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

• Published in: Organic & biomolecular chemistry Vol. 23; no. 24; pp. 5872 - 5881
• Main Authors: Chagas, Thaynan A. B, Piscelli, Bruno A, Santos, Hugo, Lima, Sâmia R, Cormanich, Rodrigo A, Fernandes, Fábio S, Coelho, Fernando
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 18.06.2025
• Subjects: Enantiomers; Natural products; Nucleophiles; Oxadiazoles
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/d5ob00540j

In this work, we present the first enantioselective Morita-Baylis-Hillman reaction using a vinyl heterocycle as the 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 an 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. We report an enantioselective Morita-Baylis-Hillman reaction using vinyl-1,2,4-oxadiazoles as nucleophiles. Computational studies provided insights into the observed enantioselectivity and helped to identify the factors controlling it.