Diastereoselective synthesis of cyclosaligenyl-nucleosyl-phosphotriesters.
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 (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.
Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
Edwuin H
EH
Rios Morales
Jan
J
Balzarini
Chris
C
Meier
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D054306:Dideoxynucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D009711:Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D018119:Stavudine / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics
D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D009711:Nucleotides; D010755:Organophosphates; C401422:cyclosaligenyl 3'-azido-2',3'-dideoxythymidine monophosphate; D015215:Zidovudine; D018119:Stavudine