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.

Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

“…Apart from differences in feasibility and precision, these different kinds of experiments may also differ in terms of the information that they provide . Recent reviews on KIE applications for mechanistic studies include asymmetric, organometallic, and C−H bond activation reactions. Aside from mechanistic investigations, KIE experiments have proven to be indispensable tools for understanding tunnelling and dynamic phenomena…”

“…1) KIEs determined from the absolute rates of two parallel reactions;2)KIEs determined from an intermolecular competition between deuterium-labelled and unlabelled substrate in the same reaction flask;a nd 3) KIEs determined from an intramolecular competition, for example, by placing adirecting group (DG) between the C À Hand C À D bonds.A part from differences in feasibility and precision, these different kinds of experiments may also differ in terms of the information that they provide. [27] Recent reviews on KIE applications for mechanistic studies include asymmetric, [28] organometallic, [29] and C À Hb ond activation [27] reactions.A side from mechanistic investigations,K IE experiments have proven to be indispensable tools for understanding tunnelling [30] and dynamic phenomena. [31] In chemical synthesis,K IEs have been utilized only occasionally,f or example,t os upress side product formation in cyclization reactions, [32] to facilitate CÀHb ond functionalization (Scheme 4), [33] or to prevent ortho lithiation.…”

Stereoselection in the Corey–Bakshi–Shibata Reduction: Insight from Kinetic Isotope Effects and Transition‐Structure Modeling

“…[2] Steric kinetic isotope effects (KIEs) offer a means of investigating steric interactions quantitatively. [1] Enantiofacial discrimination depends upon the effective discrimination of the large (R L ) and small (R S ) substituents (Scheme 1).…”

“…Steric repulsion is accepted as a key director of stereoselection; however, direct measures of steric interaction at the transition state (TS) are difficult to obtain. [2] Steric kinetic isotope effects (KIEs) offer a means of investigating steric interactions quantitatively. [3] Herein, we leverage a combined experimental and computational approach toward answering the following questions regarding stereoselection in the CBS reduction of 2',5'-dimethylisobutyrophenone (1) using the oxazaborolidine (2) as a catalyst.…”

From Bifunctional to Trifunctional (Tricomponent Nucleophile–Transition Metal–Lewis Acid) Catalysis: The Catalytic, Enantioselective α-Fluorination of Acid Chlorides

“…17 For example, observation of a primary KIE upon introduction of deuterium labels in the α-position of the acid chloride would indicate rate-determining dehydrohalogenation, whereas an inverse secondary isotope effect could point instead towards rate limiting fluorination ( scenario a , Figure 4). The rate of product formation for α,α-dideuteriophenylacetylchloride compared with phenylacetyl chloride gave an observed KIE of 3.12, which indicates that dehydrohalogenation may be rate limiting.…”