Novel dexoxadrol derivatives with an expanded oxygenheterocycle (1,3‐dioxane instead of 1,3‐dioxolane), an enlarged distance between the two heterocycles, and an additional oxo group in the 4‐position of the piperidine ring were synthesized and pharmacologically evaluated. The synthesis comprises a hetero‐Diels–Alder reaction of imines with Danishefsky's diene (3), followed by a Lewis acid catalyzed conjugate reduction of the resulting dihydropyridones and hydrogenolytic debenzylation. The required aldehydes were synthesized by transacetalization of benzophenone dimethyl acetal (8) with pentane‐1,3,5‐triol (7), butane‐1,2,4‐triol (15), and 4‐benzyloxybutane‐1,3‐diol (31), respectively, and subsequent Swern oxidation. Homodexoxadrols 39 were synthesized by the Cagliotti method with the use of p‐toluenesulfonylhydrazide and NaBH4 for the removal of the oxo group. The diastereomers were separated and the relative configuration was assigned by X‐ray crystal structure analysis and comparison of spectroscopic and chromatographic data. Receptor binding studies with the radioligand [3H]‐(+)‐MK‐801 demonstrated that an expanded O‐heterocycle, an enlarged distance between the heterocycles, and an additional oxo group led to a considerable loss of affinity towards the phencyclidine binding site of the NMDA receptor.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)