A divergent synthesis of podophyllotoxin derivatives from simple and readily available starting materials through a late-stage functionalization strategy by rhodium catalysis is reported here. This strategy uses the ketone and oxime in substrates as directing groups. Four kinds of novel podophyllotoxin derivatives have been obtained without any erosion of the enantiopurity, thus indicating the broad substrate scope of this method. Additionally, by using the newly developed strategy, 9 aa, which exhibited excellent anticancer activity, can be prepared by a sequential transformation. In particularly, 9 aa suppressed HeLa cells with IC 50 values of 74.5 nM, thus providing a promising lead compound for future drug discovery.