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Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxysugar nucleosides serve as versatile precursor for the stereo-defined synthesis of these nucleoside derivatives on the basis of its ring opening with organoaluminum or organosilicon reagents. In this review article, novel methods for the synthesis of nucleoside analogues branched at the 1' and 4'-position will be described. During this study, we could discover an anti-HIV agent, 4'-ethynylstavudine (Festinavir). Festinavir showed more potent anti-HIV activity than the parent compound stavudine (d4T). Other significant properties of Festinavir are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors. Detailed profile of the antiviral activities, biology and pharmacology of Festinavir are also described.

Preparation of 1',2 '-, 3 ',4 '-, and 4 ',5 '-epoxy derivatives of nucleosides and their use for the stereoselective synthesis of 1'- and 4 '-branched analogues are described.

Upon epoxidation with dimethyldioxirane, the 2',5'-bis-O-silyl derivatives of 9-(3-deoxy-beta-D-glycero-pent-3-enofuranosyl)adenine gave the respective "3',4'-up" epoxides exclusively. Reaction between these epoxides and Me3Al was investigated in detail. It was found that the stereoselectivity of epoxide ring opening (anti versus syn) varied significantly upon changing the amount of Me3Al, the solvent, the O-silyl protecting group, and the reaction temperature. A possible reaction mechanism is proposed.

Epoxidation of 3',5'-O-(di-tert-butylsilylene)-1',2'-unsaturated uridine (11) with dimethyldioxirane proceeded from the alpha-face to give the 1',2'-alpha-epoxide 12. Upon reacting with organoaluminum reagents, the 1',2'-alpha-epoxide 12 underwent preferential syn-opening of the epoxide ring to yield the beta-anomers of 1'-methyl- (13beta), 1'-ethyl- (14beta), 1'-isobutyl- (15beta), 1'-ethynyl- (16beta), 1'-vinyl- (17beta), and 1'-phenyl- (18beta) uridine derivatives, although the corresponding alpha-anomers were also formed except for the reaction with triphenylaluminum. It was found, however, that protection of the N(3)-position of 11 either with a benzyloxymethyl or benzoyl group led to the exclusive formation of the desired beta-anomers. A possible explanation for the observed stereochemical outcome is presented. A similar strategy was found to be applicable to the synthesis of 1'-branched adenosine analogues, which include protected angustmycin C (37).

Dimethyldioxirane-mediated epoxidation of 3',5'-O-(di-t-butylsilylene)-1',2'-dehydro uridine (6) proceeded face-selectively to give 1',2'-alpha-epoxyuracil nucleoside (7). When 7 was treated with Me3Al, an anomeric mixture of the target 1'-C-alpha-methyluridine derivative 8 and its epimer 9 (86%, 8/9 = 5/1) was obtained. On the other hand, N3-protection improved the stereoselectivity in the ring-opening reaction. Thus, N3-benzyloxymethyl (BOM)-1',2'-epoxy nucleoside 11 obtained from 10 gave the target 12 as the sole product.