neutralize electrical charges. In such form, phosphorylated nucleosides can easily penetrate cell membranes. Inside the cell, the masking groups are removed via enzymatic and/or chemical hydrolysis, which lead to the release of the corresponding nucleoside 5'-monophosphate (ddNMP). Then, cellular kinases in a stepwise manner phosphorylate ddNMP ultimately to its 2',3'-dideoxynucleoside 5'-triphosphate (ddNTP), an anti-HIV active species (Scheme 1) [9; 12; 13].  
Initially, when developing the concept of pronucleotides, it was assumed as an absolutely necessary condition that the electric charges in the prodrug molecule were completely masked. Following this paradigm, various pronucleotide strategies were proposed, which were based mainly on esters or amides as potential protective groups for 5'-phosphate moiety of ddNMP (e.g., studies of [PERSON] [11; 14; 15], [PERSON] [16; 17; 18; 19], [PERSON] [20; 21], [PERSON] [22; 23], and others groups). However, over the years, it has been observed that certain types of pronucleotides endowed with negative charges could also effectively penetrate cell membranes, and showed high biological activity (e.g., the research of the [PERSON] [24; 25; 26; 27; 28] and [PERSON] groups [23; 29; 30]). This challenged the validity of the generally accepted postulate of electrical neutrality as the basic criterion for the effective transport of pronucleotides through cell membranes, but at the same time it opened up new possibilities for extending the spectrum of the designed pronucleotides to include new ionic structural features.  
The pronucleotide strategy for delivering monophosphorylated antiviral nucleosides to the cell did not, however, completely solve the problem of the effective in vivo generation of an active metabolite, ddNTP. Sometimes the enzymatic phosphorylation of 2',3'-dideoxynucleoside monophosphates to di- and ultimately to triphosphates is very difficult or has undesirable kinetics. Typically, such problems arise during the conversion of a monophosphorylated nucleoside into its corresponding diphosphate. For example, AZT is a good substrate for thymidine kinase, similarly to natural thymidine, but thymidylate kinase converts AZTMP into AZTDP much less efficiently than TMP into TDP [10]. Thus, in such situations it would be advantageous to deliver the pronucleotides to the cells in the form of suitably protected diphosphates of antiviral nucleosides in order to bypass enzymatic phosphorylation to ddNDP. While the final phosphorylation of dideoxynucleoside diphosphates to the corresponding triphosphates is usually fast and effective, it was also tempting to develop triphosphate pronucleotides so that in vivo generation of the final active metabolite would be completely independent of cellular phosphorylation processes.  
Despite the apparent advantages of such approaches, the first studies on the use of di- and triphosphate pronucleotides against HIV appeared two decades after the concept of anti-HIV monophosphate pronucleotides emerged [31]. This delay, most likely, was due to synthetic difficulties and the extreme lability of the anhydride bond in uncharged di- and triphosphates, containing masking groups in aqueous media. However, the reports from the [PERSON] group [24; 25; 26; 27; 28], showing that monophosphate pronucleotides with electric charges are both stable and can cross the cell membranes, revived the interest of both chemists and biologists in \(2^{\prime}\),\(3^{\prime}\)-dideoxynucleoside di- and triphosphates as potential pronucleotides.  
In this review, we present chemical methods for the formation of the anhydride polyphosphate linkages together with their applications to the synthesis of \(2^{\prime}\),\(3^{\prime}\)-dideoxynucleoside di- and triphosphates, as a new generation of anti-HIV pronucleotides.  
For recent reviews on the related topics, see also [PERSON] (2012) [32] [PERSON] et al. (2014) [33], [PERSON] and [PERSON] (2015) [34], [PERSON] (2015) [35], [PERSON] and [PERSON] (2017) [36], [PERSON] and [PERSON] (2017) [37], and [PERSON] (2018) [38].