Multidimensional Correlations in Asymmetric Catalysis through Parameterization of Uncatalyzed Transition States

Abstract

The study of the chiral anion phase transfer (CAPT) catalyzed oxidative amination of tetrahydroisoquinolines via multidimensional correlation analysis (MCA) is revisited. The parameterization of the transition states (TSs) for the uncatalyzed reaction, the introduction of conformational descriptors, and the use of computed interaction energies and distances as parameters allowed access to a considerably simplified mathematical correlation of substrate and catalyst structure to enantioselectivity. The equation obtained is suggestive of key interactions occurring at the TS. Specifically, the CAPT catalyst is proposed to coordinate the intermediate iminium cation by P=O···H–O hydrogen bond and by N···H–C electrostatic interaction. The conformational freedom of the substrate’s benzyl substituent is also found to be important in order to provide an efficient mode of molecular recognition.

Internal acidity scale and reactivity evaluation of chiral phosphoric acids with different 3,3′-substituents in Brønsted acid catalysis

“…This model is capable of distinguishing certain crucial non-covalent interactions present between the catalyst and the substrate. 29,30 In 2016, Goodman et al introduced some parameters to describe the steric bulk of the 3,3 0 -substituents of the catalysts. Thus, they could show that the stereoselectivity of the asymmetric transfer hydrogenation of imines ( Fig.…”

Enantioselective Synthesis ofN,S‐Acetals by an Oxidative Pummerer‐Type Transformation using Phase‐Transfer Catalysis

“…Descriptors for compounds 4a–4h (for a full set of substrates, see Supporting Information) were calculated from the uncatalyzed cyclization TS of the corresponding thionium cation. [22] Comparison of the enantioselectivity and the corresponding parameters resulted in the statistical model in Figure 1b (R 2 =0.86, intercept=0.13, L1O=0.81), which contains two parameters condensed in only one term. The simple equation obtained can be readily interpreted.…”

Enantioselective fluorination of homoallylic alcohols enabled by the tuning of non-covalent interactions

“…As NCIs are hypothesized to drive the enantioselective catalysis, we aimed to apply our recently reported computed interaction energies ( E π) and distances ( D π) as parameters in multidimensional correlation analysis 15 as they are descriptive of π-stacking and CH–π interactions at the TS level. 12 , 18 , 36 This method provides a direct analysis tool that enables data driven hypotheses of weak interactions likely involved in the stereochemistry determining step. 12 , 37 Additionally, this approach allows for a union of the knowledge gained from multidimensional, experimentally-derived statistical analysis and TS modeling.…”