Rational design of naphthoquinone-based antibacterial agents through iridium-catalyzed enantioselective β-allenylation of 2-hydroxynaphthoquinones

Abstract

Against the backdrop of the established biological properties of 2-hydroxynaphthoquinone (lawsone) and related compounds, the rational design of chiral β-butyl lawsone derivatives as potential antibacterial agents, their enantioselective synthesis and investigation of their antibacterial properties are described. The synthesis is accomplished through enantioselective β-allenylation of 2-hydroxynaphthoquinones with allenylic alcohols under the cooperative catalysis of an Ir(I)/(phosphoramidite,olefin) complex and Lewis acidic La(OTf)₃, followed by catalytic hydrogenation. In a rare example of the use of hydroxynapthoquinones in transition metal catalysis, β-allenylic lawsone derivatives are obtained generally in high yield with outstanding enantioselectivity (up to >99.9 : 0.1 er). The β-butyl lawsone derivatives, bearing a stereogenic center adjacent to the naphthoquinone core, showed high potency against Gram-positive bacterial strain MRSA (methicillin-resistant Staphylococcus aureus) with a minimum inhibitory concentration (MIC) as low as 1.5 μg mL⁻¹ and low toxicity to mammalian cell lines such as HEK and HeLa. The bactericidal activity of these compounds is found to depend not just on the substituent at the stereocenter but also on their absolute configuration.