Abstract

One of the largely unexplored areas of computational organic chemistry is the source of facial selectivity from prochiral ketones. Most of the available literature provides reaction pathways highlighting the lowest activation barrier, but this approach leaves the origin of the enantioselectivity unaddressed at the molecular level. Instead, the interactions that enable energetic differentiation in the transition states must be investigated for any useful information to be acquired for predictive purposes. The focus of this work is on the enantioselective CBS (Corey-Bakshi-Shibata) reduction as it has been extensively studied experimentally.
This work aims, first, to evaluate the complexation of substituted boranes with a prochiral ketone, acetophenone, for better understanding the modes of complexation during a reduction reaction, and second, to assess the source of facial selectivity of the enantioselective reduction of a different ketone, t-butyl methyl ketone, with borane using an oxazaborolidine catalyst. A systematic investigation of weak-bonding interactions in the complexes and their transition states is carried out computationally using electronic structure theory. A quantitative relationship between the electron demand on boron and the complexation energy is established from electron density analyses providing a binding cut-off of 0.19 e·Å^–3. In the CBS reduction of t-butyl methyl ketone, the calculated enantiomeric excess is 99 % or greater in favour of the R-configured product by transition state theory. The source of facial selectivity is uncovered through changes in features of the geometries and the electron densities as the responsible complexes as well as their transition states for hydride transfer are compared.