RESUMEN
The key macrocyclization step in the synthesis of simeprevir, a hepatitis C virus (HCV) antiviral drug, was studied. N-Boc substitution on the diene precursor changes the site of insertion of the metathesis catalyst and, consequently, the kinetic model of the ring closing metathesis (RCM), enabling a further increase in the macrocyclization efficiency under simulated high dilution (SHD) conditions. NMR of the inserted species of both first and second generation RCM catalysts are reported and discussed.
Asunto(s)
Antivirales/farmacología , Péptido Hidrolasas/metabolismo , Inhibidores de Proteasas/farmacología , Simeprevir/farmacología , Antivirales/síntesis química , Antivirales/química , Ciclización , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Hepatitis C/tratamiento farmacológico , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Simeprevir/síntesis química , Simeprevir/químicaRESUMEN
A series of tetrasubstituted fluoroalkenes were synthesized in good yield and high E/Z selectivity (up to 96/4) by Wittig reaction between α-heterosubstituted ketones and α-fluorophosphonium ylides. A detailed study of factors that control stereoselectivity in these reactions shows that stereoselectivity is the result of stabilizing CH···F and N···CâO interactions in the addition TS leading to the E isomer. This analysis provides a rationale for the observed decrease in selectivity for reactions of stabilized ylides with α-alkoxy aldehydes.