## 3 Anti-HIV Pronucleotides-Nucleotide Reverse-Transcriptase Inhibitors (NttTIs)
### Triphosphate Esters of 2',3'-Dideoxynucleosides  
It has been long believed that the delivery of a triphosphate prodrug to the cell is impossible due to the high polarity of such compounds and the inherent lability of the anhydride bond in fully masked NTP. Additionally, due to susceptibility to phosphatases, it was assumed that these compounds are short-lived in vivo [109]. Despite these concerns, the [PERSON] group, encouraged by the positive results of the Di_PP_ro approach, synthesized triphosphate analogs, called TriPP_ro pronucleotides, with a similar arrangement of masking groups on the terminal P\({}_{\gamma}\) -phosphate residue as for the Di_PP_ro derivatives, expecting their metabolism to lead directly to biologically active ddNTs, without the involvement of cellular kinases (Scheme 21) [113, 114, 115, 38]. In the initial studies, symmetrical acyloxybenzyl-masking groups with C1-C17 alkyl, alkoxyl, and aminoalkyl chains were used (compound of type **39a**, R\({}^{1}\) = R\({}^{2}\), Scheme 21) [113; 114; 115]. These compounds were synthesized analogously to the nucleoside diphosphonate analogs discussed above (Scheme 20), using ddNDPs (prepared via the _cycloS_al approach, cf. Scheme 12) instead of ddNMPs, as the nucleotide components [113]. In addition, triphosphates of type **40** (Nucl = d4T) with only one benzyl-masking group, the expected metabolites of compounds **39**, were prepared to determine the stability under various experimental conditions. Since the route via a partial hydrolysis of the corresponding dibenyl derivatives, analogously to monobenzyl compounds in the Di_PP_ro series [111], was not very effective, monobenzyl Tri_PP_ro's **40** were obtained (albeit with moderate yields) by reacting benzyl _cycloS_al esters with ddNDPs [113]. It was found that dibenzyl Tri_PP_Pro **39** (Nucl = d4T) bearing alkyl chains up to C11 were efficiently cleaved enzymatically to monobenzyl derivatives **40**, and then to the expected d4 TNTPs. Although their anti-HIV activity and cytotoxicity in CEM cells were similar to that of the parent nucleoside, these compounds retained their full anti-HIV potency in TK' cells, where d4T was totally inactive [113]. These results demonstrated that ionic nucleoside triphosphates with the appropriate lipophilic masking groups can enter cells and deliver an active nucleotide, probably in the form of the corresponding nucleoside triphosphate. In follow-up studies, [PERSON] et al. described an alternative method for the preparation of pronucleotides of type **39** (Scheme 22) [114; 115]. A key reagent in this method, the pyrophosphorylating agent of type **41**, was obtained by the transesterification of diphenyl H-phosphonate [116] with the appropriate benzyl alcohol, followed by chlorination with \(N\)-chlorovesuccinimide and the reaction with inorganic phosphate. Its activation with trifluoroacetic anhydride and the subsequent reactions with \(N\)-methylimidazole and ddNMPs led to Tri_PP_ro-nucleotides in 35-85% yields. **Scheme 22. ** H-Phosphonate approach to the preparation of Tri_PP_ro-nucleotides **39** [115]. The previous results on the highly selective conversion of unsymmetrical Di_PP_ros into the corresponding ddNDPs encouraged [PERSON]'s group to apply the same strategy also to Tri_PPPP_ro-nucleotides. They synthetized a series of triphosphate derivatives of type **39b** (Figure 8), in which one benzyl group contained an acyl with a short (C2-C6) alkyl chain, while the other benzyl group, an acyl with a long (C14-C17) alkyl chain, or triethyleneglycol linked via succinic or glutararic diester [117]. The shorter-chain acyl group was expected to be more susceptible to enzymatic hydrolysis than the longer-chain acyl group, thus providing the better pharmacokinetics of the pronucleotide. However, these expectations did not come true.