Stereoselective synthesis of trisubstituted alkenes

Three novel methods for the stereoselective synthesis of trisubstituted alkenes were investigated. Firstly the nickel(0)-catalysed coupling reaction of Grignard reagents with α-alkyl-substituted 3,4-dihydro-(2H)-pyrans and (Z)-1,2-disubstituted acyclic enol ethers was studied. The high stereoselectivity of the procedure was exploited in a synthesis of the aggregation pheromone of the square-necked grain beetle. Secondly, it was discovered that mono- and disubstituted enol carbamates could also undergo the nickel(0)-catalysed coupling reaction with Grignard reagents. A study of the scope and limitations was undertaken and the reaction was found to be efficient and highly stereoselective. Thirdly, α-stannylated enol carbamates were coupled and lithium dialkylcuprates to yield metallated alkenes, which were quenched with alkyl halides to give trisubstituted alkenes. The reaction was highly stereoselective and broad in scope. It was applied to the synthesis of the C(16)-C(23) fragment of the potent immunosuppressant Tsukubaenolide (FK 506).