Modular Synthesis of O-Containing Mono- and Dispiro-Scaffolds: From Simple Alkenes to Targeted Functionalization of Natural Products

Abstract We report an efficient and modular synthetic platform for the assembly of structurally diverse O-containing mono- and dispirocycles, leveraging the Zr-catalyzed cycloalumination of alkenes (Dzhemilev reaction) as the key complexity-generating step. This strategy involves the sequential transformation of in situ-generated aluminacyclopentanes and various lactones into 1-(ω-hydroxyalkyl)cyclopentanols, which undergo facile cyclization to yield target spirolactones and spirotetrahydrofurans in high yields. The methodology enables both the iterative construction of complex spiranes and the directed modification of natural products, such as sclareolide. Beyond establishing this methodology, we demonstrate its biological utility by modulating the antitumor activity of the resulting derivatives. Flow cytometry studies on hematological tumor (Jurkat, K562, and HL-60) and normal cell lines revealed that introducing spiro-fragments facilitates a transition toward selective, mitochondria-mediated pro-apoptotic action. Comprehensive in silico ADME profiling indicated that while these structural modifications grant excellent passive membrane permeability and low systemic toxicity, the elongated aliphatic chains significantly elevate lipophilicity, leading to restricted aqueous solubility and high plasma protein binding. This uncovers a crucial pharmacokinetic trade-off between mitochondrial potency and systemic bioavailability. Ultimately, our findings expand the available chemical space, bridging fundamental organometallic chemistry with functionalized scaffold design.