Versatile Synthesis of Cyclopentenones via Skeletal Editing of Phenols

Cyclopentenones feature prominently in synthetic and medicinal chemistry because of their ability to act as covalent warheads and their versatility as synthetic intermediates. Yet, skeletal editing methods to access cyclopentenones are not well developed, making scaffold hopping at late stage unworkable. Here, we present a versatile approach to 2-cyclopentenones via the p- and o-carbon deletion of phenols. Deletion is achieved through a combination of oxidative dearomatization, photorearrangement, and tandem decarboxylation/alkene positional isomerization. Through a slight adaptation, this platform also allowed the ring contraction of guaiacols to access 2-(methoxycarbonyl)-2-cyclopentenones. We applied this methodology to the skeletal editing of a range of phenols, including natural products, and conducted a detailed mechanistic study. Cyclopentenones accessed by this method were tested for cytotoxicity against a panel of cancer cell lines, leading to the identification of a novel anticancer hit compound with a probable covalent mechanism of action.