Polarizability matters in enantio-selection

Abstract

The prevalence of chirality, or, handedness in biological world is a fundamental phenomenon and a characteristic hallmark of life. Thus, understanding the origin of enantio-selection, i.e., the sense and magnitude of asymmetric induction, has been a long-pursued goal in asymmetric catalysis. Herein, we demonstrated a polarizability-derived electronic effect that was shown to be capable of rationalizing a broad range of stereochemical observations made in the field of asymmetric catalysis. This effect provided a consistent enantio-control model for the prediction of major enantiomers formed in a ruthenium-catalyzed asymmetric transfer hydrogenations of ketones. Direct and quantitative linear free energy relationships between substrates' local polarizabilities and observed enantio-selectivity were also revealed in three widely known asymmetric catalytic systems covering both reductions and oxidations. This broadly applicable polarizability-based electronic effect, in conjunction with conventional wisdom mainly leveraging on steric effect considerations, should aid rational design of enantio-selective processes for better production of chiral substances.

Fig. 1. The essential role of local electronic polarizability in enantio-control (this work).

a Correlation of local polarizability on the sense of chiral induction in Ru-catalyzed asymmetric transfer hydrogenation of ketones; b Linear free energy relationship (LFER) of substrate local polarizability on enantio-selection in widely known catalytic asymmetric systems. R²: coefficient of determination.

Fig. 2. Correlation of substrate substituent local electronic polarizability on the sense of asymmetric induction in Ru-catalyzed asymmetric transfer hydrogenation of aryl hetero-aryl ketones.

a Substrates of aryl pyridyl ketones. b Substrates of aryl thiazolyl ketones. c Substrates of aryl quinolinyl ketones. d Substrates of aryl isoquinolinyl ketones. e Other types of aryl hetero-aryl ketones. The red carbon’s local polarizability is larger than the blue carbon’s local polarizability. The red and blue numbers underneath each alcohol structures respectively denote the local polarizability values of the red and blue carbon atoms of the corresponding ketones.

Fig. 3. Correlation of substrate substituent local electronic polarizability on the sense of asymmetric induction in Ru-catalyzed asymmetric transfer hydrogenation of aryl alkyl, di-aryl, di-hetero aryl and di-alkyl ketones.

a Substrates of aryl alkyl ketones. b Substrates of di-aryl ketones. c Substrates of di-alkyl ketones. d Substrates of di-hetero-aryl ketones. The red carbon’s local polarizability is larger than the blue carbon’s local polarizability. The red and blue numbers underneath each alcohol structures respectively denote the local polarizability values of the red and blue carbon atoms of the corresponding ketones. The absolute configurations of C47 and C48 were determined by ECD (see details in the Supplementary Information).

Fig. 4. Linear free energy relationship (LFER) analysis of substrate local polarizabilities on enantio-selections.

a Asymmetric transfer hydrogenation of di-aryl ketones by means of a Noyori-Ikariya catalyst. b Asymmetric reduction of di-aryl ketones catalyzed by two Corey–Bakshi–Shibata oxazaborolidine catalysts. c Sharpless asymmetric dihydroxylation of aryl substituted terminal alkenes by a cinchona alkaloid-derived ligand. Atomic units (a. u.).