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 acids. 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 β-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), Co(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 acid 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 α,β-unsaturated compounds and nucleophiles such as nitroalkane, malonate, thioglycolate, and indoles have been accomplished. The first asymmetric haloamination of chalcones 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 c...

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 C-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 co...

An efficient lanthanide(III)-catalyzed diastereo- and enantioselective Michael addition of 3-substituted benzofuran-2(3H)-ones to 4-oxo-enoates was developed. The desired adducts with contiguous quaternary-tertiary stereocenters were obtained in up to 99% yield with up to >95/5 dr and 98% ee.

To improve the mechanical properties of bone tissue and achieve the desired bone tissue regeneration for orthopedic surgery, newly designed hydroxyapatite/polyurethane (HA/PU) porous scaffolds were developed via in situ polymerization. The results showed that the molecular modification of PU soft segments by glyceride of castor oil (GCO) can increase the scaffold compressive strength by 48% and the elastic modulus by 96%. When nano-HA (n-HA) particles were incorporated into the GCO-PU matrix, the compressive strength and elastic modulus further increased by 49 and 74%, from 2.91 to 4.34 MPa and from 95 to 165.36 MPa, respectively. The n-HA particles with fine dispersity not only improved the interface bonding with the GCO-PU matrix but also provided effective bioactivity for bonding with bone tissue. The hierarchical structure and mechanical quality of the n-HA/GCO-PU composite scaffold were determined to be appropriate for the growth of cells and the regeneration of bony tissues, demonstrating promising prospects for bone repair and regeneration.

Although high enantioselectivity of [2,3]-sigmatropic rearrangement of sulfonium ylides (Doyle-Kirmse reaction) has proven surprisingly elusive using classic chiral Rh(II) and Cu(I) catalysts, in principle it is due to the difficulty in fine discrimination of the heterotopic lone pairs of sulfur and chirality inversion at sulfur of sulfonium ylides. Here, we show that the synergistic merger of new α-diazo pyrazoleamides and a chiral N, N'-dioxide-nickel(II) complex catalyst enables a highly enantioselective Doyle-Kirmse reaction. The pyrazoleamide substituent serves as both an activating and a directing group for the ready formation of a metal-carbene- and Lewis-acid-bonded ylide intermediate in the assistance of a dual-tasking nickel(II) complex. An alternative chiral Lewis-acid-bonded ylide pathway greatly improves the product enantiopurity even for the reaction of a symmetric diallylsulfane. The majority of transformations over a series of aryl- or vinyl-substituted α-diazo pyrazoleamindes and sulfides proceed rapidly (within 5-20 min in most cases) with excellent results (up to 99% yield and 96% ee), providing a breakthrough in enantioselective Doyle-Kirmse reaction.

A class of conformationally flexible ligands composed of a tertiary amino oxide-amide backbone and a straight-chain alkyl spacer was developed. These C 2 -symmetric chiral N,N'-dioxide ligands could be straightforwardly synthesized from readily available amino acids and amines. They act as neutral tetradentate ligands to bind a wide variety of metal ions. Non-planar cis-α M(N,N'-dioxide) complexes enable an intriguing and easily fine-tuned chiral platform for a number of asymmetric reactions. Privileged N,N'dioxide ligands frequently show wide substrate generality and exceptional levels of stereocontrol for a specific catalytic reaction. We describe approaches to the ligand design and synthesis, structure and bonding in coordination complexes, and the recent developments in asymmetric catalysis. † Electronic supplementary information (ESI) available. See

The enantioselective synthesis of 3-functionalized oxindole derivatives has experienced an explosive development. This minireview introduces the recent application of rare earth (RE) metal complex catalysts in the synthesis of targeted frameworks. The direct addition reactions of 3-substituted oxindoles or isatins are described, together with a discussion of the catalytic mechanism and related transformations to pharmaceuticals.

Transforming amino acids into novel catalysts and ligands is a remarkable subset of new catalyst development in order to imitate enzymatic efficiencies. Their ability to perform a variety of asymmetric catalytic reactions is complimented by their ready availability, rich transformations, stability and easy procedure. Herein, we focused on describing our endeavor of developing new catalysts and ligands from primary and secondary amino acids. It includes C2‐symmetric N,N'‐dioxides, guanidine‐amides, bispidine‐based diamines, and other organic salts. The account covered a brief introduction about their discovery, representative applications and related mechanisms.