Quaternary stereogenic centers are of great importance because of their prevalence in a series of bioactive natural products and pharmaceuticals. Although the catalytic asymmetric construction of these highly congested centers poses a formidable challenge, this field has been extensively explored in the past few decades, and several elegant strategies, such as the asymmetric conjugate addition to β,β‐disubstituted nitroalkenes, have been developed. The resultant β‐nitro quaternary stereocenters can be conveniently transformed into the corresponding β‐amino quaternary stereocenters commonly found in bioactive compounds. This review summarizes the recent advances in the construction of all‐carbon quaternary or hetero‐carbon quaternary stereocenters via metal‐catalyzed and organocatalyzed asymmetric conjugate addition to β,β‐disubstituted nitroalkenes, focusing on the scope, applications, and mechanisms of these reactions.

A tetrasubstituted carbon atom connected by three sp3 or sp2-carbons with single nitrogen, i.e., the α-tertiary amine (ATA) functional group, is an essential structure of diverse naturally occurring alkaloids and pharmaceuticals. The synthetic approach toward ATA structures is intricate, therefore, a straightforward catalytic method has remained a substantial challenge. Here we show an efficient water-accelerated organocatalytic method to directly access ATA incorporating homoallylic amine structures by exploiting readily accessible general ketones as useful starting material. The synergistic action of a hydrophobic Brønsted acid in combination with a squaramide hydrogen-bonding donor under aqueous condition enabled the facile formation of the desired moiety. The developed exceptionally mild but powerful system facilitated a broad substrate scope, and enabled efficient multi-gram scalability.

A broadly applicable biomimetic enantioselective decarboxylative catalytic aldol reaction of trifluoromethyl ketones with malonic acid half-thioesters (MAHTs) is described. Utilizing cinchona-based thioureas as highly efficient polyketide synthase-mimic catalysts, chiral tertiary aldols, β-trifluoromethyl-β-hydroxy thioesters, were obtained in up to 99% yield and 95% ee. Facile transformation of the thioester moiety of the aldol adducts showcases the synthetic utility of this biomimetic aldol protocol to deliver a range of chiral trifluoromethylated tertiary aldol pharmacophores.

Sulfur(VI) fluoride exchange (SuFEx) is recognized as another emerging tool for click chemistry. The preparation of the functionalized alkyl sulfonyl fluorides as key SuFEx hubs via C(sp 3 )− C(sp 3 ) bond formation is exceptionally challenging. We report herein a new efficient method for accessing alkyl sulfonyl fluorides incorporating γ-geminal dithioester via phosphazene catalysis. The aqueous, neutral organosuperbase catalytic system amplifies the reactivity by taking advantage of the hydrophobic amplification. SuFEx-active products are applied to the click connection of bioactive molecules. Density functional theory studies show that the selective outcome of the product is guided by an ion-pair organosuperbase catalyst assembly that is potentially stabilized by a hydrogen-bonding interaction between the catalyst and the DTM in the C(sp 3 )−C(sp 3 ) bond-forming transition structure.

Water enables the highly challenging enantioselective Michael addition of sterically congested β-trifluoromethylβ-arylor -alkyl-substituted nitroolefins with dithiomalonates. Under on-water conditions, the reaction rates were remarkably accelerated as a result of enforced hydrophobic interactions between catalysts and reactants. Takemoto-type thiourea catalysts are very effective for this transformation, affording highly enantioenriched Michael adducts that provide simple access to chiral γ-aminobutyric acid (GABA) analogues with a β-trifluoromethylated quaternary stereocenter.

Herein, a water‐accelerated, N‐heterocyclic carbene (NHC)‐catalyzed aza‐Michael addition reaction was reported to access β‐aminosulfonyl fluorides, which are key hubs of the sulfur(VI) fluoride exchange (SuFEx) reaction. As a crucial reaction medium, water considerably enhanced the reaction rate with excellent chemo‐ and site‐selectivity (up to >99 : 1) compared to conventional solvents. In addition, the late‐stage ligation of bioactive molecules with the aliphatic β‐amino SuFEx hub was demonstrated. Mechanistic studies on experimental, analytical, and computational approaches support noncovalent activation over NHC catalysis “on‐water”.

β‐Sulfido sulfonyl fluoride and its derivatives have been gaining attention recently in the fields of medicinal chemistry and material science. The conventional method for the synthesis of functionalized alkyl sulfonyl fluorides requires several chemical transformations. Therefore, a direct establishment of such chemical structures remains challenging, and an efficient catalytic approach is highly desired. Herein a significant “on‐water” hydrophobic amplification was achieved, enabling a high‐turnover catalytic thia‐Michael addition to produce unprecedented β‐arylated‐β‐sulfido sulfonyl fluorides. Amounts as low as 100 ppm (0.01 mol %) of the phosphazene superbase were sufficient to successfully catalyze the reaction with excellent chemo‐/site‐selectivity and with optimal functional group tolerance. Several β‐arylated ethene sulfonyl fluorides were converted into thia‐Michael adducts up to >99 % yields. The mild conditions, high turnover, neutral pH, and scalability of the sustainable catalytic process benefit the preparation of potential pharmaceuticals (e. g., polyisoprenylated methylated protein methyl esterase inhibitors) and organic materials (e. g., electrolyte additives).

A-series nerve agents are extremely toxic organophosphorus chemical warfare agents (CWAs) that incorporate PO functional groups. Their colorless, tasteless, and odorless nature makes rapid and efficient detection challenging. Here, we report an unprecedented N-triflyl phosphoric triamide (N-TPT) receptor, which is a new class of triple hydrogen bonding donor molecular sensors for CWA recognition via noncovalent host−guest-type interactions. The highly robust trifurcate structures were designed based on density functional theory (DFT) computations and synthesized from N-triflyl phosphorimidoyl trichloride by simple stepwise processes. Quartz crystal microbalance (QCM) analysis allowed robust detection of typical CWA simulants, such as dimethyl methylphosphonate. The concentration-dependent QCM profiles were fitted with the Sips isotherm model, revealing that the thermodynamic parameters of the binding behaviors are roughly correlated with the calculated results. Developed N-TPT receptors show higher binding abilities than previously reported receptors and reasonable selectivity over other volatile compounds.