Hexafluoroisopropanol-Mediated Cascade Cyclization for Construction of α-Amino-γ-spirolactones

Given the ubiquity of spirolactones in pharmaceutical agents, natural products, and small-molecule chemical probes, considerable research has been devoted to streamlining their synthesis. Yet, the preparation of α-amino-γ-spirolactones, which combine two key motifs in drug discovery─spirocycle and amine units─remains underdeveloped. Here, we demonstrate that readily accessible building blocks─amines, glyoxylic acid, and unactivated alkenes─can be rapidly converted to complex three-dimensional α-amino-γ-spirolactones and related compounds employing a hexafluoroisopropanol-promoted cascade cyclization. This protocol is general, efficient, scalable, and applicable to the mid- and late-stage functionalization of medicinally relevant molecules, while displaying excellent sustainability metrics. All those features, along with preliminary results indicating the potential bioactivity of spirolactones against cancer cells, make the reported methodology a promising tool for drug discovery.