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Issue 16, 2021
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Understanding the mechanism of the chiral phosphoric acid-catalyzed aza-Cope rearrangement

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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.

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

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Article information


Submitted
08 Dec 2020
Accepted
16 Mar 2021
First published
30 Mar 2021

This article is Open Access

Org. Biomol. Chem., 2021,19, 3656-3664
Article type
Paper

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

B. N. Falcone and M. N. Grayson, Org. Biomol. Chem., 2021, 19, 3656
DOI: 10.1039/D0OB02458A

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