ABSTRACT
A methodology for the asymmetric peroxidation of γ,δ-unsaturated ß-keto esters is presented. Using a cinchona-derived organocatalyst, the target δ-peroxy-ß-keto esters were obtained in high enantiomeric ratios of up to 95:5. Additionally, these δ-peroxy esters can be readily reduced to chiral δ-hydroxy-ß-keto esters without impacting the ß-keto ester functionality. Importantly, this chemistry opens up a concise route to chiral 1,2-dioxolanes, a common motif in many bioactive natural products, via a novel P2O5-mediated cyclisation of the corresponding δ-peroxy-ß-hydroxy esters.
Subject(s)
Biological Products , Diet, Ketogenic , Esters , Catalysis , StereoisomerismABSTRACT
AIM: Chagas disease is a tropical disease caused by the hemoflagellate protozoan Trypanosoma cruzi. There is no vaccine for Chagas disease and available drugs (e.g., benznidazole) are effective only during the acute phase, displaying a variable curative activity in the established chronic form of the disease. New leads with high efficacy and better toxicity profiles are urgently required. Materials & methods: A library of novel quinine derivatives was synthesized using Heck chemistry and evaluated against the various developmental forms of T. cruzi. RESULTS AND CONCLUSION: Several novel quinine analogs with trypanocidal activity have been identified with the para-nitro-substituted derivative displaying a submicromolar IC50, which is 83-times lower than quinine and three-times lower than benznidazole. Transmission electron microscopy analysis demonstrated that these compounds induced a marked vacuolization of the kinetoplast of intracellular amastigotes and cell-derived trypomastigotes.