Homochiral catalysts that can effect asymmetric transformations are invaluable in the production of optically active molecules. Researchers are actively pursuing the design of new ligands and organocatalysts by exploiting concepts derived from the application of bifunctional and C(2)-symmetric catalysts. Many homochiral catalysts containing amines, ethers, alcohols, and phosphines as electron-pair donors have been successfully developed. Amine N-oxides are highly polar substances. Despite their pronounced capacity as electron-pair donors, N-oxides have been underutilized in asymmetric reactions; they have only made a visible impact on the field in the preceding decade. Systematic studies have instead largely focused on pyridine- or quinoline-based scaffolds in organosilicon and coordination chemistry. The application of chiral tertiary amine N-oxides has not been widely pursued because of the difficulty of controlling the chirality at the tetrahedral nitrogen of the N-oxide moiety. In this Account, we outline the design of a new family of C(2)-symmetric N,N'-dioxides from readily available chiral amino adds. We then discuss the application of these chiral amine N-oxides as useful metal ligands and organocatalysts for asymmetric reactions. The high nucleophilicity of the oxygen in N-oxides is ideal for organocatalytic reactions that rely on nucleophilic activation of organosilicon reagents. These catalysts have been successfully applied in the asymmetric addition of trimethylsilylcyanide to aldehydes, ketones, aldimines, and ketimines, with good yields and excellent enantioselectivities. Asymmetric organocatalytic chlorination of beta-ketoesters with N-chlorosuccinimide has also been achieved through hydrogen bond activation. The molecular framework of these N,N'-dioxides, with their multiple O-donors, also serves as a new tetradentate ligand that can coordinate a range of metal ions, including Cu(I), Cu(II), Ni(II), Mg(II), Fe(II), C(II), In(III), Sc(III), La(III), Y(III), Nd(III), and others. These versatile metal complexes are efficient catalysts for a variety of asymmetric reactions. Asymmetric cycloadditions have been achieved with these chiral Lewis add catalysts. We have also found success with asymmetric nucleophilic additions to C=O or C=N bonds; substrates include 3-substituted 2-oxindoles, alkenes, enamides, enecarbamates, diazoacetate esters, nitroalkanes, glycine Schiff bases, and phosphate. Notably, the first catalytic asymmetric Roskamp reaction was realized, which was successful because of the high efficiency of the catalyst. Asymmetric conjugate additions between alpha,beta-unsaturated compounds and nucleophiles such as nitroalkane, malonate, thioglycolate, and indoles have been accomplished. The first asymmetric haloamination of dial cones was discovered, and the reaction proceeded with high regio- and enantioselectivity. In some cases, we were able to reduce the catalyst loading to just 0.01-0.05 mol % while maintaining excellent outcomes. Some particularly interesting phenomena were observed over the course of the research. These include a remarkable amplification of the asymmetry in a sulfa-Michael reaction, as well as the reversal of enantioselectivity after alteration of the central metal or the subunits of the ligand in two other reactions. These unusual results have facilitated a deeper understanding of the catalytic mechanism.
