Chemo-, Regio- and Diastereoselective Synthesis of Azaspiro Tetra-/Pentacyclic Scaffolds with Anticancer Activity

We report an efficient and highly selective synthesis of azaspiro polycyclic scaffolds with excellent chemo-, regio-, and diastereoselectivities. This method exhibits broad substrate scope (44 examples), and the resulting tetracyclic compounds can be readily elaborated to complex pentacyclic lactams (8 examples). DFT calculations demonstrate thermodynamic control over the diastereoselectivity. Notably, the lead compound <b>7h</b> exhibiting nanomolar cytotoxicity against PANC-1 cells (IC₅₀ = 92 nM), underscoring the potential for generating natural product-like antitumor agents.