|dc.description.abstract||In Chapter 1, we report the observation that chiral squaramide hydrogen-bond (H-bond) donor catalysts act cooperatively with trialkylsilyl trifluoromethanesulfonates (silyl triflates) to promote enantioselective (4+3) cycloaddition reactions. An experimental and computational investigation of the mechanism of this reaction identified a squaramide-silyl triflate complex as the resting state of the catalyst. This resting state promotes rate-limiting ionization of acetals to access reactive, chiral oxyallyl cation-triflate ion pairs. The study demonstrates that squaramide H-bond donors can generate extremely reactive Lewis acids from silyl triflates that provide access to high-energy cationic intermediates and subsequently control enantioselective additions into these electrophiles through an ion-pairing mechanism.
In Chapter 2, we discuss the application of iodine(I/IIII) catalysis to diastereoselective 1,2-difluorination reactions of alkenes with HF-pyridine as a nucleophilic fluoride source and Brønsted acid activator. The combination of HF-pyridine, a simple aryl iodide catalyst, and a commercially available oxidant allows for difluorination reactions of sterically and electronically varied alkenes. The characterization of anchimeric assistance pathways that alter the diastereomeric outcomes in several 1,2-difluorination reactions formed the basis for subsequent enantioselective reactions reported in Chapters 3–5, while the observation that electron-deficient alkenes are activated by iodine(III) inspired the 1,3-difunctionalization reactions reported in Chapter 6.
The development of an enantioselective, catalytic 1,1-difluorination of styrenes is disclosed in Chapter 3. The electrophilic nature of C-I(III) bonds allows for stereospecific skeletal rearrangements through a phenonium ion to provide difluoromethyl groups. A temperature-dependent analysis of selectivity suggested that non-covalent, attractive interactions between the catalyst and the substrate in the enantiodetermining transition structure play a key role in governing selectivity.
Enantioselective reactions of substituted cinnamamide derivatives can provide both 1,1- and 1,2- difluorination products in different selectivities and proportions. The subtle interplay between the steric and electronic factors responsible for product ratio and selectivity outcomes in enantioselective difluorination reactions is discussed in Chapter 4. Further extension of the anchimeric assistance observed in 1,2-difluorination reactions to enantioselective fluorolactonization reactions is described in Chapter 5.
A general catalytic approach relying on the high electrophilicity of iodine(III) species obtained via Brønsted acid activation for 1,3-difunctionalization reactions of unactivated cyclopropanes is outlined in Chapter 6. Initially, catalytic 1,3-difluorination reactions of cyclopropanes that provide structurally diverse products are demonstrated. Fluorines disposed in a 1,3-relationship impart a significant conformational bias in order to minimize dipolar repulsion. Crystallographic and solution state evidence support the ability of 1,3-difluorides to control conformation of organic molecules through dipole minimization. The outcomes of stereospecific 1,3-difluorination reactions suggest an activation mechanism similar to that observed for alkenes. The generality of this catalytic, electrophilic cyclopropane activation strategy is further demonstrated in the synthesis of 1,3-diols, 1,3-amino alcohols, and 1,3-diamines.
Finally, in Chapter 7, we present our efforts to mimic the activation mode of fluorinase enzymes using pyrrole H-bond donors to control the nucleophilicity and basicity of fluoride in substitution reactions with CsF. Identification of a catalyst that interacts with both cesium and fluoride enabled selective substitution reactions and minimized elimination pathways. Mechanistic studies directly resulted in an improved catalyst for S¬N2 reactions with alkali metal fluoride salts and mesylate electrophiles.||