Herein, we report the first total synthesis of marine ladder polyether gymnocin B (1) based on a two-phase strategy. In Phase I, inspired by the proposed biosynthesis, epoxide-opening cascades assemble 10 out of 15 cyclic ether rings making up the molecular core. In the subsequent Phase II, coalescence elevates the molecular complexity further by coupling of these subunits. Our two-phase synthetic approach significantly improved the step efficiency of the synthesis of this class of natural products.