Synthesis Of D-Ribose 1-Phosphonates Analogues

The glycosyl phosphonates as analogues of natural phosphates, bearing the carbon-phosphorous bond which is incapable of hydrolyzed by"ordinary"phosphatases, have excellent biological activities. Desired products in this paper, (dialkyl)-1-phosphonate-D-ribose, are key intermediates of numerous vital phosphonates. In order to optimize the synthesis and separation, anomers of 1-(dialkyl)-2,5-anhydro-D-riobofuranosyl phosphonates were synthesized by Horner-Emmons reactions in which three different protected D-ribose derivatives were used as the starting materials, respectively.In route one, the introduction of phosphonate moiety to 2,3-O-isopropylidene-5- O-trityl-D-ribofuranose was accomplished through Horner-Emmons'two-phase reaction. Separation of anomers of carbohydrate phosphonates was limited to preparative TLC plates due to the extreme similarity of their polarities. Desired products were obtained after deprotection with the action of trifluroacetic acid with total 30% yield. In route two, 2,3-O-isopropyledene-5-O-pivaloyl-D-ribofuranose reacted with tetraalkyl methlenediphosphonate to give1-(diethyl)-2,3-O-isopropyledene-5-O-pivaloyl- D-ribofuranosyl phosphonate. Sodium ethoxide was used to remove the pivaloyl group. The anomers were isolated and then hydrolyzed under acidic condition to provide the desired products and, average total yield reached about 36%.In the third route, the D-ribose 1-phosphonates derivatives were obtained through Horner-Emmons reaction. After separating the anomers, and desired products were obtained through deprotection under the condition of Pd/C and H2 respectively. The average total yield was about 40%.We also tried the preparation of (dipivoxil)-1-phosphonate-D-ribofuranose. Unfortunately, it was found that neither the transesterification of 1-(dimethyl)-2,3,5-O -tribenzyl-α(-β)-D-ribofuranose phosphonate with chloromethyl pivalate, nor the Horner-Emmons reaction of protected D-ribose's primary alcohol with tetra(pivaloyloxymethyl) methlenediphosphonate could afford the targeted product.