Study On The Synthesis Method Of A Novel Fluorine-containing Phosphate Simulant

Research of natural phosphates mimics have been attracted much attention for their important role in the development of potential enzyme inhibitors and as useful probes in the elucidation of biochemical process.We are interested in the two classes of fluorine-containing phosphate mimics:α,α-difluoromethylenephostones and α-fluorovinylphosphonates.Despite the use of biological isostere principle to getα,α-difluoromethylenephosphonates in acyclic phosphate mimics has made great progress,in contrast,synthetic methods and the biological activities of cyclic phosphate mimics-α,α-difluoromethylenephostones still remain unexplored.On the other hand,α-fluorovinylphosphonates have been used as precursors for α-fluorophosphonates(compoundsthat have been reported to be better phosphate mimics than the difluoromethylenederivatives)via hydrogenation reactions.Additionally,monofluoroalkene as a peptide bond isosteresomea-fluorovinylphosphonates display interesting biologicalactivities.This dissertation focused on the developing some novel efficient methods toconstruct a,a-difluoromethylenephostones and α-fluorovinylphosphonates through the studies of high reactive fluorine-containing building blocks-α,α-difluoromethylene-β-allenicphosphonates.Through studies of the synthesis of these compounds,we may provide a good foundation for the development of new enzyme inhibitors and further broaden the application of fluorine-containing cyclic phosphonate in medical field.The dissertationconsists ofthree parts:1.Six-membered y-SCH3-substituted α,α-difluoromethylenephostoneswere synthesized in moderate to good yields with high regionselectivity from the DMTSF mediated intramolecular cyclization of a,a-difluoromethylene-p-allenic phosphonic acid monoesters.2.The Pd(PPh3)4-catalyzed regioselectivecarbonylation of α,α-difluoromethylene-β-allenic phosphonic acid diesters with ArOH and COin 1atm allows to produceα-fluorovinyl-y-acyolphosphonates inmoderate to high yields andwith high Z or E selectivity by controlling the solvent or reaction time.3.We successfully synthesized the corresponding adeninenucleotideanaloguesbyeight steps using the bromo-cyclization product as starting material.