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Diastereoselective Synthesis of cyclo Saligenyl‐Nucleosyl‐Phosphotriesters
Author(s) -
Rios Morales Edwuin H.,
Balzarini Jan,
Meier Chris
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201002657
Subject(s) - diastereomer , stereochemistry , chemistry , chiral auxiliary , enantioselective synthesis , organic chemistry , catalysis
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.