The effects on cell proliferation of retinoids has led to the investigation
of structurally related compounds as potential antineoplastic drugs. The
finding many years ago that the cyclobexyl moiety in the naturally occur-
ring compound can be replaced by a tetrahydronapthalene has simplified
work in this area. It is of interest that in each of the examples that follow
a benzene ring serves as a surrogate for the unsaturated carbon chain
found in natural retinoids. The tetralin-based compoundtamibarotene
( 59 ) has been tested as an agent for treating leukemias. Reaction of the
diol ( 53 ) with hydrogen chloride affords the corresponding dichloro
derivative ( 54 ). Aluminum chloride mediated Friedel–Crafts alkylation
of acetanilide with the dichloride affords the tetralin ( 55 ). Basic hydrolysis
leads to the primary amine ( 56 ). Acylation of the primary amino group
with the half acid chloride half ester from terephthalic acid ( 57 ) leads to
the amide ( 58 ). Basic hydrolysis of the ester grouping then affords 59.^9
OHOH53HCl
ClCl54NHCOCH 355NHCOCH 3
NaOH56NH 2ClOCCO 2 CH 357HNOCO 2 CH 358NaOHHNOCO 2 H59The retinoid-like compoundbexarotene( 63 ) is approved for treating
skin lesions associated with T-cell lymphomas. The starting tetralin ( 60 )
is probably obtained by alkylation of toluene with dichloride ( 54 ).
Friedel–Crafts acylation with the acid chloride ( 57 ), gives the ketone
( 61 ). This intermediate is then treated with the ylide from triphenylmethyl-
phosphonium bromide. The carbonyl oxygen in the product ( 62 )isnow
replaced by a methylene group. Saponfication of the ester affords the
free acid and thus 63.^10
76 CARBOCYCLIC COMPOUNDS FUSED TO A BENZENE RING