Cooperative Asymmetric Catalysis with Squaramide H-Bond Donors and Lewis Acids

Abstract

A new mode of cooperative catalysis with chiral squaramide hydrogen-bond donors and trialkylsilyl trifluoromethanesulfonates (triflates) for asymmetric nucleophilic additions to oxocarbenium ions was explored. Evidence is provided for a dual role of the squaramide catalyst: rate acceleration through activation of the silicon Lewis acid and enantioinduction through triflate anion-binding. In the first chapter, we present examples of current methodologies used for activation of Brønsted and Lewis acids in organocatalysis. In the rest of this thesis, we explore the mechanism and applications of cooperative catalysis with chiral squaramide hydrogen-bond donors and trialkylsilyl triflates.

In Chapter 2, we show that in the presence of trialkylsilyl triflate, chiral squaramides can catalyze highly enantioselective (4+3) cycloaddition reactions of pyruvic aldehyde dimethyl acetal derivatives with furans. Detailed mechanistic studies reveal the formation of a resting state complex between the squaramide catalyst and the trialkylsilyl triflate, which leads to enhanced Lewis acidity of silicon. The chiral squaramide catalyst then controls the stereoselectivity of the subsequent nucleophilic addition to the oxocarbenium through binding of the triflate anion.

Chapter 3 describes the development of an asymmetric squaramide and trialkylsilyl triflate co-catalyzed nucleophilic substitution of acetals. High enantioselectivities are achieved in this transformation with a range of nucleophiles spanning five orders of magnitude in nucleophilicity parameter, from methallyltrimethylsilane to silyl ketene acetal. In Chapter 4, we expand this new reactivity concept to aldehyde substrates. A synthetically practical chiral squaramide is shown to catalyze an asymmetric Mukaiyama aldol reaction with moderate enantioselectivities.