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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
252
Pharmaceutical Chemistry of Natural Products
7. If the double bond is not between sequentially numbered carbons, both the carbons are
indicated in the name.
8. The ring juncture or backbone carbons are shown in the structure of 5α-cholestane with a
heavy dark line.
H
H
H
H
HO
H
H
H
H
H
H
H
O
O
HH
H
OH
OH
HO
O
O
Et
Cholestane (C )
27
Cholesterol
(Cholest-5-en-3 -ol)␣
3 ,5 -Cyclocholestane (C )27␣␣
Pregnane (C )
21
Progesterone
(pregn-4-ene-3,20-dione)
Hydrocortisone (11,17 ,21-
trihydroxypregn-4-ene-3,20-dione)
a
B-Homo-5 -pregnane
HH
H
OH
H
O
HO
O
HOOC
HOOC
H
H
H
H
CH
3
O
Androstane (C )
19
Testosterone
(17 -hydroxyandrost-
4-en-3-one)

Dehydroepiandrosterone
(DHEA) (3 -hydroxyandrost-
5-en-17-one)

5 ,19−nor-
androst-3-one

2,3-Seco-5 -androstane-
2,3-dioic acid

H
H
HH
HO
Estrane (C )
18
17 -Estradiol [Estra- 1,
3,5(10)triene-3,17 −diol]
D

OH
Steroid skeleton (stem) name Steroid skeleton containing compounds
Figure 6.1 Steroid stem name and naming of their derivatives
Steroids and Hormones
253
9. Solid lines denote groups above the plane of the nucleus (β-confi guration) and dotted
or broken lines denote groups below the plane (α). If the confi guration of substituent is
unknown, its bond to the nucleus is drawn as a wavy line (ξ).
10. Circles were sometimes used to indicate α-hydrogens and dark dots to indicate
β-hydrogens.
11. If the steroid contains a three-membered ring, it is indicated by the prefi x ‘cyclo’, preceded
by the numbers of positions concerned.
12. The confi guration of the H at C-5 is always indicated in the name.
13. Compounds with 5α-cholestane belong to allo series while compounds derived from 5β-
cholestane belong to the normal series.
14. Any contraction of the steroid ring is indicated by the prefi x ‘nor’ preceded by a small capital
letter indicating the ring affected.
15. Any enlargement of the steroid ring is indicated by the prefi x ‘homo’ preceded by a small
capital letter indicating the ring affected.
16. When a methyl group is missing from the side chain, it is again indicated by the prefi x ‘nor’
with the number of carbon atom from which it has disappeared.
17. If any ring fi ssion occurs in steroid with the addition of a hydrogen atom to each new terminal
group, it is indicated by the numbers showing the positions of the bond broken, followed by
the prefi x ‘seco’.
18. On the basis of following priorities, suffi x for the stem name is selected: carboxylic acid (or
derivative) > carbonyl > alcohol > amine > ether.
19. The carbon number of the substituent (and stereochemistry, if present) is placed in front of
the suffi x.
Various examples are shown in Figure 6.1 to illustrate these rules.
Stereochemistry
The stereochemistry of the rings markedly affects the biological activity of a given class of steroids.
There are six asymmetric carbon atoms (5, 8, 9, 10, 13 and 14) in the nucleus. Therefore, 64
(2
6
) optically active forms are possible. Cholestane, androstane and pregnane can exist into two
conformations, namely chair form and boat form. Chair conformation is more stable than boat
conformation due to less angle strain, and hence all cyclohexane rings in the steroid nucleus exist
in the chair confi rmation.
Hydrogens or functional groups on the β-side of the molecule are denoted by solid lines and
the α-side is denoted by dotted lines.
The hydrogen atom at C-5 has α-confi guration, which is opposite from the C-19 angular methyl
group (β), making the A/B ring juncture trans. The confi guration of the 8β and 9α-hydrogens, and
the 14α-hydrogen and C-18 angular methyl group denotes trans fusion for rings B/C and C/D.
The cis or trans relationship of the four rings may be expressed in terms of the backbone. The
compound 5α-cholestane is said to have a trans–anti–trans–anti–trans backbone. In this structure,
all the fused rings have trans (diequatorial) stereochemistry. The term anti is used in backbone
notation to defi ne the orientation of rings that are connected to each other and have a trans-type
relationship. 5β-Cholestane has a cis–anti–trans–anti–trans backbone in which the A/B rings are
fused cis. The term syn is used in a similar fashion as anti to defi ne a cis-type relationship.
254
Pharmaceutical Chemistry of Natural Products
Conformational representation of 5 -Cholestane
5 -Cholestane
H
HH
H
␣e H
 H
a
a H
H
␣a
be H
H ␣a
CH
3
CH
3
e H
e H
␣a H
H
␣a
H
␣ ’a
a
CH
3
CH
3
e’
Planar and conformational structure of 5 -Cholestane
5 -Cholestanea
H
HH
H
e␣
e
␣a
CH
3
CH
3
␣
e
␣a
e H
H ␣a
H ␣a
H ␣a
H ␣a’

e’
CH
3
CH
3

a
Conformational representation of 5 -Cholestanea
Planar and conformational structure of 5 -Cholestanea
Qualitative Chemical Tests for Steroids
1. Salkowski reaction: To 2 mL of the extract add 2 mL chloroform and 2 mL concentrated
sulphuric acid and shake well. The chloroform layer appears red and the acid layer shows
greenish yellow fl uorescence.
2. Liebermann–Burchard reaction: Mix 2 mL of the extract with chloroform, add 1–2 mL acetic
anhydride and two drops of concentrated sulphuric acid along the sides of test tube. First red,
then blue and fi nally green colour appears.
3. Liebermann’s reaction: Mix 3 mL of the extract with 3 mL of acetic anhydride, heat it and then
cool. Add few drops of concentrated sulphuric acid. Blue colour appears.
STEROLS
Sterols are the crystalline steroids which contain an alcoholic group. They differ from common
alcohols in being solid and due to this reason these are called sterols. Sterols are components of
Steroids and Hormones
255
virtually all plant and animal cells. They contain one alcohol functional group and may be either
saturated (plant sterols) or unsaturated (all animal sterols and many plant sterols). Sterols are
waxy, colourless solids soluble in most of the organic solvents and insoluble in water.
Based on their sources, sterols are classifi ed as follows:
1. Zoosterols: Sterols obtained from animal sources (e.g. cholesterol, cholestanol and
coprostanol).
2. Phytosterols: Sterols obtained from plant sources (e.g. ergosterol and stigmasterol).
3. Mycosterols: Sterols obtained from yeast and fungi (e.g. ergosterol).
4. Miscellaneous: These occur naturally (e.g. zymosterol, episterol and iophenol).
Some of the sterols are obtained from more than one source. For example, ergosterol is
obtained from plants as well as from yeast and fungi.
Cholesterol
Cholesterol
HH
H
HO
Cholesterol is present in all mammalian tissues either in the free state or esterifi ed with fatty
acids. The microsomal and cytosol fraction of the cell is responsible for cholesterol synthesis.
Large quantities of cholesterol are present in human body, especially in the brain and nervous
tissues. Liver, kidney, spleen and skin also contain fairly signifi cant amounts of cholesterol.
Dietary cholesterol is obtained only from animal sources such as meat, liver, brain and egg yolk.
Cholesterol was initially isolated from human gall stones. Various other sources of cholesterol
include fi sh liver oils, the brain and spinal cord of cattle. Lanoline, the fat from wool, consists of a
mixture of cholesteryl palmitate, stearate and oleate. Cholesterol is a white crystalline solid. It is
optically active, laevorotatory in nature. In the plasma lipoproteins, cholesterol is present in two
forms: (i) in an esterifi ed form with long-chain fatty acids (about 70–75%); (ii) as free cholesterol
(about 25–30%). The latter form of cholesterol readily exchanges between different lipoproteins
and also with the cell membrane.
Physiological importance of cholesterol in the body is as follows:
1. It transports fat to the liver in the form of cholesterol ester for oxidation.
2. It controls the red cells from being easily haemolysed.
3. It is the essential constituent of cells.
4. It aids in the permeability of the cells.
5. It functions as the defensive action.
256
Pharmaceutical Chemistry of Natural Products
6. It assists in the formation of vitamin D
3
, bile acids and bile salts, corticosteroid hormones,
androgens, oestrogens and progesterone.
7. The solid matter of the human brain is 17% cholesterol.
8. Gall stones consist almost entirely of cholesterol.
9. Steroidal sapogenins and several groups of the steroid alkaloids are based on cholesterol
framework structure.
10. Mammalian steroid hormones and bile acids are derived enzymatically from cholesterol.
Colour reactions: Cholesterol and other sterols respond to the following colour reactions:
1. Salkowski reaction
2. Liebermann–Burchard reaction
3. Liebermann’s reaction.
Isolation: The source of cholesterol is treated with ethanol and then centrifuged to get ethanolic
solution of cholesterol. An ethanolic solution of digitonin is added to this ethanolic solution of
cholesterol and a large white precipitate of cholesterol digitonide is obtained. From this molecular
complex cholesterol can be recovered by either of the following ways:
Method A: The complex is broken down into its constituents by pyridine. Then ether is added
when cholesterol remains in the solution while digitonin gets precipitated. Finally, the solution is
evaporated to get rid of the solvent so as to obtain cholesterol.
Method B: An alternative method is to dissolve the complex in dimethyl sulphoxide and
then heat on a steam bath to dissociate the complex. When this solution is cooled, cholesterol is
deposited.
Lanosterol
Lanosterol
HO
1
2
3
5
4
10
11
8
7
6
12
14
13
17
16
15
9
1. It is an optically active compound which occurs in wool fat along with its derivative,
dihydrolanosterol (lanosterol).
2. It is closely related to sterols in both structure and stereochemistry.
3. It is isolated from yeast and also forms a latex along with a pentacyclic triterpene.
Steroids and Hormones
257
Stigmasterol
1
2
3
10
19
5
4
6
7
8
9
11
12
13
17
16
15
14
20
21
22
23
24
28
26
27
25
Stigmasterol
HO
H
H
H
18
1. It is a white crystalline solid with a melting point of 170°C.
2. It is present either in the free state or in the form of glycosides.
3. It is widely distributed in plants and is available especially from Calabar beans and soya
beans.
4. It is optically active and isolated as the sparingly soluble acetate tetrabromide.
Ergosterol
Ergosterol
HO
5
6
H
H
7
8
1
2
3
4
9
10
11
12
13
14
15
16
17
18
19
20
22
23
21
24
25
26
27
1. Ergosterol is provitamin-D
2
.
2. In 1920, it was found that rickets responded favourably to treatment either with sunlight or
by the supplementing the diet with cod liver oil.
3. At fi rst it was considered that cholesterol was the provitamin which gets converted into the
vitamin.
4. Subsequently, it was found that ergosterol is the provitamin and that the provitamin nature
of cholesterol was due to contamination with small amount of ergosterol.
258
Pharmaceutical Chemistry of Natural Products
Miscellaneous Sterols
HO
H
H
Zymosterol
HO
H
H
H
Episterol
HO
H
H
H
Iophenol
HO
H
H
H
Brassicasterol
Structural elucidation of cholesterol (Cholest-5-en-3a-ol)
HO
H
H
H
I. Nucleus
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
22
23
21
24
25
26
27
III. Side chain
IV. Angular methyl group
II. Hydroxyl group
and double bond
Steroids and Hormones
259
The structural elucidation of cholesterol is discussed in the following heads:
1. Structure of nucleus
2. Position of the hydroxyl group and double bond
3. Nature and position of the side chain
4. Position of the angular methyl groups
Let us discuss each of these points in detail.
Structure of Nucleus
1. Molecular formula: The molecular formula of cholesterol is found to be C
27
H
46
O.
2. Presence of Diels’ hydrocarbon: Cholesterol when subjected to selenium distillation
yields Diels’ hydrocarbon, indicating that cholesterol is having Diels’ hydrocarbon nucleus
in it.
HO
H
H
H
Cholesterol
Se
Diels’ hydrocarbon
CH
3
360°C
3. Presence of hydroxyl group and a double bond: By acetylation and bromine test,
cholesterol is found to possess one hydroxyl group and one double bond. This is further
confi rmed by the following reaction.
4. Reduction and oxidation: Reduction of cholesterol with hydrogen and platinum yields
cholestanol, which upon oxidation with chromic acid yields cholestanone. The cholestanone
when reduced in presence of zinc and amalgam yields cholestane.
IIIIIIIV
Cholesterol Cholestanol Cholestanone Cholestane
CHO
27 46
CHO
27 48
CHO
27 46
CH
27 48
H –Pt
2
CrO
3
Zn Hg–
HCl
Inference from the above reaction:
(a) The formation of cholestanol (C
27
H
48
O) from cholesterol (C
27
H
46
O) reveals the presence of
the double bond.
(b) The formation of a ketonic compound cholestanol (C
27
H
48
O) from cholesterol (C
27
H
46
O)
reveals the presence of cholesterol as a 2° alcohol.
260
Pharmaceutical Chemistry of Natural Products
(c) Cholestane (C
27
H
48
, IV), the saturated hydrocarbon of cholesterol complies with the
general formula (C
n
H
2n–6
) for tetracyclic compounds, and hence cholesterol is confi rmed as
a tetracyclic alcohol.
Position of the Hydroxyl Group and Double Bond
1. Oxidation of cholestanone with nitric acid followed by pyrolysis:
I
Cholesterol
III
Cholestanone
VI
Ketone
CHO
27 46
CHO
27 46
CH
26 44
O
(i) H –Pt
2
HNO
3
(ii)CrO
3
V
Dicarboxylic acid
(two isomeric products)
CHO
27 46 4
300°C
Pyrolysis
From the products of the above reaction the following conclusions are drawn.
(a) The oxidation of ketonic compound (III) to a dicarboxylic acid (V) with the same carbon
atoms indicates that the ketonic group is linked to the ring (dicarboxylic acid with lesser
number of carbon atoms would have been formed, if the ketone is present in the side
chain).
(b) The conversion of dicarboxylic acid (V) to ketone (VI) reveals that (V) is either 1,6- or
1,7-dicarboxylic acid (Blanc rule). Now we see that this dicarboxylic acid is obtained from
the hydroxyl group of cholesterol which cannot be present in ring D, as it would form 1,5-
dicarboxylic acid instead of 1,6- or 1,7-dicarboxylic acid in the above reaction. Therefore,
the hydroxyl group may be either in ring A, B or C.
(c) The formation of two isomeric dicarboxylic acids (V) suggests that the keto group in
cholestanone is fl anked by a methylene group on either side (–CH
2
COCH
2
–). Study of the
proposed structure (I) of cholesterol or the structure of Diels’ hydrocarbon (Refer point (2)
under the section ‘Structure of Nucleus’) indicates that such an arrangement is possible
only if the hydroxyl group is present in ring A and in position 2 or 3.
O
A
HOOC
HOOC
HNO
3
A
HOOC
HOOC
Cholestanone, III
HNO
3
2. Reaction of cholestanone with methyl magnesium iodide and followed by
selenium dehydrogenation: Upon reaction of cholestanone (III) with methyl magnesium
iodide followed by selenium dehydrogenation, 3,7-dimethylcyclopentanophenanthrene
(VII) is obtained, the structure of which is confi rmed by synthesis.
O
A
Cholestanone, III
VII
Se
CH MgI
3
A
OH
HC
3
7
CH
3
CH
3
3’
Steroids and Hormones
261
From the structure of (VII), it is revealed that the hydroxyl group in cholesterol is present in
position 3 which corresponds with the position 7 in (VII).
3. Position of the double bond: Let us consider the following set of reactions:
I
VIII
IX
Cholesterol Cholestranetriol
CHO
27 46
C H O
27 48 3
H
2
O
2
CrO
3
Hydroxycholestanedione
CH COOH
3
CHO
27 44 3
(i) H O
(ii) Zn–CH
COOH
⫺
2
3
Cholestanedione
CHO
27 44 2
X
Pyridazine derivatives
NH NH
22
Tetracarboxylic acid
CHO
27 44 8
XI
CrO
3
From the products of the above reactions, the following conclusions are drawn:
(a) The formation of (VIII) from (I) reveals the hydroxylation of the double bond.
OH
A
B
I
OH
OH
OH
VIII
OH
O
O
IX
HO
22
CH COOH
3
CrO
3
heat
–H
2
O
O
O
a
b
g
COOH
COOH
HOOC
HOOC
H
XI
O
O
H
X
N
N
H
Zn CH COOH
3
–
NH
2
–NH
2
CrO
3
Pyridazine derivative