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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5987_Библиотеки_им_академика_М_И_Перельмана.pdf
412
Pharmaceutical Chemistry of Natural Products
The ketone obtained above with the molecular formula of C
13
H
22
O was found to be
identical with α,β-dihydropseudo ionone (geranyl acetone) obtained from geranyl chloride
and sodium acetoacetate.
CH Cl
2
Geranyl chloride
NaHC
COOC H
52
COCH
3
⫹
O
COOC H
52
(i) Hydrolysis
(ii) Decarboxylation
O
Geranyl acetone
(CHO)
13 22
During the formation of ketone C
13
H
22
O from its precursor farneseonitrile of farnesenic
acid, two carbon atoms are lost (a reaction characteristic of α,β-unsaturated carbonyl
compounds). This suggests that farnesenic acid must have an α,β-unsaturated carbonyl-
type group.
RC CHCOR RC O ⫹ CH CO.R
3
OH
⫺
⫹HO
2
where, R = H or alkyl group
It must have structure (I) and when farnesenic acid is converted back to farnesol, the
farnesol will have structure (II).
CrO
3
CH OH
2
Farnesol (II)
CHO
Farnesal
(i) NH OH
(ii) Ac O
2
2
CN
Farnesenonitrile
(i) KOH
(ii) H
+
COOH
Farnesenic acid, I
O
Geranyl acetone
⫹
⫹
CH COOH
3
Terpenoids
413
The structure (II) for farnesol as proposed by Kerschbaum is confi rmed by its ozonolysis
to acetone, laevulaldehyde and glycolaldehyde.
O
3
CH OH
2
Farnesol, II
⫹
O
CHO
OHC
O
Laevulaldehyde
CH OH—CHO
2
Glycoaldehyde
Acetone
⫹
Laevulaldehyde
O
⫹
6. Synthesis: The above structure of farnesol is confi rmed by synthesis.
trans-Geranyl acetone
(i) PCl
(ii) NaNH /liq. NH
5
23
O
C
CNa
CH
2
O
C
C.CH OH
2
i) LiAlH /AlCl
ii) I
43
2
(CH )
33
CuLi
CH OH
2
I
CH OH
2
Farnesol
Monocyclic Sesquiterpenoids
These terpenoids contain 15 carbons in their structure, with one cyclic ring. Some of the important
compounds of this class are described below:
414
Pharmaceutical Chemistry of Natural Products
Zingiberene
Zingiberene or
2-Methyl-5-(6-methylhept-5-en-2-yl)cyclohexa-1,3-diene
Zingiberene is obtained from ginger oil which in turn is obtained from Zingiber offi cinale (Family:
Zingiberaceae). It is optically active and the (–) form is the main constituent of ginger oil. Zinger
oil contains monoterpene hydrocarbons, sesquiterpene hydrocarbons, oxygenated mono and
sesquiterpenes. The aroma or fl avour of zingiberene is due to the presence of monoterpenes
(e.g. cineole) and sesquiterpenes (e.g. zingiberene and nerolidol), while the pungency is due to
gingerols. Medicinally it is used as stomachic, carminative and fl avouring agent.
Structural elucidation
1. Molecular formula: The molecular formula of zingiberene is found to be C
15
H
24
.
2. Presence of three double bonds: By the usual standard chemical reactions, zingiberene
is found to possess three double bonds.
Pt black
C
15
H
24
+ 3H
2
C
15
H
30
3. Presence of monocyclic ring: On the basis of its saturated molecular formula C
15
H
30
,
which corresponds to C
n
H
2n
, it is assumed that zingiberene is monocyclic.
4. Presence of conjugated double bonds: From the following observations, the presence
of conjugated double bonds in zingiberene is confi rmed.
(a) Its molecular refraction value is 61.37 which is higher than that of monocyclic
sesquiterpenoids (67.87) and hence zingiberene exhibits optical exaltation and at least
two double bonds must be conjugated.
(b) The UV absorption spectrum (λ
max
: 260 nm) indicates the conjugated double bond.
(c) It forms adduct with maleic anhydride which confi rms conjugation in zingiberene.
(d) Zingiberene on reduction with sodium and alcohol forms dihydrozingiberene which
further confi rms the presence of conjugated double bonds in zingiberene.
CH
15 24
Zingiberene Dihydrozingiberene
CH
15 26
Na/C H OH
25
Dihydrozingiberene has molecular refraction value of 68.37 which is similar to
calculated value (68.25) of dihydrozingiberene. Hence, dihydrozingiberene must be
having two isolated double bonds and is produced by the reduction of one of the
conjugated double bonds of zingiberene.
Terpenoids
415
(e) Zingiberene on dehydrogenation forms cadalene which gives an insight about the
carbon skeleton of zingiberene.
CH
15 24
Zingiberene
Cadalene
(f) Zingiberene on ozonolysis yields acetone, laevulinic acid and succinic acid similar to
bisabolene, which reveals that the zingiberene has the same skeleton as bisabolene.
Therefore, by disregarding the position of the double bonds, the carbon framework is
assigned to zingiberene as mentioned below.
(g) Dehydrogenation of hexahydrozingiberene over palladized charcoal to 6-p-tolyl-2-
methylheptane (I), which on oxidation with chromic acid yields acetic, oxalic and
terephthalic acids confi rms the carbon skeleton of zingiberene.
Hexahydrozingiberene
Pd/C
CrO
3
COOH
COOH
⫹
CH COOH
3
HOOC
COOH
Terephthalic acid
I
⫹
416
Pharmaceutical Chemistry of Natural Products
The formation of acetone as one of the products during ozonolysis reveals that one
of the double bonds must be present as isopropylidene group. The dihydrozingiberene
obtained by the reduction of zingiberene on oxidation with potassium permanganate
yields ketodicarboxylic acid (C
12
H
20
O
5
). This on further oxidation with sodium
hypobromite forms a tricarboxylic acid (C
11
H
18
O
6
) along with bromoform, which
reveals that the ketodicarboxylic acid has a COCH
3
group. Therefore, the structure of
dihydrozingiberene is proposed as follows:
Dihydrozingiberene
(CH)
15 26
KMnO
4
COOH
COOH
COCH
3
Ketodicarboxylic acid
(CHO)
12 20 5
NaOBr
⫺CHBr
3
COOH
COOH
COOH
Tricarboxylic acid
()CHO
11 18 6
The formation of 2,6-dimethylocta-2,7-diene (II) and methyl-4-methylphthalate
(III) by the pyrolysis of the zingiberene adduct with dimethyl acetylene dicarboxylate
helps to establish the position of the third double bond.
Zingiberene
⫹
CCOOCH
3
CCOOCH
3
Dimethyl acetylene-
dicarboxylate
C.COOCH
3
C.COCH
3
1
2
3
4
5
6
Adduct
Pyrolysis
⫹
COOCH
3
H COOC
3
IIIII
Terpenoids
417
5. Synthesis: The above proposed structure of zingiberene is confi rmed by synthesis.
⫹
O
BrMg
OCH
3
OCH
3
OH
⫺HO
2
Methyl heptenone
p-Anisyl magnesium bromide
OCH
3
Na/C H OH/NH
(Birch reduction)
25 3
OCH
3
H
⫹
O
CH MgI
H
3
2
O
OH
Anhydrous oxalic acid
⫺HO
2
Zingiberene
Bicyclic Sesquiterpenoids
The structure of terpenoids contains 15 carbons and two cyclic rings.
Cadinene
It is an important example of this class of terpenoids. It is an optically active liquid and is a widely
distributed sesquiterpenoid found in oleum cadinum, oil of cubebs, galbanum oils, juniper wood
and oils of angostura rind. It is used as spice or condiment.
418
Pharmaceutical Chemistry of Natural Products
H
Cadinene
Miscellaneous Sesquiterpenoids
Artemisinin
Artemisinin is a cadinene class of sesquiterpenoid isolated from the Chinese herb Artemisia annua
(Family: Asteraceae). It is used in the Chinese traditional system of medicine for the treatment of
fever. It has an endoperoxide bridge in its structure and is found to possess antimalarial activity.
O
H
CH
3
HC
3
H
H
O
O
O
O
Artemisinin
Gossypol and related sesquiterpenes
These are stress compounds (which are formed in plants due to factors like injury and disturbance
to the metabolism) found in the subepidermal glands, immature fl ower buds and seed kernels of
cotton plant Gossypium hirsutum Linn (Family: Malvaceae). It is used as a male antifertility agent
and also as an insecticidal agent. In China, it is used in the treatment of menorrhagia, leiomyoma
and endometritis.
HO
OH
CHO
HO
OH
OH
OH
CHO
Gossypol
Terpenoids
419
DITERPENOIDS
Diterpenoids are compounds containing C
20
in their structure, biogenetically derived from geranyl
pyrophosphates. As in the other group of terpenoids, the isoprene units may link with each
other and form acyclic diterpenoid (e.g. bixin and phytol), monocyclic diterpenoid (vitamin A), dicyclic
diterpenoid (e.g. agathic acid) and tricyclic diterpenoid (e.g. abietic acid). Some of the important
diterpenoids are described below.
Phytol
CH OH
2
Phytol is an acyclic diterpenoid, obtained by the alkaline hydrolysis of chlorophyll. The phytyl
group is also a part of the molecules of vitamins E and K.
Vitamin A
The vitamin A group consists of vitamin A
1
(retinol), vitamin A
2
(retinal), neovitamin Aα and
neovitamin Aβ. These vitamin A groups belong to the apocarotenoid group and are diterpenoids.
When we mention vitamin A, it indicates vitamin A
1
. It is obtained from fi sh oil (particularly,
shark liver oil) and used in the treatment of night blindness.
CH CH.C CH.CH CH C CH.CH OH
2
CH
3
CH
3
Vitamin A (retinol)
1
Vitamin A (3,4-Dehydroretinol)
2
CH CH.C CH.CH CH C CH.CH OH
2
CH
3
CH
3
420
Pharmaceutical Chemistry of Natural Products
Abietic Acid
HOOC
H
H
Abietic acid is the chief constituent of resin or colophony and is the most important diterpenoid.
Colophony mainly contains resin acids which are unsaturated and hence reactive. Pine tree
exudates (resins) on steam distillation give volatile essential oils (turpentine oils) and nonvolatile
substances known as resin. The main constituent of turpentine oils is α-pinene while the main
constituent of resin or resin acids (organic acids obtained from resin) is abietic acid.
Ginkgolides
These diterpenoids are isolated from leaf extracts of the tree Ginkgo biloba (Family: Ginkgoaceae).
The dried leaves contain diterpenoid lactones, ginkgolide A, B, C, J and M, which are collectively
called ginkgolides. The extract of the leaves are used an antiasthmatic, bronchodilator and
neuroprotective.
O
O
O
O
O
O
O
OH
C
CH
3
CH
3
CH
3
R
2
R
3
R
1
Ginkgolide
A
B
C
J
M
R
1
OH
OH
OH
OH
H
R
2
H
OH
OH
H
OH
R
3
H
H
OH
OH
OH
Taxo l
Taxol is a diterpenoid alkaloid isolated from pacifi c yew, i.e. Taxus brevifolia (Family: Taxaceae). The
diterpenoidal skeleton is biosynthetically derived from geranyl geranyl pyrophosphate, whereas
the nitrogen containing portion is derived from phenylalanine. Taxol is used as an important
anticancer drug, recommended in the treatment of ovarian cancer, breast cancer, small cell lung
cancer and cancers of neck and head.
Terpenoids
421
OCOCH
3
O
OH
HO
N
H
O
O
O
O
O
O
O
O
OH
CH
3
Taxol
TRITERPENOIDS
The structure of triterpenoids contains 30 carbon atoms and the compounds are isolated from
both plants and animals. The important triterpenoids are squalene (acyclic), ambrein (tricyclic),
lanosterol (tetracyclic) and amyrins (pentacyclic). Some of the important triterpenoids are
described below:
Squalene
Squalene
Squalene occurs chiefl y in the fi shes of the family Squalidae. The most important source is liver
oil of certain species of sharks. It is also found in cod liver oil, olive oil and several other vegetable
oils.