AbstractThe diastereoselective domino‐Knoevenagel‐IMHDA reactions of 5,6‐dihydro‐2H‐pyran derivatives containing an o‐formylaryl amine or ether moiety were performed with active methylene reagents. In the spiro heterocyclic products representing a novel skeleton, a tetrahydroquinoline or chroman unit is fused with two pyran rings and the bridgehead carbon atoms are chirality centers formed diastereoselectively. Depending on the substitution pattern, a domino Knoevenagel‐[1,5]‐hydride shift‐cyclization sequence was identified as a competing pathway, which resulted in the formation of tetrahydroquinoline derivatives with a 5,6‐dihydro‐2H‐pyran‐3‐yl substituent. The relative configurations of the products were determined by means of the characteristic NOE correlations and single crystal X‐ray diffraction analysis. Antiproliferative activity assays of two products against A2780 and WM35 human cancer cell lines showed low micromolar IC₅₀ values down to 2.99 μM.