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.

2D. Ilangeswaran

Oestrone forms a monoacetate & monomethyl ether. So the2nd O atom may be a hydroxyl group.

Since oestrone couples with diazonium salts in alkalinesolution the –OH group may be phenolic.

When distilled with Zn dust it forms chrysene, whichreveals that oestrone is structurally related to steroids.

The X-ray studies showed that it contains steroid nucleuswith keto and –OH groups are present at opposite ends of themolecule.

On catalytic hydrogenation it takes up 4 moles of hydrogento give octahydrooestrone, C18H30O2. Here 1 mole ofhydrogen is used to reduce keto group and the remaining 3moles are used to reduce 3 = bonds, hence we can expect abenzenoid 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.

H3CO

CH2MgBr

+CH3

O

H3CO

CH3

OH

- H2O

H3CO

CH3 AlCl3

H3CO

CH3

Se

320 °C

H3CO

7-Methoxy-1,2-cyclopentenophenanthrene

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.

Now the job is to fix the –C=O group. The above skeletonaccounts only for 17 C atoms.

Later in 1935 Cook et al. showed the presence of an angularmethyl group at position 13.

When methyl ether of oestrone is treated with methylmagnesium bromide and other reagents as given below thefinal product is 7-methoxy-3’,3’-dimethyl-1,2-cyclopentenophenanthrene, V.

OH

A B

C D

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.

H3CO

OCH3

H

I

CH3MgI

H3CO

OHCH3

H

CH3

II

KHSO4

(-H2O)

H3CO

CH3

CH3

H2 - Pt

H3CO

CH3

CH3

Se

H3CO

CH3

CH3

III IV V

Thus the structure of oestrone is given below

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

OH

O

H H

H

Oestrone

H

HO

CH3COOMe

H3COVI

+ BrCH2CO2Me + Zn

H

H

CH3COOMe

H3CO

OH

CH2CO2Me

POCl3

C5H5N

CH3

CHCO2Me

COOMeH2

-Pd/C

(sepn.)

CH3

CH2CO2Me

COOMe

H

(i) aq. MeOH - KOH

(ii) H+

CH3

CH2CO2H

COOMe

H

VII

(COCl)2

CH3

CH2COCl

COOMe

H

(i) CH2N2

(ii) AgOH/MeOH

CH3

CH2CH2CO2Me

COOMe

H

(i) KOH; 180 °C

(ii) PbCO3; 320 °C

H

H

CH3

H3CO

H

O

C5H5N.HCl H

H

CH3

H

O

OH

(+)(-) - Oestrone

8D. Ilangeswaran

Johnson et al. in 1958,1962 have also carried outtotal synthesis of oestrone. In this synthesis each step wasstereospecific.

MeO

CH2Br C2HNa

DMF MeO

CH

Et2NH

CH2O MeO

NEt2

H2SO4

Hg2+

MeO

CH2

O

OH-

O

O

CH3

MeO

O

O

O

CH3

TsOH

MeO

CH3

O

H2 - Ni

MeO

CH3

O

H

K/NH2

NH4Cl

MeO

CH3

OH

HH

H (i) CrO3

(ii) HBr/AcOH

OH

CH3

O

HH

H

(+ or - ) Oestrone

Torgov et al. synthesized oestrone in 1960-1962 as follows.

MeO

O

CH2=CHMgBr

MeO

OH

CH2

O

O

CH3

OH-

MeO

O

CH3O

TsOH

CH3O

MeO

H2 - Ni

CH3O

MeO

H

(i) K / NH2

(ii) CrO3

CH3O

MeO

H

H

H

C5H5N.HCl

CH3O

OH

H

H

H

(+ or -) Oestrone

10D. Ilangeswaran

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.

11D. Ilangeswaran

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.

12D. Ilangeswaran

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.

13D. Ilangeswaran

OH

OH

H

HHCH2N2

H3CO

OH

H

HH

ZnCl2

H3CO

CH3

H

HHSe

Dehydrogenation H3CO

CH3

OH

OH

H

HHOH

OH

H

HH

Oetradiol - 17

Oetradiol - 17 Oetradiol - 17

7-Methoxy-3'-methyl-1,2-cyclopenteno

phenanthrene

14D. Ilangeswaran

Conversion of Estrone into Estradiol

OH

O

H

HH

Al(iPrO)3

OR LiAlH4 OH

OH

H

HH

Estrone Estradiol

15D. Ilangeswaran

Conversion of Estrone into Estriol

OH

O

H

HH

Estrone

Isopropyl

AcetateAcO

OAc

H

HH

PhCO3H

AcO

OAc

H

HH

O

LiAlH4

OH

OH

H

HH

OH

Estriol

16D. Ilangeswaran

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.

17D. Ilangeswaran

• 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.

18D. Ilangeswaran

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.

OCH3

H

OH

IEquilenin

Na

C2H5OH

OCH3

H

OH

H

H

IIIOestrone

OH

CH3 CH3

II

Synthesis

Bachmann synthesized compound IV.

Using IV, Johnson synthesized equilenin as follows.NH2

HO3S

KOH

Cleve's acid

NH2

OH

(CH3CO)2O

NHCOCH3

OH

(i) (CH3)2SO4 - NaOH

(ii) Hydrolysis

NH2

H3CO

(i) NaNO2-H2SO4

(ii) KI

I

H3CO

(i) Mg

(ii)O

H

H

H

HH3CO

CH2OH

PBr3

H3CO

CH2Br

Malonic ester

synthesis H3CO

COOH(i) SOCl2

(ii) SnCl4 H3CO

O

IV

H3CO

O

IV

Johnson's synthesis starting from (IV)

HCO2C2H5

CH3ONaH3CO

O

CHO

NH2OH.HCl

CH3CO2H O

N

OH

OH

N

OHTautomn. - H2O

O

N

Isoxazole

(CH3)3COK

O-K

+

CN

CH3I

O

CNCH3

Methyl succinate

(CH3)3COK

CNCH3

CO2CH3

CH2CO2CH3

Thorpe

reaction

21D. Ilangeswaran

CH3

CO2CH3

CO2K

NH

(i) Ba(OH)2

(ii) HCl

CH3

COOH

O

boil with

C5H5N.HCl - HCl

CH3O

H2

Pd - C

CH3

H

H3CO

O

V

VI

HCl

CH3CO2H

CH3

H

OH

O

VII

22D. Ilangeswaran

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.

23D. Ilangeswaran

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.

24D. Ilangeswaran

Progesterone from Stigmasterol

AcO

CH3

CH3

CH3

CH3

CH3

CH3

H

HH

Br2

Stigmasteryl acetateAcO

CH3

CH3

CH3

CH3

CH3

CH3

H

HH

BrBr

O3

AcO

CH3

CH3

CH3 COOH

H

HH

BrBr

Zn

CH3CO2H

AcO

CH3

CH3

CH3 COOH

H

HH

Acetate of

3 -hydroxybisnorchol-5-enic acid

(i) C2H5OH - HCl

(ii) C6H5MgBr

(iii) - H2O

Butenandt et al. in 1943

25D. Ilangeswaran

AcO

CH3

CH3

CH3 CPh2

H

HH

(i) Br2

(ii) CrO3

AcO

CH3

CH3

O

H

HH

BrBr

CH3

(i) Zn/AcOH

AcO

CH3

CH3

O

H

HH

CH3

Pregnenolone

(ii) Hydrol.

Oppenauer oxidation

O

CH3

CH3

O

H

HH

CH3

Progesterone

26D. Ilangeswaran

Progesterone from Cholesterol

CH3

CH3

CH3

CH3

CH3

OH

H

HH

Cholesterol

CH3

CH3O

OH

H

HH

Dehydroepiandrosterone

(i) Ac2O

(ii) HCN

CH3

CH3OH

AcO

H

HH

CN

POCl3

CH3

CH3

AcO

H

HH

CN

CH3MgBr

CH3

CH3

AcO

H

HH

CH3

O

(i) H2/Raney Ni

(ii) Hydrol.

CH3

CH3

OH

H

HH

CH3

O

Oppenauer

oxidation

CH3

CH3

O

H

HH

CH3

O

PregnenoloneProgesterone

Butenandt et al. 1939

27D. Ilangeswaran

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

O

OH

CH3

CH3

H

H H

CH3

O

CH3

Diosgenin

Ac2O

200 °C

O

AcO

CH3

CH3

H

H H

CH3

O

CH3

AcCrO3

AcO

CH3

CH3

H

H H

CH3

O

(i) H2 - Pd

(ii) Hydrol.Oppenauer

oxidation

CH3

CH3

O

H

HH

CH3

O

Progesterone

CH3

CH3

OH

H

HH

CH3

O

Pregnenolone

Diosegnin occurs as a glycoside in the root of Trillium erectum

28D. Ilangeswaran

Progesterone from Pregnanediol

OH

CH3

CH3

CH3

OHH

H

HH

H

Pregnanediol

CrO3

O

CH3

CH3

H

HH

H

CH3

O

Br2

O

CH3

CH3

H

HH

HBr

CH3

O

C5H5N

(-HBr)

O

CH3

CH3

H

HH

CH3

O

Pregnanedione

Progesterone

Butenandt et al.in 1934

29D. Ilangeswaran

Progesterone from Ergosterol

OH

CH3

CH3

CH3CH3

CH3

CH3

HH

Ergosterol

Oppenauer

oxidation

O

CH3

CH3

CH3CH3

CH3

CH3

HH

Ergosterone

HCl in

CH3OH

CH3

CH3

CH3CH3

CH3

CH3

HH

MeO

HCl

O

CH3

CH3

CH3CH3

CH3

CH3

HH

H

Isoergosterone

H2

Pd - C

Shepherd et al. 1955, more practical synthesis (note the

enamine step)

30D. Ilangeswaran

O

CH3

CH3

CH3CH3

CH3

CH3

HH

H O3

O

CH3

CH3

CH3CHO

HH

H C5H10NH

O

CH3

CH3

CH3

HH

N

H Na2Cr2O7

AcOH

O

CH3

CH3

CH3O

HH

H

Progesterone

31D. Ilangeswaran

TestosteroneAmong 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. 32D. Ilangeswaran

Physiological ActionI. 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.

33D. Ilangeswaran

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.

34D. Ilangeswaran

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.

35D. Ilangeswaran

O

OH

H

HH

OH

O

H

HH

O

O

H

HH

Oxidation

Oppenauer oxn.

Testosterone (I)

Dehydroepiandrosterone

Androst-4-ene-3,17-dione

36D. Ilangeswaran

5. Synthesis: Ruzicka & Butenandt (1935)

OH

H

HH

(i) Ac2O

(ii) Br2AcO

H

HH

BrBr

CrO3 - AcOH

O

AcO

H

HH

BrBr

(i) Zn - AcOH

(ii) HOH

O

OH

H

HH

CholesterolCholesteryl acetate dibromide

Dehydroepiandrosterone

37D. Ilangeswaran

(i) Ac2O

(ii) Na - C3H7OH

OH

AcO

H

HH

(i) PhCOCl

(ii) mild hydrolysis

(CH3OH/NaOH)

OCOPh

OH

H

HH

Oppenauer

Oxidation

OCOPh

O

H

HHHydrolysis

KOH

OH

O

H

HH

Testosterone

38D. Ilangeswaran