Synthesis of novel retinoid X receptor-selective retinoids

Retinoids 1-5 have been identified as potent RXR agonists for evaluation in the treatment of noninsulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1-5 have been developed. The core tetrahydr onaphthalene 7, employed in the synthesis of 1 and 2, was prepared in 98% y ield using an AlCl3-catalyzed (0.03 equiv) Friedel-Crafts alkylation of tol uene with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel -Crafts acylation of 7 with chloromethylnicotinate 9 was developed to prepa re ketone 10 in 68% yield. Chelate-controlled addition of MeMgCl to 10 foll owed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a f ive-step synthesis of 1 in 33% yield. FeCl3-catalyzed (0.05 equiv) Friedel- Crafts acylation of 7 with chloromethyl-tereplithalate 14 afforded ketone 1 5 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 desire d 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. Tr ansmetalation of 29 and reaction with Weinreb amides 30b or 36 afforded ket ones 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.