Qi-Lin Zhou

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.

Monodentate Chiral Spiro Phosphoramidites: Efficient Ligands for Rhodium-Catalyzed Enantioselective Hydrogenation of Enamides**

Optically active -arylalkylamines are an important class of compounds that are widely used in organic and pharmaceutical synthesis, and much effort has been made to develop efficient asymmetric synthetic methods for them.[1] Asymmetric catalytic hydrogenation of enamides, initiated by Kagan et al. ,[2] provides a direct and convenient route to chiral amine derivatives. However, many well-known chiral diphosphane ligands, such as DIOP, BINAP, and CHIRAPHOS, which are extremely successful in the asymmetric hydrogenation of dehydroamino acid derivatives, do not give high enantioselectivity in the hydrogenation of enamides.[3, 4] A breakthrough was achieved by Burk et al.[4a] with the introduction of BPE and DuPHOS ligands, which gave excellent enantioselectivity in the Rh-catalyzed asymmetric hydrogenation of enamides. Lately, some other P ligands were also reported to be efficient in the hydrogenation of enamides.[4b, 5] However, all ligands that gave a high degree of enantiocontrol are bidentate. To our knowledge, no efficient chiral monodentate ligand has been reported for the asymmetric hydrogenation of enamides, although some monodentate P ligands were successfully used in the hydrogenation of dehydroamino acid derivatives.[6] Here we describe highly efficient monodentate chiral ligands 1 containing a 1,1 -spirobiindane backbone for the Rh-catalyzed asymmetric hydrogenation of -arylethenylamine derivatives [Eq. (1)] with excellent enantioselectivities (up to 99.7% ee). The chiral monodentate phosphoramidite ligands 1 (abbreviated SIPHOS) were conveniently synthesized in good yields from enantiomerically pure 1,1 -spirobiindane-7,7 -diol, which was easily prepared from 3-methoxybenzaldehyde by using the procedure described by Birman et al.[7] We demonstrated recently that the Rh complex of (S)-1a (R CH3) is a highly efficient catalyst in the asymmetric hydrogenation of dehydroamino acid and itaconic acid derivatives with up to 99.3% ee. Therefore, we were prompted to investigate the utility of this catalyst in the asymmetric hydrogenation of -phenylenamide 4a and an excellent enantioselectivity (up to 98.8% ee) was achieved. This showed, for the first time, that monodentate phosphorus ligands can be effective in the enantiocontrol of asymmetric hydrogenation of enamides. The results in Table 1 show that the enantioselectivity of the reaction was sensitive to the solvent used, and toluene is the solvent of choice. In contrast, the hydrogen pressure has a negligible influence on the enantioselectivity. For example, in the hydrogenation of 4a with Rh/(S)-1a catalyst in toluene, the ee values of product 5a at 25 C under 10 atm and 100 atm H2 were 96% and 96.2%, respectively (Table 1, entries 1 and 2). The investigation of catalyst loading showed that 0.5 mol% catalyst was sufficient to give a high enantioselectivity, while the ee value of the product dropped drastically with 0.1 mol% catalyst.

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 Asymmetric Hydrogenation of Cyclic Enamines

The first highly enantioselective iridium-catalyzed hydrogenation of cyclic enamines has been developed. This new reaction provided an efficient method for the synthesis of optically active cyclic tertiary amines including natural product crispine A.

An Additional Coordination Group Leads to Extremely Efficient Chiral Iridium Catalysts for Asymmetric Hydrogenation of Ketones

The production of enantiopure chiral compounds is important for pharmaceutical and agrochemical industries because enantiomers can exhibit distinct biological activities. Therefore, processes that directly produce the desired enantiomer are desirable. First reported by Knowles, Horner et al. in 1968, catalytic asymmetric hydrogenation of unsaturated compounds such as olefins, ketones, and imines is one of the most commonly used methods for producing enantiopure chiral compounds. Great progress has been made in this field, and many chiral catalysts are developed for a wide range of unsaturated substrates. It is noteworthy that some of these synthetic chiral catalysts, which are much smaller and simpler than enzymes, exhibit activities and selectivities comparable to those of enzymes: in some cases, one molecule of catalyst can produce millions of new molecules enantioselectively. For example, the diphosphine/diamine ruthenium catalyst reported by Noyori et al. and the iridium ferrocenyl catalyst Ir-(R,S)Xyliphos developed by a team from Novartis (Scheme 1)

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.

Enantioselective Rhodium‐Catalyzed Addition of Arylboronic Acids to α‐Ketoesters

The transition-metal-catalyzed asymmetric addition of organometallic reagents to carbonyl compounds to produce enantiomer-enriched secondary or tertiary alcohols is a powerful tool for the construction of carbon–carbon bonds. Many organometallic reagents have been successfully used in this addition reaction. However, a drawback for most organometallic reagents is their sensitivity to moisture and air, both of which impede the practical applications of these asymmetric carbon–carbon bond-forming reactions. As an exception, arylboronic acids are very stable to air and moisture. The catalytic enantioselective addition of arylboronic acids to carbonyl compounds has became a current focus for research, and a number of efficient chiral catalysts have been developed for the catalytic asymmetric addition of arylboronic acids to aldehydes and aldimines. However, the catalytic asymmetric addition of arylboronic acids to ketones, which are less active relative to aldehydes and aldimines, is more difficult, and only limited progress has been achieved. In 2006, Hayashi et al. reported the asymmetric addition of arylboronic acids to isatins, cyclic aketoamides, catalyzed by a rhodium/MeO-Mop (MeO-Mop = 2-methoxy-2’-diphenylphosphino-1,1’-binaphthyl) complex in high enantioselectivities (72–91 % ee). By using a chiral phosphoramidite ligand derived from H8-binol (binol = 2,2’dihydroxy-1,1’-binaphthyl), de Vries, Minnard, Feringa and et al. obtained 55 % ee in the same reaction. The chiral phosphoramidite ligand was also used in the asymmetric addition of arylboronic acids to trifluoromethyl ketones with good enantioselectivities (50–83 % ee). The intramolecular asymmetric addition of arylboronic acids to ketones catalyzed by a cationic palladium complex of binap (binap = 2,2’bis(diphenylphosphanyl)-1,1’-binaphthyl) to give cyclic tertiary alcohols in high enantioselectivities (53–96% ee) was reported by Lu et al. To the best of our knowledge, the catalytic enantioselective addition of arylboronic acids to aketoesters to provide tertiary a-hydroxyesters has not yet been reported. In the search for highly efficient methods to construct chiral 2-hydroxydiarylacetates, desirable chiral intermediates for the synthesis of antagonists of muscarinic receptors, we became interested in the enantioselective addition of arylboronic acids to the a-aryland a-alkenyl-a-ketoesters. The Rh/ShiP (ShiP = aryl(1,1’-spirobiindane-7,7’-diyl)phosphite) catalysts (1) recently developed by us were found to be

Highly efficient hydrogenation of biomass-derived levulinic acid to γ-valerolactone catalyzed by iridium pincer complexes

A highly efficient catalytic method for hydrogenation of biomass-derived levulinic acid has been developed and the iridium trihydride complexes of PNP pincer ligands were found to be extremely active catalysts for this transformation, providing γ-valerolactone in high yields with TONs as high as 71000.