Synthesis of Testosterone from cholesterol

Ac2O CrO3-AcOH
Br2
HO AcO AcO
Br Br
Br Br
cholesterol
Zn-AcOH
hydrolysis
OCOC6H5 OH O

C6H5COCl Ac2O
mild hydrolysis Na-C3H7OH
HO AcO HO
dehydroepiandrosterone
oppenauer
oxidation
OCOC6H5 OH

hydrolysis

O O
testosterone

Testosterone from cholesterol: Cholesterol on acetylation, bromination followed by oxidation yields

dehydroepiandrosterone. Acetylation followed by selective hydrogenation reduces the C-17
carbonyl group. Benzoylation followed by selective hydrolysis and oppenauer oxidation yields
testosterone.
Synthesis of progesterone from stigmasterol acetate: Bromination followed by ozonization and
debromination of stigmasterol acetate yields acetylbisnorcholenic acid, which on reaction with
Grignard reagent yields diphenylethylene derivative. Bromination followed by oxidation,
debromination and hydrolysis yields pregnenolone. Oppeneauer oxidation of pregnenolone yields
progesterone
Synthesis of progesterone from cholesterol: The process involves treating chlolesterol with acetic
anhydride and bromine yielding dibromo derivative, which on oxidation followed by debromination
yields dehydroepiandrosterone. One carbon of chain was introduced by treatment with HCN.
Grignard reaction and selective hydrogenation of the conjugated double bond affords pregnenolone

Synthesis of progesterone from diosgenin: Heating diosgenin in a sealed tube at 200oC with acetic
anhydride leads to opening of spiro ketal ring, followed by oxidation with chromium trioxide
introduces two carbon chain at C-17. Selective reduction, hydrolysis followed by oppenauer
oxidation yields progesterone.

O O
Ac2O Ac
200oC
HO AcO
Diosgenin CrO3

CH3 CH3 CH3

C O C O C O

H2-Pd
Oppenauer
oxidation hydrolysis

O HO AcO
Synthesis of Oestrone

1: Johnson synthesis

2: Hughes synthesis
Biosynthesis of Cholesterol; Biosynthesis of cholesterol is believed to start with labelled acetic acid.
Acetic acid which acts as active acetate combines with coenzyme A to form active acetate, which
rearranges to aceto acetyl CoA. This combines with one molecule of active acetate to form
hyroxymethylglutarate having R configuration. It is then reduced by NADPH to mevaldic acid, which
is further reduced to mevalonic acid. Since mevalonic acid contains six carbon atoms, one carbon is
lost by phosphorylation process to yield isoprene unit. Two phosphorylation of mevalonic acid
followed by loss of molecule of carbon dioxide and water to form 3-methylbutyl-3-enyl(isopentyl)
pyrophosphate (A) which isomerises to 3-methylbut-2-enyl(β,β dimethylallyl) pyrophosphate (B). (A)
and (B) combine to give geranyl pryrophosphate with A acting as nucleophile and B acting as
electrophile (head to tail union). Geranyl pyrophosphate again combines with (A) to form farnesyl
pyrophosphate. Two farnesyl pyrophosphate molecules undergo tail to tail union to give squalene
via NADPH. Oxidosqualene undergo multicyclization intiated by epoxide cleavage to give protosterol
carbonium ion two undergo two methyl shifts to give lanosterol .

The methyl group at C-14 is first oxidized t hydroxymethyl and then to carboxyl group
followed by decarboxylation to give 14-desmethyl lanosterol. Removal of 4,4-gem dimethyl group
proceed through oxidation to hydroxymethyl and then to carboxyl group which decarboxylate to
give zymosterol. Isomerization of double bond from 8,9 to 7,8 and then to 5,6 followed by reduction
of double bond at C-24 and C-25 gives cholesterol.
 O O
C C CH3COSCoA
2 CH3 COOH + 2 CoA-SH 2 CH3 COSCoA H3C SCoA
active acetate acetoacetyl
+ +
2H2O CoA-SH

Me OH Me OH OH
Me
NADPH NADP+ NADPH NADP+
HOOC CH2OH HOOC CHO HOOC COSCoA
R-Mevalonic acid Mevaldic acid
R-Hydroxymethyl
glutarate
ATP ADP

Me Me
Me OH Me OH
ATP ADP -H2O, -CO2
CH2OPP CH2OPP
HOOC CH2OP HOOC CH2OPP
A B

Me Me
(A) PPO
H
CH2OPP CH2OPP

PPO
(B) OPP
Me Trans geranyl pyrophosphate Farnesyl pyrophosphate

PPO PPO

squalene
H

H H H

H
HO HO O
lanosterol
protosterol carbonium ion 2,3-oxidosqualene

HO HO
HO
14-desmethyl Zymosterol O Cholesterol
lanosterol P= P OH
OH
Biosynthesis of cholesterol to other steroids

O O O
OH

HO HO HO HO
cholesterol pregnenolone 17-hydroxy pregnenolone dehydroepiandrosterone

O O O
OH

O O O
progesterone 17-hydroxy progesterone androstenedione
O CH2OH CH2OH O OH
O
OH

O HO O
O
deoxycorticosterone 11-deoxy cortisol Estrone Testosterone

O CH2OH OH
O CH2OH
HO HO
OH

HO
O
O
corticosterone cortisol

O CH2OH
HO OHC

O
aldosterone