The synthesis and biological evaluation of truncated spirastrellolide A analogues comprised of the southern hemisphere against protein phosphatase 2A are described. A convergent synthesis was designed featuring two gold-catalyzed cyclization reactions, specifically, a dehydrative cyclization of monoallylic diols for the synthesis of the tetrahydropyran (A-ring) and a regioselective spiroketalization for the efficient generation of the [6,6]-spiroketal (B, C-ring system). The synthesis of the southern hemisphere of spirastrellolide A was achieved involving the longest linear sequence of 19 steps. A total of eight spirastrellolide A analogues were synthesized, and preliminary PP2A enzyme assay inhibition studies were performed for the first time on analogues of the southern hemisphere. Several analogues showed inhibition, which is a positive indication and perhaps suggests that the unsaturated spiroketal fragment might be crucial to induce PP2A inhibition.