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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 new type of anti-tumor natural product that has attracted much attention in recent years.According to the structure-activity relationship analysis, Fostriecin analogue 4 containing difluoromethylene is designed and synthesized.Fostriecin The structure was synthesized by chelating-controlled addition reaction and Stille coupling reaction of fragment a, b, c.The following key reactions were used in the synthesis of fluorine-containing fragment a: (Z) -alkenyl iodide 8 and bromodifluoride The coupling reaction of ethyl acetate under copper powder and enzyme kinetic resolution to construct the chiral center at C-5 The key steps in the synthesis of methylketone fragment b include enzymatic resolution to construct C-11 Asymmetric reduction of the α, β-unsaturated ketone with a chiral center and CBS 23. Starting from the commercially available starting material, the longest linear step of 18 steps gave a total yield of 1.28% Methyl group 42. However, the target molecule 4 was not obtained when the protective group was removed for 42. This may be due to the strong electron-withdrawing effect of the gem-difluoromethylene group, which increases the degree of polarization of the lactone ring and thus Resulting in lactone ring prone to hydrolysis ring-opening reaction.