Wei-Cheng Yuan

Organocatalytic direct asymmetric aldol reactions of 3-isothiocyanato oxindoles to ketones: stereocontrolled synthesis of spirooxindoles bearing highly congested contiguous tetrasubstituted stereocenters.

The first example of a direct catalytic asymmetric intermolecular aldol reaction of 3-isothiocyanato oxindoles to simple ketones with bifunctional thiourea-tertiary amine as catalyst is reported. This strategy provides a promising approach for the asymmetric synthesis of a range of enantioenriched spirocyclic oxindoles bearing two highly congested contiguous tetrasubstituted carbon stereocenters. Versatile transformations of the spirocyclic oxindole products into other structurally diverse spirocyclic oxindoles have also been demonstrated.

FeCl3-Catalyzed Stereoselective Construction of Spirooxindole Tetrahydroquinolines via Tandem 1,5-Hydride Transfer/Ring Closure

An efficient FeCl(3)-catalyzed stereoselective intramolecular tandem 1,5-hydride transfer/ring closure reaction was developed. The method allows for the formation of structurally diverse spirooxindole tetrahydroquinolines in high yields (up to 98%) with good to excellent levels of diastereoselectivity (up to 99:1 dr). The catalytic enantioselective variant of this process was also investigated preliminarily with a chiral BINOL-derived phosphoric acid.

Highly diastereo- and enantioselective Michael additions of 3-substituted oxindoles to maleimides catalyzed by chiral bifunctional thiourea-tertiary amine.

A highly diastereo- and enantioselective Michael addition reaction with respect to prochiral 3-substituted oxindoles and maleimides by a chiral bifunctional thiourea-tertiary amine catalyst was investigated for the first time. The corresponding adducts, containing a quaternary center at the C3-position of the oxindole as well as a vicinal tertiary center, were generally obtained in good to high yields (up to 92%) with high to excellent diastereo- (up to 99:1 dr) and enantioselectivities (up to 99% ee).

Highly efficient and stereoselective construction of dispiro-[oxazolidine-2-thione]bisoxindoles and dispiro[imidazolidine-2-thione]bisoxindoles.

An efficient and stereoselective reaction between 3-isothiocyanato oxindoles and isatins/isatinimines has been developed to afford structurally diverse dispiro[oxazolidine-2-thione]bisoxindoles and dispiro[imidazolidine-2-thione]bisoxindoles in excellent results under mild conditions. The potential of asymmetric induction by means of a chiral auxiliary was explored. The isomers are separable, and products could be isolated as single diastereomers by column chromatography. Further synthetic transformations of the reaction product were also successfully realized.

Organocatalytic enantioselective hydroxymethylation of oxindoles with paraformaldehyde as C1 unit.

A bifunctional thiourea-tertiary amine-catalyzed asymmetric hydroxymethylation of 3-substituted oxindoles using paraformaldehyde as the C1 unit was developed. A wide scope of oxindoles, bearing C3 sterically congested quaternary carbon centers, were smoothly obtained in good to excellent yields (up to 99%) and high enantioselectivities (up to 91% ee) under mild reaction conditions. A more significant feature of this approach employs cheap and readily available paraformaldehyde as a hydroxymethylation C1 unit, which is activated by chiral bifunctional thiourea organocatalysts.

3-isothiocyanato oxindoles serving as powerful and versatile precursors to structurally diverse dispirocyclic thiopyrrolidineoxindoles through a cascade Michael/cyclization process with amino-thiocarbamate catalysts.

Cascading catalysis: 3-Isothiocyanato oxindoles act as powerful and versatile precursors for a range of structurally diverse dispirocyclic thiopyrrolidineoxindoles containing two spiro-quaternary and three contiguous stereogenic centers in quantitative yields with excellent disatereo- and enantioselectivities by only using 1 mol % amino-thiocarbamate catalyst.

Asymmetric Michael/Cyclization Cascade Reaction of 3-Isothiocyanato Oxindoles and 3-Nitroindoles with Amino-Thiocarbamate Catalysts: Enantioselective Synthesis of Polycyclic Spirooxindoles

An unprecedented organocatalytic asymmetric Michael/cyclization cascade reaction of 3-isothiocyanato oxindoles and 3-nitroindoles has been disclosed. A wide range of enantioenriched polycyclic spirooxindoles, containing three contiguous chiral centers with two of them having quaternary stereocenters, could be smoothly obtained with satisfactory results (up to 99% yield, >99:1 dr, and 96% ee). This method is very promising because the reaction is scalable, and the versatile transformations of the products into other spirocyclic oxindoles are also feasible.

Highly enantioselective [3+2] coupling of indoles with quinone monoimines promoted by a chiral phosphoric acid.

Highly enantioselective [3+2] coupling of 3-substituted indoles with quinone monoimines promoted by a chiral phosphoric acid has been reported. A large variety of benzofuroindolines were prepared in moderate to good yields (up to 98%) with generally excellent enantioselectivities (up to 99% ee).

Diastereo- and Enantioselective Conjugate Addition of 3-Substituted Oxindoles to Nitroolefins Catalyzed by a Chiral Ni(OAc)2-Diamine Complex under Mild Conditions

A simple catalyst system assembled from an enantiomerically pure diamine ligand and Ni(OAc)(2) efficiently generates chiral metal enolates derived from 3-substituted oxindoles bearing an N-1 carbonyl group. The enolates smoothly undergo diastereo- and enantioselective conjugate addition to a wide range of nitroolefins under mild reaction conditions, furnishing 3,3-disubstituted oxindole products bearing two vicinal quaternary/tertiary stereocenters in 74-95% yields and 60:40 to 99:1 dr, 71-97% ee.

Highly Diastereoselective and Enantioselective Synthesis of α‐Hydroxy β‐Amino Acid Derivatives: Lewis Base Catalyzed Hydrosilylation of α‐Acetoxy β‐Enamino Esters

Chiral a-hydroxy b-amino acid moieties are important structural components in a wide variety of biologically active compounds as well as natural products, of which the side chains of Taxol and its analogues are the most famous examples. Consequently, the synthesis of chiral a-hydroxy b-amino acid derivatives has attracted considerable attention. Some syntheses include the Sharpless asymmetric aminohydroxylation, asymmetric dihydroxylation, ring opening of chiral epoxides, asymmetric nitroaldol reactions, asymmetric Mannich reaction, asymmetric 1,3dipolar cycloaddition, and other transformations. Among the successful strategies developed for obtaining optically active a-hydroxy b-amino acid derivatives, those that lead to substrates containing certain functional groups are of great significance. Accordingly, it can be reasoned that direct asymmetric reduction of the corresponding C=N double bond in substrates would be the most straightforward way to construct chiral a-hydroxy b-amino acid derivatives. However, to the best of our knowledge, the research on the abovementioned reaction has not yet been reported. Recently, asymmetric reactions involving the Lewis base activation of Lewis acids has attracted much attention. Among these reactions, chiral Lewis base catalyzed asymmetric hydrosilylation of C=N double bonds has become an important approach to chiral nitrogen-containing compounds because of the mild reaction conditions, cheap reagents, and the environmentally benign nature of this transformation. Several groups have achieved impressive progress in this field. During our ongoing studies on chiral Lewis base catalyzed asymmetric hydrosilylation of C=N double bond compounds such as b-enamino esters, we envisioned that the design and synthesis of b-enamino esters bearing various functional groups on the a position would provide a wide range of precursors to a-substituted b-amino acid derivatives. Therefore, we first tried to introduce an acetoxy group to the a position of b-enamino esters so as to generate a-acetoxy benamino ester 1 in which every functional group was finely assembled as depicted in Figure 1. (1S,2S)-2-Amino-1-(4-nitrophenyl)propane-1,3-diol (2) is the intermediate of chloramphenicol. It is very cheap and easily accessible. The two hydroxy groups can undergo condensation with a ketone or an aldehyde to generate a six-membered ring. Thus it occurred to us that we could make a novel chiral, rigid picolinamide Lewis base catalyst through the same transformation. We reasoned that this rigid catalyst might be highly selective in promoting asymmetric hydrosilylation of C=N double bonds. Hence we synthesized catalysts through two facile steps. As can be seen in Scheme 1, 2 was condensed with picolinic acid to give amide 3. The two hydroxy groups of amide 3 were then condensed with formaldehyde or a ketone to generate the cyclic catalysts 4a–4d.