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Steroids

Steroids are lipids derived from the triterpenoid lanosterol


• Structures are based on a tetracyclic ring system
• Four rings designated A, B, C, and D
• Numbering begins in A ring
• A, B, and C rings adopt chair conformations but do not undergo cyclohexane ring-flips
In systematic nomenclature of the R group at position 17 determines the base name
of an individual steroid.
CONFORMATIONS:
There are four rings in a steroid skeleton and hence there are three fusion points. A/B,
B/C and C/D rings share two carbons each (fusion). Every fusion center can either be
cis- or trans-fused
Two cyclohexane rings can be joined in either a manner
Cis fusion gives cis –decalin - Both groups at ring-junction positions (angular
positions) are on same side of two rings.
Trans fusion gives trans –decalin - Both Groups at ring junction are on opposite
sides.
CONFORMATIONS:
Steroids can have either a cis or trans fusion of the A and B rings Other ring fusions
(B-C and C-D) are usually trans.
A-B trans steroid has C19 angular methyl group up, and the C5 hydrogen atom down,
on opposite sides of the molecule.
A-B cis steroid has both C19 angular methyl group and C5 hydrogen atom on the same
side the molecule.
The structures most likely feasible are :

trans-trans-trans (most natural and synthetic steroids have this skeleton,


e.g., 5a-dihydrotestosterone)

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.

It is present in the form of palmitate,stearate,oleate esters.


26
Numbering: 27

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

Ethanolic solution of cholesterol

+ ethanolic solution of digitonin

White precipitate of cholesterol digitonide

pyridine Dimethyl sulfoxide / heating

Breakdown of cholesterol and digitonin Breakdown of cholesterol and digitonin


Ether
cooling

Ether solution Digitonin precipitate Cholesterol is deposited

evaporation

cholesterol
Constitution of cholesterol:
Structure of nucleus.

Position of hydroxyl group and double bond.

Nature of position and side chain.

Position of angular methyl groups.


Structure of nucleus:
۩ Molecular formulae: C27H46O.

۩ Forms monoacetate on acetylation indicating one hydroxyl group.

۩ It adds 2 bromine atoms forming cholesterol dibromide indicating presence of one


double bond.

H2-Pt CrO3 Zn-Hg/ Hcl


cholesterol cholestanol cholestanone cholestane
(C27H460) (C27H480) (C27H46O) (C27H48)
A B C D

۩ A to B proves presence of double bond.

۩ B to C shows presence of secondary alcohol.

۩ The saturated parent hydrocarbon D of cholesterol corresponds to general


formulae (CnH2n-6) for tetra cyclic compounds hence it is tetra cyclic alcohol.

Total no. of rings is given by: (No. of carbons + 1 ─ no. of hydrogens / 2)


۩ On selenium distillation at 360oc cholesterol gives diels hydrocarbon and
chrysene, the formation of diels hydrocarbon suggests that cholesterol has diels
hydrocarbon nucleus in its structure.

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

two isomeric dicarboxylic acids


(C27H46O4)

pyrolysis
3600
ketone

From the above reactions the following reactions are concluded:


۩ The oxidation of Cholestanone to dicarboxylic acid having same no. of carbon atoms
as original ketone indicates that keto group must be present in the ring. If in the side
chain it gives acid with less no. of carbon atoms.
۩ pyrolysis of dicarboxylic acid to ketone with less no. of carbon atoms reveals
that dicarboxylic acid is 1,6 or 1,7 dicarboxylic acid (blancs rule).

۩ 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.

۩ When cholestanone is oxidized actually 2 isomeric dicarboxylic acids are


obtained which indicates that keto group is flanked on either side by methylene
group so that CH2-CO-CH2.

COOH
HNO3 HOOC

O
-OH AT 3
HOOC

HOOC
HOOC

COOH

O
HNO3

HOOC

-OH AT 2 HOOC

If proposed structure for cholesterol is examined such an arrangement is only


possible if hydroxyl group is present in ring A.
۩ The position of hydroxyl group at position 3 is further confirmed by following reactions

H H

H H H H
HO HO
CHOLESTEROL
cholestanol

H
CH3MgI
HO H H

CH3 O cholestanone

Se
360o

CH3

H3C
diels hydrocarbons

The above reaction is formulated as follows if hydroxyl group is present in position 3


All the above reactions are given as:

H H

H H H H
HO HO
CHOLESTEROL
cholestanol

HOOC
H H

HOOC O cholestanone

two isomeris products

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

From the above reactions the following reactions are concluded:


۩ The conversion of A to B represents the hydroxylation of double bond.

۩ B on oxidation gives a diketone indiating that in B two of OH groups are secondary


in nature and third is tertieary one (which resists oxidation).

۩ 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

copper oxide cholestenone KMno4 keto acid CO2


cholesterol

۩ From above reaction oxidation of B to C with loss of one carbon atom


indicates that keto group and double bond in B are in same ring.

۩ 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.

copper oxide KMno4

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

isohexyl methyl ketone

۩ 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

۩ The conversion of D to ketone E indicates that α carbon of acid is secondary in


nature so that there is alkyl group on α carbon in D .(if no alkyl group on α carbon
then acid has been formed instead of ketone ).

۩ 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

Point of attachment of side chain to nucleus:

The dicarboxylic acid formed on heating with aceticanhydride forms an


anhydride suggesting that it is dicarboxylic acid (blanc rule).

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).

On selenium distillation at 360c cholesterol gives diels hydrocarbon indicating


that side chain is attached to C17 in cholesterol because selenium
dehydrogenation may degrade a side chain to a methyl group.

X-ray crystallographs also support 17th position of side chain.


The following reaction as follows:

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.

The keto acid on clemmenson reduction followed by twice B W degradation gives a


tertiary acid so one of the angular methyl groups must be present on C10.

zn-Hg/Hcl HOOC

COOH 2 B-W
COOH
O

On selenium distillation at 360c cholesterol gives diels hydrocarbon and


chrysene, the formation of chrysene is explained that there is an angular methyl
groups at either C13 or C14 which enters 5 membered ring to form a 6 membered
(this evidence not complete because here C 14 also explained chrysene.)

Acotobilianic anhydride on distillation with selenium gives 1,2-dimethyl


phenanthrene indicating that methyl group is present in position 13, had it been on
c14 ,then only monomethyl phenanthrene wiuld have been formed.
Angular methyl at C13:
O
CH3
COOH
O
COOH
O CH3

acotobilianic acid acotobilianic anhydride 1,2-dimethyl


phenanthrene

Angular methyl at C14:


O

COOH
O
COOH
O CH3

acotobilianic acid acotobilianic anhydride monomethyl


phenanthrene
O OH
H
CH3 CH2 LiAlH4
HC

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

Chemistry of natural products ----- vol.2------Agarwal

Text book of organic chemistry ----- vol.2------I.L.Finar


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