Synthesis Of A Novel Cyclic Phosphate Mimetic - Alpha, Alpha-difluoromethylene Phosphinolide

Research of natural phosphate mimics has 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.Despite the use of biological isostere principle to get ?,?-difluoromethylenephosphonates in acyclic phosphate mimics has made great progress,in contrast,synthetic methods and the biological activities of cyclic phosphate mimics-?,?-difluoromethylenephostones still remain unexplored.This dissertation focused on the developing some novel efficient methods to construct ?,?-difluoromethylenephostones through the studies of organometal mediated reactions of high reactive fluorine-containing building blocks-?,?-difluoromethylene-?-allenic phosphonates and further applying these methods to synthesis nucleotide analogues which have potential bioactivities.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 dissertation consists of three parts:1.From the CuX2 mediated intramolecular cyclization studies of?,?-difluoromethylene-?-allenic phosphonic acid monoesters,six-membered y-bromo/chloro-substituted ?,?-difluoromethylenephostones were synthesized in moderate to good yields with high regioselectivity.In CuCl2 mediated cyclization,chloro-substituted a,a-difluoromethylenephostones can be achieved whereas the electrophile-induced cyclization by using weak electrophile such as Cl2 and NCS failed from the previous studies.2.For the first time,the highly regio-and stereoselective Pd(OAc)2/PPh3 catalyzed hydroarylation of ?,?-difluoromethylene-?-allenic phosphonates with aryl boronic acid in the absence of acid or base were achieved.Due to the time,intramolecular cyclization studies of these substrates still have not been conducted.3.In application of the cyclization reaction to synthesis nucleotide analogs with potential biological activity we successfully synthesized the corresponding uracil nucleotide analogues by five steps.