Nucleosides and Nucleotides. 173. Synthesis of Cyclic IDP-carbocyclic-ribose, a Stable Mimic of Cyclic ADP-ribose. Significant Facilitation of the Intramolecular Condensation Reaction of <i>N</i>-1-(Carbocyclic-ribosyl)inosine 5‘,6‘‘-Diphosphate Derivatives by an 8-Bromo-Substitution at the Hypoxanthine Moiety

Abstract

Cyclic ADP-ribose (cADPR, 1 ) is a general mediator involved in cellular Ca 2+ signaling. However, both the biological and chemical instability of cADPR limit studies on its physiological role. We designed cyclic ADP-carbocyclic-ribose ( 3 ) and its inosine congener 4 as stable mimics of cADPR and successfully synthesized 4 . Starting with cyclopentadiene, the optically active carbocyclic unit 8 was constructed via enzymatic optical resolution. S N 2 reactions of 8 with inosine derivative 7 and the 8-bromoinosine derivative 25 gave the N -1-substituted derivatives 6 and 26, which were converted to the corresponding diphosphate derivatives 5 and 22 . The intramolecular condensation reactions between the two phosphate groups of 5 and 22 were investigated. Although the reaction with inosine derivative 5 did not produce any of the cyclization product 20, treatment of the corresponding 8-bromoinosine derivative 22 with EDC gave the desired intramolecular condensation product 29 in 23% yield. Thus, the significant effect of the 8-bromo group at the hypoxanthine moiety in facilitating the key intramolecular condensation reaction between the phosphate groups of the substrate 22 was recognized. This is possibly due to conformational restriction of the molecule in a syn-form around its glycosyl linkage. The 8-bromo and isopropylidene groups were removed in succession to give the target compound 4 . This is the first total synthesis of this type of cyclic nucleotide.