The antiviral nucleoside 9-β-D-arabinofuranosyladenine (ara-A) is rapidly deaminated by adenosine deaminase, and its deamination product 9-β-D-arabinofuranosylhypoxanthine (ara-H) is considerably less active. A more desirable approach is to develop a deamination resistant ara-A derivative. We report here the synthesis of carbocyclic arabinosyladenine (C-ara-A), an adenosine deaminase resistant ara-A analogue with in vitro antiviral and antitumor activity. Hydrolysis of epoxide 1 (2% H2SO4, 100 °C, 1 h) and subsequent acetylation gave a mixture of 2 and 3. The major isomer 2 [(±)-4a-acetamido-2β,3α-diacetoxy-1α-cyclopentanemethyl acetate] was separated, and mild acidic hydrolysis (2 N HCl, 70 °C, 1 h) gave amine 4. Amine 4 was condensed with 5-amino-4,6-dichloropyrimidine to give 6, ring closure of 6 with diethoxymethyl acetate gave 7, and treatment of 7 with liquid ammonia afforded C-ara-A (8). C-ara-A is completely resistant to deamination by calf intestinal adenosine deaminase and does not inhibit the enzymatic deamination of either ara-A or adenosine. Both ara-A and C-ara-A exhibited LD50 concentrations of 1 × 10⁻⁶ M against P-388 mouse lymphoid leukemia cells. In vitro antiviral assays against herpes simplex virus type 1 (HSV-1) and vaccinia virus (VV) showed C-ara-A had significant activity with virus ratings (VR) of 1.5-3.5, and the minimum effective dose for 50% inhibition (MED50) was about 9 μg/mL, which is noncytotoxic to host cells. The easy accessibility, hydrolytic stability, adenosine deaminase resistance, and significant antiviral activity make C-ara-A an excellent candidate for chemotherapeutic evaluation. Further studies on its metabolism, antiviral spectrum, and therapeutic effects in animals are continuing.