Influence of Amino Acid Stereocenters on the Formation of Bicyclic N,O‑Acetals

• Published in: Journal of organic chemistry Vol. 79; no. 6; pp. 2556 - 2563
• Main Authors: Jiménez-Osés, Gonzalo, Aydillo, Carlos, Busto, Jesús H, Zurbano, María M, Peregrina, Jesús M, Avenoza, Alberto
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.03.2014; Amer Chemical Soc
• Subjects: Acetals - chemistry; Amino Acids - chemistry; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; Serine - chemistry; Stereoisomerism; Thermodynamics; Threonine - chemistry; PYRAMIDAL NITROGEN; ASYMMETRIC-SYNTHESIS; STEREOSELECTIVE-SYNTHESIS; SERINE; NATURAL STERIC ANALYSIS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo500015c

In recent years, our group has reported the highly diastereoselective acid-catalyzed N,O-acetalization/intramolecular transcarbamoylation cascade of reactions between protected α-amino acid derivatives (Ser and Thr) and tetramethoxyalkanes. The resulting oligocyclic N,O-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 allo-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.