The chiral carbocyclic nucleosides 2 and 3 were prepared from aristeromycin. The 4'-hydroxy compound 2 displays good antiviral activity against HSV-1 and HSV-2 with low toxicity. Carbocyclic nucleosides are usually less active as antivirals than their furanose counterparts. However, their main advantage is their metabolic stability to phosphorylase enzymes which cleave the glycosidic linkage of normal nucleosides. Our aim was to combine the metabolic stability of carbocyclic nucleosides with the biological advantage of their furanose equivalents. While replacement of the furanose ring oxygen for carbon makes the system more metabolically stable to base cleavage by phosphorylase at the 1'position, it also makes the corresponding 4'position less electronegative and hence alters the electronic environment of the functionally important 5'- and 3'-hydroxyls. A way to make the 5'- and 3'-hydroxyls in the carbocyclic ring more electronically similar to their furanose equivalents would be to put an electronegative substituent back into the ring at the 4'position such as a 4'-hydroxy, or a less bulky 4'-fluoro substituent. With this strategy in mind we decided to prepare the 4'-hydroxy and 4'-fluoro analogues, 2 and 3, of carbocyclic 2'-deoxy guanosine (2'-CDG) 1 which has good activity against Herpes Simplex virus type 1 (HSV-1) and type 2 (HSV-2) but is toxic to Vero cells at 300 pg/ml. With the increasing demand for new drugs to be enantiomerically pure, recent attention has focussed on routes to chiral carbocyclic nucleosides. We chose aristeromycin 4, a naturally occurring optically pure carbocyclic nucleoside, which is readily available by fermentation of Streptomyces citricolor, as our starting material. The synthetic approach used combines the elements of adenine to guanine base interconversion and the introduction of 4'-substituents that we have successfully used in the carbocyclic 2'-ara-fluoroguanosine (C-AFG) series. Aristeromycin 4 was converted in two stages into the hydrobromide salt 5 in 86% yield. Treatment of this salt with triethylamine in dimethylformamide (20min, room temperature) cleaved the oxadiazole ring to give the N-6cyano N-1-oxide intermediate, which was O-methylated with methyl iodide (3h, room temperature) to afford, after protection of the 3'- and 5'-hydroxyls (1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane, imidazole, 45min) the intermediate alcohol 6 in 52% yield overall. Deoxygenation of the alcohol 6 was achieved by treatment with phenyl chlorothiocarbonate in dichloromethane in the presence of dimethylaminopyridine (2h, 50°C), followed by reduction of the resulting thiocarbonate 7 with tributyl tin hydride in the presence of 2,2'-azobis(2-methylpropionitrile) (6h, 76°C, under a nitrogen atmosphere) to give the 2'-deoxy intermediate 8 in 43% overall yield. Desilylation of 8 with 3M hydrochloric acid in dioxane (5h, room temperature) and reaction of the resulting diol with methyltriphenoxyphosphonium iodide in dimethylformamide (3h, room temperature) gave the 5'-iodide 9 in 38% yield. Treatment of 9 with pyridine at 70°C gave the 4',5'-olefin, which on protection with trityl chloride afforded the intermediate olefin 10 in an overall yield of 45%. Osmylation of 10 with osmium tetroxide in pyridine occurred predominantly from the β-face and afforded, after tritylation, the separable 4'α-12 and 4'β-11 hydroxyl derivatives in 60% yield in a ratio of 1:6. Base interconversion via the Dimroth rearrangement was achieved by refluxing an ethanolic solution of 12 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.5h) to afford the 2-amino-6-methoxyamino purine derivative 13 in 49% yield. Stepwise hydrolysis of 13 first by treatment with aqueous acetic acid (30min, 85°C) followed by refluxing the product in 3M hydrochloric acid (3h) afforded carbocyclic 4'α-hydroxy-2'-deoxyguanosine 2 in 50% yield. In the same way 11 was converted via the intermediate 14 into carbocyclic 4'β-hydroxy-2'-deoxyguanosine 15 in 35% overall yield. Treatment of the 4'β-hydroxy derivative 11 with diethylaminosulphur trifluoride (DAST) in dichloromethane (30min, 5°C) introduced fluorine with inversion of configuration to give 16 in low yield (20%). Dimroth rearrangement of 16 followed by acid hydrolysis gave 4'α-fluoro-2'-deoxy carbocyclic guanosine 3: [α]_D +120 (c 1.0, DMSO), m.p. 170-174°C in 20% overall yield. The 4'-substituted carbocyclic nucleosides 2, 15, and 3 were tested in vitro for selective inhibition of HSV-1 and HSV-2 replication in Vero cells (Table 1) as previously described. The nucleoside analogues acyclovir (ACV) and 2'-CDG 1 were used as positive controls. The 4'β-hydroxy analogue 15 was only weakly active against HSV-1 and HSV-2, whereas both the 4'α-hydroxy derivative 2 and the 4'α-fluoro derivative 3 were comparable in activity to ACV against HSV-1 and HSV-2. The 4'α-fluoro analogue 3 was toxic to Vero cells at 100 μg/ml and 2'-CDG 1 was toxic to Vero cells at 300 μg/ml, whereas the 4'α-hydroxy analogue 2 was not toxic at 900 μg/ml.