Studies on the total synthesis of (-)-apoptolidin

An approach to the total synthesis of a highly selective apoptosis inducer, apoptolidin (1), is described. As part of these studies, a methodology as the route to the differentiated syn-1,2-diol by a two-directional chain extension of a C2 symmetric four carbon diepoxide has been developed. By applying this novel methodology, the synthetic route suitable for multigram preparation of the vinyl iodide subunit of apoptolidin was developed. The first-generation approach for the southern hemisphere of the macrolide via a successful coupling reaction between a lactone subunit and vinyllithium reagent derived from the vinyl iodide subunit was thwarted by the unsuccessful dihydroxylation reaction. Through a later-stage functionalization route the Weinreb amide subunit has been developed for the second-generation approach, from which the enantiomerically pure and suitably functionalized southern hemisphere of the macrolide has been achieved, featuring a coupling reaction between the Weinreb amide subunit and vinyllithium reagent followed by a Sharpless asymmetric dihydroxylation reaction. In addition to these studies, the improved syntheses of the triene pieces for the northern hemisphere of the macrolide has been developed featuring Suzuki coupling reactions. Finally, the assembly of the northern and southern hemispheres by an esterification reaction or an intermolecular Suzuki coupling reaction was explored. Approach applying a mild Suzuki coupling reaction successfully coupled the northern and southern hemispheres together. Future studies involving the macrolactonization, glycosylation followed by global deprotection necessary to complete the total synthesis of (-)-apoptolidin are discussed.