Synthesis of Novel Retinoid X Receptor-Selective Retinoids

Retinoids 1−5 have been identified as potent RXR agonists for evaluation in the treatment of non-insulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1−5 have been developed. The core tetrahydronaphthalene 7, employed in the synthesis of 1 and 2, was prepared in 98% yield using an AlCl₃-catalyzed (0.03 equiv) Friedel−Crafts alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel−Crafts acylation of 7 with chloromethylnicotinate 9 was developed to prepare ketone 10 in 68% yield. Chelate-controlled addition of MeMgCl to 10 followed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis of 1 in 33% yield. FeCl₃-catalyzed (0.05 equiv) Friedel−Crafts acylation of 7 with chloromethylterephthalate 14 afforded ketone 15 in 81% yield. Saponification of 15 and reaction with 50% aqueous NH₂OH in AcOH afforded a 9:1 mixture of cis and trans oximes, from which the desired cis-oxime 2 was isolated in 43% yield. The core bromo-dihydronaphthalene 29 required for the synthesis of 3−5 was prepared by a Shapiro reaction. Transmetalation of 29 and reaction with Weinreb amides 30b or 36 afforded ketones 32 and 37, which were converted into 3−5 using chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids 41 and 42 with vinyl triflate 43 provided an alternative approach to the synthesis of this class of compounds.