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 and cyclohexenyl boronate 18 afforded ethyl 9-cis-retinoate (12) in high yield. Both coupling partners of the Suzuki reaction are better reacted immediately after generation from their precursors, tetraenylstannane 10 and cyclohexenyl iodide 13. The geometrically homogeneous tetraenylstannane 10, comprising the polyenic side chain of ethyl 9-cis-retinoate and its ring-demethylated analogues, was synthesized by a stereoselective Horner-Wadsworth-Emmons reaction. On the other hand, easily available cyclohexanones are ideal starting materials for preparation of the cyclohexenyl boronates required for the synthesis of the ring-modified 9-cis-retinoic acid analogues. For hindered cyclohexanones, hydrazones were converted to cyclohexenyl iodides. Iodine-lithium exchange and trapping with B(OMe)(3) then afforded the cyclohexenyl boronates. If the precursor cyclohexanone has secondary carbons, the alkenyllithium species was conveniently formed by elimination of the C,N-dilithiated intermediate obtained upon treating the trisylhydrazone with n-BuLi (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-bisdemethylretinoic acid 7. Both Suzuki and Stille coupling reactions took place under mild conditions, and the preservation of the retinoid side-chain geometry was therefore secured.
Pazos
Y
Y
Departamento de Química Orgánica, Facultade de Ciencias, Universidade de Vigo 36200 Vigo, Spain.
Iglesias
B
B
de Lera
A R
AR
D000077556:Alitretinoin; D003640:Dealkylation; D007202:Indicators and Reagents; D013237:Stereoisomerism; D014212:Tretinoin / Q000138:chemical synthesis*
D007202:Indicators and Reagents; D000077556:Alitretinoin; D014212:Tretinoin