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Diastereoselective Synthesis of cyclo Saligenyl‐Nucleosyl‐Phosphotriesters

2010; Wiley; Volume: 17; Issue: 5 Linguagem: Inglês

10.1002/chem.201002657

1521-3765

Edwuin Hander Rios Morales, Jan Balzarini, Chris Meier,

HIV/AIDS drug development and treatment

Abstract A diastereoselective synthesis of cyclo Sal‐phosphotriesters ( cyclo Sal= cyclo Saligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cyclo Sal‐pronucleotides. In previously described synthesis routes, the cyclo Sal‐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‐ cyclo Sal‐phosphotriesters in 48 and ≥95 % de ( de =diastereomeric excess). However, this approach failed to give the important group of 3‐substituted cyclo Sal‐nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of ( R P )‐ and ( S P )‐3‐methyl‐ cyclo Sal‐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.