The first total syntheses of the piericidin related natural products Mer-A2026B and JBIR-02 are reported. Key features of the synthetic approach involve an Ir-catalyzed one-pot C-H activation/oxidation procedure for the preparation of the hydroxypyridine, a vinylogous Mukaiyama aldol reaction, and a final Negishi cross-coupling of an advanced pyridine derivative with an allylic side chain precursor. In addition, the absolute configuration of Mer-A2026B (9R,10R) and JBIR-02 (9R,10R) was established.