The Importance of 1,5-Oxygen⋅⋅⋅Chalcogen Interactions in Enantioselective Isochalcogenourea Catalysis.

Claire M Young,Andrew M Woods,Terry K Smith,Patrick H Willoughby,Dominic J Pascoe,Scott L Cockroft,Calum Mclaughlin,Kenneth B Ling,Rylie K Morris,Alix Houpliere,Aileen B Frost,Alex Elmi,Andrew D Smith,Alexandra M Z Slawin

doi:10.1002/anie.201914421

Abstract

The importance of 1,5-O⋅⋅⋅chalcogen (Ch) interactions in isochalcogenourea catalysis (Ch=O, S, Se) is investigated. Conformational analyses of N-acyl isochalcogenouronium species and comparison with kinetic data demonstrate the significance of 1,5-O⋅⋅⋅Ch interactions in enantioselective catalysis. Importantly, the selenium analogue demonstrates enhanced rate and selectivity profiles across a range of reaction processes including nitronate conjugate addition and formal [4+2] cycloadditions. A gram-scale synthesis of the most active selenium analogue was developed using a previously unreported seleno-Hugerschoff reaction, allowing the challenging kinetic resolutions of tertiary alcohols to be performed at 500 ppm catalyst loading. Density functional theory (DFT) and natural bond orbital (NBO) calculations support the role of orbital delocalization (occurring by intramolecular chalcogen bonding) in determining the conformation, equilibrium population, and reactivity of N-acylated intermediates.

Highlights

The importance of 1,5-O chalcogen (Ch) interactions in isochalcogenourea catalysis (Ch = O, S, Se) is investigated
The nature of 1,5-Ch Ch interactions was recently investigated by the Cockroft group using a model system bearing a close structural similarity to the N-acylated isothiourea catalysts utilized within the Smith group and others.[16]
By analogy to pnictogen and halogen bonding interactions, which increase in strength with increasing atomic number, we postulated that a series of catalyst congeners 1-Ch where Ch =

Summary

Introduction

The nature of 1,5-Ch Ch interactions was recently investigated by the Cockroft group using a model system bearing a close structural similarity to the N-acylated isothiourea catalysts utilized within the Smith group and others.[16] The combined experimental and theoretical investigation suggested that such intramolecular chalcogen bonds were dominated by orbital delocalization between a lone-pair donor and an antibonding acceptor orbital (e.g. nO→σ*S-C).[17] Building on this work, and by analogy to pnictogen and halogen bonding interactions, which increase in strength with increasing atomic number, we postulated that a series of catalyst congeners 1-Ch where Ch =

Results

Conclusion