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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
262
Pharmaceutical Chemistry of Natural Products
(b) The formation of a diketone (IX) from cholestanetriol (VIII) upon oxidation reveals that in
(VIII) two of the –OH groups are 2° in nature and the third –OH (resistant to oxidation) is
3°.
(c) The formation tetracarboxylic acid (XI) from cholestanedione (X) upon oxidation without
decreasing any carbon atom suggests that the two ketonic groups in (X) are present in
different rings (carbon atom would have been lost during oxidation if it is in the same
ring). In other words, the double bond and the hydroxyl group in cholesterol are present
in two different rings and as we have already seen that the hydroxyl group of cholesterol
is present in ring A, the double bond must therefore be present in either ring B, C or D.
(d) As the compound cholestanedione (X) can form a pyridazine derivative with hydrazine,
the two ketonic groups of (X) are in γ-positions with respect to each other which is possible
only if the double bond is present in between C-5 and C-6, and thus all the above reactions
can be depicted as below.
(e) Further confi rmation of double bond position: The position of double bond is further proved by
the following set of reactions:
IXI
Cholesterol Cholestenone
Copper oxide
KMnO
4
Keto acid + CO
2
(O)
290°C
XIII
This reaction led to the following conclusions:
(i) Upon oxidation of (XII) to (XIII) one carbon atom is lost, which indicates that the keto
group and the double bond in (XII) are in the same ring. Moreover, UV absorption spectrum
of (XII), λ
max
240 nm, shows that the keto group and the double bond are conjugated. This
can be explained by assuming that there is a migration of the double bond of cholesterol
during the formation of cholestenone (XII) which is possible only if the double bond is
present in between C-5 and C-6.
OH
Copper oxide
290°
I
O
KMnO
4
{o}
XII
HOOC
O
+ CO
2
XIII
Nature and Position of the Side Chain
1. Acetylation followed by oxidation of cholesterol: On acetylation followed by
oxidation, cholesterol forms acetate of a hydroxyketone and a steam-volatile ketone called
isohexylmethyl ketone.
Cholesterol
CrO
3
Cholesteryl acetate
O
Isohexylmethyl ketone
Acetate of a hydroxy ketone
CH CH CH CH
222
+ H
3
C
CH
3
CH
3
Ac O
2
Steroids and Hormones
263
The formation of these products reveals that isohexylmethyl ketone side chain is present in
cholesterol and it is attached to the nucleus of cholesterol through the carbon atom oxidized to
C=O group.
2. From the foregoing discussion we came to know that the coprostane (and hence cholesterol)
contains a side chain of eight carbon atoms arranged in the following order.
R
—CH—CH —CH —CH —CH
222
CH
3
CH
3
CH
3
12
3
4
5
6
C
n
The nature of side chain has also been explained by the application of Barbier–Wieland
degradation (B–W). This method shows the ring of the nucleus that is attached to the side
chain.
3. Point of attachment of the side chain to the nucleus (R):
(a) The dicarboxylic acid, aetiobilianic acid (obtained above), on heating with acetic
anhydride forms an anhydride which suggests that it is a 1,5-dicarboxylic acid (Blanc
rule). From a fi ve-membered ring, only the 1,5-dicarboxylic acid can be obtained;
therefore, the side chain is attached to the fi ve-membered ring D.
(b) On selenium dehydrogenation, cholesterol yields Diels’ hydrocarbon, which reveals
that the side chain is attached to C-17 in cholesterol. This position is further proved by
X-ray photographs and surface fi lm measurements.
HO
H
H
H
Cholesterol
Oxidation
Aetiobilianic acid
COOH
COOH
Position of the Angular Methyl Groups
The cyclopentanophenanthrene nucleus (17 carbon atoms) and the side chain (8 carbon
atoms) of cholesterol accounts for 25 carbon atoms out of 27 carbon atoms of cholesterol.
The remaining two carbon atoms are found to be present as angular methyl groups by the
following facts.
264
Pharmaceutical Chemistry of Natural Products
1. The keto acid (XIII) on Clemmensen reduction followed by two B–W degradations gives a
tertiary acid, so one of the angular groups must be present on C-10.
HOOC
O
A
B
Zn–Hg
HCl
HOOC
2BW–
HOOC
2. Cholesterol on selenium dehydrogenation yields Diels’ hydrocarbon and chrysene; the
formation of the latter is explained by the fact that there is an angular methyl group at
either C-13 or C-14 which enters the fi ve-membered ring (D) of cholesterol to form a
six-membered ring of chrysene.
+
HO
H
H
H
Cholesterol
Se
Diels’ hydrocarbon Chrysene
CH
3
3. Upon distillation with selenium, aetiobilianic anhydride gives 1,2-dimethyl phenanthrene,
which reveals that the methyl group is present in position 13; had it been on C-14, only
monomethyl phenanthrene would have been formed.
COOH
Aetiobilianic acid
Heat
O
O
O
Se
Aetiobilianic anhydride
COOH
B
C
13
14
10
CH
3
CH
3
A
B
C
1,2-Dimethyl phenanthrene
A
Steroids and Hormones
265
COOH
O
O
O
COOH
13
14
10
CH
3
A
B
C
Monomethyl phenanthrene
Synthesis of cholesterol ( Woodward synthesis).
HCO
3
HO
O
H
O
O
H
O
OH
H
OH
HCl
OH
O
H
(O)
O
O
+
Butadiene
O
H
CH
3
(CH)SO
32 4
HCO
3
HCO
3
CH
3
(i) HNO
3
(ii) Sn–HCl
HCO
3
HCO
3
CH
3
NH
2
FeCl
3
4-Methoxy-2,5-toluquinone
HCO
3
O
CH
3
O
2-Methoxy- -Cresolp
HCO
3
LiAlH
4
(i) OH
–
(ii) OH
+
HCO
3
HC
HC
CH
2
CH
2
HCO
3
CH
3
HCO
3
(i) (CH CO) O
32
(ii) Zn–(CH CO) O
32
HCOCH
225
CH ONa
3
266
Pharmaceutical Chemistry of Natural Products
(Michael condensation)
H
O
CHO
KOH
O
H
CHOH
C H COCH=CH
25 2
(CH ) COK
33
C
H
2
HC
2
OC
HC
2
CH
3
O
H
OsO
4
O
H
OH
OH
Mixture
O
H
O
O
(Selective reduction)
H
H
H
O
H
O
O
H
O
H
O
O
H
CHOH
COOH
O
O
to protect CO group
O
H
O
O
H
CHN
O
Mixture
O
O
O
H
H
H
H
O
HC
3
HC
3
(i) Resolution
(ii) (CH ) CO, H
32
+
C(CH )
32
HC
3
C(CH )
32
HC
3
CH ONa
3
HCO C H
225
C(CH )
32
HC
3
C H NHCH
65 3
C(CH )
32
CH
3
CH
65
HC
3
(ii) Hydrolysis
(i) CH =CHCN
2
C(CH )
32
(i) Resolution
(ii) (CH CO O
3
)
2
CH CO Na
32
C(CH )
32
C
CH MgBr
3
H –Pd/SrCO
23
Steroids and Hormones
267
CHO
CHO
H
H
Boil in Dioxane
H
CHO
(i) K Cr O
227
(ii) CH N
O
H
O
CO
O
O
O
H
H
NaOH
(Cyclization)
C
O
O
H
H
O
HC
3
C(CH )
32
C(CH )
32
HIO
4
H
H
O
CO CH
23
(i) Resolve
(ii) (+)-form
(iii) H –Pt
2
H
H
HO
CO CH
23
H
H
CrO
3
H
H
CO CH
23
H
H
H
H
H COCO
3
COCH
3
H
H
(i) NaBH
(ii) Hydrolysis
4
(i) (CH CO) O
(ii) SOCl
32
2
(iii) Cd(CH )
32
H
H
HO
CO H
2
H
H
(CH ) CH(CH ) MgBr
(Isohexyl magnesium bromide)
32 23
O
268
Pharmaceutical Chemistry of Natural Products
H
H
H COCO
3
H
H
Na Cr O
227
HSO
24
Heat
–H O
2
H
H
H COCO
3
H
H
H
H
O
H
H
(i) H –Pt
(ii) NaOH
2
H
H
HO
H
H
Cholestanol
Br /HBr
2
H
H
O
H
H
Br
Pyridine
H
H
O
H
CH COCl
(CH CO) O
3
32
H
H
HO
H
Cholesterol
(i) LiAlH
4
(ii) HCl
H
H
H CCOO
3
H
HO
BILE ACIDS
1. Bile acids are isolated from the bile (a secretion of the liver which is stored in the gall bladder)
of various animals as well as humans.
Steroids and Hormones
269
2. They occur as bile salts, i.e. the sodium salt of conjugated acids of either RCONHCH
2
COOH
or RCONHCH
2
SO
3
H type.
3. In other words, they occur as sodium salts of amides with either glycine (NH
2
CH
2
COOH)
or taurine (NH
2
CH
2
CH
2
SO
3
H). For example, glycocholic acid (glycone + cholic acid) and
taurocholic acid (taurine + cholic acid).
4. Generally they are found to be hydroxyl derivatives of either 5β-cholanic acid (cholanic acid)
or 5α-cholanic acid (allocholanic acid).
5. More than 20 natural bile acids have been characterized. The structures of cholanic acid
and allocholanic acid and their derivatives are given below. The most abundant bile acids
in human bile are cholic acid (25–60% of the total bile acids), deoxycholic acid (5–25% of
the total bile acids), chenodeoxycholic acid (30–50% of the total bile acids) and lithocholic
acid.
5
6
H
H
7
8
H
COOH
H
1
2
3
4
9
10
11
12
13
14 15
16
17
18
19
20
21
22
23
24
H
H
H
COOH
H
5
6
H
H
7
8
H
COOH
H
1
2
3
4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
HO
OH
OH
Deoxycholic acid
5
6
H H
7
8
H
COOH
H
1
2
3
4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
HO
OH
Lithocholic acid
5
6
H
H
7
8
H
COOH
H
1
2
3
4
9
10
11
12
13
14 15
16
17
18
19
20
21
22
23
24
HO
Chenodeoxycholic acid
5
6
H
H
7
8
H
COOH
H
1
2
3
4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
HO
OH
5
6
H
H
7
8
H
COOH
H
1
2
3
4
9
10
11
12
13
14 15
16
17
18
19
20
21
22
23
24
HO
OH
a-Hydroxycholic acid
5 -Cholanic acid
(Cholanic acid)
b
5 -Cholanic acid
(Allocholanic acid)
a Cholic acid
270
Pharmaceutical Chemistry of Natural Products
6. Bile acids differ from each other in the position and number of hydroxyl groups. In bile acids,
the position of the hydroxyl groups may be any of the following positions: 3, 6, 7, 11, 12 and
23.
7. With many acids, esters, alcohols, ethers, phenols and hydrocarbons, deoxycholic acid forms
a large number of extremely stable inclusion compounds called choleic acids.
8. The bile acids in the bile entering the intestine are rapidly absorbed into the blood, taken
back by the liver and reutilized. This is called enterohepatic circulation of bile salts. Unabsorbed
bile acids are attacked by bacteria and decomposed into various products which are excreted
in faeces.
9. 5β-Cholanic acid or 5α-cholanic acid is produced when bile acid is dehydrated by heating in
a vacuum followed by catalytic reduction.
H
H
H
COOH
H
Lithocholic acid
5
6
H H
7
8
H
COOH
H
1
2
3
4
9
10
11
12
13
14 15
16
17
18
19
20
21
22
23
24
HO
–H O
2
H
H
H
COOH
H
Cholenic acid
or
H
H
H
COOH
H
H
2
–Pt
5 -Cholanic acidb
The 5β-cholanic acid (cholanic acid) or 5α-cholanic acid (allocholanic acid) is prepared
synthetically from cholesterol as follows.
5-Cholanic Acid
H
H
H
HO
Oppenauer
Oxidation
O
HO
H
H –Pt
2
Cholesterol Cholest-4-en-3-one
5 -Cholestane-3 -ol
(Coprostanol)
bb
Steroids and Hormones
271
H
COOH
H
H H
CrO
3
5 -Cholanic acidβ
(i) CrO
(ii) Zn–Hg/HCl
3
5 -Cholestane
(Coprostanol)
b
5␣-Cholanic Acid
H
H
H
HO
Cholesterol
HO
O
H
H
COOH
H
H
H
H
H
H –Pt
2
5 Cholestan-3 -olab–
CrO
3
(O)
CrO
3
5 Cholestan-3-onea–
Zn–Hg/HCl
5 Cholestanea–
5 Cholanic acida–
Functions of Bile Acids
The important functions of the bile acids are as follows:
1. They help in the absorption of cholesterol, fat soluble vitamins (A, D, K, etc.) by forming
water-soluble complexes.