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 N-1-(CARBOCYCLIC-RIBOSYL)INOSINE 5',6''-DIPHOSPHATE DERIVATIVES BY AN 8-BROMO-SUBSTITUTION AT THE HYPOXANTHINE MOIETY

Cyclic ADP-ribose (cADPR, 1) is a general mediator involved in cellula r Ca2+ signaling. However, both the biological and chemical instabilit y of cADPR limit studies on its physiological role. We designed cyclic ADP-carbocyclic-ribose (3) and its inosine congener 4 as stable mimic s of cADPR and successfully synthesized 4. Starting with cyclopentadie ne, the optically active carbocyclic unit 8 was constructed via enzyma tic optical resolution. S(N)2 reactions of 8 with inosine derivative 7 and the 8-bromoinosine derivative 25 gave the N-1-substituted derivat ives 6 and 26, which were converted to the corresponding diphosphate d erivatives 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 cyclizat ion product 20, treatment of the corresponding 8-bromoinosine derivati ve 22 with EDC gave the desired intramolecular condensation product 29 in 23% yield. Thus, the significant effect of the 8-bromo group at th e hypoxanthine moiety in facilitating the key intramolecular condensat ion reaction between the phosphate groups of the substrate 22 was reco gnized. This is possibly due to conformational restriction of the mole cule in a syn-form around its glycosyl linkage. The 8-bromo and isopro pylidene groups were removed in succession to give the target compound 4. This is the first total synthesis of this type of cyclic nucleotid e.