2-Methoxyestradiol (II), a natural metabolite of estradiol (I), has been recently found to inhibit the growth of cancer cells in vivo through antiangiogenesis and is currently under phase II clinical trials for prostate cancer and breast cancer with little cytotoxicity.  We here report a three-step synthesis starting from estradiol (I) via ortho-directed lithiation and methoxylation (Scheme).