Organic Letters · 2008 · 113 citations · 17 references
Combinatorial ChemistryBioorganic ChemistryNmr SpectroscopyMolecular BiologyEfficient SynthesisHeterocycle ChemistryAntiviral DrugPharmaceutical ChemistryMedicinal ChemistryAntiviral Drug DevelopmentReaction IntermediateDiene SubstrateBiochemistryKey Rcm ReactionPharmacologyAntiviral CompoundBiomolecular EngineeringNatural SciencesAntiviral TherapyMedicineSynthetic ChemistryDrug Discovery
We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using 1H NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.
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