Synthetic Approaches to Ribosyl Adenosine 5′,5′′-Diphosphate Fragment of Poly(ADP-ribose)

Ribosyl adenosine 5',5"-diphosphate is a poly(ADP-ribose) fragment covalently bonded to a protein during post-translational modification. Poly(ADP-ribose) is involved in several biological processes such as DNA repair and cancerization. Herein, we report the development of two synthetic approaches to the poly(ADP-ribose) fragment via a common precursor. The major difficulty in the synthesis of the fragment is the alpha-(1"-> 2')-glycosidic bond formation between the ribose and adenosine because of the lack of neighboring group participation and low reactivity of the 2'-hydroxyl group. The first approach employed an indirect method that involved stepwise assembly of the ribosyl adenosine framework by O-ribofuranosylation of a commercially available ribose acceptor and subsequent N-glycosylation of N-6-benzoyl adenine (14 linear longest sequence (LLS) steps, 11 pots, 6.8 % overall yield). In the second approach, the direct O-ribofuranosylation of a known 6-chloropurine riboside acceptor was adopted (12 LLS steps, 10 pots, 4.8 % overall yield). Thus, two practical synthetic approaches to the target fragment were successfully established in terms of the number of LLS steps, pots, and overall yield. Furthermore, the precursor was converted into a conjugation-ready building block, primed for application in ADP-ribose oligomer synthesis.