Fostriecin is a promising leading anticancer compound. The α,β-unsaturated lactone in Fostriecin is believed to be the critical pharmacophore, which can covalently bind to the Cys269 residue of the PP2A subunit via a Michael 1,4-conjugate addition. We reasoned that the introduction of strong electron-withdrawing gem-difluoromethylene to replace the methylene group at the γ position of the lactone ring would lead to fostriecin analogue 4 with enhanced enzymatic binding affinity. Accordingly, the synthesis of fostriecin analogue 4 was investigated. The skeleton of target molecule 4 was established convergently from fragments a, b and c via an magnesium mediated chelation-controlled addition and Stille coupling using Pd(CH₃CN)Cl₂ as catalyst. The key steps of synthesizing fragment a included the coupling between alkenyl iodide 8 and ethyl bromodifluoroacetate in the presence of copper powder and the establishment of C-5 stereocenter via lipase AK catalyzed kinetic resolution. The construction of C-11 and C-9 stereocenters in fragment b were realized by the lipase AK catalyzed kinetic resolution and CBS asymmetric reduction of α,β-unsaturated ketone 23 (BH₃·PhNEt₂ as reductive agent), respectively. The connection of fragments a and b proceeded through the magnesium mediated chelation-controlled addition procedures: fragment a (vinyl stannane) was firstly converted to vinyl lithium reagent 27 by the treatment of BuLi (1.05 equiv.) at -78 ℃, then the i-PrMgCl (2.0 equiv.) solution in THF was added dropwise to produce the critical magnesium-ate complex intermediate A, finally the addition of fragment b solution in THF to the magnesium-ate complex A gave the coupled product 29. The Stille coupling of fragment c with vinyl iodide 39 prepared from 29 in the presence of Pd(CH₃CN)Cl₂ gave target molecule skeleton 40 in 85% yield. Finally, the protected fostriecin analogue 42 was successfully synthesized by a longest linear steps of 18 steps in 1.28% overall yield. However, the deprotection of compound 42 failed to give the target molecular 4. This could be caused by the instability of the fluorinated lactone in which the strong electron- withdrawing gem-difluoromethylene group enhanced the polarization of the lactone function.

Key words: Fostriecin, difluoromethylene, α,β-unsaturated δ-lactone, enzymatic kinetic resolution, 1,5-oxidative cyclization, hydrolysis of fluorinated lactone