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-1-
TERPENOIDS
-2-
TERPENOIDS
Introduction
As most of the fundamental knowledge that is common with medicinal
chemistry. The distinguishing feature is that this area involves the study
of natural products from plants, animals, or microbes. The products may
be therapeutically useful or toxic. Natural products chemistry endeavors
to examine the natural source, mechanisms whereby the source
biosynthetically constructs the product, processes whereby the product
can be isolated from the source and techniques used to identify the
product. These studies lay the groundwork for the pharmacological
evaluation of a potentially useful natural product or biochemical
investigation of a natural toxin. A plan of study in natural products
chemistry would emphasize courses in natural products and medicinal
chemistry, chemistry, botany, and microbiology with support courses in
pharmacology and pharmaceutics.
The terpenoids form a group of compounds the majority of which occur
in the plant kingdom; a few terpenoids have been obtained from other
sources. The simpler mono- and sesqui-terpenoids are the chief
constituents of the essential oils; these are the volatile oils obtained from
the sap and tissues of certain plants and trees. The essential oils have been
used in perfumery from the earliest times. The di- and tri-terpenoids
which are not steam volatile, are obtained from plant and tree gums and
resins. The tetraterpenoids form a group of compound known as the
Carotenoids. Rubber is the most important polyterpenoid.
Most natural terpenoid hydrocarbons have the molecular formula (C5H8)n,
and the value of n is used as a basis for classification.
-3-
Number of
carbon atoms
(1)
10
Monoterpenoids (C10H16)
(2)
15
Sesquiterpenoids (C15H24)
(3)
20
Diterpenoids (C20H32)
(4)
25
Sesterterpenoids (C25H40)
(5)
30
Triterpenoids (C30H48)
(6)
40
(7)
>8
> 40
Class
Polyterpenoids (C5H8)n
C
Monoterpenoid
C C C C C C C C
head
tail
tail head
C
C C C C C C C C C C C C
-4-
Sesquiterpenoid
C
C
C
C
C
C
acyclic structure
C
C
C
C
C
p-cymene structure
Bicyclic monoterpenoids contain a six-membered ring and a three-, fouror five-membered ring; all three types are known.
C
C
C
C
CC C
C
C
C
C
C
C
CC C
C
C
C
C
C
C
CC C
C
C
C
-5-
-6-
-7-
-8-
Monoterpenoids:
The monoterpenoids may be subdivided into three groups: acyclic,
monocyclic, and bicyclic. This classification affords a convenient means
of study of the monoterpenoids.
Acyclic Monoterpenoids:
Myrcene
-9-
CH2
H3C
C
H3C
CH CH2 CH2 C
6
CH CH2
2
(I)
(II)
The systematic name of the compound is obtained by the use of the rule
for acyclic polyenes. Thus, myrcene is 7-methyl-3-methyleneocta-1,6diene.
We can now represent the process of ozonolysis and oxidation of the
ketoaldehyde as shown.
O3
2CH2O
+
O
CHO
CHO
CrO3
CO2H
+
CO2
CO2H
Citral
C
C
C
C
C
(I)
(II)
-11-
laevulic acids. Thus, if citral has structure (III), the formation of these
oxidation products may be accounted for:
CO2H
CHO
(i) KMnO4
(ii) CrO3
CO2H
+
O
CO 2H
(III)
The structure is supported by the work of Verley (1897), who found that
aqueous potassium carbonate converted citral into 6-methylhept-5-en-2one (IV) and acetaldehyde. The formation of these products is readily
explained by assuming (III) undergoes cleavage at the ,-double bond;
this cleavage by alkaline reagents is a general reaction of ,-unsaturated
oxo compounds.
CHO
O
OH
(III)
CHO
CH3
(IV)
-12-
Stereochemistry of citral
Examination of the formula of citral shows that two geometrical isomers
are possible. The functional group (aldehyde) is trans or cis with respect
to the methylene group of the main chain. Both isomers occur in natural
citral, e.g., two semicarbazones are formed by citral; both forms of citral
itself have also been obtained: citral-a (also known as geranial) has a b.p.
118-119C/20 mm., and citral-b (also known as neral) has a b.p. 117118C/20 mm. The configuration of these two forms have been
determined from a consideration of the ring closures of the corresponding
alcohols (geraniol).
H
CHO
CHO
-13-
Geraniol
CH2OH
* H
dil.
H2SO4
dil.
H2SO4
CH2OH
OH
geraniol
(trans or E)
-terpineol
nerol
(cis or Z)
-14-
Linalool
Citronellal, C10H18O.
This is an optically active compound which occurs in citronella oil.
Citronellal is an aldehyde; reduction with sodium amalgam converts it
into the alcohol citronellol, C10H20O, and oxidation gives citronellic acid,
-15-
CHO
CrO3
CO2H
CO2H
citronellal
CHO
citronellal
-16-
Na/Hg
CH2OH
citronellol
Monocyclic Monoterpenoids
Nomenclature:
For the purposes of nomenclature of the monocyclic monoterpenoids, the
fully saturated compound p-methyl-isopropyl-cyclohexane, hexahydro-pcymene or p-menthane, C10H20, is used as the parent substance; it is a
synthetic compound, b.p. 170C.
p-Menthane is (I), and (II) is a conventional method of drawing formula
(I). The positions of substituents and double bonds are indicated by
numbers, the method of numbering being shown in (I) and (II).
7 CH
3
H2C 6
H2C5
9
H3C
CH
2 CH2
3 CH
2
CH
CH
8
6
5
1
4
2
3
10
CH3
(I)
10
(II)
-p-menthene;
2-p-menthene;
p-menth-2-ene;
p-methene-2
p-meth1(7)-ene
-17-
p-mentha1,4(8)-diene
-Terpineol:
This is an optically active monoterpenoid that occurs naturally in the (+)-,
(-)- and ()-forms; it is a solid, m.p. (of the racemic modification) 35C.
The molecular formula of -terpineol is C10H18O, and the oxygen atom is
present as a tertiary alcoholic group (as shown by the reactions of terpineol). Since -terpineol adds on two bromine atoms, it therefore
contains one double bond. Thus the parent (saturated) hydrocarbon of terpineol has the molecular formula C10H20. This corresponds to CnH2n, the
general formula of the (monocyclic) cycloalkanes, and so it follows that
-terpineol is a monocyclic compound.
When heated with sulphuric acid, -terpineol forms some p-cymene.
Taking this in conjunction with the tentative proposal that -terpineol is
monocyclic, it is reasonable to infer that -terpineol contains the pcymene skeleton. Thus we may conclude that -terpineol is probably pmenthane with one double bond and a tertiary alcoholic group.
The positions of these functional groups were ascertained by Wallach
(1893, 1895) by means of graded oxidation.
Oxidation of -terpineol (1) with alkaline potassium permanganate (1%)
hydroxylates the double bond to produce the trihydroxy compound (2),
C10H20O3. This on oxidation with chromic acid (Chromium trioxide in
acetic acid) produces the compound 4 which has molecular formula of
C10H16O3. This compound was shown to contain a ketonic group and that
it was neutral. It gave no reaction with sodium carbonate solution. When
4 was refluxed with excess of standard hydroxide solution, and then back
titrated it was found that alkali had been consumed corresponding to one
-18-
KMnO4
O
COOH
CrO3
1% alkaline
CH3COOH
OH
OH
OH
COOH
HOOC
O
O
6
Terepic acid
KMnO4
O
O
5
Terpenylic acid
warm alk.
KMnO4
- CH3COOH
O
O
4
-19-
(i) MeMgBr
(ii) H+
O
OH
Two other terpineols are also known: - and -terpineol; the latter occurs
naturally.
OH
OH
-terpineol
m.p. 32-33C
-terpineol
m.p. 68-70C
-20-
Carvone
Carvone, C10H14O, b.p. 230C/755 nm.
This occurs in various essential oils, e.g., spearmint and caraway oils, in
optically active forms and also as the racemic modification.
The structure of carvone is largely based on the fact that carvone may be
prepared from -terpineol as follows:
Cl
NOCl
NOH
isomn.
OH
(I)
Cl
NO
OH
(II)
EtONa
(-HCl)
OH
(III)
NOH
H2SO4
OH
(IV)
(V)
Carvone
-21-
-22-
Limonene
Limonene
- H2O
Or
OH
-Terpineol
The carbon skeleton and the position of one double bond in limonene are
known. The position of the other double bond, however remains uncertain
from this preparation; 1 or 2 is possible.
-23-
Proof of position 8.
Structure 1 contains a chiral center C-4, and hence can exhibit optical
activity. Structure 2 is symmetric and so cannot be optically active.
Therefore 1 must be limonene.
Chemical proof for position 8 is afforded by the following reactions:
Limonene
1
NOCl
KOH Carvoxime
EtOH
3
Cl
NO
NOCl
NOH
KOH
isom.
NOH
EtOH
-24-
[4H]
OH
O
(I)
Pulegone
(II)
Menthol
-25-
1
4
Me H
Me OH H
2
3
OH
OH
Pri
H
4
OH Pri
neomenthol
menthol
Me H
1
OH
Me OH Pri
Pri
4
OH
OH H
neoisomenthol
isomenthol
OH
(II)
Menthol
(III)
Menthone
-26-
COOEt
COOEt
heat
Na
- CO
O
COOEt
O
COOEt
1) EtONa
2) Me2CHI
COOH
1) EtONa
Ca salt
heat
COOH
2) H+
O
EtOOC
Menthone
NaBH4
4H
EtOH
OH
Menthone
Menthol
-27-
Pulegone
Bicyclic Monoterpenoids
The bicyclic monoterpenoids may be divided into three classes according
to the size of the second ring, the first being a six-membered ring in each
class.
10
1
7
7
9
9
8
thujane
carane
10
2
3
1
8
7
6
9
7
4
5
Pinane
1
6
5
7 9
bornane
(camphane)
2
7
norbornane
derivative
(isocamphane)
6
7
5
4
norbornane
derivative
(fenchane)
1
6
5
1
2
norbornane
derivative
(isobornylane)
7
3
4
norbornane
It is important to note that the two rings do not lie in one plane, but are
almost perpendicular to each other.
-28-
Car-3-ene
Car-2-ene
-thujane
(+)-sabinene
-29-
COOH
COOEt
Ac2O
COOEt
Na
i) HBr
EtOH
ii) KCN
CN
CH2OH
HOOC
i) HCl
ii) EtOH/HCl
COOEt
COOEt
COOEt
i) SOCl2
NPh2
Partial
hydrolysis
COOH
ii) Ph2NH
COOEt
H2SO4
COOH
i) SOCl2
i) KOH
ii) MeCdCl
NPh2
NPh2
ii) HCl
O
OH
trans-Pinonic acid
COOH
COOEt
H+
ClCH2COOEt
OEt
EtONa
Ethyl Pinonate
COOEt
O
140oC
CHO
COOH
KMnO4
EtOH/HCl
OH
OH
OEt
O
OH
Glycidic ester
COOEt
-30-
Na
(Dieckmann)
HCl
NH2
i) NH2OH
ii) (H)
COOEt
i) MeI
ii) AgOH
+
-Pinene
NMe3+OH-
Distillation
Reduced pressure
-Pinene
The final step gives a mixture of two compounds - and -pinene. This
was identified by the preparation of nitrosyl chloride; this proves that one
of the pinenes is but does not prove which is and which is . The
reaction of the pinenes with diazoacetic ester to form pyrazoline
derivatives which on heating alone or with cupper powder, decompose to
produce cyclopropane derivatives.
COOEt
HOOC
[O]
i) N2CHCOOEt
COOH
HOOC
-Pinene
HOOC
i) N2CHCOOEt
COOEt
[O]
COOH
HOOC
-Pinene
When the two pinenes were subjected to this treatment, and the resulting
compounds oxidized, -pinene gave 1-methylcyclopropane-1,2,3-tricarboxylic acid and -pinene gave cyclopropane-1,2,3-tricarboxylic acid.
These products are in accord with the structures assigned to - and pinenes.
-31-
OH
Na/Hg
H2O
HI
Zn
CH3CO 2H
2
7
bornane
(ii) Camphor may also be converted into bornane by means of WolffKishner reduction.
O
N2H4
NHNH2
C2H5ONa
heat
-32-
N2
Camphor
CO 2H
[O]
CO 2H
[O]
CO 2H
CO 2H
(I)
(II)
[O]
-CO2
OH
CO2H [O]
O
CO 2H
HO 2C
CO2H
(III)
-33-
-34-
Sesquiterpenoids
The sesquiterpenoids, in general, form the higher boiling fraction of the
essential oils; this provides their chief source. Wallach (1887) was the
first to suggest that the sesquiterpenoid structure is built up of three
isoprene units; this has been shown to be the case for the majority of the
known sesquiterpenoids, but there are some exceptions.
The sesquiterpenoids are classified into four groups according to the
number of rings present in the structure. If we use the isoprene rule, then
when three isoprene units are linked (head to tail) to form an acyclic
sesquiterpenoid hydrocarbon, the latter will contain four double bonds.
Each isoprene unit contains two double bonds, but one disappears for
each pair that is connected:
C
C
C C C + C C C C + C
C
C C C C
C C
Class of sesquiterpenoids
C C C
C C C
C C C
Acyclic
Monocyclic
Bicyclic
Tricyclic
-35-
Acyclic Sesquiterpenoids
Examples of acyclic sesquiterpenoids:
1- Farnesene
-farnesene
-farnesene
2- Farnesol
-36-
CrO 3
CH2OH
(I)
CHO
(i) NH2OH
(ii) Ac2O
(II)
(i) KOH
(ii) H+
CN
(III)
CO 2H
+
O
(IV)
(V)
-37-
(i) PCl5/luitidine
(ii) NaNH2/liq. NH3 C
CH2O
CNa
(i) LAH/AlCl3
(ii) I2
trans-geranylacetone
CH2OH
Me2CuLi
I
CH2OH
CH2OH
3-Nerolidol
HO
-38-
EtOOC
EtOOC
Cl
+
i) Bu(OH)2
EtONa
ii) HCl
O
Geranyl chloride
i) NaNH2
ii) HC CH
ii) H2O
Na
moist ether
HO
HO
(+)-Nerolidol
Diterpenoids
Vitamin A1 and A2 are monocyclic diterpenoids. They are usually
classified as belonging to the apocarotenoid group.
Vitamin A1.
Vitamin A1 influences growth in animals and also increase resistance to
disease. Night blindness is due to Vitamin A1 deficency in the human diet
and prolonged deficiency leads to xerophthalmia (hardening of the
cornea). Vitamin A1 occurs free as esters in fats, in fish, livers and in
blood. It was usually isolated as a viscous yellow oil, but later it was
-39-
COOEt
i) Zn/BrCH2CH = CHCOOEt
OH
ii) H+
COOH
CH3Li
O
i) BrMg
COEt
ii) H+
CHO
(i)
(ii)
LAH
-40-
OEt
OH
Triterpenoids
Squalene, C30H50, b.p. 240-242C/4 mm.
It has been isolated from the liver oils of sharks. Other sources are olive
oil and several other vegetable oils. Squalene has also been detected in
leaves. Catalytic hydrogenation (nickel) converts squalene into
perhydrosqualene, C30H62; therefore squalene has six double bonds, and is
acyclic. Ozonolysis of squalene gives, among other products, laevulic
acid; this suggests that the group (I) is present in squalene. Since
squalene cannot be reduced by sodium and amyl alcohol, there are no
conjugated double bonds present in the molecule. Perhydrosqualene was
found to be identical with the product obtained by subjecting hexahydrofarnesyl bromide to the Wurtz reaction. This led Karrer et al. (1931) to
synthesis squalene (II) from farnesyl bromide by a Wurtz reaction.
(I)
CH2Br
2
Mg
(II)
squalene (all-trans)
-41-
Polyterpenoids
Polymeric isoprenoid hydrocarbons have also been identified. Rubber is
undoubtedly the best known and most widely used compound of this
kind. It occurs as a colloidal suspension called latex in a number of
plants, ranging from the dandelion to the rubber tree (Hevea brasiliensis).
Rubber is a polyene, and exhibits all the expected reactions of the C=C
function. Bromine, hydrogen chloride and hydrogen all add with a
stoichiometry of one molar equivalent per isoprene unit. Ozonolysis of
rubber generates a mixture of levulinic acid ( CH3COCH2CH2CO2H ) and
the corresponding aldehyde. Pyrolysis of rubber produces the diene
isoprene along with other products.
The double bonds in rubber all have a Z-configuration, which causes this
macromolecule to adopt a kinked or coiled conformation. This is reflected
in the physical properties of rubber. Despite its high molecular weight
(about one million), crude latex rubber is a soft, sticky, elastic substance.
Chemical modification of this material is normal for commercial
applications. Gutta-percha (structure above) is a naturally occurring Eisomer of rubber. Here the hydrocarbon chains adopt a uniform zig-zag or
rod like conformation, which produces a more rigid and tough substance.
Uses of gutta-percha include electrical insulation and the covering of golf
balls.
-42-
Rubber
Rubber (caoutchouc) is obtained from latex, which is an emulsion of
rubber particles in water that is obtained from the inner bark of many
types of trees which grow in the tropics and sub-tropics. When the bark of
the rubber trees is cut, latex slowly exudes from the cut. Addition of the
acetic acid coagulates the rubber, which is then separated from the liquor
and either pressed into blocks or rolled into sheets, and finally dried in a
current of warm air, or smoked.
+
OHC
O
rubber
+
-44-
OHC
O
+
OHC
O
CHO
CO2
-45-
+ HO2C
CO 2H
Gutta-percha
Gutta-percha. (Is obtained from the bark of various trees). It is isomeric
with rubber; their structures are the same, as shown by the methods of
analysis that were used for rubber. X-ray diffraction studies (Bunn, 1942)
have shown that rubber is composed of long chains built up to isoprene
units arranged in the cis-form, whereas gutta-percha is the trans-form.
Gutta-percha is hard and has a very low elasticity.
Synthetic rubbers. There are many synthetic rubbers in use, each type
possessing certain desirable properties. A great deal of work has been
-46-
done on the synthesis of natural rubber, but the difficulty has been to
obtain the isoprene units in the all cis-configuration. This has now been
achieved by means of the Ziegler-Natta catalysts, e.g., a triethylaluminium-titanium chloride complex to which has been added finely
divided lithium. The product obtained in this way is identical with natural
rubber.
-47-
STEROIDS
-48-
-49-
STEROIDS
Introduction
The important class of lipids called steroids are actually metabolic
terpenoid derivatives of terpenes, but they are customarily treated as a
separate group. Steroids may be recognized by their tetracyclic skeleton,
consisting of three fused six-membered and one five-membered ring, as
shown in the diagram to the right. The four rings are designated A, B, C
& D as noted below. The substituents designated by R are often alkyl
groups, but may also have functionality. The R group at the A:B ring
fusion is most commonly methyl or hydrogen, that at the C:D fusion is
usually methyl. The substituent at C-17 varies considerably, and is
usually larger than methyl if it is not a functional group. The most
common locations of functional groups are C-3, C-4, C-7, C-11, C-12 &
C-17. Ring A is sometimes aromatic.
Steroids are solid alcohols that are widely distributed in animal and plant
kingdoms. The basic skeleton consists of 17 carbon atoms arranged in the
form of perhydrocyclopentenophenanthrene. A steroid could be defined in
another way, as any compound which gives Diels hydrocarbon when
distilled with selenium.
14
HO
HO
Sterol
Lanosterol
Classification of Steroids
Steroids include many compounds of great importance to life. They could
be classified into the following groups:
I- Sterols
Such as cholesterol, the characteristic steroid of higher animals,
ergosterol which is converted to vitamin D by irradiation as well as the
common phytosterols, -sitosterol and stigmasterol.
21
20
18
19
24
23
17
22
26
25
27
14
H
HO
HO
Ergosterol
Cholesterol
H
H
HO
HO
Stigmasterol
-sitosterol
-51-
Cholesterol
plasma membranes can be extracted by HDLs and esterified by the HDLassociated enzyme LCAT. The cholesterol acquired from peripheral
tissues by HDLs can then be transferred to VLDLs and LDLs via the
action of cholesteryl ester transfer protein (apo-D) which is associated
with HDLs. Reverse cholesterol transport allows peripheral cholesterol to
be returned to the liver in LDLs. Ultimately, cholesterol is excreted in the
bile as free cholesterol or as bile salts following conversion to bile acids
in the liver.
II- Vitamin D group
They are about seven compounds (vitamin D1-D7) with the ring B being
opened. Vitamin D2 (or calciferol) is formed from ergosterol by the
sunlight irradiation.
HO
[1,7] H-shift
HO
Ergosterol
HO
Calciferol
-53-
OH
COOH
H
H
HO
H
OH
Cholic acid
IV- Sex hormones
These could be divided into:
(1) Oestrogens: Characterized by ring A being aromatic, and hence
without the C-19 methyl group. They are responsible for development
and maintenance of the female secondary sex organs. An example is
-Oestradiol, main female sex hormone.
OH
H
H
HO
-Oestradiol
Testosterone
(3) Gestogens: Are hormones which are responsible for the maintenance
of pregnancy. An example is progesterone.
-54-
H
H
Progesterone
V- Adrenocortical hormones
Produced by the cortex of the adrenal glands. A lack of these hormones
leads to multiple symptoms e.g. muscular weakness, change in
carbohydrate and protein metabolism, disturbance of electrolyte balance,
etc. and eventually death. An example is cortisone.
CH2OH
C
O
O
OH
Cortisone
VI- Cardenolides
Are plant steroid which occur as glycosides. Cardiac glycosides have
powerful cardiotonic activity and can be used for treatment of heart
failure. These compounds are characterized by having a lactone group.
An example is strophanthidin.
O
23
22
21
20
OHC
OH
HO
OH
Strophanthidin
-55-
VII- Sapogenins
Are the aglycones of saponins. The first source of steroidal saponins was
Digitalis purpurea, more important as a source of the cardiac glycosides.
Sapogenins are characterized structurally by the presence of both furan
and pyran rings and spiro carbon atom (named spirostane). An example is
diosgenin.
OO
HO
Diosgenin
-56-
Mycosterol
Ergosterol: C28H44O
This occurs in yeast, Ergosterol forms an esters e.g. an acetate with acetic
anhydride, thus there is a hydroxyl group present in ergosterol.
HO
22
21
23
20
24
26
25
O3
+ OHC
27
28
H
Ergosterol
unsaturation. The side chain must contain only one double bond, since if
more than one were present, more than one fragment would have been
removed on ozonolysis, when heated with maleic anhydride at 135C,
ergosterol forms an adduct, and so it follows that the two double bonds
(in the nucleus) are conjugated. Now ergosterol has an absorption
maximum at 282 nm. Conjugated acyclic dienes absorb in the region of
220-250 nm, but if the diene is in a ring system, then the absorption is
-57-
shifted to the region 260-290 nm. Thus the two double bonds in the
nucleus of ergosterol are in one of the rings.
The ultraviolet light effect on ergosterol resulted in the isolation of
vitamin D2 or ergocalciferol.
HO
HO
Ergosterol
Vitamin D2
(Ergocalciferol)
-58-
+ CH2O
O3
O
(C13H20O3)
H
HO
Vitamin D2
CrO3
or KMnO 4
H
(C21H34O)
OHC
-59-
Bile Acids
The bile acids occur in bile (a secretion of the liver which is stored in the
gall bladder) of most animals combined as amides with either glycine
(NH2CH2COOH) or taurine (NH2CH2CH2SO3H), e.g. glycocholic acid (=
glycine + cholic acid), tauro-cholic acid (= taurine + cholic acid). The bile
acids are present as sodium salts.
22
21
12
19
1
2
11
9
10
18
13
23
20
17
COOH
COOH
H
16
14
15
7
4
-cholanic acid
(allo-cholanic acid)
-cholanic acid
(cholanic acid)
Most of the bile acids are hydroxy derivatives of either 5-cholanic acid
or 5-cholanic acid.
About twenty natural bile acids have been characterized and many others
are synthetic. The position of the hydroxyl group are any of the following
3, 6, 7, 11, 12 and 23 and in almost all of natural bile acids the
configuration of the hydroxyl groups are -. Some of the more important
natural bile acids are:
Name
m.p. C
Hydroxy groups
Cholic acid
195
3, 7, 12
Doexycholic acid
172
3, 12
Lithocholic acid
186
140
3, 7
-60-
The structures of 5-cholanic acid (cholanic acid) and 5cholanic acid (allo cholanic acid):
These acids may be derived from 5-cholestane (coprostane) and 5cholestane, respectively, as follows. At the same time, these reactions
shows the relationship between the bile acids and the sterols.
H
H
oppenauer
oxid
HO
H2-pt
O
Cholest-4-en-3-one
Cholesterol
COOH
HO
CrO3
(i) CrO3
(ii) Zn-Hg/HCl
-Cholestan-3-ol
(coprostanol)
-Cholestane
(coprostane)
-Cholanic acid
CrO3
H2-pt
HO
HO
Cholesterol
-Cholestan-3-ol
-Cholestan-3-one
COOH
H
CrO3
Zn/Hg
HCl
H
-Cholestane
-Cholanic acid
-61-
COOH
H
H
H
HO
H
HO
OH
Lithocholic acid
Cholic acid
COOH
H
H
HO
H
OH
-62-
-63-
Steroid hormones
Introduction:
Hormones are substances which are secreted by the ductless glands, and
only minute amounts are necessary to produce the various physiological
reactions in the body. As a group, hormones do not resemble one another
chemically, and their classification is based on their physiological
activity. The sex hormones belong to the steroid class of compounds, and
are produced in the gonads (testes in the male, and ovaries in the female).
Their activity appears to be controlled by the hormones that are produced
in the anterior lobe of the pituitary gland. Because of this, the sex
hormones are sometimes called the secondary sex hormones, and the
hormones of the anterior lobe of the pituitary (which are protein in
nature) are called the primary sex hormones.
Sex hormones:
The sex hormones are of three types: the androgens (male hormones), the
oestrogens (female hormones) and gestogens (the corpus luteum
hormones). The sex hormones are responsible for the sexual processes,
and for the secondary characteristics which differentiate males from
females.
-64-
Androgens
Androsterone: C19H30O2, m.p. 183C, []D +94
It was first isolated by Butenandt et al. (1931) from male urine (about 15
mg from 15000 litres of urine). Androsterone behaves as a saturated
compound, and since it forms mono-esters, one oxygen atom is present as
a hydroxyl group. The functional nature of the other oxygen atom was
shown to be oxo, since androsterone forms an oxime, etc. The parent
hydrocarbon of androsterone, C19H30O2, is therefore C19H32, and since this
corresponds to the general formula CnH2n-6, the molecules is tetracyclic
(D.B.E. of C19H30O2 = 19 + 1 30/2 = 5; 1 double bond due to C=O, and
so there are four rings). This led to the suggestion that androsterone
probably contains the steroid nucleus, and since it is a hydroxyketone, it
was thought that it is possibly related to oestrone. Butenandt (1932)
therefore proposed a structure which was proved correct by Ruzicka
(1934) as follows.
O
H
H
AcO
(i) CrO3
(ii) hydrolysis
HO
H
-cholestanyl -acetate
H
epiandrosterone
O
H
H
AcO
(i) CrO 3
(ii) hydrolysis
HO
H
-cholestanyl -acetate
H
H
androsterone
-65-
AcONa
AcOH-Ac2O
H
H
OH
H
H
+
AcO
H
39%
54%
OH
NaOH
O
O
H
H
H
H
HO
H
AcOH aq.
PhCO2H
H
H
O
LiAlH4
H
O
O
H
H
HO
OH
OH
H
H
TsOH, PhH
HO
O
Oppenauer
oxidn.
HO
dehydroepiandrosterone
OH
OH
(i) B2H6
(ii) Ac2O
H
H
O
H
H
TsOH, PhH
H
H
O
O
(i) B2H6
(iii) H2O2,OH
H
H
H
H
(iii) H+
HO
H
androsterone
-67-
Testosterone
Testosterone: C19H28O2, m.p. 155C, []D +109
OH
H
H
Synthesis of Dehydroepiandrosterone:
Synthesis of Testosterone:
-68-
OH
O
H
H
(i) Ac2O
(ii) Na-C3O7OH
(i) PhCOCl
(ii) Mild hydrolysis
AcO
HO
Dehydroepiandrosterone
OCOPh
Oppenauer
Oxid
H
H
OCOPh
HO
H
OH
H
H
Testosterone
Oestrogens
-69-
hydrolysis
KOH
H
H
Oestrone
It has been known for a long time that there are hormones which control
the uterine cycle, but it was not until that Butenandt and Doisy
independently isolated the active substance oestrone from the urine of
pregnant women. Oestrone is the first known member of the sex
hormones, and soon after its discovery two other hormones were isolated,
oestriol, and oestradiol.
(+) Oestrone, m.p. 259C, []D +170, has the molecular formula
C18H22O2. It behaves as a ketone, and contains one hydroxyl group (this
hydroxyl group is phenolic).
O
H
H
HO
Oestrone
-70-
OH
H
H
H
HO
HO
Oestradiol-17
Oestradiol-17
O
H
H
HO
controll
benzoylat
Na/Hg
Red.
HO
Dehydroepiandrosterone
OCOC6H5
OCOC6H5
H2
H
H
HO
H
HO
-71-
oxid
H
H
OH
H
control
oxid
HO
HO
Oestrone
Oestradiol
NOH
Zn dust
CH3COOH
H
H
CH3O
CH3O
OH
OH
OH
O
Na
(CH3)2CHOH
H
H
CH3O
CH3O
OH
OH
H
H
HO
Oestriol
-72-
H
H
HO
PhCO3H
isopropenyl
acetate
H
H
AcO
OH
AcO O
AcO
LiALH4
H
H
OH
H
HO
Oestriol
-73-
(+)-Equilenin
(+)-Equilenin: C18H18O2, m.p. 258-259C, []D +87
This has been isolated from the urine of pregnant amres by Girard et al.
(1932); it is not a very potent oestrogen.
CH3
CH3
CH3O
HO
(II)
O
H
Na
C2H5OH
HO
(I)
equilenin
(III)
oestrone
The first synthesis was by Bachmann et al. (1940), but was somewhat
improved by Johnson et al. (1947). In the following chart, compound (IV)
is synthesized by the method of Bachmann, and the rest of the synthesis is
that of Johnson, who started with compound (IV) [Johnsons synthesis
involves fewer steps than Bachmanns].
NH2
NH2
(CH3CO)2O
KOH
HO 3S
NHCOCH3
HO
HO
Cleve's acid
CH2OH
NH2
I
(i) NaNO2-H2SO 4
(ii) KI
CH3O
CH3O
CH2Br
CH2
CH3O
CH2
(i) Mg
(ii) H2C
CH2
O
CH2
CH2
CH3O
CH2
CO 2H (i) SOCl2
(ii) SnCl4
malonic ester
synthesis
CH3O
PBr3
O
CH3O
(IV)
-74-
(IV)
CH
OH
N
OH
N
OH
CN
-H2O
CH3
CN
O
NH2OH.HCl
O CH3CO2H
O HCO2C2H5
CH3ONa
CH3O
CH3O
CH
methyl succinate
(CH3)3COK
N (CH3)3COK
+
OK
CH3
CN
CCH2CO2CH3
CO2CH3
-75-
H3C
(Thorpe
reaction)
CH3I
NH
CO2K
CO2CH3
Artificial hormones
Many compounds with oestrogenic activity but not of steroid structure
have been prepared synthetically.
Stilboestrol: (4,4-dihydroxydiethylstilbene)
Was prepared by Dodds et al. (1939) as follows:
2CH3O
CHO
KCN
anisoin
anisaldehyde
CH3O
SnCl2
OCH3
CHOHCO
CH3O
CH2CO
C2H5
C H ONa
CH3O
OCH3 2 5
C2H5I
OCH3
CHCO
C2H5MgI
deoxyanisoin
C2H5 C2H5
CH3O
CH C
OCH3
OH
C2H5 C2H5
PBr3
CH3O
(-H2O)
OCH3
ethanolic
KOH
C2H5 C2H5
HO
stilboestrol
H3C
C
CH2
trans-stilboestrol
-76-
OH
OH
CH CHCH3
HBr
CHBrCH2CH3
CH3O
NaNH2
liq. NH3
anethole
CH CH
CH3O
OCH3
alkali
HO
CH CH2
OH
C2H5 C2H5
CH2 CH3
(I)
Hexoestrol: (dihydrostilboestrol)
May be prepared from anethole hydrobromide as follows:
2 CH3O
CHBrC2H5
Na
CH CH
CH3O
OCH3
C2H5 C2H5
ethanolic
KOH
HO
CH CH
OH
C2H5 C2H5
hexoestrol
-77-
Gestogens
Progesterone
-78-
-79-
-80-
Adrenocortical Hormones
Introduction:
In the adrenal glands (of mammals) there are two regions, the medulla
which produces adrenaline, and the cortex which produces steroid
hormones. The production of these adrenocortical hormones or corticoids
is controlled by the hormone produced in the anterior lobe of the pituitary,
the so-called adrenocorticortrophic hormone, ACTH. The corticoids have
many physiological functions, but their main functions are the control of
carbohydrate and protein metabolism and the control of the balance of
water and electrolytes.
CH2OAc
CO
C(OH)CN
O
H
H
AcO
HCN
H
H
AcO
H
CH2OH
CH2OAc
CCN
CCN
O
H
HO
O
Ac2O
(i) POCl3-C5H5N(-H2O)
(ii) KOH
OsO4
H
H
H
HO
-81-
CH2OAc
CN
C O
OsO2
O
(i) CrO3
(ii) Na2SO3
O
H
H
HO
OH
H
H
CH2OAc
CH2OH
CO
CO
OH
O
(i) -HBr
(ii) hydrolysis
Br
CO
CH2OH
H
H
H
O
cortisone
-82-
OH
(i) Ac2O
(ii) Br2