An asymmetric and theoretical approach to the Morita–Baylis–Hillman reaction using vinyl-1,2,4-oxadiazoles as nucleophiles

Abstract

In this work, we present the first enantioselective Morita–Baylis–Hillman reaction using a vinyl-heterocycle as nucleophilic partner. The reaction between vinyl-1,2,4-oxadiazoles and N-substituted isatins is catalyzed by β-isocupreidine (β-ICD), yielding compounds in up to 95% yield and up to 98:2 er. The enantioselectivity of the reaction was investigated through theoretical calculations, which allowed us to identify the factors influencing the enantioselectivity, explain the preference for the formation of the R enantiomer, and understand the low or absent enantioselectivity when isatin containing a nitro group is employed. Moreover, the methodology developed enabled the synthesis of chiral analogues of the natural products Phidianidine A and Phidianidine B, offering unique opportunities to obtain structurally diverse chiral 1,2,4-oxadiazoles.