Cascade Remodeling through Late-Stage Electrophilic Fluorination in a Bis-Spiroketal Framework

Cascade reactions efficiently generate molecular complexity but are often incompatible with the late-stage diversification of highly functionalized natural products due to competing degradation pathways. Herein, we demonstrate that electrophilic fluorination can serve as a variable control element, selectively capturing transient nucleophiles to install fragment-deactivating C-F bonds that redirect subsequent reactivity away from default degradation. In a derivative of the antibiotic salinomycin, sequential fluorination events gate a multistep structural cascade, converting a single precursor into diverse, unprecedented scaffolds. Stepwise reagent selection enables divergent cascade routing through enol ether manifolds to achieve controlled scaffold remodeling. These results demonstrate late-stage electrophilic fluorination as a switchable fragment-deactivation strategy for directing complex cascade transformations and unlocking new natural product architectures.