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.