Asymmetric Synthesis and Bioactivity Evaluation of Chiral Oxazoline Skeleton Molecules

The utilization of novel organic synthesis methods is increasingly critical in the development of innovative agrochemicals. In this study, we designed and synthesized a series of chiral oxazoline derivatives using a one-pot method. This method involved first catalyzing the asymmetric aldol addition reaction of oxazolinyl esters with paraformaldehyde, followed by esterification with various pharmacophore-containing carboxylic acids. Unexpectedly, many of the target compounds exhibited promising antifungal and antioomycete activities, with their absolute configurations showing pronounced enantioselective activities. Notably, compound (<i>R</i>)-<b>5c</b> demonstrated significant biological activities against <i>Valsa mali</i> and <i>Phytophthora capsica</i> (EC₅₀ = 1.023 mg/L and EC₅₀ = 0.149 mg/L, respectively), which were markedly superior to its enantiomer (<i>S</i>)-<b>5c</b> (EC₅₀ = 9.565 mg/L and EC₅₀ = 0.924 mg/L, respectively). <i>In vivo</i> experiments confirmed that this compound exhibited both curative and protective effects against <i>V. mali</i> and <i>P. capsici</i>. CLSM and SEM analyses further indicated that compounds <b>5c</b> had distinct physiological effects on <i>P. capsici</i> hyphae. Moreover, acute toxicity tests in zebrafish (<i>Danio rerio</i>) revealed that compound (<i>R</i>)-<b>5c</b> had significantly lower toxicity compared to the control drugs <b>tebuconazole</b> and <b>dimethomorph</b>. Consequently, this study provides valuable insights for the development of novel chiral oxazoline analogues as potential antifungal and antioomycete agrochemicals.