Oestrone

It is known for a long time that the uterine cycle has been
controlled by hormones.
But the first evidence for this claim was given by Butenandt &
Doisy in 1929 after they isolated the active substance oestrone
from the urine of pregnant women.
Oestrone is the first known member of sex hormone.
Its m.p. is 259oC, [ ]D is +170o.
Molecular formula is C18H22O2.
It forms an oxime. Hence one O atom may be ketonic in
nature.

D. Ilangeswaran 2
 Oestrone forms a monoacetate & monomethyl ether. So the
2nd O atom may be a hydroxyl group.
Since oestrone couples with diazonium salts in alkaline
solution the –OH group may be phenolic.
When distilled with Zn dust it forms chrysene, which
reveals that oestrone is structurally related to steroids.
The X-ray studies showed that it contains steroid nucleus
with keto and –OH groups are present at opposite ends of the
molecule.
On catalytic hydrogenation it takes up 4 moles of hydrogen
to give octahydrooestrone, C18H30O2. Here 1 mole of
hydrogen is used to reduce keto group and the remaining 3
moles are used to reduce 3 = bonds, hence we can expect a
benzenoid ring in oestrone if these 3 = bonds are seen in one
ring.
 The presence of phenolic –OH group accounted the
benzenoid ring in it.
When methyl ether of oestrone is subjected to Wolff-Kishner
reduction followed by Se distillation, 7-methoxy-1,2-
cyclopentenophenanthrene is formed.
The structure of this compound was established by the
following synthesis. OH
CH2MgBr
O
H3C
H3C - H2O
+
H3CO H3CO

H3C Se
AlCl3
CH3
320 °C
H3CO H3CO H3CO
7-Methoxy-1,2-cyclopenteno
phenanthrene
 Thus the benzene ring in oestrone is ring A, and the
phenolic –OH group is at position 3. Hence we can sketch the
skeleton of oestrone as follows.

C D

A B
HO

Now the job is to fix the –C=O group. The above skeleton
accounts only for 17 C atoms.
Later in 1935 Cook et al. showed the presence of an angular
methyl group at position 13.
When methyl ether of oestrone is treated with methyl
magnesium bromide and other reagents as given below the
final product is 7-methoxy-3’,3’-dimethyl-1,2-
cyclopentenophenanthrene, V.
 The formation of V can be explained only if there is a keto
group at position 17 & an angular methyl group at position 13.
It should be noted in the given reactions below, the
dehydration is accompanied by the migration of angular methyl
group. Several known examples are there for this kind of
migration. O CH OH
CH3 3
CH3

CH3MgI KHSO4
H H
(-H2O)
H3CO H3CO

I II

CH3 CH3 CH3

CH3 CH3 CH3

H2 - Pt Se
H3CO H3CO H3CO

IV V
III
 Thus the structure of oestrone is given below
O
CH3

H H

HO
Oestrone

Synthesis:
The above structure of oestrone has been confirmed by
its synthesis by Anner and Miescher in 1948.
They started the synthesis using phenanthrene derivative,
VI, which was synthesized by Bachmann et al. in 1942.
 CH3 CH3
COOMe COOMe

H H
CH2CO2Me
O POCl3
H + BrCH2CO2Me + Zn H OH
H3CO C5H5N
H3CO
VI

CH3 CH3 CH3

COOMe - COOMe COOMe
H2 Pd/C (i) aq. MeOH - KOH
(sepn.) (ii) H+ CH2CO2H
CHCO 2Me CH2CO2Me
H H

VII
CH3 CH3
COOMe COOMe
(COCl)2 (i) CH2N2 (i) KOH; 180 °C
(ii) AgOH/MeOH (ii) PbCO3; 320 °C
CH2COCl CH2CH2CO2Me
H H

O
O CH3
CH3

C5H5N.HCl H
H
H H
H H HO
H3CO
(+)(-) - Oestrone

D. Ilangeswaran 8
 Johnson et al. in 1958,1962 have also carried out
total synthesis of oestrone. In this synthesis each step was
stereospecific.
CH
NEt 2

CH2Br C2HNa Et2NH

H2SO4
MeO DMF CH2O
MeO MeO Hg2+
O
CH2 O CH3 O
CH3
H3C
O O
O TsOH
O
MeO OH- MeO
MeO
O
CH3 OH O
CH3 CH3
H2 - Ni K/NH2
H (i) CrO3 H
H NH4Cl (ii) HBr/AcOH
H H
H H
MeO
MeO HO
(+ or - ) Oestrone
Torgov et al. synthesized oestrone in 1960-1962 as follows.
O
CH2
O CH3 O
H3C
OH
CH2=CHMgBr O
MeO O
MeO OH-
MeO

O O
CH3 CH3

TsOH
(i) K / NH2
H2 - Ni
H (ii) CrO3
MeO MeO

O
CH3
O
CH3
H
H C5H5N.HCl
H H
H H HO
MeO
(+ or -) Oestrone

D. Ilangeswaran 10
OESTRADIOL

 There are two stereoisomers α- and -. Of these two

- form is more active.
 The - isomer was isolated from the ovaries of sows
by Doisy et.al. in 1935. The α- isomer was isolated
from the pregnant urine of mares by Wintersteiner
et. al. in 1938.
 The m.p. of α- isomer is 178oC and that of -
isomer is 222oC. The [α]D for α = +81o, for = +54o.

D. Ilangeswaran 11
Constitution

1. Molecular formula: C18H24O2.

2. Presence of two –OH groups: Easy formation of
diacetyl derivative confirm this.
3. Nature of –OH groups: One is phenolic while the
other one is secondary alcoholic since on oxidation
oestradiol yields oestrone.
4. When oestrone on reduction yields oestradiol.
Hence oestradiol can have the same C skeletal
framework as oestrone.

D. Ilangeswaran 12
The phenolic methyl ester of estradiol on
heating with ZnCl2 undergoes a
rearrangement with the migration of angular
methyl group to cyclopentane ring.
The rearranged product on Se
dehydrogenation yields 7-methoxy-3’-
methyl-1,2-cyclopentenophenanthrene.
On these facts the structure of estradiol
would be assigned as I.

D. Ilangeswaran 13
 OH OH

H H
ZnCl2
CH2N2
H H H H
HO H3CO
Oetradiol - 17

CH3 CH3

H
Se
H H
Dehydrogenation H3CO
H3CO
7-Methoxy-3'-methyl-1,2-cyclopenteno
phenanthrene

OH OH

H H

H H H H
HO HO
Oetradiol - 17 Oetradiol - 17
D. Ilangeswaran 14
 Conversion of Estrone into Estradiol
O OH

H H
Al(iPrO)3
H H H H
OR LiAlH4
HO HO
Estrone Estradiol

D. Ilangeswaran 15
 Conversion of Estrone into Estriol
O OAc

H H
Isopropyl PhCO3H
H H Acetate H H
HO AcO
Estrone

OAc OH
O
H H OH
LiAlH4

H H H
H
AcO HO
Estriol

D. Ilangeswaran 16
 Equilenin
This has been isolated from pregnant mares by Girard et al. in
1932.
It has m.p. 258-259oC and [ ]D +87o.
Molecular formula is C18H18O2.
The reactions of equilenin show that a phenolic hydroxyl
group and a ketonic group present.
It also contain five double bonds.

D. Ilangeswaran 17
• When methyl ether of equilenin is treated with methyl
magnesium bromide, then the alcohol dehydrated,
catalytically reduced finally dehydrogenated with se. The
product is 7-methoxy-3’,3’-dimethyl-1,2-
cyclopentenophenanthrene, the same product as in
oestrone.
• Hence oestrone & equilenin are having the same structural
unit except the later has two more double bonds.
• The absorbtion spectrum of equilenin shows that it is a
naphthalene derivative.
• As ring A in oestrone is benzenoid, it appears probable that
ring B in equilenin is also benzenoid.
• Hence rings A & B form naphthalene nucleus in equilenin.

D. Ilangeswaran 18
 All the foregoing reactions of equilenin can be readily
explained by assuming that I is structure of equilenin.
Further evidence to this structure is given by Marker et al.
as equilenin may be readily reduced to oestrone by Na/ethanol
mixture.

CH3 O
CH3 O
H3C CH3

Na H

H C2H5OH
HO H H
HO HO
II I III
Equilenin Oestrone
 Synthesis
Bachmann synthesized compound IV.
Using IV, Johnson synthesized equilenin as follows.
NH2 NH2 NHCOCH 3

KOH (CH3CO)2O (i) (CH3)2SO4 - NaOH

HO 3S HO (ii) Hydrolysis
HO
Cleve's acid
CH2OH
NH2 I

(i) NaNO2-H2SO4 (i) Mg PBr3

H3CO (ii) KI H3CO

H H H3CO
(ii) H H
O

CH2Br

COOH
Malonic ester (i) SOCl2 O

H3CO synthesis H3CO (ii) SnCl4 H CO

3
IV
Johnson's synthesis starting from (IV)
CHO

N
O HCO2C2H5
O NH2OH.HCl
OH
H3CO CH3ONa CH3CO2H O
H3CO
IV

CN
N N
Tautomn. - H2O (CH3)3COK
OH - +
OH O OK

Isoxazole
CH3
CN CH3
Methyl succinate CN
CH3I Thorpe
O (CH3)3COK
CH2CO2CH3 reaction
CO2CH3

D. Ilangeswaran 21
 CH3 NH
CH3 O CH3 O
(i) Ba(OH)2 boil with H2
CO2K
CO2CH3 (ii) HCl C5H5N.HCl - HCl
COOH
Pd - C

V
CH3 O CH3 O

HCl

H CH3CO2H H
H3CO HO

VI VII

D. Ilangeswaran 22
 Progesterone
This was first isolated in a pure form by Butenandt et al. in
1934 from the corpora lutea of pregnant sows.
Molecular formula is C21H30O2.
Its m.p. 128oC and [ ]D +192o.
The chemical reactions of progesterone show that there are 2
keto groups present.
On catalytic reduction it adds on 3 moles of hydrogen to form
a dialcohol, C21H36O2.
So there may be one = bond.

D. Ilangeswaran 23
The parent hydrocarbon of progesterone is C21H36 which
corresponds to the general formula CnH2n-6 of a tetracyclic
compound.
X-ray studies reveals that progesterone contains steroid
nucleus.
This is further supported as progesterone is obtained from
stigmasterol & cholesterol.
The absorption spectrum shows that it is an , -unsaturated
ketone. Hence the double bond may be present between
position 4 an d 5.
The various synthesis of progesterone given below confirm
its structure.

D. Ilangeswaran 24
 Butenandt et al. in 1943

Progesterone from Stigmasterol

CH3 CH3
H3C H3C
CH3 CH3
CH3 CH3
CH3 CH3
CH3 H CH3 H
Br2 O3

H H H H
AcO AcO
Stigmasteryl acetate Br
Br

H3C COOH H3C COOH

CH3 CH3
(i) C2H5OH - HCl
CH3 H Zn CH3 H (ii) C6H5MgBr
CH3CO2H
H H H H (iii) - H2O
AcO AcO
Br
Br Acetate of
3 -hydroxybisnorchol-5-enic
acid

D. Ilangeswaran 25
 H3C H3C H3C
CPh2 O O
CH3 CH3 CH3

CH3 H (i) Br2 CH3 H CH3 H

(i) Zn/AcOH
H H
(ii) CrO3 (ii) Hydrol.
H H H H
AcO AcO AcO
Br Pregnenolone
Br

H3C Oppenauer oxidation

O
CH3

CH3 H

H H

O
Progesterone

D. Ilangeswaran 26
 Butenandt et al. 1939
Progesterone from Cholesterol
H3C
CH3 CH3 O
CH3

CH3
CH3 H CH3 H
(i) Ac2O
H H H H (ii) HCN
HO HO
Cholesterol H3C
Dehydroepiandrosterone
OH CN O
CH3 CH3 CH3
CN
CH3 H CH3 H CH3 H
POCl3 CH3MgBr
H H H H H H
AcO AcO AcO
H3C
H3C
O
O CH3
CH3

Oppenauer CH3 H
(i) H2/Raney Ni CH3 H
(ii) Hydrol. oxidation
H H
H H
O
HO
Pregnenolone Progesterone

D. Ilangeswaran 27
 Diosegnin occurs as a glycoside in the root of Trillium erectum

Progesterone from Diosgenin (Marker et al. 1940,1941)

H3C H3C

CH3 CH3 CH3 CH3

O O
O O
CH3 H CH3 H Ac
Ac2O CrO3
H H H H
200 °C
HO AcO
Diosgenin

H3C H3C H3C

O O
CH3 O CH3 CH3
(i) H2 - Pd
CH3 H CH3 H Oppenauer CH3 H
(ii) Hydrol. oxidation
H H H H H H
AcO HO O
Pregnenolone Progesterone

D. Ilangeswaran 28
 Butenandt et al.in 1934

Progesterone from Pregnanediol

CH3
H OH H3C H3C
CH3 O CH3 O
CH3

CH3 H Br2 CH3 H

CrO3 CH3 H

H H H H
H H
HO O
H O H
H
Pregnanediol Pregnanedione Br
C5H5N
H3C
(-HBr)
CH3 O

CH3 H

H H

O
Progesterone

D. Ilangeswaran 29
 Shepherd et al. 1955, more practical synthesis (note the
enamine step)
Progesterone from Ergosterol
CH3 CH3
H3C H3C
CH3 CH3
CH3 CH3 CH3
CH3

CH3 Oppenauer CH3

HCl in

H H
oxidation H H CH3OH
HO O
Ergosterol Ergosterone
CH3
H3C
CH3 CH3
H3C
CH3 CH3 CH3
CH3 CH3
HCl CH3 H H2
CH3
H H Pd - C
H H O
MeO
Isoergosterone

D. Ilangeswaran 30
 CH3
H3C H3C
CH3 CHO
CH3 CH3 CH3

CH3 H O3 CH3 H C5H10NH

H H H H
O O

H3C
H3C O
N
CH3
CH3

CH3 H
CH3 H Na2Cr2O7

AcOH H H
H H
O
O
Progesterone

D. Ilangeswaran 31
Testosterone
Among the 5 derivatives of androgens that
function as steroid hormones the most potent
is testosterone.
Testosterone was isolated by E. Laquer et. al.
in 1935 from testes. About 10 g of
testosterone is obtained from 100 Kg of
testes.
Its m.p. is 155oC, [α]D = +109o and
λmax = 240nm.
D. Ilangeswaran 32
Physiological Action
I. Testosterone is a real male sex hormone while other
androgens are metabolic products of testosterone.
II. It stimulates the development of secondary male sex
characteristics.
III. It assists in bringing about the descent of the testes in
cryptorchidism.
IV. It inhibits the secretion of anterior pituitary gonadotropins.
V. Testosterone and its derivatives have been found useful in
the treatment of advanced metastatic carcinoma of breast.
VI. Rarely, it may produce jaundice.
VII. It is used in the treatment of the menopausal syndrome
combined with estrogens.

D. Ilangeswaran 33
Constitution
1. Molecular formula; C19H28O2.
2. Presence of tetracyclic system: The molecular
formula of parent HC is C19H32 & this
corresponds to the general formula CnH2n-6.
3. Presence of α, - unsaturated keto group: As
testosterone is very sensitive to alkali with the
λmax = 240nm confirms the presence of α, -
unsaturated keto group. Further because of this
facts it is suggested that testosterone may be
structurally related to progesterone.
D. Ilangeswaran 34
4. Oxidation: In 1935 K. David oxidised
testosterone to a diketone namely androst-4-
ene-3,17-dione and its structure is well
known. This diketone also obtained during
the Oppenauer oxidation of
dehydroepiandrosterone. The formation of
diketone can be explained if the structure I
is assigned to testosterone.

D. Ilangeswaran 35
 OH

H H Oxidation
O
O
H
Testosterone (I)
H H
O O
Oppenauer oxn.
Androst-4-ene-3,17-dione
H

H H
HO
Dehydroepiandrosterone

D. Ilangeswaran 36
5. Synthesis: Ruzicka & Butenandt (1935)

H H
(i) Ac2O
H H H H
(ii) Br2
HO AcO
Br
Br
Cholesterol
Cholesteryl acetate dibromide
O
O
H
H (i) Zn - AcOH
CrO3 - AcOH (ii) HOH H H
H H
HO
AcO
Br
Br Dehydroepiandrosterone

D. Ilangeswaran 37
 OH OCOPh

(i) Ac2O H H
(i) PhCOCl
(ii) Na - C3H7OH H H (ii) mild hydrolysis H H
AcO (CH3OH/NaOH) HO

OH
OCOPh
H
H
Oppenauer Hydrolysis H H
H H
Oxidation KOH O
O
Testosterone

D. Ilangeswaran 38