10.1021/jo500015c.s003 Gonzalo Jiménez-Osés Gonzalo Jiménez-Osés Carlos Aydillo Carlos Aydillo Jesús H. Busto Jesús H. Busto María M. Zurbano María M. Zurbano Jesús M. Peregrina Jesús M. Peregrina Alberto Avenoza Alberto Avenoza Influence of Amino Acid Stereocenters on the Formation of Bicyclic <i>N</i>,<i>O</i>‑Acetals American Chemical Society 2014 diastereoselective chiral building blocks acid derivatives 2014-03-21 00:00:00 Dataset https://acs.figshare.com/articles/dataset/Influence_of_Amino_Acid_Stereocenters_on_the_Formation_of_Bicyclic_i_N_i_i_O_i_Acetals/2312803 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.