Ming-Hua Xu

An advance on exploring N-tert-butanesulfinyl imines in asymmetric synthesis of chiral amines.

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 SmI(2)-mediated asymmetric syntheses of alpha,gamma-substituted gamma-butyrolactones, we found that simple homocoupling of chiral N- tert-butanesulfinyl imines in the presence of SmI(2) produced enantiopure vicinal C2-symmetric diamines in high yield. In addition, C2-unsymmetric chiral diamines are readily prepared through SmI(2)-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 SmI(2), 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.

Simple Branched Sulfur–Olefins as Chiral Ligands for Rh-Catalyzed Asymmetric Arylation of Cyclic Ketimines: Highly Enantioselective Construction of Tetrasubstituted Carbon Stereocenters

New, simple, sulfinamide-based branched olefin ligands have been developed and successfully used in Rh-catalyzed asymmetric arylations of cyclic ketimines, providing efficient and highly enantioselective access to valuable benzosultams and benzosulfamidates containing a stereogenic quaternary carbon center. This is the first example of applying a sulfur-olefin ligand in catalytic asymmetric addition of imines.

Remarkable salt effect on In-mediated allylation of N-tert-butanesulfinyl imines in aqueous media: highly practical asymmetric synthesis of chiral homoallylic amines and isoindolinones.

A highly practical and efficient asymmetric synthesis of chiral homoallylic amines by In-mediated allylation of chiral N-tert-butanesulfinyl imines in aqueous media at room temperature was developed. With 2-formylbenzoate imine substrates, the method allows the highly enantioselective achievement of a variety of pharmacologically important 3-allyl isoindolinone compounds.

Rhodium‐Catalyzed Asymmetric Conjugate Addition of Organoboronic Acids to Nitroalkenes Using Chiral Bicyclo[3.3.0] Diene Ligands

In recent years, the use of transition-metal-catalyzed reactions have been an important and general method in carbon carbon and carbon heteroatom bond-forming synthesis. Among them, the rhodium-catalyzed asymmetric conjugate addition of organoboronic acids to electron-deficient olefins, pioneered by Miyaura, Hayashi, and co-workers, has been established as one of the most powerful and convenient tools for the enantioselective synthesis of b-substituted functionalized compounds. In particular, excellent results were achieved in the addition to a,b-unsaturated carbonyl compounds. However, despite the great synthetic importance of nitro compounds, it is surprising that far fewer studies reported the efficient asymmetric addition of boronic acids to nitroalkenes, most likely because of the difficulty in controlling the reaction stereoselectivity. In fact, high enantioselectivities were only achieved by the Hayashi group in the asymmetric addition of organoboronic acids to a-substituted 1-nitroalkenes using a rhodium/binap (binap = 2,2-bis(diphenylphosphanyl)-1,1 -binaphthyl) catalyst. In other reports, low levels of enantiomeric enrichment (< 50% ee) were often observed with general 1-nitroalkene substrates that lack a substitutents. Therefore, the development of a capable catalyst system for efficient asymmetric boronic acid addition to nitroalkenes is highly desirable. Herein, we report our preliminary results on the rhodium-catalyzed asymmetric addition of organoboronic acids to nitroalkenes that lack a substitutents; high enantiocontrol is afforded using chiral bicyclo[3.3.0] diene ligands. In 2007, we reported our discovery of a new family of C2symmetric chiral diene ligands bearing a simple bicyclo[3.3.0] backbone; these ligands were successfully applied in the rhodium-catalyzed enantioselective arylation of N-tosylarylimines and the 1,4-addition of arylboronic acids to a,bunsaturated carbonyl compounds under mild conditions. Inspired by these successes, we wondered whether these rhodium/diene complexes could also act as effective catalysts for the asymmetric addition of boronic acids to nitroalkenes. In spite of the recent significant advances, there has been no report on the use of chiral diene ligands in this field. Our initial investigation was carried out by examining the reaction of nitrostyrene 2 with para-anisylboronic acid (3) in the presence of chiral diene ligand 1 a (3 mol%) under the reaction conditions previously reported for the arylation of N-tosylarylimines with arylboronic acids (Scheme 1). How-

Chiral diene as the ligand for the synthesis of axially chiral compounds via palladium-catalyzed Suzuki-Miyaura coupling reaction.

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.

Design of chiral sulfoxide-olefins as a new class of sulfur-based olefin ligands for asymmetric catalysis.

The design and development of a novel class of chiral sulfur-olefin hybrid ligands with high synthetic feasibility are described. These new sulfoxide-olefin ligands showed excellent catalytic activities and enantioselectivities (up to 98% ee) in rhodium-catalyzed asymmetric 1,4-addition reactions of aryl boronic acids to α,β-unsaturated carbonyl compounds.

Highly Practical Catalytic Asymmetric 1,4-Addition of Arylboronic Acids in Water Using New Hydrophilic Chiral Bicyclo[3.3.0] Diene Ligands

The first Rh-diene-catalyzed aqueous asymmetric 1,4-addition of alpha,beta-unsaturated carbonyl compounds with arylboronic acids has been realized. By using a hydrophilic bicyclo[3.3.0] diene ligand, the reactions can be performed successfully in neat water at room temperature to afford the corresponding products in good yields and with very high enantioselectivities for both cyclic and linear substrates.

Catalytic Enantioselective Synthesis of Chiral Phthalides by Efficient Reductive Cyclization of 2-Acylarylcarboxylates under Aqueous Transfer Hydrogenation Conditions

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.

Simple sulfur–olefins as new promising chiral ligands for asymmetric catalysis

Since 2003, the discovery of chiral dienes as steering ligands in asymmetric processes has opened the field of chiral chelating olefin catalysis. However, despite the impressive advances, the development of readily accessible and catalytically promising chiral olefins has been much less successful. In very recent years, chiral sulfur-containing olefins have emerged as a new exciting class of hybrid ligands for asymmetric catalysis. This article summarizes our efforts in developing extremely simple chiral sulfur-olefins as ligands for a variety of transition-metal-catalyzed asymmetric transformations, and the recent progress by other groups in the design and use of sulfinamide- or sulfoxide-based olefins in asymmetric catalysis.

One-Pot Synthesis of Chiral α-Methylene-γ-lactams with Excellent Diastereoselectivities and Enantioselectivities

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.