Strain-enabled radical spirocyclization cascades: rapid access to spirocyclobutyl lactones and – lactams

Abstract

Spirocyclobutane derivatives have gained significant attention in drug discovery programs due to their broad spectrum of biological activities and clinical applications. Ring-strain in organic molecules is a powerful tool to promote reactivity by releasing strain energy, allowing the construction of complex molecules selectively and efficiently. Herein, we report the first strain-enabled radical spirocyclization cascades for the synthesis of functionalized spirocyclobutyl lactones and – lactams, which are finding increasing applications in medicinal chemistry. The reaction of interelement compounds with bicyclobutane (BCB) allyl esters and – amides proceeds with high chemoselectivity under simple, catalyst-free conditions using blue light irradiation. The reaction has been successfully extended to synthesize bis-spirocycles. To introduce a more diverse set of functional groups, we have developed a dual photoredox/nickel catalytic system capable of mediating the carbosulfonylation of BCB allyl amides. The reaction shows broad applicability across various (hetero)aryl halides, aryl sulfinates, and BCB allyl amides, operates under mild conditions and demonstrates excellent functional group compatibility. The functional groups introduced during the cascade reactions served as versatile handles for further synthetic elaboration.