含有二氟亚甲基的Fostriecin类似物的设计和合成研究

Design and Synthetic Investigation toward gem-difluoromethylenated Fostriecin Analogue

Fostriecin是近年来备受瞩目的新型抗肿瘤天然产物.根据构效关系分析,设计了具有潜在更高活性的含有二氟亚甲基的Fostriecin类似物4,并进行了合成研究.目标分子的骨架结构由片段a,b,c经螯合控制的加成反应和Stille偶联反应汇聚合成.在含氟片段a的合成中应用了以下关键反应:(Z)-烯基碘8与溴二氟乙酸乙酯在铜粉作用下的偶联反应;酶动力学拆分构建C-5位的手性中心.合成甲基酮片段b的关键步骤包括:酶动力学拆分构建C-11位的手性中心和CBS不对称还原α,β-不饱和酮23.从商业可得的原料出发,经最长线性步骤18步以1.28%的总产率成功地得到未脱保护的含有二氟亚甲基的Fostriecin类似物42.但在对42脱除保护基时,没有得到目标分子4.这可能是由于偕二氟亚甲基的强吸电子作用使内酯环极化程度增大,从而导致内酯环易发生水解开环反应.

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）Cl2gave 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 electronwithdrawing gem-difluoromethylene group enhanced the polarization of the lactone function.