Study On Phosphate Esterification And Ring-open Reaction Of Chiral 2,3-epoxy Alcohol

Objective: A series of chiral epoxy alcohols were synthesized by the appropriate epoxidation method,the phosphate ester groups were introduced into these chiral 2,3-epoxypropanol structures to preparation of the corresponding 2,3-epoxypropanol phosphate compounds;the ring-open reaction of 3-phenyl-2,3-epoxypropanol was studied.In addition,the anti-tumor activity of the synthesized compounds were explored preliminarily.Methods: The asymmetric epoxidation of Sharpless was used to synthesize chiral 2,3-epoxypropanols.Diphenyl phosphate was introduced into the 2,3-epoxypropanol molecules by phosphate esterification.Other functional groups were also introduced by ring-open reaction,in which the effects of the solvent,reaction time,reaction temperature,the amount of n-propanol,the amount of boron trifluoride ether solution on the ring-open of 3-phenyl-2,3-epoxypropanol were investigated in order to screen the favorable condition for increasing the yield and isomer excess ratio.The inhibitory effects of the synthesized 2,3-epoxypropanol derivatives on the proliferation of three kinds of cancer cells were detected by CCK8.Results: The yield of phosphate esterification products can reach to 95%,ee value can up to89% by using diphenyl chlorophosphate.The yield and the isomer excess ratio of the ring-opening product 3-phenyl-3-propoxypropane-1,2-diol can reach to 61% and 67% respectively when boron trifluoride systemwas used to catalyze the ring-opening reaction,anhydrous ethyl acetate as solvent,the amount of n-propanol was 4 eq.,the boron trifluoride ether solution was 0.2 eq.,the reaction temperature was 0 ℃ and the reaction time was 30 min.(R)-(3-phenyl-2,3-epoxy propyl)diphenyl phosphate,(R)-(2-methyl-3-phenyl-2,3-epoxy propyl)diphenyl phosphate,(R)-(2-pentyl-3-phenyl-2,3-epoxy propyl)diphenyl phosphate,(R)-(3-ethynyloxiran-2-yl)methyl diphenyl phosphate and3-phenyl-3-propoxypropane-1,2-diol were medicated to the human cervical carcinoma Hela cells,the human breast cancer 231 cells and the human Liver cancer Hep G2 cells for 24 hours or 48 hours,(R)-(2-pentyl-3-phenyl-2,3-epoxy propyl)diphenyl phosphate had the inhibitory effect on Hela cell,and(R)-(3-ethynyloxiran-2-yl)methyl diphenyl phosphate had the inhibitory effect on all of the three cells,others had the same results as the negative control group.Conclusion: A method of introducing a phosphate group into the 2,3-epoxypropanol structure has been established and the chirality of the epoxy alcohol is preserved,the yield is above 95%.The method of ring-open reaction for3-phenyl-2,3-epoxypropanol was established and optimized to increase the yield and isomer excess.The results of cell experiments showed that the(R)-(3-ethynyloxiran-2-yl)methyl diphenyl phosphate had the better inhibitory effect on Hela and Hep G2 cells than that of 5-fluorouracil,it also showed tha the effect of inhibiting the proliferation of tumor cells was enhanced by the introduction of phosphate groups in the(R)-2-pentyl-3-phenyl-2,3-epoxypropanol structure.