Kinetic isotope effects in asymmetric reactions

Abstract

Kinetic isotope effects are exquisitely sensitive probes of transition structure. As such, kinetic isotope effects offer a uniquely useful probe for the symmetry-breaking process that is inherent to stereoselective reactions. In this Concept article, we explore the role of steric and electronic effects in stereocontrol, and we relate these concepts to recent studies carried out in our laboratory. We also explore the way in which kinetic isotope effects serve as useful points of contact with computational models of transition structures. Finally, we discuss future opportunities for kinetic isotope effects to play a role in asymmetric catalyst development.

Figure 1

Simple model for primary ²H KIEs resulting from differences in zero-point energy in the reactants.

Figure 2

Simple model for secondary ²H KIEs resulting from differences in zero-point energy in a vibrational coordinate that is orthogonal to the reaction coordinate.

Figure 3

Anharmonicity in C–H(D) bonds results in the C–H bond having a greater steric presence through differences in average bond length (<r>) and differences in wavefunction dispersion, σ(r). Offset of <r_D> from the peak of the probability distribution for the C–D bond is the result of asymmetry due to increased sampling of the more anharmonic part of the potential.

Figure 4

A) ²H KIEs measured for the (–)-DIP-Cl reduction of 4′-methylisobutyrophenone. B) Stereoview of the computed transition structure for the same reaction.

Figure 5

A) ²H KIEs measured for the (S)-Me-CBS-catalyzed reduction of 2′,5′-dimethylisobutyrophenone. B) Stereoview of the computed transition structure for the same reaction, including the BH₃ reductant coordinated to the (S)-Me-CBS catalyst.

Figure 6

Nearest neighbor interactions of the A) pro-S and B) pro-R methyl groups at the CBS reduction transition state. Distances denote closest H–H contacts. Full transition structures corresponding to the arrangements in A and B are shown in C and D, respectively.

Scheme 1

Groups that are enantiotopic in the reactant become diastereotopic in the transition state, such as in this DIP-Cl (B-chlorodiisopino-campheylborane) reduction example. IPc= isopinocampheyl.

Scheme 2

Model transition structures for major and minor stereochemical pathways in A) aldol reactions using Z-boron enolates as nucleophiles and B) a Claisen rearrangement. TS=transition state.

Scheme 3

Steric ²H KIEs measured in classic systems are significant and inverse.

Scheme 4

Qualitative transition structure models for A) favored re attack and B) unfavored si attack in the DIP-Cl reduction system.

Scheme 5

The method for measuring ²H KIEs at enantiotopic groups utilizes two competition reactions to yield A) KIE_R and B) KIE_P.

Scheme 6

Method for measuring ¹³C KIEs at enantiotopic groups.

Scheme 7

A) ¹³C KIEs measured for the (–)-DIP-Cl reduction of 4′-methylisobutyrophenone. B) ¹³C KIEs computed by using a transition structure optimized using the B3LYP functional and the 6-31G* basis set.

Scheme 8

The CBS reduction with the variant of the catalyst used here (inset).

Scheme 9

A) ¹³C KIEs measured for the (S)-Me-CBS-catalyzed reduction of 2′,5′-dimethylisobutyrophenone. B) ¹³C KIEs computed by using a transition structure optimized using the B3LYP functional and the 6–31 + G(d,p) basis set.

Scheme 10

Archetypical intramolecular proline-catalyzed aldol reaction.

Scheme 11

Experimentally determined ¹³C KIEs measured using A) the Singleton method and B) the method presented herein that distinguishes between enantiotopic groups.

Scheme 12

Reaction steps and transition-structure models corresponding to A) carbinolamine formation, B) iminium formation, and C) C–C bond formation.

Scheme 13

Computed ¹³C KIEs for rate-determining A) carbinolamine formation, B) iminium formation, and C) C–C bond formation. These values were computed from transition structure and reactant models optimized at B3LYP/6–31 + G(d,p) using an IEFPCM model for solvent.