Asymmetric Cycloaddition and Cyclization Reactions Catalyzed by Chiral N,N'-Dioxide-Metal Complexes

Catalytic asymmetric cycloadditions and cascade cyclizations are a major focus for the enantioselective construction of chiral carbo- and heterocycles. A number of chiral Lewis acids and organocatalysts have been designed for such reactions. The development of broadly applicable catalysts bearing novel chiral backbones to meet the demands of various applications is an ongoing challenge. Approximately 10 years ago, we introduced a group of conformationally flexible C₂-symmetric N,N'-dioxide amide compounds, which represent a new class of privileged ligands. The coordination of the four oxygens of a chiral N,N'-dioxide around a central metal generates an octahedral tricyclometalated Lewis acid catalyst that can carry out various enantioselective reactions. In this Account, we summarize our recent studies on asymmetric cycloadditions between various dienophiles and dienes, dipoles and dipolarophiles, and cascade cyclizations catalyzed by chiral N,N'-dioxide-metal complexes. In principle, these unique chiral catalysts lower the LUMO energy of electron-deficient 2π components or heterodienes by coordination with the functional groups via various binding modes. With N-Boc-3-alkenyloxindole and alkylidene malonate as the electron-deficient 2π components, N,N'-dioxide-metal complexes provided excellent catalytic activities and asymmetric inductions for a variety of transformations, including [2 + 1], [3 + 2], [4 + 2], and [8 + 2] cycloadditions. Mechanistically, these substrates could be efficiently activated through bidentate coordination. The strategy was also useful for asymmetric cascade cyclizations to form polycyclic adducts. Monodentate or bidentate coordination of other α,β-unsubstituted carbonyl compounds to metal centers enabled both normal Diels-Alder reactions and inverse-electron-demand hetero-Diels-Alder reactions as well as [2 + 2] additions. Furthermore, hetero-Diels-Alder reactions of aldehydes, ketones, and imines are well-tolerated and afford various heterocycles. This includes allowing the concise synthesis of the antimalarial compound KAE609. Asymmetric Michael/cyclization reactions of bidentate α,β-unsaturated pyrazolamides gave efficient access to the chiral drugs (-)-paroxetine and (R)-thiazesim. The formal [3 + 2] cycloadditions of donor-acceptor epoxides and aziridines enantioselectively gave a series of five-membered oxo- and aza-heterocycles. The reaction of cyclopropane diketones showed unprecedented reactivities and provided a new route for the synthesis of dihydropyrrole and benzimidazole derivatives. General models for the catalytic reactions emerged from knowledge of the absolute configurations of the products of several reactions and X-ray crystal structures of the catalysts. In the field of chirality created by the coordination of an N,N'-dioxide to a metal center, the bonding of one or two reactants establishes a perfect reaction template for generation of the target adducts. Representative examples have been used to demonstrate how the substructures of the ligands and other reaction components affect the stereoselectivity and how metal salts impact the reactivity. These results reveal the importance of tunability and compatibility of the ligands and metal precursors for achieving high stereoinduction and activity.