UC Irvine

Progress towards the total synthesis of N-methylwelwitindolinone C isothiocyanate is reported. The tetracyclic core is established by a key alkylation–type 2 intramolecular Diels– Alder cascade reaction, forming three new carbon-carbon bonds and five stereocenters in one step. Mechanistic studies suggest that alkylation proceeds via a zinc enolate intermediate instead of a silyl ketene aminal, shortening the synthesis by one step. Elaboration of the welwitindolinone core was accomplished with novel use of chlorinating agent MoCl5 to selectively convert a ketone to the vinyl chloride found in the natural product. To circumvent the problematic differentiation of two esters and install a bridgehead amine at an early stage in the synthesis, a series of new dienophiles were prepared. Ultimately selective protection of a diol intermediate allowed for differentiation, but methylation to install the final quaternary center proved to be challenging and remains one of the last hurdles in completing the synthesis.