Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 3656-3664 |
| Number of pages | 9 |
| Journal | Organic & Biomolecular Chemistry |
| Volume | 19 |
| Early online date | 30 Mar 2021 |
| DOIs | |
| Publication status | Published - 28 Apr 2021 |
Funding
The authors would like to thank Centro de Cómputos de Alto Rendimiento (CeCAR) and the Irish Centre for High-End Computing (ICHEC) for granting use of computational resources which allowed us to perform the experiments included in this work. Part of this research was funded by the Synthesis and Solid State Pharmaceutical Centre (SSPC), supported by Science Foundation Ireland (SFI) and cofunded under the European Regional Department Fund (SFI 12/RC/ 2275_p2/R18867). M.N.G. thanks the University of Bath for financial support. Dr. Zhongyue Yang is thanked for his helpful discussions regarding this work.