Li-Wen Xu

Asymmetric Michael addition mediated by novel cinchona alkaloid-derived bifunctional catalysts containing sulfonamides.

Novel cinchona alkaloid-derived bifunctional organocatalysts containing sulfonamide groups were utilized to promote Michael addition of bicyclic alpha-substituted beta-ketoesters to nitroolefins. The desired Michael adducts with all-carbon quaternary centers were constructed in high yield and with excellent enantioselectivity, demonstrating the great potential of cinchona alkaloid-derived sulfonamides in asymmetric catalysis.

Identification of Modular Chiral Bisphosphines Effective for Cu(I)-Catalyzed Asymmetric Allylation and Propargylation of Ketones

New modular chiral phosphines effective for two distinct Cu(I)-catalyzed asymmetric tetrasubstituted-carbon-forming reactions, namely, allylation and propargylation of ketones, were identified. The optimized phosphine 8 was readily synthesized on a gram scale in high yield via three facile transformations (O-alkylation, bisaminal formation, and phosphination) from commercially available materials. In both reactions, excellent enantioselectivity (up to 98% ee) was produced from a range of substrates, including aromatic and aliphatic ketones, using 0.1-5 mol % catalyst loading. Specifically, catalytic enantioselective propargylation was the first example, affording synthetically useful chiral building blocks that have not been easily accessed to date. In addition to the enantioselectivity, the high catalytic activity of the CuOAc-8 complex is noteworthy. Preliminary studies to elucidate the structure-catalyst activity relationship suggested that the high catalytic activity of the Cu-8 complex is due to the extraordinarily wide bite angle ( angleP-Cu-P = 137.8 degrees ), leading to the stabilization of the active monomeric catalytically active species. Furthermore, mechanistically intriguing nonconventional hydrogen bonds existed between the acetate ligand of Cu and the bisaminal hydrogen atoms, stabilizing the distorted tetrahedral coordination state of the Cu atom.

The Direct Asymmetric Vinylogous Aldol Reaction of Furanones with α‐Ketoesters: Access to Chiral γ‐Butenolides and Glycerol Derivatives

The creation of quaternary stereogenic centers is still a challenge in organic synthesis even though significant progress has been made in the past few decades. As part of our ongoing research efforts towards the efficient generation of quaternary stereogenic centers, we were interested in organic molecules containing a tertiary hydroxy group. Structures that contain tertiary alcohols are very important in the biological sciences and pharmaceutical industry. In particular, enantiomerically pure glycerol derivatives having a quaternary center are key chiral structural motifs that are present in many pharmaceuticals, and they are also versatile synthetic intermediates. Although many excellent methods have been devised for the synthesis of chiral tertiary alcohols, the asymmetric preparation of glycerol derivatives having a quaternary center is still a formidable task. To the best of our knowledge, only two examples have been reported in the literature. In 1992, Harada, Oku, and co-workers reported a synthetic approach utilizing menthone as a chiral auxiliary. Very recently, Kang and co-workers elegantly employed chiral copper complexes to carry out the enantioselective desymmetrization of meso-2-substituted glycerols, and obtained 2-substituted 1,2,3-propanetriols with excellent enantioselectivity. It is thus our goal to develop an efficient organocatalytic variant to allow easy access to 2-substituted chiral glycerol derivatives. We focused on the vinylogous aldol reaction between furanones and a-ketoesters (Scheme 1). The g-butenolides that would result from these reactions are common structural motifs in bioactive molecules. Moreover, they can be readily converted into tertiary-alcohol-containing glycerol derivatives. The vinylogous aldol reaction has been investigated intensively in the past few decades, and although it is commonplace to employ 2-silyloxyfurans as nucleophiles, the direct utilization of 2-furanone derivatives in the vinylogous aldol reactions is rare, probably because of their low reactivity. Zhang and co-workers first utilized a,b-dichloro-gbutenolides in the direct vinylogous aldol reaction. Recently, Terada and co-workers reported an enantioselective vinylogous aldol reaction of furanone derivatives with aldehydes catalyzed by a chiral guanidine. Feng and coworkers subsequently disclosed a thiourea-catalyzed direct vinylogous aldol reaction of furanones with aldehydes. Herein, we document the first direct asymmetric vinylogous aldol reaction of 3,4-dichlorofuran-2(5H)-one with a-ketoesters, catalyzed by an l-tryptophan-derived bifunctional catalyst, that leads to an efficient synthesis of chiral gbutenolides and 2-substituted glycerol derivatives. We recently introduced a novel tertiary amine/thiourea bifunctional catalyst derived from l-tryptophan, and showed its effectiveness in the Mannich reaction of fluorinated ketoesters. To extend the applications of these aminoacid-based bifunctional catalysts, we prepared a number of l-tryptophan-derived organic catalysts and examined their catalytic effects in the vinylogous aldol reaction of 3,4dichlorofuran-2(5H)-one (1a) with the phenylglyoxylates 2 (Table 1). The reaction was quite slow in the presence of Trp-1 alone (Table 1, entry 1), but the rate of the reaction could be substantially improved with the addition of molecular sieves (4 ; Table 1, entry 2). An examination of the ester moieties in the different a-ketoesters revealed that tert-butyl phenylglyoxylate (2c) offered the best diastereoselectivity and enantioselectivity (Table 1, entry 4). Changing the concentration of the reaction mixture yielded the product with a 91% ee (Table 1, entry 6). Notably, in contrast to the high stereoselectivity induced by the tryptophan-derived organic catalysts, quinidine QD-1, 6’-demethylated quinidine QD2, quinidine-derived sulfonamide QD-3, and quinidineScheme 1. Construction of g-butenolides and glycerol derivatives through the vinylogous aldol reaction.

A green, ionic liquid and quaternary ammonium salt-catalyzed aza-Michael reaction of α,β-ethylenic compounds with amines in water

The first environmentally benign, highly efficient conjugate addition of aliphatic amines to α,β-unsaturated compounds catalysed by simple quaternary ammonium salts and ionic liquids in the green solvent, water, is described.

Asymmetric Reductive Mannich Reaction to Ketimines Catalyzed by a Cu(I) Complex

A highly diastereoselective reductive Mannich coupling of ketimines and alpha,beta-unsaturated esters was developed using CuOAc-PPh(3) or CuOAc-MePPh(2) complex as a catalyst (5 mol %) and pinacolborane as a reducing reagent. The reaction was easily conducted at room temperature, and the substrate generality was broad. This platform methodology was extended to the first catalytic asymmetric reductive Mannich reaction of ketimines using CuOAc-DIFLUORPHOS as the catalyst (10 mol %). Switching the reducing reagent from pinacolborane to (EtO)(3)SiH was key to inducing the high enantioselectivity (82-93% ee). High diastereoselectivity was also maintained (3:1 approximately 30:1). Thus, products containing contiguous tetra- and trisubstituted carbons were catalytically synthesized with high stereoselectivities. Products were converted to alpha,beta,beta-trisubstituted (beta(2,3,3)) amino acid derivatives without any racemization and epimerization through simple treatment under acidic conditions. This method is the first entry of the catalytic asymmetric synthesis of beta(2,3,3)-amino acid derivatives, which constitute important chiral building blocks of biologically significant molecules.

Aromatic Amide‐Derived Non‐Biaryl Atropisomers as Highly Efficient Ligands in Silver‐Catalyzed Asymmetric Cycloaddition Reactions

The synthesis of a series of aromatic amide-derived non-biaryl atropisomers with a phosphine group and multiple stereogenic centers is reported. The novel phosphine ligands exhibit high diastereo- and enantioselectivities (up to >99:1 d.r., 95-99 % ee) as well as yields in the silver-catalyzed asymmetric [3+2] cycloaddition of aldiminoesters with nitroalkenes, which provides a highly enantioselective strategy for the synthesis of optically pure nitro-substituted pyrrolidines. In addition, the experimental results with regard to the carbon stereogenic center as well as the amide stereochemistry confirmed the potential of hemilabile atropisomers as chiral ligand in catalytic asymmetric [3+2] cycloaddition reaction.

An efficient and inexpensive catalyst system for the aza-Michael reactions of enones with carbamatesElectronic supplementary information (ESI) available: experimental. See http://www.rsc.org/suppdata/cc/b3/b307733k/

A new strategy which uses very cheap FeCl3 as an effective catalyst in the presence of Me3SiCl has been developed for the conjugate addition of enones and chalcone with unactivated weakly nucleophilic carbamates.

A novel and effective Ni complex catalyst system for the coupling reactions of carbon dioxide and epoxides

The coupling of carbon dioxide and mono-substituted terminal epoxides or cyclohexene oxide to form cyclic carbonates under a Ni complex catalyst system without using additional organic solvents was achieved in excellent selectivity and TOF.

Enantioselective copper-catalyzed azide-alkyne click cycloaddition to desymmetrization of maleimide-based bis(alkynes).

A copper catalyst system derived from TaoPhos and CuF2 was used successfully for catalytic asymmetric Huisgen [3+2] cycloaddition of azides and alkynes to give optically pure products containing succinimide- and triazole-substituted quaternary carbon stereogenic centers. The desired products were obtained in good yields (60-80 %) and 85:15 to >99:1 enantiomeric ratio (e.r.) in this click cycloaddition reaction.

Silicon-based Lewis acid assisted cinchona alkaloid catalysis: highly enantioselective aza-Michael reaction under solvent-free conditions.

The study showed that a combination of an achiral silicon-based Lewis acid and chiral Lewis base, such as iodotrimethylsilane (TMSI) and cinchonine, generated a highly enantioselective catalyst system under solvent-free conditions which gave aromatic β-amino ketones with up to >99% ee. Mechanistic studies demonstrate the enhanced asymmetric induction may be due to the combined and competitive activation of a carbonyl moiety of chalcone with cinchonine and the silicon-based Lewis acid in the aza-Michael reaction.