Diastereoselective synthesis of cyclosaligenyl-nucleosyl-phosphotriesters

Article abstract of DOI:10.1002/chem.201002657

A diastereoselective synthesis of cycloSal-phosphotriesters (cycloSal=cycloSaligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cycloSal-pronucleotides. In previously described synthesis routes, the cycloSal-compounds were always obtained as 1:1 diastereomeric mixtures that could be separated in only rare cases. However, it was shown that the diastereomers have different antiviral activity, toxicity, and hydrolysis stabilities. Here, first a chiral thiazoline derivative was used to prepare nonsubstituted and 5-methyl-cycloSal- phosphotriesters in 48 and ≥95%a de (de=diastereomeric excess). However, this approach failed to give the important group of 3-substituted cycloSal-nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of (R_P)- and (S_P)-3-methyl-cycloSal- phosphotriesters as well. The antiviral activity was found to be five- to 20-fold different between the two individual diastereomers, which proved the importance of this approach. Chiral chemical Trojan horses: cycloSal-nucleotides (cycloSal=cycloSaligenyl) of thymidine and cycloSal-pronucleotides of 3′-azido-3′-deoxythymidine (AZT) and 3′-deoxy-2′, 3′-didehydrothymidine (d4T) were prepared by a diastereoselective route for the first time by using a chiral auxiliary approach with up to ≥95%a de (see scheme). The procedure is suitable to synthesize cycloSal-phosphotriesters with different substitution patterns in the aromatic residue.