
16
C H OH/H SO
25 2 4
␣-Pinene
Hydration
400
Pharmaceutical Chemistry of Natural Products
As the structure of α-terpineol is known, its formation by hydration of α-pinene leads
to the following points:
(a) α-Pinene possesses one six-membered ring having the double bond of α-terpineol.
(b) In α-terpineol, hydroxyl group is present at C
8
but it is not present in α-pinene, and
therefore, this carbon atom (C
8
) is involved in the formation of other ring of α-pinene.
There are three possibilities (as represented by dotted lines in the side structure) for the
C
8
to form other ring of α-pinene and hence its complete structure which can be easily
cleaved on hydration to form α-terpineol can be drawn as shown below.
H
2
O
␣-Terpineol
OH
␣-Pinene
There are four possibilities: one of them is discarded based on Bredt’s rule (which
states that a double bond cannot be formed by a carbon atom occupying the bridge-
head of bicyclic system). Among the other three possibilities one gives four-membered
ring and the other two give three-membered ring. Determination of four or three-
membered structure is performed by oxidative degradation of α-pinene.
(c) The gem-dimethyl group (–CH(CH
3
)
2
) of α-terpineol is not present in the six-membered
ring of α-pinene and hence it must be present in the other ring.
5. Oxidative degradation of ␣-pinene: As shown in the following scheme, Baeyer degraded
α-pinene into cis-norpinic acid.
␣-Pinene
Pinene glycol
Pinonic acid
1% Alk. KMnO
4
Warm alk. KMnO
4
(C , I)
10
(C , II)
10
(C , III)
10
NaOBr
( CHBr )⫺
3
Pinic acid
(i) Br
2
(ii) Ba(OH)
2
(iii) CrO
3
cis-Norpinic acid
(C , IV)
9
(C H O , V)
8412
The above set of oxidative degradation led to the following conclusions:
(a) When (I) is converted to (II), the double bond of (I) is hydroxylated.
(b) We have already established that the double bond is present in the six-membered ring.
Hence, oxidation of the glycolic group of (II) to (III) indicates that the six-membered
ring having glycolic group and double bond is oxidized.
(c) Because the oxidation of (III) yields bromoform as one of the oxidation products,
compound (III) must have an acetyl (–COCH
3
) group (haloform reaction).
(d) As cis-norpinic acid is found to be a saturated dicarboxylic acid, its molecular formula
may also be written as C
6
H
10
(COOH)
2
. As mentioned above, the gem-dimethyl group
Terpenoids
401
(–CH(CH
3
)
2
) is present in ring other than six-membered ring which remains unbroken
during the above oxidation reactions; therefore, the gem-dimethyl group –(–CH(CH
3
)
2
)
must be present in the cis-norpinic acid. Hence the extended formula for cis-norpinic
acid is proposed as –(CH
3
)
2
C
4
H
4
(COOH)
2
which reveals that the saturated parent
hydrocarbon of this acid is C
4
H
8
and hence the acid must be a cyclobutane derivative.
Later the acid was identifi ed as 1,1-dimethylcyclobutane-2,4-dicarboxylic acid by
synthesis.
O
NC
C
OC H
52
OC H
52
O
C
O
NC
⫹
⫹
Acetone
Ethyl cyanoacetate
(2 moles)
Ammonia
HNH
2
CH
52
OH
NC
O
NC
O
NH
CH
52
ONa
NC
O
O
NH
NC
Na
Na
CI
2
H
2
NC
NC
NH
O
O
(i) OH
(ii) H
⫺
⫹
COOH
HOOC
COOH
HOOC
200°C
COOH
HOOC
(C
2
H CO) O
3
Hydrolysis
COOH
COOH
O
O
O
trans-Norpinic acid cis-Norpinic anhydride cis-Norpinic acid
From the foregoing observations, the structure of α-pinene is proposed as (I), which
explains all the reactions.
1% Alk. KMnO
4
␣-Pinene
KMnO
4
OH
OH
O
COOH
Pinene glycol Pinonic acid
NaOBr
( CHBr )⫺
3