Straightforward Synthesis of the Poly(ADP-ribose) Branched Core Structure

Poly(ADP-ribosyl)ation is a post-translational modification that produces poly(ADP-ribose) with a branched structure every 20-50 units; such branching structure has been previously suggested to be involved in regulating chromatin remodeling. To elucidate its detailed functions, we developed a straightforward method for the synthesis of the poly(ADP-ribose) branched core structure, alpha-D-ribofuranosyl-(1 "' -> 2 '')-alpha-D-ribofur-anosyl-(1 '' -> 2 ')-adenosine 5 ',5 '',5 "'-trisphosphate 1, from 6-chloropurine ribofuranoside 4 in 10 steps and 6.1% overall yield. The structure poses synthetic challenges for constructing iterative alpha-1,2-cis-glycosidic bonds in the presence of a purine base and the installation of three phosphate groups at primary hydroxyl groups. Iterative glycosidic bonds were formed by alpha-1,2-cis-selective ribofuranosylation using 2-O-(2-naphthylmethyl)-protected thiogly-coside donor 6 and a thiophilic bismuth promoter. After the construction of diribofuranosyl adenosine 5 had been constructed, it was chemo-and regioselectively phosphorylated at a later stage. Subsequent deprotection provided the synthetic target 1.