Towards the Design of Optically Active Thiophene S-Oxides using Quantum Chemistry.

Abstract

The importance of axially chiral biaryls has risen steeply in the recent decades. This structural motif proved to be successful in catalytic asymmetric synthesis and the configuration of the biaryl axis is decisive for the biological activity. A new approach for the atroposelective synthesis of biaryls would be through a cycloaddition between an enantiopure phenyl-substituted thiophene S-oxide and an alkyne. Importantly, the chiral center of the thiophene S-oxide needs to be stable enough to avoid pyramidal inversion during the cycloaddition. Considering that the racemization of thiophene monoxides has been scarcely investigated so far, we perform a thorough quantum chemical study on the inversion barriers of a large number of chiral thiophene S-oxide derivatives. Our main goal is to identify substitution patterns leading to stable atropisomers at room temperature. Appealingly, the role of stereoelectronic effects and the position of the substituents as well as the importance of aromaticity on the pyramidal inversion barrier are elucidated for the first time.