Design And Synthesis Of Difluoromethylenated Analogue Of Discodermolide

Natural products and their analogues provide a vast resource for discovery of pharmaceutical agents.Introduction of fluorine to an organic molecule often results in unpredictable change because of its unique properties.The fluorine-containing bioactive organic molecule has gained more and more chemists' interest in recent years.Discodermolide,isolated from the marine sponge Discodermia dissoluta,was found to have an excellent bioactivity against a broad range of tumor cells through a mechanism of microtubule stabilization,in a similar fashion to Taxol,blocking the cell cycle at the G2/M phase,halting mitosis and causing subsequent cell death at apoptosis.Discodermolide shows higher bioactivity than Taxol,especially retains antiproliferative activity in multi-drug resistant(MDR) cell lines,which are resistant to Taxol.Unfortunately,it showed serious adverse toxicity in the Phase I clinical trial which had to be suspended.According to the relationships between activity and structure(RAS),we designed a difluoromethylenated analogue of discodermolide in the hope of finding a new compound with excellent bioactivity and lower toxicity,and the synthesis was attempted as followes.Partâ… .Starting from L-malic acid,the segment C1-C8 4 was achived in a linear sequence of 8 steps,with an overall yield of 21%.Through the investigation of the reaction conditons,we found an excellent solvent system DMF/H₂O(2/1,v/v) for the In-stimulated difluoropropargylation of aldehyde 8.The target segment 4 was achieved through the syn hydrogenation of 7 and oxidative lactonation of 5.The absolute structure of 4 was confirmed by its X-Ray diffraction.It was suggested the conformation of the lactone moiety adopted a half-chair form,which is similar to the conformation of the lactone of discodermolide when bingding to the tubulin in H₂O.Partâ…¡.Segment C9-C14 31 was prepared from Roche ester 3 in 9 steps with 41%overall yield.In the Evans type of asymmetric Aldol reaction,satisfed results were obtained when expensive n-Bu₂BOTf was replaced by cheap TICl₄.The construction of the key intermediate Z-trisubstituted vinyl iodide 31 was accomplished from the dibromoolefin 32 via an efficient modified Tanino-Miyashita's approach in high yield.Partâ…¢.The synthesis of fragment C9-C15 60 was achieved with a sequence of 10 steps in an overall yield of 17%.The key intermediate 51 was obtained by using a Ti-mediated aldol reaction between ethyl ketone 43 and aldehyde 49,derived from Roche ester 3,followed by reduction by LiBH₄ in one-pot procedure.The Z-trisubstituted olefin was constructed by dehydration via introducing a lactone ring.Partâ…£.According to the Smith's and Novartis' strategies,the fragement C15-C21 77 was synthesized from the Roche ester in 11 steps with 36%yield.The route was optimized by avoiding the use of dangerous AlMe₃.Partâ…¤.We tried the linkage of the fragments,and achieved the linkage of the fragement C9-C14 and C15-C24 by Suzuki-coupling reaction.However,the union of the fragment C1-C8 and C9-C14 failed and further study was needed.