A simple and efficient hydroxide-mediated SNAr rearrangement was reported to synthesize new depside derivatives containing the diaryl ether skeleton from the natural product barbatic acid. The prepared compounds were determined using1H NMR,13C NMR, HRMS, and X-ray crystallographic analysis and were also screened in vitro for cytotoxicity against three cancer cell lines and one normal cell line. The evaluation results showed that compound3bpossessed the best antiproliferative activity against liver cancer HepG2 cell line and low toxicity, which made it worth further study.