A highly efficient three-component reaction of 2-formyl benzoic acid, ammonia and 4-hydroxycoumarin or indole in water was developed. With this highly environmentally benign protocol, a series of isoindolinone derivatives were efficiently produced in good to excellent yields.

Rhodium-catalyzed asymmetric arylation (RCAA) reactions provide one of the most straightforward and powerful ways to introduce aryl fragments in an enantioselective manner. The discovery of novel chiral ligands and catalytic systems is a major focus in generating optical chiralities for RCAA reactions. In the past decade, the chelating functionalities in ligands have been significantly expanded from traditional phosphorus to interesting diene, bissulfoxide, and their hybrids. Herein we highlight the research on these distinct families of chiral ligands and describe their applications in the RCAA of arylmetals to activated alkenes, aldehydes, ketones and imines, and RCAA-tandem reactions.Keywords: activated alkenes; bissulfoxide ligands; conjugate addition; diene ligands; hybrid ligands; imines; phosphorus ligands; rhodium-catalyzed asymmetric arylation; tandem reactions;

A highly enantioselective rhodium-catalyzed arylation of aliphatic N-tosylaldimines has been developed. The combination of chiral bicyclo[3.3.0]octadiene ligands, an active rhodium hydroxide complex, and neutral reaction conditions is the key to achieving high yield and enantioselectivity. The application of this method is demonstrated by the enantioselective synthesis of chiral 2-aryl pyrrolidines and piperidines in a one-pot procedure. Furthermore, excellent results are also obtained for the imine substrates with the more readily cleavable N-nosyl protecting group.

An efficient one-pot asymmetric synthesis of highly substituted γ-lactams containing α-methylene groups has been successfully developed. A wide range of γ-lactams could be obtained in high yields with excellent diastereomeric ratios of up to 99:1 in favor of trans isomers. In particular, excellent enantioselectivities of the two newly formed stereogenic centers with up to 99% ee were observed.

An extremely mild and practical approach for the preparation of enantiomerically enriched β-aryl substituted homoallylic amines bearing two adjacent stereogenic centers was realized by room temperature zinc-mediated highly stereoselective cinnamylation of N-sulfinyl imines.

The first palladium−diene-catalyzed asymmetric Suzuki−Miyaura coupling reaction has been achieved. A number of functionalized biaryls were obtained in high yields and in moderate to high enantioselectivities. The existence of an ortho-formyl group greatly improves the catalyst efficiency and permits further synthetic elaborations.

A new diamine ligand for asymmetric transfer hydrogenation (ATH) was discovered. The reductive cyclization of 2-acylarylcarboxylates was found to proceed highly stereoselectively by the new Ru complex-catalyzed ATH and subsequent in situ lactonization under aqueous conditions. It enables efficient access to a wide variety of 3-substituted phthalides in enantiomerically pure form.

Although catalytic asymmetric synthesis has undergone tremendous growth in the last 30 years, chiral auxiliary-aided asymmetric synthesis continues to attract considerable attention. Chiral N-tert-butanesulfinamide, as pioneered by Ellman and co-workers, is undoubtedly one of the most efficient auxiliaries developed to date; it allows the preparation, through simple conversion, of a diverse range of enantiopure amines, which are ubiquitous in natural products and biologically active molecules. Following on from our studies of the SmI2-mediated asymmetric syntheses of α,γ-substituted γ-butyrolactones, we found that simple homocoupling of chiral N-tert-butanesulfinyl imines in the presence of SmI2 produced enantiopure vicinal C2-symmetric diamines in high yield. In addition, C2-unsymmetric chiral diamines are readily prepared through SmI2-mediated cross-couplings of N-tert-butanesulfinyl imines and nitrones; these transformations represented the first successful examples of asymmetric cross-coupling between two different imine species. Subsequently, we discovered another useful reaction induced by SmI2, the efficient cross-coupling of N-tert-butanesulfinyl imines and aldehydes, which provides ready access to enantiopure anti-1,2-amino alcohols. The synthetic applicability of this reaction was demonstrated through its use in the facile total syntheses of (3R,4S)-statine, d-erythro-sphinganine, (+)-CP-99,994, and (+)-L-733,060. The Zn/In-mediated allylation of chiral N-tert-butanesulfinyl imines yields homoallylic amines. After pondering the reaction mechanism, we developed optimal reaction conditions for reversing the stereogenic outcome, thereby allowing the preparation of enantiopure homoallylic amines of either handedness from single enantiomers of the (R)- or (S)-sulfinyl imine. When a benzoyl-substituted allyl bromide is used for allylation, the reaction proceeds smoothly to give 2-vinyl-substituted anti-1,2-amino alcohols in high yields and diastereoselectivities, another simple method for preparing enantiopure amino alcohols. We employed these reactions in the syntheses of enantiopure allylglycine, 3-allyl-isoindolinones, and (−)-cytoxazone. Further studies led to the discovery that the allylations of N-tert-butanesulfinyl aldimines can be performed in water. The reactions described in this Account are among the simplest and most efficient synthetic methods available for preparing enantio-enriched diamines, amino alcohols, homoallylic amines, and other amine derivatives. These reactions are additionally attractive because of the ready availability of the starting materials, the simplicity of the reaction conditions, and the high degree of stereochemical control. Their applications in the total syntheses of several biologically interesting molecules illustrate the versatility of these transformations; we hope that they will stimulate the development of new synthetic methods.

A series of new (R)-1-(2-diarylmethylthio/sulfinyl)ethyl-piperidine-3-carboxylic acid hydrochlorides 5a–d/6a–d and (R)-1-(3-diarylmethylthio)propyl-piperidine-3-carboxylic acid hydrochlorides 5′a–d were synthesized and evaluated as γ-aminobutyric acid uptake inhibitors through cultured cell lines expressing mouse GAT1. Biological screening results demonstrated that the compounds 6a–d with diarylmethylsulfinyl ethyl side chain show more potent GAT1 inhibitory activities than 5a–d/5′a–d with diarylmethylthio ethyl/propyl moieties. Some of them, such as 6a, exhibited excellent inhibitions of [3H]-GABA uptake in cultured cells, which is 496-fold higher than (R)-nipecotic acid and 11.5 times less than tiagabine. The synthesis and structure–activity relationships are discussed.The synthesis of the novel uptake inhibitor 6a (IC50 = 0.92 μm) is reported.

A new category of β-amino alcohols with a bicyclo[3.3.0]octane scaffold has been synthesized and used in the direct asymmetric nitroaldol reaction (Henry reaction). Up to 74% ee was obtained with the addition of nitromethane to relatively bulky aldehydes.Graphic(1S,2S,5S,6S)-Bicyclo[3.3.0]octan-2,6-dione diepoxideC10H14O2[α]D20=+108.8 (c 2.15, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1S,2S,5S,6S)(1S,2S,5S,6S,1′R,1″R)-2,6-Bis(1-phenylethyl-amino-methyl)-bicyclo[3.3.0]octan-2,6-diolC16H36N2O2[α]D20=+56.5 (c 0.85, CHCl3)Source of chirality: enzymatic resolution, (R)-1-phenylethylamineAbsolute configuration: (1S,2S,5S,6S,1′R,1″R)(1S,2S,5S,6S,1′S,1″S)-2,6-Bis(1-phenylethyl-amino-methyl)-bicyclo[3.3.0]octan-2,6-diolC16H36N2O2[α]D20=−12.5 (c 3.20, CHCl3)Source of chirality: enzymatic resolution, (S)-1-phenylethylamineAbsolute configuration: (1S,2S,5S,6S,1′S,1″S)(1S,5S,6S)-Bicyclo[3.3.0]octan-2,6-dione 2-epoxide 6-ethylene ketalC11H16O3[α]D20=+63.6 (c 1.15, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1S,5S,6S)(1S,5S,6S,1′R)-6-Hydroxy-6-(1-phenylethyl-amino-methyl)-bicyclo[3.3.0]octan-2-one ethylene ketalC18H24NO3[α]D20=+70.7 (c 1.35, CHCl3)Source of chirality: enzymatic resolution, (R)-1-phenylethylamineAbsolute configuration:(1S,5S,6S,1′R)(1S,5S,6S,1′R)-6-Hydroxy-6-(1-phenylethyl-amino-methyl)-bicyclo[3.3.0]octan-2-oneC17H23NO2[α]D20=+146.5 (c 0.85, CHCl3)Source of chirality: enzymatic resolution, (R)-1-phenylethylamineAbsolute configuration: (1S,5S,6S,1′R)(1R,2R,5R,6R)-Bicyclo[3.3.0]octan-2,6-dione diepoxideC10H14O2[α]D20=−111.6 (c 1.20, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R,2R,5R,6R)(1R,2R,5R,6R,1′S,1″S)-2,6-Bis(1-phenylethyl-amino-methyl)-bicyclo[3.3.0]octan-2,6-diolC16H36N2O2[α]D20=−53.0 (c 1.55, CHCl3)Source of chirality: enzymatic resolution, (S)-1-phenylethylamineAbsolute configuration: (1R,2R,5R,6R,1′S,1″S)

A new recyclable PEG-bound bi-cinchona alkaloid ligand has been developed for homogeneous catalytic asymmetric aminohydroxylation; it can be easily recovered by precipitation and reused more than five times without any significant loss in its catalytic efficiency.A new efficient PEG-bound bi-cinchona alkaloid ligand for homogeneous aminohydroxylation; it can be easily recovered and reused more than five times without any significant loss in its catalytic efficiency.

Salidroside is a natural glycoside with pharmacological activities of resisting anoxia, microwave radiation and fatigue, improving oxygen lack, and postponing ageing. In this work, salidroside and other natural glucosides such as cinnamyl O-β-d-glucopyranoside and 4-methoxybenzyl O-β-d-glucopyranoside were efficiently synthesized via an environmentally benign and energy economic process. In the synthetic process, apple seed, easily available from discards of fruit processing factories, was employed as a natural and green catalyst. Moreover, all of the catalyst, solvent and excessive substrate was reused or recycled. The biocatalytic reaction was carried out in a clean and less toxic medium of aqueous tert-butanol and the glucoside produced was selectively removed from reaction mixture by alumina column adsorption, making excessive substrate (aglycon) recyclable for a repeated use in the next batch of reaction. For improvement of the biocatalyst stability, apple seed meal was further cross-linked by glutaraldehyde, yielding a net-like porous structure within which the dissociating proteins were immobilized, resulting in improved permeability of the biocatalyst. After the simple cross-linking treatment, the half-life of apple seed catalyst was significantly improved from 29 days to 51 days. The productivity of the bioreactor in the case of salidroside can reach ca. 1.9 g l−1 d−1, affording the product in up to 99.3% purity after refinement.

Various alkyl β-d-glucopyranosides were synthesized via a very simple procedure, by using Prunus dulcis (almond) kernel meal as an inexpensive biocatalyst. The P. dulcis (almond) meal is more robust than commercially available one and recyclable. Some popular fruits seed, including Prunus persica (peach), Prunus armeniaca (apricot), Malus pumila (apple), and Eriobotrya japonica (loquat), were tested as potential sources of the glucosidase in the form of meal. It was found that P. persica kernel meal and M. pumila seed meal not only had higher activity but also showed some complementary substrate specificities to that of almond β-glucosidase.

An extremely mild and practical approach for the preparation of enantiomerically enriched β-aryl substituted homoallylic amines bearing two adjacent stereogenic centers was realized by room temperature zinc-mediated highly stereoselective cinnamylation of N-sulfinyl imines.