Shou-Fei Zhu

Transition Metal-Catalyzed Enantioselective Hydrogenation of Enamines and Imines

Transition metal-catalyzed enantioselective hydrogenation of enamides and enamines is one of the most important methods for the preparation of optically active amines. This review describes the recent developments of highly efficient catalytic asymmetric hydrogenation of enamides, and enamines. It specifically focuses on the substrates because hydrogenation of enamides and enamines is highly dependent on the substrates although the chiral metal catalysts play a significant role.

Transition-Metal-Catalyzed Enantioselective Heteroatom–Hydrogen Bond Insertion Reactions

Carbon-heteroatom bonds (C-X) are ubiquitous and are among the most reactive components of organic compounds. Therefore investigations of the construction of C-X bonds are fundamental and vibrant fields in organic chemistry. Transition-metal-catalyzed heteroatom-hydrogen bond (X-H) insertions via a metal carbene or carbenoid intermediate represent one of the most efficient approaches to form C-X bonds. Because of the availability of substrates, neutral and mild reaction conditions, and high reactivity of these transformations, researchers have widely applied transition-metal-catalyzed X-H insertions in organic synthesis. Researchers have developed a variety of rhodium-catalyzed asymmetric C-H insertion reactions with high to excellent enantioselectivities for a wide range of substrates. However, at the time that we launched our research, very few highly enantioselective X-H insertions had been documented primarily because of a lack of efficient chiral catalysts and indistinct insertion mechanisms. In this Account, we describe our recent studies of copper- and iron-catalyzed asymmetric X-H insertion reactions by using chiral spiro-bisoxazoline and diimine ligands. The copper complexes of chiral spiro-bisoxazoline ligands proved to be highly enantioselective catalysts for N-H insertions of α-diazoesters into anilines, O-H insertions of α-diazoesters into phenols and water, O-H insertions of α-diazophosphonates into alcohols, and S-H insertions of α-diazoesters into mercaptans. The iron complexes of chiral spiro-bisoxazoline ligands afforded the O-H insertion of α-diazoesters into alcohols and water with unprecedented enantioselectivities. The copper complexes of chiral spiro-diimine ligands exhibited excellent reactivity and enantioselectivity in the Si-H insertion of α-diazoacetates into a wide range of silanes. These transition-metal-catalyzed X-H insertions have many potential applications in organic synthesis because the insertion products, including chiral α-aminoesters, α-hydroxyesters, α-hydroxyphosphonates, α-mercaptoesters, and α-silyl esters, are important building blocks for the synthesis of biologically active compounds. The electronic properties of α-diazoesters and anilines markedly affected the enantioselectivity of N-H insertion reaction, which supports a stepwise ylide insertion mechanism. A novel binuclear spiro copper complex was isolated and fully characterized using X-ray diffraction analysis and ESI-MS analysis. The positive nonlinear effect indicated that binuclear copper complexes were the catalytically active species. The 14-electron copper centers, trans coordination model, perfect C(2)-symmetric chiral pocket, and Cu-Cu interaction facilitate the performance of the chiral spiro catalysts in X-H insertion reactions.

Asymmetric NH Insertion Reaction Cooperatively Catalyzed by Rhodium and Chiral Spiro Phosphoric Acids

Nitrogen-containing organic compounds, such as a-amino acids and alkaloids, are important biologically active compounds, thus the development of efficient and enantioselective methods for the construction of carbon–nitrogen bonds is a fundamental goal in modern organic synthesis. Transitionmetal-catalyzed carbene insertion into N H bonds is one of the most efficient methods to construct carbon–nitrogen bonds and the development of asymmetric versions of the N H insertion reaction has attracted considerable attention. In initial studies, chiral dirhodium catalysts were tested in intramolecular and intermolecular N H insertion reactions, however, only low to modest enantioselectivities (< 50% ee) were achieved. Since these reports, other transition metals including copper and silver have been used as catalysts, and gave enantioselectivities up to 48% ee. Recently, we reported a highly enantioselective N H insertion reaction (up to 98% ee) using a copper complex with chiral spiro bisoxazoline ligands. Subsequently, two other types of chiral copper catalysts have been developed, one with a planar chiral bipyridine ligand and the other with a binolderivative ligand, and both of these catalysts give high enantioselectivities in N H insertion reactions. Although progress on copper-catalyzed asymmetric N H insertion reactions has been substantial, they still have serious limitations. For instance, all the copper-catalyzed N H insertion reactions require high catalyst loading (5– 10 mol%) for satisfactory yields and enantioselectivities, thus more-efficient chiral catalysts are highly desirable. Because the activity of dirhodium(II) catalysts is usually superior to that of copper catalysts in nonenantioselective N H insertion reactions, the possibility of using dirhodium catalysts to achieve highly enantioselective N H insertion reactions is an intriguing one. Recently, Saito et al. reported that dirhodium(II) carboxylates and cinchona alkaloids cooperatively catalyze the asymmetric N H insertion reactions of a-diazo-a-arylacetates with anilines. The combined catalysts exhibit excellent reactivity but only modest enantioselectivity (up to 71% ee). It is generally accepted that the rhodium-catalyzed N H insertion most likely proceeds via an ylide intermediate (Scheme 1A). We speculated that the subsequent protontransfer step could be facilitated by a chiral phosphoric acid species via a seven-membered-ring transition state, and that, consequently, chiral induction could be accomplished in this step (Scheme 1B). The groups of Yu and Platz have reported that either water or alcohols can assist proton transfer in O H insertion reactions, as indicated by density functional theory calculations and ultrafast time-resolved IR spectroscopy studies. These studies stimulated our interest in exploring asymmetric N H insertion in the presence of a proton-transfer catalyst. As part of our ongoing work on the development of asymmetric carbene insertion reactions, we report herein the asymmetric N H insertion reaction cooperatively catalyzed by dirhodium(II) carboxylates and chiral spiro phosphoric acids (SPAs). Excellent reactivity and high enantioselectivity (up to 95% ee) were achieved in the presence of as little as 0.1 mol% of catalyst. In our initial study, we carried out the insertion of methyl a-diazo-a-phenylacetate (3a) into the N H bond of tert-butyl carbamate (BocNH2) in CHCl3 at 25 8C using 1 mol% of [Rh2(OAc)4] and 10 mol% of chiral SPAs 1 as the catalysts (Table 1). SPAs 1 were prepared by a simple condensation of P(O)Cl3 with 6,6’-disubstituted-1,1’-spirobiindane-7,7’-diols 2, followed by hydrolysis (Scheme 2). Diols 2 were synthesized from spinol (1,1’-spirobiindane-7,7’-diol), as described previously. In the presence of (R)-1a, the N H insertion reaction proceeded within 5 minutes to afford the insertion product in excellent yield with 11% ee (Table 1, entry 2). Control experiments showed that the SPAs alone did not promote the insertion reaction. A range of SPAs with various substituents at the 6 and 6’ positions were evaluated (Table 1, entries 3–9). All the tested SPAs afforded high yields in the N H insertion reaction. SPA (R)-1h, which bears a 6,6’-di(naphth-2-yl) group, afforded the Scheme 1. Proposed mechanism for chiral phosphoric acid induced asymmetric N H insertion.

Enantioselective iron-catalysed O–H bond insertions

The ready availability, low price and environmentally benign character of iron mean that it is an ideal alternative to precious metals in catalysis. Recent growth in the number of iron-catalysed reactions reported reflects an increasing demand for sustainable chemistry. Only a limited number of chiral iron catalysts have been reported and these have, in general, proven less enantioselective than other transition-metal catalysts, thus limiting their appeal. Here, we report that iron complexes of spiro-bisoxazoline ligands are highly efficient catalysts for asymmetric O–H bond insertion reactions. These complexes catalyse insertions into the O–H bond of a wide variety of alcohols and even water, with exceptional enantioselectivities under mild reaction conditions. The selectivities surpass those obtained with other transition-metal catalysts. This study should inspire and encourage the use of iron instead of traditional precious metals in the development of greener catalysts for catalytic asymmetric synthesis. Iron is an abundant, low cost and environmentally benign metal. Here, iron complexes are shown to be the most effective catalysts for asymmetric O–H insertion reactions. These results should encourage the use of iron, rather than more traditional precious metals, in the development of greener organometallic catalysts for asymmetric transformations.

Iridium-Catalyzed Enantioselective Hydrogenation of α,β-Unsaturated Carboxylic Acids

A highly efficient iridium-catalyzed hydrogenation of alpha,beta-unsaturated carboxylic acids has been developed by using chiral spiro-phosphino-oxazoline ligands, affording alpha-substituted chiral carboxylic acids in exceptionally high enantioselectivities and reactivities.

Well-Defined Binuclear Chiral Spiro Copper Catalysts for Enantioselective N–H Insertion

An asymmetric N-H insertion of α-diazoesters with anilines catalyzed by well-defined copper complexes of chiral spiro bisoxazoline ligands was studied in detail. The copper-catalyzed asymmetric N-H insertion of a wide range of α-alkyl-α-diazoacetates with anilines was accomplished with excellent enantioselectivity (up to 98% ee) and provided an efficient method for the preparation of optically active α-amino acid derivatives. A correlation study of the electronic properties of the substrates with the enantioselectivity of the N-H insertion reaction supports a stepwise insertion mechanism, and the significant first-order kinetic isotope effect proves that the proton transfer is most likely the rate-limiting step. A binuclear chiral spiro copper catalyst having 14-electron copper centers, a trans coordination model, a perfect C(2)-symmetric chiral pocket, and significant Cu-Cu interaction was isolated and extensively studied. The novel structure of the binuclear chiral spiro copper catalyst leads to unique reactivity as well as enantioselectivity in the N-H insertion reaction.

Enantioselective Copper-Catalyzed Intramolecular O-H Insertion: An Efficient Approach to Chiral 2-Carboxy Cyclic Ethers

A copper-catalyzed asymmetric intramolecular O-H insertion of ω-hydroxy-α-diazoesters has been accomplished by using chiral spiro bisoxazoline ligands. This highly enantioselective intramolecular O-H insertion reaction provides an efficient approach to a variety of synthetically important chiral 2-carboxy cyclic ethers with different ring sizes as well as substitution patterns.

Nickel-catalyzed enantioselective alkylative coupling of alkynes and aldehydes: synthesis of chiral allylic alcohols with tetrasubstituted olefins.

A highly efficient nickel-catalyzed asymmetric alkylative coupling of alkynes, aldehydes, and dimethylzinc has been realized by using bulky spirobiindane phosphoramidite ligands, affording allylic alcohols with a tetrasubstituted olefin functionality in high yields, high regioselectivities, and excellent enantioselectivities.

Copper‐Catalyzed Highly Enantioselective Carbenoid Insertion into SiH Bonds

Chiral silanes are versatile intermediates for stereoselective transformations in organic synthesis. Transition-metal-catalyzed carbenoid insertion into Si H bonds provides a direct and efficient method for the synthesis of silane-containing compounds. The most popular catalysts used in Si H bondinsertion reactions have been copper(I) and rhodium(II) complexes. In 1996, Doyle and Moody reported the first asymmetric Si H bond-insertion reaction of a-diazophenylacetates, catalyzed by a chiral dirhodium(II) carboxylate and carboxamidate complexes with moderate enantioselectivities (up to 47% ee). A year later, Davies and co-workers achieved high enantioselectivities (up to 95 % ee) in the Si H bond insertion of a-vinyldiazoacetates catalyzed by rhodium(II) N-[p-(dodecylphenyl)-sulfonyl]prolinate. Recently, Ge and Corey reported a Si H bond insertion of an a-diazoketone with a N-nonafluorobutanesulfonylproline rhodium(II) catalyst to prepare 6-silyl-2-cyclohexenones with 94% ee. Several other chiral rhodium(II) catalysts have also been used in the Si H bond-insertion reaction with different diazo compounds, with no marked improvement in enantiocontrol. Although copper catalysts had been applied to Si H bond-insertion reactions before rhodium catalysts, the copper-catalyzed asymmetric Si H bond insertion has not been widely exploited. The only example of a coppercatalyzed asymmetric Si H bond-insertion reaction was reported by Panek and Jacobsen. Using a copper chiralSchiff-base complex as a catalyst, they obtained Si H bondinsertion products in high yields with up to 88 % ee, for the reaction of a-diazophenylacetate with trialkylsilanes. In previous studies, we accomplished highly enantioselective insertions of a-diazoesters into N H bonds of anilines and O H bonds of phenols and water, using copper complexes of chiral spiro-bisoxazoline ligands 1 (spirobox; Scheme 1). We report herein a copper/chiral spiro-diimine-complexcatalyzed asymmetric carbenoid insertion into the Si H bond, with high yields and excellent enantioselectivities (up to 99 % ee). The reaction of methyl a-diazophenylacetate (3a) and dimethylphenylsilane (4a) was performed in CH2Cl2 at 25 8C with a copper catalyst generated in situ from 5 mol% CuCl and 6 mol % ligand. Firstly, we developed and examined various chiral spiro-bisoxazoline ligands (1a–d) (Scheme 1). All copper complexes of ligands 1a–d catalyzed the reaction, affording the Si H insertion product methyl 2-dimethylphenylsilyl-2-phenylacetate (5a), in high yields, with the ligand (Ra,S,S)-1a being the most enantioselective (81% ee) (Table 1, entry 2). Comparison of enantioselectivities of ligands (Ra,S,S)-1a and (Sa,S,S)-1a clearly revealed that the combination of chiralities in the ligand (Ra,S,S)-1a is matched in terms of enantioselectivity (Table 1, entries 1 and 2). With ligand (Ra,S,S)-1a, the reaction conditions were then carefully optimized for maximum enantioselectivity. However, no additional positive effect was detected. To further improve the enantioselectivity of the Si H bond-insertion reaction, we turned our attention to new diimine ligands 2a–e, incorporating a chiral spirobiindane backbone. The chiral spiro diimines 2a–e (abbreviated as SIDIM) were prepared by a facile condensation of enantiopure (R)-1,1’-spirobiindane-7,7’-diamine (R)-6 with different aromatic aldehydes (Scheme 2, for detailed synthesis of ligands 2a–e, see the Supporting Information). Encouragingly, the SIDIM ligand (R)-2a had much higher activity and enantioselectivity than the spirobox ligands 1a–d in the Si H insertion reaction of methyl a-diazophenylacetate. The reaction was complete in 1 h at 0 8C, and the Si H insertion product was obtained in 95% yield with 93 % ee Scheme 1. Copper-catalyzed insertion of a-diazoesters 3 into Si H bonds. L = chiral spiro-bisoxazoline (spirobox) or spiro-diimine (SIDIM) ligand.

Enantioselective Hydrogenation of α-Aryloxy and α-Alkoxy α,β-Unsaturated Carboxylic Acids Catalyzed by Chiral Spiro Iridium/Phosphino-Oxazoline Complexes

The iridium-catalyzed highly enantioselective hydrogenation of alpha-aryloxy and alpha-alkoxy-substituted alpha,beta-unsaturated carboxylic acids was developed. By using chiral spiro phosphino-oxazoline ligands, the hydrogenation proceeded smoothly to produce various alpha-aryloxy- and alpha-alkoxy-substituted carboxylic acids with extremely high enantioselectivities (ee up to 99.8%) and reactivities (TON up to 10,000) under mild conditions. The hydrogenation of alpha-benzyloxy-substituted alpha,beta-unsaturated acids provided an efficient alternative for the synthesis of chiral alpha-hydroxy acids after an easy deprotection. A mechanism involving a catalytic cycle between Ir(I) and Ir(III) was proposed on the basis of the coordination model of the unsaturated acids with the iridium metal center. The rationality of the catalytic cycle, with an olefin dihydride complex as the key intermediate, was supported by the deuterium-labeling studies. The X-ray diffraction analysis of the single crystal of catalyst revealed that the rigid and sterically hindered chiral environment created by the spiro phosphino-oxazoline ligands is the essential factor that permits the catalyst to obtain excellent chiral discrimination. A chiral induction model was suggested on the basis of the catalyst structure and the product configuration.