The Suzuki coupling reaction in the stereocontrolled synthesis of 9-cis-retinoic acid and its ring-demethylated analogues

The thallium-accelerated Suzuki coupling reaction of tetraenyl iodide 19 an d cyclohexenyl boronate 18 afforded ethyl 9-cis-retinoate (12) in high yiel d. Both coupling partners of the Suzuki reaction are better reacted immedia tely after generation from their precursors, tetraenylstannane 10 and cyclo hexenyl iodide 13. The geometrically homogeneous tetraenylstannane 10, comp rising the polyenic side chain of ethyl 9-cis-retinoate and its ring-demeth ylated analogues, was synthesized by a stereoselective Horner-Wadsworth-Emm ons reaction. On the other hand, easily available cyclohexanones are ideal starting materials for preparation of the cyclohexenyl boronates required f or the synthesis of the ring-modified 9-cis-retinoic acid analogues. For hi ndered cyclohexanones hydrazones were converted to cyclohexenyl iodides. Io dine-lithium exchange and trapping with B(OMe)(3) then afforded the cyclohe xenyl boronates. If the precursor cyclohexanone has secondary carbons, the alkenyllithium species was conveniently formed by elimination of the C,N-di lithiated intermediate obtained upon treating the trisylhydrazone with n-Bu Li (Shapiro reaction). None of the above procedures allowed the generation of the more substituted organolithium from 2-methylcyclohexanone. However, the alternative Stille cross-coupling of 34 and 10 afforded 9-cis-1,1-bisde methylretinoic acid 7. Both Suzuki and Stille coupling reactions took place under mild conditions, and the preservation of the retinoid side-chain geo metry was therefore secured.