Bioinspired Concise Synthesis of Caged 1,6-Epoxyfuro[3,4- <i>c</i> ]pyrans via a Brønsted Acid-Catalyzed Cascade Reaction

“Escaping flatland” by increasing molecular complexity has become widely recognized in medicinal chemistry. Traditional approaches to accessing three-dimensional (3D) architectures have largely relied on strained small-ring systems as bioisosteric replacements for planar sp 2 -hybridized carbons. In contrast, the direct transformation of sp 2 ‑rich frameworks into sp 3 ‑rich, three-dimensional skeletons remains both challenging and underexplored. This is particularly relevant for highly congested 1,6‑epoxyfuro[3,4‑ c ]pyrans, which hold promise in drug discovery but have been hindered by inefficient synthetic routes. Herein, we report a bioinspired versatile Brønsted acid‑catalyzed cascade annulation that addresses these limitations. This method provides a route to diverse 1,6‑epoxyfuro[3,4‑ c ]pyrans and accomplishes the one‑step total synthesis of catunaregin and epicatunaregin from readily available coniferyl alcohol and ( Z )‑hex‑3‑ene‑2,5‑dione. The reaction proceeds under mild conditions with broad substrate scope, high diastereoselectivity, and fast kinetics. Starting from simple materials, this strategy constructs five bonds and converts six carbon atoms from sp 2 to sp 3 hybridization in a single operation. The step and atom economy sheds light on the value of this transformation.