Asymmetric Catalysis of Ionic 1,2-Rearrangements

Abstract

In Chapter 1, we report the development and study of an aryl-iodide-catalyzed Wagner–Meerwein rearrangement reaction. This process converts styrenes bearing cumyl, t-butyl, and i-propyl substitution into enantioenriched 1,3-difluorinated molecules. Hammett analysis, KIE experiments, and DFT calculations revealed that these reactions proceed through distinct selectivity-determining steps that depend on the nature of the migrating group. Substrates bearing aryl migrating groups proceed via selectivity-determining rearrangement, whereas those with methyl migrating groups proceed via selectivity-determining fluorination. Both mechanisms are controlled with high selectivity by the same chiral aryl-iodide catalyst, providing a compelling illustration of generality across reaction mechanisms in asymmetric catalysis. In Chapter 2, we detail the discovery of a catalytic strategy for controlling Matteson rearrangements with enantioselectivity. These reactions transform dichloromethane and organoboron pinacol esters into α-chloro boronic esters, versatile carbon building blocks that can undergo two stereospecific elaborations to afford molecules bearing trisubstituted stereocenters with myriad substitution patterns. While initial explorations centered around the use of hydrogen-bond donors (HBDs) as catalysts, we discovered that lithium-isothiourea-boronate complexes—formed via reaction of thioureas with the substrate in initial optimization studies—catalyze the rearrangement with extraordinary levels of enantioselectivity. These lithium boronate salts were characterized by NMR, IR, and solid-state studies to reveal a well-defined structure featuring a five-membered lithium chelate with the cation located in a highly dissymmetric pocket. Supported by NMR and DFT experiments, the catalyst is proposed to promote rearrangement through a dual–lithium-induced chloride abstraction mechanism. In Chapter 3, we disclose the application of a new method for the measurement of 13C Kinetic Isotope Effects (KIEs) at natural abundance using 1H NMR. This method leverages single quantum suppression in the 1H spectrum (SQUASH) to effectively delete the main 1H–12C peak from the proton spectrum, enabling accurate and precise measurements of the integrals of the 1H–13C satellite peaks. KIEs were calculated using relative integrations of the 12C–H parent peak, measuring using standard 1H NMR, and 13C–H satellite peaks, measured using SQUASH. Three reactions—phenol methylation, benzaldehyde reduction, and cinnamate epoxidation—were analyzed to showcase the general utility of this tool. As 1H NMR sensitivity is approximately 64-fold greater than that of 13C, this method potentially enables up to a 4,096-fold reduction in acquisition time, potentially transforming natural abundance carbon KIE experiments into routine experiments to employ in fundamental mechanistic studies.