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

Bruno N Falcone,Matthew N Grayson

doi:10.1039/d0ob02458a

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.

Highlights

In 2008, Rueping et al.[1] reported the first catalytic enantioselective aza-Cope rearrangement[2] (Fig. 1), which consists in a sigmatropic rearrangement[3,4,5,6] involving a nitrogen-containing species of which a diastereoselective version had previously been reported.[7]
Different activation modes of the C–C bond forming step model Transition State (TS) were located, and TS-A was found to be lowest in energy
The full energy reaction profile was investigated and the obtained reaction barrier of 21.9 kcal mol−1 is consistent with the experimental results

Summary

Introduction

In 2008, Rueping et al.[1] reported the first catalytic enantioselective aza-Cope rearrangement[2] (Fig. 1), which consists in a sigmatropic rearrangement[3,4,5,6] involving a nitrogen-containing species of which a diastereoselective version had previously been reported.[7] This important reaction provides a valuable route for the synthesis of chiral homoallylic amines, useful intermediates in the synthesis of natural products,[8] and other organic compounds such as β-amino acids, aminoalcohols, aminoepoxides, pyrrolidines, and piperidines.[9,10,11] The reaction is catalyzed by a 1,1′-bi-2-naphthol-derived (BINOL-derived) phosphoric acid This kind of catalyst has been utilized in enantioselective versions of a wide range of reactions,[12,13] and has been the focus of studies of several computational works,[14,15,16,17,18,19,20] including many in our group.[21,22,23,24].

Methods

Results

Conclusion