Synthesis and Antitumor Activity Evaluation of γ-Monofluorinated and γ,γ-Difluorinated Goniothalamin Analogues

A series of novel γ,γ‐difluorinated Goniothalamin analogues 4a–4i and 6a–6i were synthesized. The key steps included the construction of C‐5 stereocenter adjacent to gem‐difluoromethylene group by way of lipase AK catalyzed kinetic resolution, the introduction of aryl group via Stille coupling, and lactonization by 1,5‐oxidative cyclization. These γ,γ‐difluorinated Goniothalamin analogues 4a–4i and their enantiomers 6a–6i, together with several corresponding γ‐monofluorinated Goniothalamin analogues were biologically evaluated against four different cancer cell lines. Compound 7h showed a nearly equivalent potency as the parent (R)‐Goniothalamin in the micromolar range. The different fluorine effects between fluoromethylene and gem‐difluoromethylene on antitumor activity were discussed through the analysis of bioassay data. A series of novel γ,γ‐difluorinated Goniothalamin analogues 4a–4i and 6a–6i were synthesized by way of lipase AK catalyzed kinetic resolution, Stille coupling and 1,5‐oxidative cyclization. These difluorinated analogues and several monofluorinated analogues were biologically evaluated together against four different cancer cell lines. From the analysis of bioassay data, it was found that adding one fluorine at the γ position of Goniothalamin was a better modification than introducing two fluorine atoms.