Stereocontrolled synthesis of 6-s-cis- and 6-s-trans-locked 9Z-retinoids by hydroxyl-accelerated Stille coupling of (Z)-tri-n-butylstannylbut-2-en-1-ol and bicyclic dienyl triflates

Analogues of 9-cis-retinoic acid with locked 6-s-cis and 6-s-trans conforma tions have been stereoselectively synthesized using a Stille coupling react ion between bicyclic dienyl triflates (5 and 6, respectively) and (Z)-tribu tylstannylbut-2-en-1-ol (7) to stablish the Z geometry of the polyenic side chain. The mild conditions (25 degrees C, 30 min) of this coupling stand i n contrast to the reluctance of the isomeric (E)-tributylstannylbut-2-en-1- ol (18) to react with triflates 5/6. The significant rate differences exper imentally observed in Stille reactions between isomeric (Z)- and (E)-tri-n- butylstannylalkenols in favor of the former isomer, even with highly hinder ed alkenyl triflates, is ascribed to internal coordination of palladium to the heteroatom in the presumably rate-limiting transmetalation step. Dienal s and trienals with an E geometry, which are not efficiently available by d irect coupling of the corresponding triflates and E-stannanes, can in turn be obtained by isomerization of their Z-isomers.