Synthesis of adenophostin A and congeners modified at glucose

A convergent route is described to the super-potent 1D-myo-inositol 1,4,5-trisphosphate receptor agonist adenophostin A (2) and analogues 5 and 7, in which the glucose bisphosphate unit is replaced by corresponding xylose bisphosphate and mannose bisphosphate units respectively. Adenosine was converted into its 2',3'-O-p-methoxybenzylidene derivative 8ab, which was selectively N-6-dimethoxytritylated by a transient protection method. 5'-O-Benzylation followed by reductive acetal cleavage gave, after separation from its 3'-O-p-methoxybenzyl isomer, the versatile glycosyl acceptor 5'-O-benzyl-N-6-dimethoxytrityl-2'-O-p-methoxybenzyladenosine 13. Coupling of 13 with selectively protected glucopyranosyl, xylopyranosyl or mannopyranosyl dimethyl phosphites gave the required 3'-O-alpha-pyranosyl adenosine derivatives. Acidic hydrolysis gave corresponding N-6-unprotected triols which were phosphitylated using bis(benzyloxy)(diisopropylamino)phosphine and imidazolium triflate without further N-6-protection. Deprotection gave the target trisphosphates 2, 5 and 7. Synthetic adenophostin A (2) was identical with a sample of natural material in all respects. Analogues 5 and 7 will be useful for structure-activity studies on the adenophostins.