Synthesis of a Tubulin Assembly Inhibitors OXi8006

2-(3'-Hydroxy-4'-methoxyphenyl)-3-(3",4",5"-trimethoxybenzoyl)-6-methoxyindole (OXi8006) was found to be a strong inhibitors of tubulin assembly and showed excellent anticancer activity (IC 50 ＝1.1 μmol/L).Reported synthetic method of OXi8006 suffered from some drawbacks, such as long steps and low overall yields.Therefore, developing more efficient and practical protocols to synthesize OXi8006 is highly desirable.Firstly, we prepared aryl acetylene from commercially available isovanillin in three steps.Then the aryl acetylene was converted to diaryl acetylene ketone by reacting with 3,4,5-trimethoxybenzaldehyde via nucleophilic addition and oxidation reaction.The key step of 2-aryl-3-aroyl-indole construction was carried out between diaryl acetylenic ketone and o-iodo aniline by performing aza-Michael addition and subsequent intramolecular Heck reaction.The yield of developed synthesis over six steps is 20%.