Highly Efficient Preparation of Chiral β ‐ or γ ‐Amino Alcohols and Pharmaceutical Intermediates by Ir/f‐Amphbinol‐Catalyzed Enantioselective Hydrogenation

Chapter IV.2 New Chiral Rh(I) and Ru(II) Complexes: Highly Efficient Catalysts for Homogeneous Asymmetric Hydrogenation

trans-RuCl(2)[(R)-xylbinap][(R)-daipen] or the S,S complex acts as an efficient catalyst for asymmetric hydrogenation of hetero-aromatic ketones. The hydrogenation proceeds with a substrate-to-catalyst molar ratio of 1000-40000 to give chiral alcohols in high ee and high yield. The enantioselectivity appears to be little affected by the properties of the hetero-aromatic ring. This method allows for asymmetric synthesis of duloxetine, an inhibitor of serotonin and norepinephrine uptake carriers.

Abstract

Chiral eta6-arene/N-tosylethylenediamine-Ru(II) complexes, known as excellent catalysts for asymmetric transfer hydrogenation of aromatic ketones in basic 2-propanol, can be used for asymmetric hydrogenation using H2 gas. Active catalysts are generated from RuCl[(S,S)-TsNCH(C6H5)CH(C6H5)NH2](eta6-p-cymene) in methanol, but not 2-propanol, or by combination of Ru[(S,S)-TsNCH(C6H5)CH(C6H5)NH](eta6-p-cymene) and CF3SO3H or other non-nucleophilic acids. This method allows, for the first time, asymmetric hydrogenation of simple ketones under acidic conditions. Hydrogenation of base-sensitive 4-chromanone and its derivatives with the S,S catalyst proceeds in methanol with a substrate-to-catalyst molar ratio of 1000-3000 (10 atm) to 7000 (100 atm), giving (S)-4-chromanols with 97% ee quantitatively. The reaction can be achieved even on a 2.4 kg scale. The mechanistic rationale for the catalytic efficiency is presented.

The combination of (pentamethylcyclopentadienyl)rhodium dichloride dimer [{RhCl2Cp*}2] and pseudodipeptide ligands, formed from N‐Boc protected amino acids and amino alcohols, resulted in efficient and selective catalysts for the asymmetric transfer hydrogenation of ketones in 2‐propanol. A number of different secondary alcohols was obtained in high yields and in excellent enantioselectivity using these in situ formed catalysts. Deuterium‐labeling experiments showed that the hydride transfer reaction occurs via the monohydridic route.

trans-RuCl2[(R)-xylbinap][(R)-daipen] or the S,S complex acts as an efficient catalyst for asymmetric hydrogenation of hetero-aromatic ketones. The hydrogenation proceeds with a substrate-to-catalyst molar ratio of 1000−40000 to give chiral alcohols in high ee and high yield. The enantioselectivity appears to be little affected by the properties of the hetero-aromatic ring. This method allows for asymmetric synthesis of duloxetine, an inhibitor of serotonin and norepinephrine uptake carriers.

Chiral alcohols are important building blocks in the pharmaceutical and fine chemical industries. The enantioselective reduction of prochiral ketones catalyzed by transition metal complexes, especially asymmetric transfer hydrogenation (ATH) and asymmetric hydrogenation (AH), is one of the most efficient and practical methods for producing chiral alcohols. In both academic laboratories and industrial operations, catalysts based on noble metals such as ruthenium, rhodium, and iridium dominated the asymmetric reduction of ketones. However, the limited availability, high price, and toxicity of these critical metals demand their replacement with abundant, nonprecious, and biocommon metals. In this respect, the reactions catalyzed by first-row transition metals, which are more abundant and benign, have attracted more and more attention. As one of the most abundant metals on earth, iron is inexpensive, environmentally benign, and of low toxicity, and as such it is a fascinating alternative to the precious metals for catalysis and sustainable chemical manufacturing. However, iron catalysts have been undeveloped compared to other transition metals. Compared with the examples of iron-catalyzed asymmetric reduction, cobalt- and nickel-catalyzed ATH and AH of ketones are even seldom reported. In early 2004, we reported the first ATH of ketones with catalysts generated in situ from iron cluster complex and chiral PNNP ligand. Since then, we have devoted ourselves to the development of ATH and AH of ketones with iron, cobalt, and nickel catalysts containing novel chiral aminophosphine ligands. In our study, the iron catalyst containing chiral aminophosphine ligands, which are expected to control the stereochemistry at the metal atom, restrict the number of possible diastereoisomers, and effectively transfer chiral information, are successful catalysts for enantioselective reduction of ketones. Among these novel chiral aminophosphine ligands, 22-membered macrocycle P2N4 exhibited extraordinary enantioselectivities when combined with iron(0) cluster Fe3(CO)12. A broad scope of ketones including aromatic, heteroaromatic, and β-ketoesters can be reduced smoothly with excellent enantioselectivities (up to 99% ee) approaching or exceeding those achievable with the noble metal catalysts. Notably, the chiral iron-based catalyst proved to be highly efficient for both ATH as well as AH of various ketones. Until now, such "universal" catalyst is very rare. Preliminary studies suggest that the AH reaction most likely involved iron particles as the active catalytic species. These research results point to a new direction in developing viable effective nonprecious metal catalysts for asymmetric reduction and probably for other asymmetric catalytic reactions as well.

When activated with base, the iron(II) complexes with tetradentate amine(imine)diphosphine ligands, (S,S)-trans-[FeCl(CO)(PAr2-NH-N-PAr′2)]BF4 (1: Ar, Ar′ = Ph; 2: Ar = Ph, Ar′ = 4-MeC6H4; 3: Ar, Ar′ = 3,5-Me2C6H3), are very active for the asymmetric transfer hydrogenation (ATH) of ketones in KOtBu/2-propanol. For ATH, better enantioselectivity, but lower catalytic activity, was observed in general when using catalyst precursors with the bulkier dixylylphosphino groups compared to those with diphenylphosphino groups. The complexes were much less active for the pressure hydrogenation of ketones, where 1 and 2 produced racemic product alcohols, while 3 yielded chiral alcohols with an enantiomeric excess of up to 70% (R) at turnover frequencies up to 80 h–1 and turnover numbers of 100 for a range of ketones at 50 °C and 20 atm H2. This is a rare example of asymmetric pressure hydrogenation using an iron complex. Unlike the case of ATH, there is no effect on the rate upon the addition of KOtBu beyond the 2 eq...

Comprehensive SummaryTransition metal‐catalyzed asymmetric hydrogenation is an efficient and direct synthetic method to access chiral compounds, which features simplicity, easy working‐up process, and high atomic economy. It typically relies on precious transition metal catalytic systems, including ruthenium, rhodium, iridium and palladium, which always face the difficulties of limited resources, high cost, and environmental contamination. Therefore, great efforts were made to apply earth‐abundant, low (non‐)toxic, and environmentally friendly transition metals, such as iron, cobalt, nickel and copper, to the asymmetric hydrogenation in the past decades, and some considerable breakthroughs have been obtained. In this review, we mainly summarized some recent research progress of nickel‐catalyzed asymmetric hydrogenation of prochiral unsaturated molecules, including olefins, imines and ketones. And continuous development of chiral nickel catalytic systems and the application of them into challenging asymmetric hydrogenation is prospected in the future. Key ScientistsTransition metal‐catalyzed asymmetric hydrogenation has been regarded as an important and direct approach to access chiral molecules. The first example of homogeneous catalytic asymmetric hydrogenation was developed by Knowles and Horner in 1968, respectively. In 1971, Kagan developed privileged chiral DIOP ligand for asymmetric hydrogenation. Halpern and Brown made deep studies on the Rh‐catalyzed asymmetric hydrogenation in 1977, respectively. Noyori developed a powerful and privileged chiral BINAP ligand in 1980. Owing to Knowles and Noyori's great contribution in the field of catalytic asymmetric hydrogenation, they were awarded the Nobel Prize in Chemistry in 2001. In 1984, Ohkubo developed pioneering earth‐abundant transition metal Ni‐catalyzed asymmetric hydrogenation of ethyl α‐methylcrotonate. A great many scientists made tremendous contribution to the development of chiral privileged ligands, such as, Bosnich, Kumada, Giongo, Takaya, Miyashima, Achiwa, Burk, Pflaltz, Chan, X. Zhang, Imamoto, Zhou, Genet, Sannicolo, Ding, Hoge, W. Zhang, Z. Zhang, Tang, these ligands owned wide application in the catalytic asymmetric hydrogenation. In addition, Zhou, Fan made deep investigation on the asymmetric hydrogenation of challenging aromatic heterocyclic compounds. Owing to the great importance of the development of the asymmetric (transfer) hydrogenation promoted by cheap transition metal catalytic systems, some researchers, such as Hamada, Gao, J. S. Zhou, Chirik, X. Zhang, Y.‐G. Zhou, W. Zhang, Lv, Dong, Fu, Deng, and Hou, made great efforts to the development of earth‐abundant nickel‐catalyzed asymmetric hydrogenation of prochiral unsaturated molecules, including olefins, imines and ketones. In addition, there are some other scientists that have also made great contribution to the development of catalytic asymmetric hydrogenation and Ni‐catalyzed asymmetric transformation, with too limited space to list all of them.

The Trost ligand, (1S,2S)‐1,2‐diaminocyclohexane‐N,N′‐bis(2′‐diphenylphosphinobenzoyl) (L), is reported for the first time as a ligand for the asymmetric hydrogenation (AH) of ketones. Ligand (S,S)‐L was screened in the presence of several metal salts and was found to form active catalysts if combined with ruthenium sources in the presence of hydrogen and a base. Reaction optimization was performed by screening different Ru sources, solvents, and bases. Under the optimized conditions, the complex formed by the combination of (S,S)‐L with RuCl3(H2O)x in the presence of Na2CO3 was able to promote the AH of several ketones at room temperature in good yields with up to 96 % ee. The reaction kinetics measured under the optimized conditions revealed the presence of a long induction period, during which the initially formed Ru species was transformed into the catalytically active complex by reaction with hydrogen. Remarkably, a ketone that is a precursor of the antiemetic drug aprepitant was hydrogenated in excellent yield with a good ee value.

Herein, a density functional theory (DFT) study was performed to investigate asymmetric ketone hydrogenation (AKH) catalyzed by Mn complexes, from the catalytic mechanism to the catalyst design. The calculated results indicated that the Mn(CO)2-PSiNSiP (A1, PSiNSiP = P(Ph)2Si(CH3)2NSi(CH3)2P(Ph)2) pincer complex has potential high catalytic activity for ketone hydrogenation. The Mn(CO)-LYB (B, LYB = P(Ph)2Si(CH3)2NSi(CH3)2P(Me)2) pincer complex was then designed to catalyze AKH with good stereoselectivity. The hydrogen transfer (HT) step is the chirality-determining step. To avoid the enantiomer of Mn(CO)2-LYB, which could eliminate the high stereoselectivity during AKH, novel Mn complexes with quadridentate ligands, such as Mn(CO)-LYC (C, LYC = P(CH3)2CH2Si(CH3)NSi(CH3)(Si(CH3)CH2P(CH3)2)CH2P(Ph)2) and Mn(CO)-LYD (D, LYD = P(CH3)2CH2Si(CH3)NSi(CH3)(Si(CH3)CH2P(CH3)2)CH2P(Cy)2), were designed to drive AKH with medium stereoselectivity. In order to increase the stereoselectivity of AKH, Mn(CO)-LYE (E, LYE = PH2CH2Si(CH3)NSi(CH3)(Si(CH3)CH2P(CH3)2)CH2P(Ph)2) and Mn(CO)-LYF (F, LYF = PH2CH2Si(CH3)NSi(CH3)(Si(CH3)CH2P(CH3)2)CH2P(Cy)2) were further designed and showed very good stereoselectivity, which is due to the lower deformation energy and stronger interactions between the ketone substrates and catalysts. This work may shed light on the design of cheap metal catalysts with a new ligand framework for the asymmetric hydrogenation (AH) of CX bonds (X = O, N).

BICHEPRu complexes, highly efficient catalysts for asymmetric hydrogenation of carbonyl compounds

A series of conjugated microporous polymers with chiral BINAP ligand built-in have been synthesized as efficient catalysts for asymmetric hydrogenation.

Optically active alcohols are important building blocks in the synthesis of fine chemicals, pharmaceuticals, agrochemicals, flavors and fragrances as well as functional materials (Arai & Ohkuma, 2011; Klingler, 2007). Furthermore, molecular hydrogen is without doubt the cleanest reducing agent, with complete atom efficiency. Therefore, the catalytic, asymmetric hydrogenation (AH) of prochiral ketones is the most practical and simplest method to access enantiomerically enriched secondary alcohols, on both the laboratory and industrial scales. Asymmetric transfer hydrogenation (ATH), on the other hand, represents an attractive alternative or complement to hydrogenation because it is easy to execute and a number of cheap chemicals can be used as hydrogen donors. For practical use and to address environmental issues a high catalyst activity (low loadings) and selectivity is preferable, as well as the employment of ‘’greener’’ solvents, mild operating conditions and recyclable catalyst systems. High turnover numbers (TONs) and turnover frequencies (TOFs), and satisfactory stereoand chemoselectivities are attainable only with a combination of welldefined metal catalysts and suitable reaction conditions. The reactivity and selectivity can be finely tuned by changing the bulkiness, chirality and electronic properties of the auxiliaries on the metal center of the catalyst.

Based on the ever-increasing demand for enantiomerically pure compounds, the development of efficient, atom-economical, and sustainable methods to produce chiral alcohols and amines is a major concern. Homogeneous asymmetric catalysis with transition-metal complexes including asymmetric hydrogenation (AH) and transfer hydrogenation (ATH) of ketones and imines through dynamic kinetic resolution (DKR) allowing the construction of up to three stereogenic centers is the main focus of the present short review, emphasizing the development of new catalytic systems combined to new classes of substrates and their applications as well.1 Introduction2 Asymmetric Hydrogenation via Dynamic Kinetic Resolution2.1 α-Substituted Ketones2.2 α-Substituted β-Keto Esters and Amides2.3 α-Substituted Esters2.4 Imine Derivatives3 Asymmetric Transfer Hydrogenation via Dynamic Kinetic Resolution3.1 α-Substituted Ketones3.2 α-Substituted β-Keto Esters, Amides, and Sulfonamides3.3 α,β-Disubstituted Cyclic Ketones3.4 β-Substituted Ketones3.5 Imine Derivatives4. Conclusion