Enantioselective Synthesis of Cα-Tetrasubstituted N-Hydroxyl-α-amino Nitriles via Cyanation of Ketonitrones Using Me2(CH2Cl)SiCN.

Here, we report an unprecedented catalytic enantioselective cyanation of ketonitrones enabled by the bifunctional cyanating reagent Me2(CH2Cl)SiCN. This approach allows facile access to optically active N-hydroxyl-α-amino nitriles that are of high synthetic value but difficult to acquire by other methods. The use of bifunctional cyanating reagent Me2(CH2Cl)SiCN not only achieves an enantioselectivity higher than that with TMSCN but also enables various diversification reactions of the resulting silylated adducts. This represents the first enantioselective catalytic nucleophilic addition reaction of unactivated ketone-derived nitrones, exhibiting the potential of such tetrasubstituted C═N bonds for asymmetric synthesis of N-hydroxy α-amino acids and other N-hydroxy tertiary amines.

Catalyst-Free and Solvent-Controlled Divergent Synthesis of Difluoromethylene-Containing S-Heterocycles.

An unprecedented catalyst-free reaction of benzo[b]thiophene-2,3-diones with difluoroenoxysilanes has been developed using either MeOH or H2O as the solvent, which constitutes a facile and efficient protocol for the solvent-controlled divergent synthesis of five- and seven-membered S-heterocycles featuring a gem-difluoromethylene group. A gram-scale synthesis and the diversification of the product transformations to other difluorinated S-heterocycles further highlight its utility.

Au-Catalyzed Formal Allylation of Diazo(thio)oxindoles: Application to Tandem Asymmetric Synthesis of Quaternary Stereocenters.

We report an efficient Au(I)-catalyzed formal allylation of diazo(thio)oxindoles using allyltrimethylsilane to give 3-allyl (thio)oxindoles, which are difficult to access by using traditional alkylation methods under basic conditions. The approach enables a highly stereoselective synthesis of quaternary (thio)oxindoles via a formal allylation-asymmetric Michael addition sequence. These adducts are versatile synthons for spirocyclic (thio)oxindoles. Initial biological studies reveal that chiral thiooxindoles show promising antiproliferation activity that is better than that of the corresponding oxindoles.

Modular synthesis of chiral 1,2-dihydropyridines via Mannich/Wittig/cycloisomerization sequence that internally reuses waste.

1,2-Dihydropyridines are valuable and reactive synthons, and particularly useful precursors to synthesize piperidines and pyridines that are among the most common structural components of pharmaceuticals. However, the catalytic enantioselective synthesis of structurally diverse 1,2-dihydropyridines is limited to enantioselective addition of nucleophiles to activated pyridines. Here, we report a modular organocatalytic Mannich/Wittig/cycloisomerization sequence as a flexible strategy to access chiral 1,2-dihydropyridines from N-Boc aldimines, aldehydes, and phosphoranes, using a chiral amine catalyst. The key step in this protocol, cycloisomerization of chiral N-Boc δ-amino α,ß-unsaturated ketones recycles the waste to improve the yield. Specifically, recycling by-product water from imine formation to gradually release the true catalyst HCl via hydrolysis of SiCl4, whilst maintaining a low concentration of HCl to suppress side reactions, and reusing waste Ph3PO from the Wittig step to modulate the acidity of HCl. This approach allows facile access to enantioenriched 2-substituted, 2,3- or 2,6-cis-disubstituted, and 2,3,6-cis-trisubstituted piperidines.