Design, synthesis, olfactory evaluation and molecular docking study of Isoxazoline carboxylate derivatives as fragrance molecules

• Published in: Flavour and fragrance journal Vol. 39; no. 3; pp. 158 - 171
• Main Authors: Büyükbayram, Muhammet, Gürer, Sonay, Çat, Yeşim, Canayakın, Oğuzhan, Altuğ, Cevher, Sağırlı, Akın
• Format: Journal Article
• Language: English
• Published: Chichester Wiley Subscription Services, Inc 01.05.2024
• Subjects: Chemical synthesis; Cycloaddition; Fragrances; isoxazoline; Molecular docking; NMR; Nuclear magnetic resonance; odour1,3‐dipolar cycloaddition; Polymethyl methacrylate; Precursors; Propionic acid; Proteins; Reagents; Regioselectivity; Stereoselectivity
• ISSN: 0882-5734; 1099-1026
• DOI: 10.1002/ffj.3778

In this research, a wide range of aldoxime derivatives with aromatic and aliphatic substituents were synthesized as precursors to nitrile oxide in cycloaddition reactions. The aldoximes were synthesized with good to high yields and showed a lack of diastereoselectivity, as confirmed by 1H NMR measurements. These aldoximes were then utilized as precursors of nitrile oxide in 1,3‐dipolar cycloaddition reactions and were treated with dipolarophilic reagents, namely methyl methacrylate (MMA) and glycidyl methacrylate (GMA), to produce isoxazoline carboxylate derivatives with high regioselectivity. The obtained compounds were characterized using various techniques, including NMR, FT‐IR, GC–MS and TOF‐LCMS analyses. The study also targets the molecular docking analysis, using Autodock 4.2.6 software, targeting the OR51E2 protein. This protein has drawn recent attention, with the hypothesis that propionic acid activates OR51E2, making it a suitable candidate for the carboxylate group within the obtained isoxazoline skeleton. Through these multifaceted investigations, this research contributes to the design and development of fragrant molecules with potential applications in the fragrance industry, offering a promising avenue for future olfactory innovations. This research describes the one‐pot synthesis of new isoxazoline‐5‐carboxylates with promising fragrant properties, and it encompasses an in‐depth molecular docking analysis using Autodock 4.2.6 software, specifically targeting the OR51E2 protein.