Diastereoselective Synthesis of cycloSaligenyl‐Nucleosyl‐Phosphotriesters

Abstract

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 % 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 (RP)‐ and (SP)‐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.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…Although the reaction conditions worked well for unsubstituted salicylic alcohol, the same sequence was surprisingly not applicable to the synthesis of 3- 85 and 5- 87 methyl- cyclo Sal derivatives due to racemization of both the chiral phosphoramidate reagents and the final nucleoside prodrugs. This led the authors to investigate the other chiral auxiliaries 191a – e (Scheme 57).…”

Linear Synthesis of Chiral cycloSal‐Pronucleotides

“…Whereas l-proline ethyl ester (16) and l-proline isopropyl ester (17) needed to be synthesized, [27] l-proline benzyl ester (18) 18 were then reacted with thiophosphoryl chloride to give the corresponding products 19-21. Subsequent reaction with salicylic alcohol 8 led to the corresponding thiophosphoramidates 22-24 with diastereoisomeric excesses of between 60 and 65 %.…”

“…The nucleoside was finally introduced stereospecifically. [17] Here, we report the stepwise development of a linear, asymmetric synthesis of cycloSal-pronucleotides using mild reaction conditions based on the use of a series of different chiral auxiliaries. The critical point was to identify a chiral auxiliary that gave high chirality transfer and acted in the final step as a suitable leaving group to allow the formation of cycloSal-phosphate triesters with excellent diastereoisomeric purity.…”

Design, Synthesis and Antiviral Evaluation of 2′- C -Methyl Branched Guanosine Pronucleotides: The Discovery of IDX184, a Potent Liver-Targeted HCV Polymerase Inhibitor

“…Among the main pronucleotide approaches hitherto reported, we can cite those using a pivaloyloxymethyl (POM) [42], an isopropyloxycarbonyloxymethy (POC) [43], a 2-(2-hydroxyethyldisulfanyl)ethyl (DTE) [44][45][46][47] or an (S-acyl-2-thioethyl) (SATE) [44][45][46]48] function as biolabile promoieties, as well as the CycloSal [49][50][51][52], the HepDirect [53,54], the ProTide [30,[55][56][57] and the phosphoramidate monoester approaches [58][59][60].…”