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

Author(s)

Chagas, Thaynan A. B. ; Piscelli, Bruno A. ; Santos, Hugo ; Lima, Samia R. ; Cormanich, Rodrigo A. ; Fernandes, Fabio S. ; Coelho, Fernando

• Document type: Journal article
• Source: ORGANIC & BIOMOLECULAR CHEMISTRY; v. 23, n. 24, p. 10-pg., 2025-05-23.

Abstract

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 beta-isocupreidine (beta-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. (AU)

• FAPESP's process: 18/03910-1 - Physicochemical studies of fluorinated organic compounds: experimental and theoretical approaches
• Grantee: Rodrigo Antonio Cormanich
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/23005-6 - Synthesis of new heterocycles exhibiting potential biological activities by exploring the Morita-Baylis-Hillman adducts as building blocks
• Grantee: Fábio de Souza Fernandes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/10156-7 - Experimental and Theoretical study of stereoelectronic effects and supramolecular assembly of organofluorinated compounds
• Grantee: Bruno de Almeida Piscelli
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 23/18007-3 - Strategies for the Synthesis of Structurally Complex Heterocycles and Evaluation of Potential Biological Activities
• Grantee: Fernando Antonio Santos Coelho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/13544-5 - Design, synthesis and biological evaluation of new antiparasitic agents having 1,2,4-oxadiazole motif in their structures
• Grantee: Thaynan Aparecida Bueno Chagas
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)