DFT Study on the Mechanism and Stereoselectivity of NHC-Catalyzed Synthesis of Substituted Trifluoromethyl Dihydropyranones with Contiguous Stereocenters

Abstract

Recently, Smith and co-workers reported an interesting work that provides a facile approach to access substituted trifluoromethyl dihydropyranones with two contiguous stereocenters by utilizing the α,β-unsaturated trifluoromethyl ketones as a substrate for NHC-catalyzed [4 + 2] cycloadditions. The most significant point of this reaction lies in the capability of introducing substituents to the C(5) position of the dihydropyranones. In the present study, we performed detailed DFT investigations toward the catalytic mechanism of this reaction, and determined origins of the diastereo- and enatioselectivities through analyses on distortion energies of two key stationary species and on components of Gibbs free energy barriers of elementary steps in which the stereocenters are generated. The theoretically predicted configuration of the main product was well-consistent with the experimental results, and the excellent correlation between the relative free energy barriers (ΔΔG(298)(0)) with the relative enthalpy barriers (ΔΔH(298)(0)) indicates that the stereoselectivity should originate from differences of enthalpy barriers rather than distinctions of the entropy item (-TΔS(298)(0)) changes. The systematic study of the substituent effect affords conclusive evidence for the catalytic mechanism we proposed but failed to give any clue to how the various electronic properties of substituents act on the experimental yields.