Total Synthesis of Floyocidin B: 4,5-Regioselective Functionalization of 2-Chloropyridines

The recently discovered natural product (NP) (+)-floyocidin B with antimicrobial activity against Mycobacterium tuberculosis displays a hitherto unknown dihydroisoquinolinone scaffold in the class of epoxyquinone NPs. 4,5-regioselective functionalization 2-chloropyridines was identified as suitable strategy leading to total syntheses and analogs. In this paper, we present long winding evolution process final synthetic pathway, including model systems for route scouting elucidation side products, which enabled us understand unique reactivity unprecedented scaffold. A special focus laid on method studies different 2-chloropyridines, disclosing an unexpected effect 2-chloro substituent regioselectivity compared 2-unsubstituted or carbon-substituted pyridines. Finally, head-to-head comparison previously described synthesis all four stereoisomers NP (−)-avicennone C revealed significant differences these structurally closely related scaffolds.