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cis-trans-trans (some natural steroids have this skeleton, e.g., cholic acids)
cis-trans-cis (few natural steroids have this skeleton, e.g. cardiac glycosides)
CONFIGURATION:
The steroid skeleton (all carbons) with its methyls (18 and 19-CH3) oriented as
coming towards the viewer (represented as a bold line) is the reference plane in defining
whether a particular hydrogen or a substituent is towards the viewer (b) or going away
from the viewer (cross-hatched, a). Thus in a two-dimensional representation, with the
18- and 19-CH3 bold, all bold substituents are b and all cross-hatched substituents are
a.
When α and β designation are applied to the hydrogen atom at position 5,the ring
system in which the A, B ring junction is trans become the 5 α series; and the ring
system in which the A, B ring junction is cis becomes the 5 β series.
Substituent groups on steroid ring system can be either axial or equatorial
• Equatorial substitution is generally more stable for steric reasons
• Cholesterol has C3 hydroxyl group equatorial
Cholesterol:
It forms about 17% of human brain and nervous tissue.first isolated from human
gall stone deposited in bile ducts so known as cholesterol.
(chol – from bile acid, stereos – solid, ol - alcohol).
It is white crystalline optically active solid with melting point 1490 c and specific
rotation (+)39o.
Source: from human gall stone,fish liver oils,brain and spinal cord of
cattle,lanoline.
25
23 24
21
18 22
20
12
11 17
19 13
H 16
1 9
2 14
10 8 15
H H
3
7
5
HO 6
4
cholesterol
Isolation: Source of cholesterol + ethanol
evaporation
cholesterol
Constitution of cholesterol:
Structure of nucleus.
CH3
H
Se
360o
H H
HO
diels hydrocarbons
cholesterol
Position of hydroxyl group and double bond:
۩ Cholestanone on oxidation with nitric acid gives a dicarboxylic acid which on pyrolysis
yields a ketone.
H2-Pt CrO3 Zn-Hg/ Hcl
cholesterol cholestanol cholestanone cholestane
(C27H460) (C27H480) (C27H46O) (C27H48)
HNO3
pyrolysis
3600
ketone
۩ But opening of ring to yield dicarboxylic acid occurs due to hydroxyl group so
that hydroxyl group not in the ring D if it is in the ring D then it gives 1,5
dicarboxylic acid, so hydroxyl group is in ring A.
COOH
HNO3 HOOC
O
-OH AT 3
HOOC
HOOC
HOOC
COOH
O
HNO3
HOOC
-OH AT 2 HOOC
H H
H H H H
HO HO
CHOLESTEROL
cholestanol
H
CH3MgI
HO H H
CH3 O cholestanone
Se
360o
CH3
H3C
diels hydrocarbons
H H
H H H H
HO HO
CHOLESTEROL
cholestanol
HOOC
H H
HOOC O cholestanone
COOH
HOOC H
H H
cholestane
O
ketone
Position of double bond:
---H2O
H2O2/ACOh CrO3 Zn-CH3COOH
cholesterol cholestanetriol hydroxycholestanedione
C27H46O
C27H48O3 C27H44O3
A B C D cholestanedione
C27H44O2
NH2NH2
pyridazine derivative CrO3
C27H4408
E tetracarboxylic acid
۩ The oxidation of D to E with out loss of any cartbon atom suggests that two ketonic
groups in D are present in different rings i,e the double bond and OH group are
present in two different rings and as we have already seen that OH group is present in
ring A double bond must be present in ring B ,C or D.
۩ Since D can form a pyridazine derivative with hydrazine the two ketonic groups of D
are in γ position with respect to each other which is only possible only if double bond is
present in between C5 and C6 and all above reactions are written as
HO O
HO OH OH
A B OH C O
N
H O
N O
H
D
O
O
HOOC E
HOOC COOH
COOH
۩ The position of double bond is further proved by following set of reactions
۩ uv absorption spectrum of B λmax 240nm shows that keto group and double
bond are conjugated.
These results can be explained on assumption that there is a migration of
double bond of cholesterol during formation of B which is possible only if the
double bond is present in between C5 and C6.
COOH
HO O O CO2
B C
A
Nature of position and side chain:
۩ Cholesterol acetate on oxidation with chromic acid forms an acetate of hydroxyl
ketone and a steam volatile ketone,(isohexyl methyl ketone).
CrO3
cholesterol cholesteryl acetate acetate of hydroxy ketone
C
CH
۩ The above reaction shows that isohexyl methyl ketone forms the side chain of
cholesterol and is attached to nucleus of cholesterol through a carbon atom oxidized
to ketone group.
The nature of side chain can further be elucidated by application of barbier-wieland
degradation.
Cholesterol is converted to 5β- cholestane.
Cro3 B-W
5B-cholestane 5b- cholanic acid
R.Cn R.Cn-3
A O
B acetone O
benzophenone
B-W B-W
acetiocholylmethyl ketone Bis nor 5B cholanic acid Nor 5B cholanic acid
R.Cn-6 E R.Cn-5 D R.Cn-4
Cro3 C
B-W HNO3
5B- ethianic acid Acetiocholane Acetiobilianic acid
R.Cn-7 R.Cn-8 R.Cn-8
F G H
These degradations lead to following conclusions:
۩ The formation of acetone from coprostane indicates that side chain terminates in a
isopropyl group.
CH3 Cro3
CH
CH3 O
ACETONE
۩ Oxidation of E to F with loss of one carbon atom suggests that the alkyl group in
E and D is methyl.
۩ Oxidation of G to H without any loss of carbon atom suggests that in the former
the ketonic group is present in the ring.
From the above we came to know that coprostane contains a side chain of 8
carbon atoms arranged in the following order.
CH3
CH3
R CH CH2 CH2 CH2 CH
CH3
1,5- dicarboxylic acid can only be obtained from 5 membered ring hence the
side chain is attached to 5 membered ring (but actual attachment point is not
revealed).
COOH
COOH
A C COOH
B
O HOOC
O
D
G F
E
COOH
COOH
H
Position of angular methyl groups:
Ring with 17 carbon atoms and side chain with 8 carbon atoms but another 2 carbon
atoms.
zn-Hg/Hcl HOOC
COOH 2 B-W
COOH
O
COOH
O
COOH
O CH3
H3CO HC
H3CO H
CH2 OH
O
4-methoxy-2,5-toluquinone butadiene
H
H H
HCL A
O
O
H3CO H
H H
OH OH
H
H
C
B
C O
O O
H
H CHO
CHOH
O
OH C
E H3C
O
H3C
D OH
O
O
CHOH
H H
HO
CHOLESTEROL
A = (Aco)2o /zinc-(Aco)2o
B = claisen condensation
C = michael condensation
D = oso4/ KOH
E = CH3ONa/C2H5COOH/CH3COCH3
Reference:
Chemistry of natural products ----- vol.2------Chatwal