Synthesis of [beta]-heteroaryl propionates via trapping of carbocations with [pi]-nucleophiles and the formal synthesis of N-methylwelwitindolinone C isothiocyanate
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A variety of heterocyclic alcohols were coupled with silyl ketene acetals and other [pi]-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide an array of substituted [beta]-heteroaryl propionates, including those with contiguous quaternary centers. This reaction also proceeds with high diastereoselectivity when the [pi]-nucleophile bears a chiral auxiliary. The formal synthesis of N-methylwelwitindolinone C isothiocyanate, a densely functionalized alkaloid with the ability to reverse multiple drug resistance, was completed featuring several key transformations. The first key transformation consisted of coupling a heterocyclic alcohol with a silyl ketene acetal to give a highly functionalized intermediate. Next, a palladium catalyzed enolate arylation followed by an intramolecular allylic alkylation successfully constructed the bicyclo(4.3.1)decane backbone of the N-methylwelwitindolinone C isothiocyanate.