London Dispersion Interactions Rather than Steric Hindrance Determine the Enantioselectivity of the Corey–Bakshi–Shibata Reduction

Abstract

The well‐known Corey–Bakshi–Shibata (CBS) reduction is a powerful method for the asymmetric synthesis of alcohols from prochiral ketones, often featuring high yields and excellent selectivities. While steric repulsion has been regarded as the key director of the observed high enantioselectivity for many years, we show that London dispersion (LD) interactions are at least as important for enantiodiscrimination. We exemplify this through a combination of detailed computational and experimental studies for a series of modified CBS catalysts equipped with dispersion energy donors (DEDs) in the catalysts and the substrates. Our results demonstrate that attractive LD interactions between the catalyst and the substrate, rather than steric repulsion, determine the selectivity. As a key outcome of our study, we were able to improve the catalyst design for some challenging CBS reductions.

Ruthenium‐Catalyzed Intermolecular Cyclization and N‐Methylation of Salicyl N‐Tosylhydrazones

“…Acetophenone (1.0 equiv) was reacted with trichloroisocyanuric acid (2.0 equiv) in presence of acetic acid (5 mL) under reflux conditions. This reaction was provided two compounds such as 2,2,2‐trichloro‐1‐phenylethan‐1‐one (32 % yield, minor) and 2,2‐dichloro‐1‐phenylethan‐1‐one (55 % yield, major) [12] . The compound 2,2,2‐trichloro‐1‐phenylethan‐1‐one was treated with 5 mol % RuCl 3 ⋅ 3H 2 O in toluene under reflux conditions.…”

Unraveling Atomic Contributions to the London Dispersion Energy: Insights into Molecular Recognition and Reactivity

“…In this context, it is of paramount importance to elucidate how functional groups or even atoms contribute to the total LD energy. For example, understanding the precise contribution of a catalyst functional group to the stabilizing LD energy of a transition state could lead to the identification of design strategies for the selective stabilization of a specific reaction pathway. , In addition, quantifying the contribution of a “dispersion energy donor” to the thermodynamic stability of a chemical species holds significant potential for stabilizing unstable bonding situations. , More generally, achieving precise measurements of the atomic contributions to the LD energy would open up unprecedented opportunities for molecular design and materials discovery.…”

An induced-fit model for asymmetric organocatalytic reactions: a case study of the activation of olefins via chiral Brønsted acid catalysts

“…Among the various types of NCIs, London dispersion (LD) has recently emerged for its ubiquitous importance in selective catalysis. [27][28][29][30][31][32][33][34][35][36] This attractive interaction is always present between atoms, molecules or groups, irrespective of their nature. Its magnitude increases with the polarizability of the interacting species and decreases with their distance.…”

“…Its fundamental role in stereoselective catalysis has been emphasized by the group of Schreiner on the Dakin-West reaction 32 and the Corey-Bakshi-Shibata reduction. 33 The group of Houk has demonstrated its importance for intramolecular Aldol reactions 34 as well as in the dual transition metal catalysis of α-allylation reactions. 35 In addition, Fürstner and coworkers used London Dispersion as a key design element for confined Bismuth-Rhodium catalysts with improved activity and selectivity.…”