Understanding the mechanism of the chiral phosphoric acid-catalyzed aza-Cope rearrangement

• Published in: Organic & biomolecular chemistry Vol. 19; no. 16; pp. 3656 - 3664
• Main Authors: Falcone, Bruno N, Grayson, Matthew N
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 28.04.2021
• Subjects: Bonding strength; Catalysts; Chemical bonds; Density functional theory; Enantiomers; Naphthol; Phosphoric acid; Substrates
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d0ob02458a

The first catalytic enantioselective aza-Cope rearrangement was reported in 2008 by Rueping et al. The reaction is catalyzed by a 1,1′-bi-2-naphthol-derived (BINOL-derived) phosphoric acid and achieved high yields and enantioselectivities (up to 97 : 3 er with 75% yield). This work utilizes Density Functional Theory to understand the mechanism of the reaction and explain the origins of the enantioselectivity. An extensive conformational search was carried out to explore the different activation modes by the catalyst and, the Transition State (TS) leading to the major product was found to be 1.3 kcal mol −1 lower in energy than the TS leading to the minor product. The origin of this stabilization was rationalized with NBO and NCI analysis: it was found that the major TS has a greater number of non-bonding interactions between the substrate and the catalyst, and shows stronger H-bond interactions between H atoms in the substrate and the O atoms in the phosphate group of the catalyst. Using Density Functional Theory, the mechanism of the enantioselective phosphoric acid-catalyzed aza-Cope rearrangement was investigated. Stabilization of the preferred reaction pathway was rationalized by studying the non-bonding interactions between substrate and catalyst.