Synthesis of novel carbocyclic adenosine analogues as inhibitors of adenosine kinase

Several new 4'-amino substituted carbocyclic adenosine analogues (6, 7, 31) were prepared as potential inhibitors of the enzyme adenosine kinase. Three different heterocyclic base moieties (adenine, 8-azaadenine, and pyrazolo[3,4-d]pyrimidine) were incorporated into carbocyclic nucleoside analogues through the use of two different synthetic strategies. In both strategies, bicyclic isoxazolidine 9 (prepared through a hetero Diels-Alder reaction with cyclopentadiene) was used as the starting material. In one route, the N-O bond was reductively cleaved, and the hydroxyl group (after inversion and ring functionalization) was used as a leaving group to incorporate the heterocyclic base moiety as the key bond-forming step. A second, more efficient and higher yielding synthetic route was developed as a general solution to the synthesis of the target 4'-amino substituted carbocyclic adenosine analogues. In this methodology, the allylic C-O bond in the bicyclic isoxazolidine 9 was cleaved with double stereoinversion under palladium(0) catalysis as the key bond-forming step to stereospecifically incorporate the heterocyclic base moiety into the cyclopentane ring. The regioselectivity of key bond-forming steps was established principally by NMR methods, especially through (13)C NMR shifts and by NOE effects seen in the analogues, as well as by HMBC/HMQC experiments.