Issue 37, 2022

Interrogating the thionium hydrogen bond as a noncovalent stereocontrolling interaction in chiral phosphate catalysis

Abstract

CH⋯O bonds are a privileged noncovalent interaction determining the energies and geometries of a large number of structures. In catalytic settings, these are invoked as a decisive feature controlling many asymmetric transformations involving aldehydes. However, little is known about their stereochemical role when the interaction involves other substrate types. We report the results of computations that show for the first time thionium hydrogen bonds to be an important noncovalent interaction in asymmetric catalysis. As a validating case study, we explored an asymmetric Pummerer rearrangement involving thionium intermediates to yield enantioenriched N,S-acetals under BINOL-derived chiral phosphate catalysis. DFT and QM/MM hybrid calculations showed that the lowest energy pathway corresponded to a transition state involving two hydrogen bonding interactions from the thionium intermediate to the catalyst. However, the enantiomer resulting from this process differed from the originally published absolute configuration. Experimental determination of the absolute configuration resolved this conflict in favor of our calculations. The reaction features required for enantioselectivity were further interrogated by statistical modeling analysis that utilized bespoke featurization techniques to enable the translation of enantioselectivity trends from intermolecular reactions to those proceeding intramolecularly. Through this suite of computational modeling techniques, a new model is revealed that provides a different explanation for the product outcome and enabled reassignment of the absolute product configuration.

Graphical abstract: Interrogating the thionium hydrogen bond as a noncovalent stereocontrolling interaction in chiral phosphate catalysis

Supplementary files

Article information

Article type
Edge Article
Submitted
18 4月 2022
Accepted
15 8月 2022
First published
16 8月 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 11065-11073

Interrogating the thionium hydrogen bond as a noncovalent stereocontrolling interaction in chiral phosphate catalysis

J. Lai and J. P. Reid, Chem. Sci., 2022, 13, 11065 DOI: 10.1039/D2SC02171D

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