Chiral Dual-Hydrogen-Bond Donors Catalyze Highly Enantioselective Cyclization Reactions

Abstract

In Chapter 1, we describe the development and mechanistic analysis of highly enantioselective bioinspired cyclization reactions of monoterpene derivatives catalyzed by chiral ureas. From a detailed series of mechanistic experiments including full kinetic analysis, Hammett studies, and kinetic isotope effect studies, we have determined that catalysis occurs via a concerted cyclization manifold promoted by the cooperative action of two units of the optimal chiral urea. A critical C–H  interaction between the urea catalyst and cationic substrate was recognized to contribute to enantiodifferentiation through a series of absolute rate measurements and density functional theory (DFT) calculations. In Chapter 2, we describe highly enantioselective cooperative catalysis between hydrogen chloride (HCl) and chiral thioureas applied to Prins cyclization reactions of alkenyl aldehyde substrates. Key structural modifications to the thiourea catalysts were shown to impart enhanced stability and performance under the highly acidic reaction conditions, with the optimal chiral catalyst inducing rate acceleration of two orders of magnitude over reactions catalyzed by HCl alone. The new method was found to proceed efficiently with low catalyst loadings, providing access to highly enantioenriched homoallylic alcohol products derived from several distinct substrate classes. In Chapter 3, we present a series of detailed mechanistic studies aimed at understanding the origins of efficient catalysis and high levels of enantioselectivity in the Prins reaction described in Chapter 2. A combination of experimental and computational studies point to a mechanism in which the chiral thiourea and HCl catalysts act cooperatively to promote enantioselective Prins reactions through the formation of a key catalytically active complex. Despite the attenuated effective acidity of HCl as a result of this complexation, enantioselectivity and rate acceleration relative to the HCl-catalyzed background reaction are achieved primarily through chloride-mediated activation of the alkene nucleophile in the rate- and enantiodetermining cyclization transition state.