(±)-3-[(Prop-2-yn-1-yl)carbamoyl]-5,6-dihydro-7-oxabicyclo[2.2.1]heptane-2-carboxylic Acid

Overexpression of protein phosphatase 5 (PP5) has been implicated in tumor cell growth, making PP5 an attractive target for the development of small-molecule anticancer therapeutics. Building on previous success in achieving selectivity within the PP2A family through scaffold functionalization that enhances active-site interactions, we propose a similar strategy for the development of PP5 inhibitors. Norcantharidin, a demethylated derivative of cantharidin, is a potent yet unselective phosphatase inhibitor, making its bicyclic framework an attractive scaffold for systematic structural modification. The synthetic approach described herein capitalizes on the inherent reactivity of the anhydride moiety to generate an amic acid derivative bearing a terminal alkyne. This functional group serves as a versatile synthetic handle for subsequent diversification under mild, neutral conditions while preserving the integrity of the bicyclic scaffold. Collectively, this modular strategy provides a foundation for the development of PP5-selective norcantharidin derivatives with enhanced tumor selectivity, improved potency, and streamlined synthetic accessibility.