Influence of Amino Acid Stereocenters on the Formation of Bicyclic <i>N</i>,<i>O</i>‑Acetals

In recent years, our group has reported the highly diastereoselective acid-catalyzed <i>N</i>,<i>O</i>-acetalization/intramolecular transcarbamoylation cascade of reactions between protected α-amino acid derivatives (Ser and Thr) and tetramethoxyalkanes. The resulting oligocyclic <i>N</i>,<i>O</i>-acetals have been used as excellent chiral building blocks for asymmetric transformations such as diastereoselective alkylation of the α-position. We now evaluate the scope of the reaction with related non-natural α-amino acid derivatives. A combined experimental and theoretical study reveals the key influence of the α-carbon substitution (serine versus α-methylserine) and the relative configuration of α-/β-carbons (threonine versus <i>allo</i>-threonine) in the thermodynamic stability of the products and, as a consequence, the stereochemical outcome of the reaction. Notably, the complete diastereoselectivity achieved with natural amino acid precursors is completely lost with their non-natural analogues.