Synthesis of the 4,5 diphosphonate analog of D,L- myo-inositol 4,5-diphosphate

Abstract

The first synthesis of the 4,5 diphosphonate analog (4,5 IPn 2; compound 2) of D,L-4,5 myo-inositol 4,5 diphosphate 1 (4,5 IP 2) is described. Key steps in the synthesis include the introduction of the diphosphonate into dimesylate 5 using sodium diethyl phosphite in DME to give 6. The 3,6 trans hydroxyl groups were introduced into 6 using the Bäckvall trans-diacetoxylation reaction. The use of the C 2 symmetry in the synthesis was utilized to introduce the final two setereocenters by osmylation of 14 to give compound 2 in an overall yield of 4.5% in only nine steps starting form readily available phthalic acid. Alternatively, the key intermediated 6 can be constructed by introducing the diphosphonate into compound 8 followed by conversion of 6. This results in an overall yield of 7% for the synthesis of 4,5 IPn 2 ( 2) from butadiene and dimethyl fumarate. Compound 2 did not mobilize calcium in rat basophilic leukemia cells but is stable in vivo and can potentially be used for the production of antibodies.