Organic Chemistry of Drug Synthesis. Volume 7

to the ring of a carbon atom at the acid oxidation stage. Oxidation of the
sulfur atoms in this intermediate with mercuric chloride in the presence
of methanol converts that carbon to the methyl ester. The product in
which the nitrile and carboxyl are cis to each other predominate in an
11 : 1 ratio over the trans isomer, probably reflecting thermodynamic
factors. Saponifaction of the ester group completes the synthesis of
cilomilast( 61 ).^11

O

CH 3 O

CH=O

54

O

CH 3 O

CH 2 Br

55

KCN O

CH 3 O

56

CN

CO 2 C 2 H 5

O

CH 3 O

57

CN

CO 2 C 2 H 5

CO 2 C 2 H 5

O

CH 3 O

58

CN

O

O

CH 3 O

CN

S

S

60

O

CH 3 O

CN

61

1. CH 3 OH CO 2 H
   HgCl 2


2. NaOH

NaOC 2 H 5

O CO 2 C 2 H 5

CH 3 O

59

CN

O

The vitamin A related compound, all trans retinoic acid, is a ligand for
cells involved in epithelial cell differentiation. It has found clinical use
under the name tretinoin ( 62 ), for treatment of skin diseases, such as acne,
and for off-label application as a skin rejuvenation agent. The recently dis-
covered closely related 9-cis isomer in addition binds to a different set of
receptors involved in skin cell growth. This new compound has been
found to control proliferation of some cancercells. The drug isthus indicated
for topical use in controlling the spread of Kaposi sarcoma lesions.
Reduction of the ester group in compound 63 , which incorporates the requi-
site future 9-cis linkage with lithium aluminum hydride, leads to the corre-
sponding alcohol. This compound is then oxidized to aldehyde 64 by means
of manganese dioxide. Condensation of the carbonyl group with the ylide
derived by treatment of the complex phosphonate ( 65 ) adds the rest of the
carbon skeleton ( 66 ). Saponification of the ester then gives the correspond-
ing acid,alitretinoin( 67 ).^12

30 ALICYCLIC COMPOUNDS