Copper mediated defluorinative allylic alkylation of difluorohomoallyl alcohol derivatives directed to an efficient synthetic method for (Z)-fluoroalkene dipeptide isosteres

Difluoroallylation of optically pure O-silylated (S)-2-methyl-3-hydroxypropanal 10a with bromodifluoropropene mediated by indium provided the corresponding difluorohomoallyl alcohol 11a with low diastereoselectivity, but without a decrease in optical purity. Defluorinative allylic alkylation of each diastereomer of the difluorohomoallyl alcohol efficiently proceeded by the reaction with trialkylaluminium and Cu(I) system or Grignard reagent and a catalytic amount of CuI system in THF to give the fluorine-substituted allylic alcohol 12 in an high yield and in an excellent Z selective manner. Subsequent imidate Claisen rearrangement of the allylic alcohol 12 proceeded with a complete 1,3-chirality transfer to give the fluoroalkene dipeptide isostere structure 14 after the final conversion of the primary alcohol 20 into the carboxylic acid form.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► High yield and highly Z selective allylic alkylation reaction of difluorohomoally alcohol derivatives with Grignard reagents and CuI catalyst leading to fluoroallyl alcohol derivatives. ► Complete 1,3-chirality transfer in the imidate Claisen rearrangement of the above fluoroallyl alcohol derivatives. ► A convienient method for the preparation of (Z)-fluoroalkene dipeptide isosteres in optically pure form.