Chemoselective derivatization of the potent antimalarial fungal metabolite 9-methoxystrobilurin G

9-Methoxystrobilurin G (IC₅₀ = 0.061 μM) is a natural β-methoxyacrylate product with potent antimalarial activity. This paper reports the development of a chemoselective semisynthetic route to C9 and C2' modified 9-methoxystrobilurin G derivatives, which are then evaluated for their antimalarial activity against Plasmodium falciparum K1. Under controlled Brønsted acidity, the C9 enol ether was selectively converted into the corresponding ketone while the C2'-O-prenyl substituent was retained, providing 9-oxostrobilurin G as a versatile intermediate for synthesizing C9-O-alkylated derivatives. In contrast, concurrent removal of the C2'-O-prenyl group and the C9 enol ether followed by reconstruction of the C9 enol ether afforded 9-methoxystrobilurin I, allowing access to acylated derivatives of the C2'-hydroxy group. Biological evaluation revealed comparable antimicrobial activities of the C9 O-ethyl derivative and the parent compound, and enhanced potency of the C2' cyclohexanecarboxylate derivative (IC₅₀ = 0.036 μM).