Asymmetric Synthesis of Sakuranetin-Relevant Flavanones for the Identification of New Chiral Antifungal Leads.

Discovery and efficient synthesis of new promising leads have a central role in agrochemical science. Reported herein is the sakuranetin-directed synergistic exploration of an asymmetric synthesis and an antifungal evaluation of chiral flavanones. A new palladium catalytic system with CarOx-type ligands was successfully identified for the highly enantioselective addition of arylboronic acids to chromones. This enabled the facile and programmable construction of a constellation of chiral flavanones (up to 98% yield and 97% ee), in which ( R )-pinostrobin was efficiently constructed without laborious protecting/deprotecting operations. Its good performance in asymmetric induction and functional tolerance expanded the chemical space of pharmaceutically important flavanones. The chiral differentiation of flavanones based on antifungal activity and a concise structure-activity relationship model was disclosed and summarized. This synergistic project culminated with acquisition of the naturally unprecedented flavanones with better antifungal potentials than sakuranetin, in which the R -enantiomer of flavanone 54 (EC 50 = 0.8 μM) demonstrated better performance than boscalid against Rhizoctonia solani . The novel scaffold and predicted new target compared with the commercial fungicides in the FRAC reinforce the value of further exploration.