Synthesis of adenophostin A and congeners modified at glucose
Marwood RD., Riley AM., Jenkins DJ., Potter BVL.
A convergent route is described to the super-potent lo-wyo-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 N6-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-N6-dimethoxytrityl-2′-O-p-methoxybenzyladenosine 13. Coupling of 13 with selectively protected glucopyranosyl, xylopyranosyl or mannopyranosyl dimethyl phosphites gave the required 3′-O-α-pyranosyl adenosine derivatives. Acidic hydrolysis gave corresponding N6-unprotected triols which were phosphitylated using bis(benzyloxy)(diisopropylamino)phosphine and imidazolium Inflate without further N6-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. © The Royal Society of Chemistry 2000.