Total synthesis of three families of natural antibiotics: Anthrabenzoxocinones, fasamycins/ naphthacemycins, and benastatins

Abstract

Due to the critical bacterial resistance and antibiotic crisis, the discovery of new antibiotics is an urgent need in the clinic than ever. Naturally occurring antibiotics have proven to be an indispensable source of the development of new antibacterial agents. Herein, we report the total synthesis of three families of biogenetically related natural antibiotics, including anthrabenzoxocinones (ABXs), fasamycins/naphthacemycins, and benastatins. The synthesis featured divergent and convergent approaches, which enabled efficient construction of the basic polycyclic skeletons in 6–10 steps on a large-scale, followed by a collective synthesis of 14 natural products and their corresponding analogs. The core scaffold of gem-dimethyl-anthracenone, a naturally occurring type II fatty acid-specific condensation enzyme (FabF-specific) antibiotic pharmacophore, was forged via a Ti(Oi-Pr)4-mediated photoenolization/Diels–Alder (PEDA) reaction between 2-isopropyl benzaldehyde and a variety of enones. A scale-up of the PEDA reaction was facilitated in an assembled continuous-flow reactor, which allowed us to overcome the issues associated with batch photochemistry. Subsequently, the synthetic natural antibiotics and their analogs would be utilized in structure–activity relationships (SAR) and mechanism studies, which should enable the discovery of new and leading antibiotic compounds.