Synthesis of Testosterone from

O

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

Ac2O C6H5COCl 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 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

H -Pd Oppenauer 2 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 . 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). again combines with (A) to form . Two farnesyl pyrophosphate molecules undergo tail to tail union to give via NADPH. Oxidosqualene undergo multicyclization intiated by epoxide cleavage to give protosterol carbonium ion two undergo two methyl shifts to give .

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 CH COSCoA H C SCoA 3 2CH3 COOH + 2CoA-SH 2CH3 COSCoA 3 active acetate acetoacetyl + + 2H2O CoA-SH OH Me Me OH Me OH NADPH NADP+ NADPH NADP+ HOOC CH2OH HOOC CHO HOOC COSCoA Mevaldic acid R-Mevalonic 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

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

CH OH O 2 O CH2OH O OH OH

HO O 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