Jian-Hua Xie

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.

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)

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.

Chiral Iridium Catalysts Bearing Spiro Pyridine‐Aminophosphine Ligands Enable Highly Efficient Asymmetric Hydrogenation of β‐Aryl β‐Ketoesters

Optically active b-hydroxy acids and their derivatives are versatile chiral building blocks for many useful molecules, including pharmaceuticals and natural products. Catalytic asymmetric hydrogenation of b-ketoesters is an efficient and economically feasible method for preparing these important chiral compounds. Pioneered by Noyori and co-workers, the chiral ruthenium diphosphine complexes [RuX2(diphosphine)] (X = Cl or Br) and their analogues have become by far the most popular catalysts for this transformation. Many of them show excellent enantioselectivity [> 99% enantiomeric excess (ee)] and extraordinarily high activity (turnover number (TON) of up to 100000) for the hydrogenation of b-alkyl b-ketoesters. However, only a few of these complexes exhibit high enantioselectivity for the hydrogenation of b-aryl b-ketoesters. Zhang et al. reported that the ruthenium catalysts bearing the ligands xylyl-obinapo (3,3’-bis(3,5-dimethylphenyl)-2,2’-bis(diphenylphosphinoxy)-1,1’-binaphthyl) and C3*-TunePhos [6] give up to 99% ee for the hydrogenation of b-aryl b-ketoesters. Using ruthenium complexes of 4,4’-substituted binap ligands (binap = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl), Lin et al. obtained up to 99.8 % ee for the hydrogenation of a range of b-aryl b-ketoesters. The highest TON (10000) was achieved by Saito and co-workers in the asymmetric hydrogenation of methyl 3-oxo-3-phenylpropanoate. Note that chiral rhodium or iridium complexes, which efficiently catalyze olefin and imine hydrogenation, are seldom used for the asymmetric hydrogenation of b-ketoesters. Furthermore, chiral [RuCl2(diphosphine)(diamine)] complexes, which catalyze the hydrogenation of simple ketones extremely efficiently, are also inert for the hydrogenation of b-ketoesters. The major reason for the inertness may be that the strong base, such as KOtBu, that is required for activation of the [RuCl2(diphosphine)(diamine)] catalysts enolizes the b-ketoester substrates instead of activating the catalysts. Recently, we developed chiral iridium catalysts containing a chiral SpiroPAP ligand, and these catalysts show excellent enantioselectivity (up to 99.9% ee) and an extremely high TON (as high as 4550 000) for the hydrogenation of simple ketones. These Ir/SpiroPAP catalysts are likely to have a “metal–ligand bifunctional catalysis” mechanism, similar to the [RuCl2(diphosphine)(diamine)] catalysts. [12] The aromatic N H of the Ir/SpiroPAP catalysts is more acidic than the aliphatic N H of [RuCl2(diphosphine)(diamine)] catalysts (the proton resonances of the NH or NH2 group of the catalysts are as follows: Ir[IrH2((R)-1a)Cl]: d = 5.3 ppm (CDCl3), [RuCl2((R)-Tol-binap)((R,R)-dpen)] (dpen = 1,2diphenylethylenediamine): d = 3.3 and 3.5 ppm (C6D6) ), thus indicating that the Ir/SpiroPAP catalysts may be more easily activated with a relatively weak base such as the enolate salt of a b-ketoester. To confirm this possibility, we tested Ir/SpiroPAP catalysts for the hydrogenation of bketoesters and found that the catalysts were extremely efficient for hydrogenation of b-aryl b-ketoesters. Herein, we report that the Ir/SpiroPAP-catalyzed asymmetric hydrogenation of b-aryl b-ketoesters 2 provide the chiral b-hydroxy esters 3 with excellent enantioselectivity (up to 99.8% ee) and extremely high TONs (as high as 1230 000) under mild reaction conditions (8 atm H2 at room temperature; Scheme 1). The reaction conditions were optimized for the hydrogenation of ethyl 3-oxo-3-phenylpropanoate (2a). When the reaction was carried out at room temperature under 8 atm of

Total synthesis of (-)-galanthamine and (-)-lycoramine via catalytic asymmetric hydrogenation and intramolecular reductive Heck cyclization.

A synthetic strategy featuring efficient ruthenium-catalyzed asymmetric hydrogenation of racemic α-aryloxy cyclic ketone via dynamic kinetic resolution and palladium-catalyzed intramolecular reductive Heck cyclization has been developed for the asymmetric total synthesis of (-)-galanthamine (20.1%, 12 steps) and (-)-lycoramine (40.2%, 10 steps).

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.