New Strategies for Stereocontrol of Highly Electrophilic Intermediates in Asymmetric Catalysis

Abstract

In Chapter 1, we review the recent developments in stereoselective alkene difunctionalization reactions catalyzed by chiral iodoarenes. This chapter focuses on synthetic advances in inter- and intramolecular reactions, with discussion of the proposed mechanisms and supporting experiments as appropriate. In Chapter 2, we report an iodoarene-catalyzed enantioselective synthesis of β,β-difluoroalkyl bromide building blocks. The transformation involves an oxidative rearrangement of α-bromostyrenes, utilizing HF–pyridine as the fluoride source and m-CPBA as the stoichiometric oxidant. A catalyst decomposition pathway was identified, which, in tandem with catalyst structure–activity relationship studies, facilitated the development of an improved catalyst providing higher enantioselectivity with lower catalyst loadings. The versatility of the difluoroalkyl bromide products was demonstrated via highly enantiospecific substitution reactions with suitably reactive nucleophiles. The origins of enantioselectivity were investigated using computed interaction energies of simplified catalyst and substrate structures, providing evidence for both CH–π and π–π transition state interactions as critical features. In Chapter 3, we describe a new approach for inducing enantioselectivity in transition-metal-catalyzed reactions. This strategy relies on neutral hydrogen-bond donors that bind anions of transition-metal complexes to achieve enantiocontrol and rate enhancement through ion pairing in concert with other noncovalent interactions. A cooperative anion-binding effect of a chiral bis-thiourea hydrogen-bond donor is demonstrated to lead to high enantioselectivity in intramolecular ruthenium-catalyzed propargylic substitution reactions. Experimental and computational mechanistic studies reveal the attractive interactions between electron-deficient arene components of the hydrogen-bond donor and the metal complex that underlie enantioinduction and the acceleration effect.