We describe the synthesis of Xyzidepsin, a depsipeptidic analogue of HDAC inhibitor Romidepsin (FK228), using a solid-phase strategy. Our latent thioester solid-phase linker was synthesized in 92% yield (three steps). Chemoselective conditions unmasked the thioester functionality and cyclized the depsipeptidic macrocycle. An IC50 value of 0.50 μM ± 0.05 was obtained for U937 cells. This synthetic route, well-suited to SAR, represents a generalizable route toward all manner of analogues, including structures with acidic and basic amino acids.