Synthesis Of Fluorine-containing Fostriecin

Fostriecin analogue Lactones were found possessing remarkable anti-cancer and anti-fungi properties,among which Fostriecin exhibited the most excellent activity.A great deal research showed that its a,β-unsaturated d-lactone played a key role in the bioactivities as the acceptor of phosphoric acid prolease(PP2A)through Michael addition reaction.Due to this unique property,lots of chemists were attracted focusing on its total synthesis and structure transformation.As we know,fluorine atom has strong electronegativity and the similarity in size but substantial difference in electrostatic properties from hydrogen atom,which makes fluorination an interesting strategy in design of biologically active compounds.The gem-difluoromethylene group(CF₂)has been proven to be a key structural unit in many fluorinated compounds of biological and pharmaceutical significance,and this group has been recognized as an isopolar-isoteric replacement for oxygen and used as one strategy for the modification of biologically active compounds.And it has been revealed by structure-activity relationship studies that substitution on 4-position carbon of the lactones could greatly change their biological activities.In view of the above fact,our group designed and synthesizedγ,γ-gemdifluoromethylene-a,β-unsaturated d-lactone by difluoroallylation and difluoropropargylation of the fluorine-containing building block in present of metal indium powder,and expected more excellent activity could be found.In this paper,we planed to introduce the CF₂ group to fluorine-containing Fostriecin 42 and expected more excellent activities could be found.The synthetic rout included three key building block:the fluorine-containing part 15,the intermediate part 26a,and the Z,Z,E-triene part B.The gem-difluoromethylene-containing group part 15 has been achieved by difluopropargylation reaction from aliphatic aldehyde.Then through Sharpless AD reaction and the resolution of homopropargylic alcohol mediated by lipase from Pseudomonas(AK),part 26a successfully obtained.But we failed when we tried to install fluorine-containing part 15 and middle part 26a.Then we optimized the former rout and redesigned the synthetic method based on convergent principle.Firstly,we planned to obtain the fluorine-containing synthon E,then attemped to join this key lactone segment with segment F through Wadsworth-Hornor-Emmmons reaction,in the following step,we constructed the 8-position carbon chiral center using Felkin-Anh asymmetric addition reaction.The third segment B could be achieved according to the reported procedure,and introduced into the target molecule through Still coupling reaction.We studied the synthesis of part E due to the limited time.