**Meet the editor**

Iyad Karamé is a professor at the Faculty of Sciences at the Lebanese University in Beirut. he is a director of the organometallic catalysis and coordination chemistry team, in the Department of Chemistry. He got his PhD degree from Claude Bernard-Lyon 1 University in France in January 2004. He was an assistant professor and a researcher (ATER) at the Ecole Normale Supérieure de

Lyon, France, for one year (2004-2005). An Invited researcher at the Leibniz Institut für Katalyse in Rostock (2005-2006) and then a researcher at the Laboratory of Organometallic Chemistry of Surface, CPE-Lyon until 2008. His principal axis of research are organometallic catalysis and synthesis of chelating macrocyles for the complexation of hard metals.

Contents

**Preface IX** 

Chapter 1 **Asymmetric Hydrogenation 3**  Tsuneo Imamoto

Chapter 3 **Hydrogenation in the Vitamins** 

**An Overview 69** 

Chapter 4 **Homogeneous Chemoselective** 

Chapter 2 **Asymmetric Hydrogenation** 

**Section 1 Hydrogenation Reactions in Fine Organic Chemistry 1** 

**and Transfer Hydrogenation of Ketones 31** 

Werner Bonrath, Jonathan Medlock, Jan Schütz, Bettina Wüstenberg and Thomas Netscher

**Hydrogenation of Heterocyclic Compounds – The Case of 1,4 Addition on Conjugated C-C and C-O Double Bonds of Arylidene Tetramic Acids 91** 

John Markopoulos and Olga Igglessi-Markopoulou

**for Post-Functional Synthesis of Trifluoromethylphenyl Diazirine Derivatives for Photoaffinity Labeling 121** 

Chapter 5 **Selective Hydrogenation and Transfer Hydrogenation** 

Geoffery D. Holman and Yasumaru Hatanaka

**Transition Metal Complexes in Homogeneous** 

Domingo Liprandi, Edgardo Cagnola, Cecilia Lederhos,

Christos S. Karaiskos, Dimitris Matiadis,

Makoto Hashimoto, Yuta Murai,

Chapter 6 **Terminal and Non Terminal Alkynes Partial Hydrogenation Catalyzed by Some** *d<sup>8</sup>*

Juan Badano and Mónica Quiroga

**and Heterogeneous Systems 137** 

Bogdan Štefane and Franc Požgan

**and Fine Chemicals Industry –** 

## Contents


X Contents


#### **Section 2 Hydrogenation Reactions in Environmental Chemistry and Renewable Energy 185**


VI Contents

Chapter 7 **Kinetic Study of the Partial Hydrogenation of** 

**and Renewable Energy 185** 

**into Green Liquid Fuels 187** 

and Felipe de Jesús Hernández-Loyo

Wan-Hui Wang and Yuichiro Himeda

T.F. Sheshko and Yu. M. Serov

**Section 3 Special Topics in Hydrogenation 289** 

**on Semiconductor Particles 291** 

Chapter 13 **Hydrogenation of Fullerene C60: Material Design** 

Chapter 12 **Photocatalytic Hydrogenation** 

Ken Tokunaga

**Hydrodesulfurization Reactions 217** 

Chapter 8 **Hydroconversion of Triglycerides** 

Chapter 10 **Recent Advances in Transition** 

**Section 2 Hydrogenation Reactions in Environmental Chemistry** 

Rogelio Sotelo-Boyás, Fernando Trejo-Zárraga

Chapter 9 **Transition Metal Sulfide Catalysts for Petroleum Upgrading –** 

**Metal-Catalysed Homogeneous Hydrogenation of Carbon Dioxide in Aqueous Media 249** 

Chapter 11 **Hydrogenation of Carbon Oxides on Catalysts Bearing Fe, Co, Ni, and Mn Nanoparticles 269** 

Shigeru Kohtani, Eito Yoshioka and Hideto Miyabe

**of Organic Semiconductors by Computation 309** 

A. Infantes-Molina, A. Romero-Pérez, D. Eliche-Quesada, J. Mérida-Robles, A. Jiménez-López and E. Rodríguez- Castellón

**1-Heptyne over Ni and Pd Supported on Alumina 159**  M. Juliana Maccarrone, Gerardo C. Torres, Cecilia Lederhos, Carolina Betti, Juan M. Badano, Mónica Quiroga and Juan Yori

Preface

both homogeneous and heterogeneous catalysis.

new progress of the hydrogenation reactions.

trifluoromethlphenyl diarizine derivatives.

alumina is discussed in chapter seven.

special topics in hydrogenation.

The domain of catalytic hydrogenation continues to grow fast, reflecting the wide range of chemical applications that can be enhanced by the easy use of molecular hydrogen. The advances in characterization techniques and their application have improved our understanding of the catalytic processes and mechanisms occurring in

The aim of this volume, although not exhaustive, is to provide a general overview of

This volume comprises a series of various contributions, as reviews or original articles, treating heterogeneously and homogeneously catalyzed hydrogenation reactions. It is composed of three parts: hydrogenation reactions in fine organic chemistry, hydrogenation reactions in environmental chemistry and renewable energy, and

Among homogeneously catalyzed hydrogenation reactions, asymmetric hydrogenation is of major importance from an industrial viewpoint; the first two

Metal catalyzed hydrogenation belongs to the most important transformations in chemical industry and is a key technology for the manufacture of life science products. The third chapter introduces the role of homogeneous and heterogeneous catalytic hydrogenation reactions in processes for the production of vitamins, carotenoids, fragrance compounds and nutraceuticals. The fourth and fifth chapters discuses two examples of chemoselective hydrogenation: the 1,4-addition on conjugated C-C and C-O double bonds of arylidene tetramic acids and the selective hydrogenation of

Chapter six describes the partial hydrogenation of alkynes catalyzed by transitions metals catalysts. Kinetic study of this reaction catalyzed by supported Ni and Pd on

In the second part of this book, the hydroconversion of triglycerides into green liquid fuels is presented in chapter eight, while chapter nine reports transition metal sulfide catalyst for petroleum hydrodesulfurization reactions. Chapter ten focuses on recent

chapters of Part I review the asymmetric hydrogenation reactions.

## Preface

The domain of catalytic hydrogenation continues to grow fast, reflecting the wide range of chemical applications that can be enhanced by the easy use of molecular hydrogen. The advances in characterization techniques and their application have improved our understanding of the catalytic processes and mechanisms occurring in both homogeneous and heterogeneous catalysis.

The aim of this volume, although not exhaustive, is to provide a general overview of new progress of the hydrogenation reactions.

This volume comprises a series of various contributions, as reviews or original articles, treating heterogeneously and homogeneously catalyzed hydrogenation reactions. It is composed of three parts: hydrogenation reactions in fine organic chemistry, hydrogenation reactions in environmental chemistry and renewable energy, and special topics in hydrogenation.

Among homogeneously catalyzed hydrogenation reactions, asymmetric hydrogenation is of major importance from an industrial viewpoint; the first two chapters of Part I review the asymmetric hydrogenation reactions.

Metal catalyzed hydrogenation belongs to the most important transformations in chemical industry and is a key technology for the manufacture of life science products. The third chapter introduces the role of homogeneous and heterogeneous catalytic hydrogenation reactions in processes for the production of vitamins, carotenoids, fragrance compounds and nutraceuticals. The fourth and fifth chapters discuses two examples of chemoselective hydrogenation: the 1,4-addition on conjugated C-C and C-O double bonds of arylidene tetramic acids and the selective hydrogenation of trifluoromethlphenyl diarizine derivatives.

Chapter six describes the partial hydrogenation of alkynes catalyzed by transitions metals catalysts. Kinetic study of this reaction catalyzed by supported Ni and Pd on alumina is discussed in chapter seven.

In the second part of this book, the hydroconversion of triglycerides into green liquid fuels is presented in chapter eight, while chapter nine reports transition metal sulfide catalyst for petroleum hydrodesulfurization reactions. Chapter ten focuses on recent advances in transition metal-catalyzed homogeneous hydrogenation of carbon dioxide in aqueous media. A work on hydrogenation of carbon oxides catalysed by nanoparticles constitutes chapter eleven.

The last and third part consists of two chapters. Chapter twelve treats photocatalytic hydrogenation on semiconducteur particles. In the last and thirteenth chapter, effect of hydrogenation on hole-transport properties of C60 is theoretically estimated and is systematically discussed by the density functional theory (DFT) calculation, taking hydrogenated fullerenes C60H*<sup>n</sup>* as examples.

This volume represents a good measure of high quality research; nevertheless, some subjects in the area of hydrogenation are not included and we look forward in the near future to complete this work by editing others volumes.

We hope you will find this book enjoyable and illuminating. Any comments you may have are of course very welcome.

We would like to take this opportunity to thank all contributors for their chapters. Their cooperation in adhering to the, at times tight, deadlines is very much appreciated. Finally, we wish to express our gratitude to the staff at INTECH for their kind assistance in bringing this book to fruition.

> **Iyad Karamé** Lebanese University Beirut

X Preface

nanoparticles constitutes chapter eleven.

hydrogenated fullerenes C60H*<sup>n</sup>* as examples.

have are of course very welcome.

future to complete this work by editing others volumes.

kind assistance in bringing this book to fruition.

advances in transition metal-catalyzed homogeneous hydrogenation of carbon dioxide in aqueous media. A work on hydrogenation of carbon oxides catalysed by

The last and third part consists of two chapters. Chapter twelve treats photocatalytic hydrogenation on semiconducteur particles. In the last and thirteenth chapter, effect of hydrogenation on hole-transport properties of C60 is theoretically estimated and is systematically discussed by the density functional theory (DFT) calculation, taking

This volume represents a good measure of high quality research; nevertheless, some subjects in the area of hydrogenation are not included and we look forward in the near

We hope you will find this book enjoyable and illuminating. Any comments you may

We would like to take this opportunity to thank all contributors for their chapters. Their cooperation in adhering to the, at times tight, deadlines is very much appreciated. Finally, we wish to express our gratitude to the staff at INTECH for their

**Iyad Karamé**

Beirut

Lebanese University

**Section 1** 

**Hydrogenation Reactions** 

**in Fine Organic Chemistry** 

**Hydrogenation Reactions in Fine Organic Chemistry** 

**Chapter 1** 

© 2012 Imamoto, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 Imamoto, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

N

<sup>H</sup> CO2H <sup>+</sup> H2

Me Ph Ph

NH2 <sup>H</sup>

30–70% ee

**Scheme 1.** Asymmetric hydrogenation of an azalactone catalyzed by silk-fibroin-supported palladium

O

Pd/Silk-fibroin HCl/H2O

**Asymmetric Hydrogenation** 

Additional information is available at the end of the chapter

enantiopure or enantiomerically enriched form.

chapter focuses on homogeneous asymmetric hydrogenation.

Me O

The asymmetric hydrogenation of prochiral unsaturated compounds, such as alkenes, ketones, and imines, is one of the most efficient and straightforward methods for the preparation of optically active compounds. This method uses dihydrogen and small amounts of chiral transition metal complexes and is now recognized as economical, operationally simple, and environmentally friendly. It is frequently used in both academia and industry for the synthesis of chiral amino acids, amines, alcohols, and alkanes in an

Asymmetric hydrogenation can basically be classified into two categories, homogeneous and heterogeneous hydrogenation. Heterogeneous hydrogenation is technically simple and has a longer history than homogeneous hydrogenation. In 1956, Akahori et al. reported the asymmetric hydrogenation of azalactones in the presence of silk-fibroin-supported palladium (Scheme 1) [1]. This pioneering work was later extended to the hydrogenation of prochiral ketones using a Raney nickel or platinum catalyst that was modified by chiral auxiliaries, such as tartaric acid or cinchona alkaloids. However, prepared heterogeneous catalysts have as yet provided moderate to good enantioselectivities but not very high selectivities, so the method is not useful in practice except in some limited cases. In sharp contrast, homogeneous hydrogenation has developed enormously in the past four decades, and has become the useful methodology in modern science and technology. Therefore, this

Tsuneo Imamoto

**1. Introduction** 

http://dx.doi.org/10.5772/48584

O N

Ph

O

### **Chapter 1**

## **Asymmetric Hydrogenation**

### Tsuneo Imamoto

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/48584

### **1. Introduction**

The asymmetric hydrogenation of prochiral unsaturated compounds, such as alkenes, ketones, and imines, is one of the most efficient and straightforward methods for the preparation of optically active compounds. This method uses dihydrogen and small amounts of chiral transition metal complexes and is now recognized as economical, operationally simple, and environmentally friendly. It is frequently used in both academia and industry for the synthesis of chiral amino acids, amines, alcohols, and alkanes in an enantiopure or enantiomerically enriched form.

Asymmetric hydrogenation can basically be classified into two categories, homogeneous and heterogeneous hydrogenation. Heterogeneous hydrogenation is technically simple and has a longer history than homogeneous hydrogenation. In 1956, Akahori et al. reported the asymmetric hydrogenation of azalactones in the presence of silk-fibroin-supported palladium (Scheme 1) [1]. This pioneering work was later extended to the hydrogenation of prochiral ketones using a Raney nickel or platinum catalyst that was modified by chiral auxiliaries, such as tartaric acid or cinchona alkaloids. However, prepared heterogeneous catalysts have as yet provided moderate to good enantioselectivities but not very high selectivities, so the method is not useful in practice except in some limited cases. In sharp contrast, homogeneous hydrogenation has developed enormously in the past four decades, and has become the useful methodology in modern science and technology. Therefore, this chapter focuses on homogeneous asymmetric hydrogenation.

**Scheme 1.** Asymmetric hydrogenation of an azalactone catalyzed by silk-fibroin-supported palladium

© 2012 Imamoto, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 Imamoto, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Homogeneous asymmetric hydrogenation was first reported independently by Knowles and Horner in 1968 [2,3]. They replaced the triphenylphosphine of the Wilkinson catalyst (RhCl(PPh3)3) with optically active methylphenyl(*n*-propyl)phosphine and examined its catalytic performance in the hydrogenation of prochiral alkenes. The optical yields were low, but catalytic asymmetric hydrogenation was shown experimentally to have occurred unequivocally in the homogeneous system (Scheme 2).

Asymmetric Hydrogenation 5

compounds with exceedingly high enantioselectivity. The method based on the Ru-BINAP catalyst system has allowed the use of asymmetric hydrogenation in the industrial production of many useful optically active compounds such as pharmaceutical ingredients,

In 1993, the research groups of Pfaltz, Helmchen, and Williams independently reported a P,N-ligand phosphinooxazoline (PHOX) [10–12]. The utility of this ligand in asymmetric hydrogenation was demonstrated by Pfaltz et al. using its iridium complex. They showed that largely unfunctionalized alkenes were enantioselectively hydrogenated by Ir-PHOX and related catalysts [13,14]. Their studies significantly expanded the scope of asymmetric hydrogenation and offered a new tool for the efficient production of chiral building blocks. In contrast, homogeneous asymmetric hydrogenation using chiral complexes of early transition metals or less-expensive late transition metals has also been investigated. Some success has been achieved in the hydrogenation of alkenes and imines with chiral catalysts containing titanium, zirconium, lanthanides, or iron. However, because of the length limitation on this chapter, rhodium-, ruthenium-, and iridium-catalyzed asymmetric

Based on extensive experiments, computations, and theoretical considerations, asymmetric hydrogenation is now highly advanced, so any broad overview of this area is difficult. Fortunately, many exhaustive reviews have been published, together with excellent accounts of asymmetric hydrogenation. The author hopes that this chapter, together with

The design and synthesis of new chiral phosphine ligands are crucial for the development of transition-metal-catalyzed asymmetric catalysis. Over the past four decades, thousands of chiral phosphine ligands have been synthesized and their catalytic efficiencies evaluated [19–21]. Figure 1 illustrates representative phosphine ligands, including P,N-hybrid ligands, that have attracted much attention because of their novelty, conceptual importance, and/or

Most of them are *C*2-symmetric bidentate diphosphine ligands. In the hydrogenation process based on *C*2-ligands, the number of structures that the catalyst–substrate complexes can adopt is reduced to half compared with those formed from *C*1-symmetric catalysts, and consequently, *C*2-symmetric ligands achieve higher enantioselectivity than *C*1-symmetric ligands. Conversely, many *C*1-symmetric ligands, including JosiPhos, Trichickenfootphos,

DIPAMP is a typical *C*2-symmetric and P-chiral (P-stereogenic) diphosphine ligand. This ligand played an outstanding role in the early stages of the history of asymmetric hydrogenation. Nevertheless, little attention had been paid to this class of P-chiral phosphine ligands for more than 15 years, mainly because of the difficulties inherent in their synthesis and apprehension about possible stereomutation at P-stereogenic centers. The author's

the review articles [15–18], will provide good references for the process.

**2. Chiral Phosphine Ligands for Asymmetric Hydrogenation** 

and PHOX, display superior enantioselectivity, depending on the reaction.

agrochemicals, and flavors [9].

hydrogenation will be described here.

practical utility.

**Scheme 2.** First example of homogeneous asymmetric hydrogenation

In 1971, Kagan et al. synthesized a chelating diphosphine ligand with two phenyl groups on each of the two phosphorus atoms [4]. The ligand, 4,5-bis[(diphenylphosphino)methyl]-2,2 dimethyl-1,3-dioxolane (DIOP), is the first example of a *C*2-symmetric phosphine ligand. Its high capacity for asymmetric induction, up to 88%, was demonstrated in the hydrogenation of -dehydroamino acids and enamides [5], and these excellent results stimulated the design and synthesis of many other *C*2-symmetric phosphine ligands. The most notable ligand reported in the period up to 1979 was 1,2-bis(*o*-anisylphenylphosphino)ethane (DIPAMP) developed by Knowles (Nobel laureate in 2001) et al. at Monsanto in 1975, which provided very high enantioselectivity values up to 96% in the hydrogenation of -dehydroamino acids [6]. The methodology was used to produce (*S*)-3-(3,4-dihydroxyphenyl)alanine (L-DOPA), which is useful in the treatment of Parkinson's disease. This was the first example of asymmetric catalysis on an industrial scale (Scheme 3) [7].

**Scheme 3.** The Monsanto process for the production of L-DOPA

Another landmark ligand was 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), developed by Noyori (Nobel laureate in 2001) et al. in 1980 [8]. The appearance of BINAP heralded marked advances in asymmetric hydrogenation and other transition-metalcatalyzed asymmetric catalyses. The methodology developed by Noyori et al. using BINAP resolved longstanding problems, such as the limited applicability of the method, which was attributed to substrate specificity and unsatisfactory catalytic activity. Thus, a wide range of prochiral alkenes and carbonyl substrates, including simple ketones, were subjected to hydrogenation with much lower catalyst loadings, to generate the corresponding saturated compounds with exceedingly high enantioselectivity. The method based on the Ru-BINAP catalyst system has allowed the use of asymmetric hydrogenation in the industrial production of many useful optically active compounds such as pharmaceutical ingredients, agrochemicals, and flavors [9].

4 Hydrogenation

Homogeneous asymmetric hydrogenation was first reported independently by Knowles and Horner in 1968 [2,3]. They replaced the triphenylphosphine of the Wilkinson catalyst (RhCl(PPh3)3) with optically active methylphenyl(*n*-propyl)phosphine and examined its catalytic performance in the hydrogenation of prochiral alkenes. The optical yields were low, but catalytic asymmetric hydrogenation was shown experimentally to have occurred

> P *n*-C3H7 Me Ph

In 1971, Kagan et al. synthesized a chelating diphosphine ligand with two phenyl groups on each of the two phosphorus atoms [4]. The ligand, 4,5-bis[(diphenylphosphino)methyl]-2,2 dimethyl-1,3-dioxolane (DIOP), is the first example of a *C*2-symmetric phosphine ligand. Its high capacity for asymmetric induction, up to 88%, was demonstrated in the hydrogenation of -dehydroamino acids and enamides [5], and these excellent results stimulated the design and synthesis of many other *C*2-symmetric phosphine ligands. The most notable ligand reported in the period up to 1979 was 1,2-bis(*o*-anisylphenylphosphino)ethane (DIPAMP) developed by Knowles (Nobel laureate in 2001) et al. at Monsanto in 1975, which provided very high enantioselectivity values up to 96% in the hydrogenation of -dehydroamino acids [6]. The methodology was used to produce (*S*)-3-(3,4-dihydroxyphenyl)alanine (L-DOPA), which is useful in the treatment of Parkinson's disease. This was the first example

Rh

R = Et 8% ee R = CO2H 15% ee

\* Ph Me H R

Another landmark ligand was 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), developed by Noyori (Nobel laureate in 2001) et al. in 1980 [8]. The appearance of BINAP heralded marked advances in asymmetric hydrogenation and other transition-metalcatalyzed asymmetric catalyses. The methodology developed by Noyori et al. using BINAP resolved longstanding problems, such as the limited applicability of the method, which was attributed to substrate specificity and unsatisfactory catalytic activity. Thus, a wide range of prochiral alkenes and carbonyl substrates, including simple ketones, were subjected to hydrogenation with much lower catalyst loadings, to generate the corresponding saturated

AcO

OMe

after recrystallization)

NHAc CO2H

96% ee (100% ee L-DOPA

H3O+

HO

OH

NH2

CO2H

unequivocally in the homogeneous system (Scheme 2).

R

Ph

**Scheme 2.** First example of homogeneous asymmetric hydrogenation

+ H2

of asymmetric catalysis on an industrial scale (Scheme 3) [7].

H2 (3 atm) [Rh((*R*,*R*)-dipamp) (cod)]BF4

98% S/C >10000

**Scheme 3.** The Monsanto process for the production of L-DOPA

NHAc CO2H

AcO

OMe

In 1993, the research groups of Pfaltz, Helmchen, and Williams independently reported a P,N-ligand phosphinooxazoline (PHOX) [10–12]. The utility of this ligand in asymmetric hydrogenation was demonstrated by Pfaltz et al. using its iridium complex. They showed that largely unfunctionalized alkenes were enantioselectively hydrogenated by Ir-PHOX and related catalysts [13,14]. Their studies significantly expanded the scope of asymmetric hydrogenation and offered a new tool for the efficient production of chiral building blocks.

In contrast, homogeneous asymmetric hydrogenation using chiral complexes of early transition metals or less-expensive late transition metals has also been investigated. Some success has been achieved in the hydrogenation of alkenes and imines with chiral catalysts containing titanium, zirconium, lanthanides, or iron. However, because of the length limitation on this chapter, rhodium-, ruthenium-, and iridium-catalyzed asymmetric hydrogenation will be described here.

Based on extensive experiments, computations, and theoretical considerations, asymmetric hydrogenation is now highly advanced, so any broad overview of this area is difficult. Fortunately, many exhaustive reviews have been published, together with excellent accounts of asymmetric hydrogenation. The author hopes that this chapter, together with the review articles [15–18], will provide good references for the process.

### **2. Chiral Phosphine Ligands for Asymmetric Hydrogenation**

The design and synthesis of new chiral phosphine ligands are crucial for the development of transition-metal-catalyzed asymmetric catalysis. Over the past four decades, thousands of chiral phosphine ligands have been synthesized and their catalytic efficiencies evaluated [19–21]. Figure 1 illustrates representative phosphine ligands, including P,N-hybrid ligands, that have attracted much attention because of their novelty, conceptual importance, and/or practical utility.

Most of them are *C*2-symmetric bidentate diphosphine ligands. In the hydrogenation process based on *C*2-ligands, the number of structures that the catalyst–substrate complexes can adopt is reduced to half compared with those formed from *C*1-symmetric catalysts, and consequently, *C*2-symmetric ligands achieve higher enantioselectivity than *C*1-symmetric ligands. Conversely, many *C*1-symmetric ligands, including JosiPhos, Trichickenfootphos, and PHOX, display superior enantioselectivity, depending on the reaction.

DIPAMP is a typical *C*2-symmetric and P-chiral (P-stereogenic) diphosphine ligand. This ligand played an outstanding role in the early stages of the history of asymmetric hydrogenation. Nevertheless, little attention had been paid to this class of P-chiral phosphine ligands for more than 15 years, mainly because of the difficulties inherent in their synthesis and apprehension about possible stereomutation at P-stereogenic centers. The author's

Asymmetric Hydrogenation 7

research group has developed efficient methods for the preparation of P-chiral phosphine ligands using phosphine–boranes as the key intermediates and prepared (*R*,*R*)-1,2-bis(*tert*butylphenylphosphino)ethane in 1990, (*S*,*S*)-1,2-bis(*tert*-butylmethylphosphino)ethane (BisP\*) in 1998, and (*R*,*R*)-bis(*tert*-butylmethylphosphino)methane (MiniPHOS) in 1999 [22–24]. Of these ligands, BisP\* and MiniPHOS display enantioselectivities higher than those of DIPAMP in Rh-catalyzed asymmetric hydrogenation. These findings triggered the synthesis of structurally analogous but more rigid P-chiral phosphine ligands, and many highly efficient and practically useful ligands have since been reported (TangPhos, Trichickenfootphos,

As mentioned above, many chiral phosphine ligands have been shown to exhibit excellent enantioselectivity and some outstanding ligands have been used in the industrial production of useful optically active compounds. However, there are no "omnipotent" ligands, and so the development of more efficient, operationally convenient, and widely applicable chiral

Rhodium-catalyzed hydrogenation is well suited to the enantioselective reduction of - and β-dehydroamino acid derivatives and enamides. Thus, chiral - and β-amino acids and secondary amine derivatives can be obtained in an enantiomerically pure or enriched form by the hydrogenation of amino-functionalized alkenes (Equations 1–3). The catalytic efficiency and enantioselectivity are largely dependent on the chiral ligands and substrates used. In general, electron-rich and structurally rigid ligands, such as DuPhos, DuanPhos, ZhangPhos, QuinoxP\*, and BenzP\*, provide the corresponding products in high to almostperfect enantioselectivity. Di- or tri-substituted alkenes are readily hydrogenated, but tetrasubstituted alkenes require higher hydrogen pressure, higher catalyst loading, and/or a

Rhodium catalysts are also used for the hydrogenation of itaconic acid derivatives, enol esters, and ethenephosphonates (Equations 4–6). As in the hydrogenation of dehydroamino acids and enamides, the oxygen functional groups capable of coordination to the rhodium atom play an important role in accelerating the reaction, as well as in the enantioselection.

Since the discovery of rhodium-catalyzed asymmetric hydrogenation, the reaction mechanism, including the catalytic cycle and the origin of the enantioselection process, has been studied extensively. Early studies using cationic rhodium complexes with *C*2 symmetric diphosphine ligands with two diaryl substituents at each phosphorus atom led to the so-called "unsaturated mechanism". This mechanism, proposed by Halpern and Brown,

phosphine ligands is still a vital research topic in the field of asymmetric catalysis.

**3. Rhodium-catalyzed Asymmetric Hydrogenation** 

higher reaction temperature to facilitate the hydrogenation reaction.

is based on the following experimental facts and considerations [25–28].

DuanPhos, QuinoxP\*, ZhangPhos, BenzP\*, etc.).

**3.1. General scope** 

**3.2. Reaction mechanism** 

**Figure 1.** Representative chiral phosphine ligands

research group has developed efficient methods for the preparation of P-chiral phosphine ligands using phosphine–boranes as the key intermediates and prepared (*R*,*R*)-1,2-bis(*tert*butylphenylphosphino)ethane in 1990, (*S*,*S*)-1,2-bis(*tert*-butylmethylphosphino)ethane (BisP\*) in 1998, and (*R*,*R*)-bis(*tert*-butylmethylphosphino)methane (MiniPHOS) in 1999 [22–24]. Of these ligands, BisP\* and MiniPHOS display enantioselectivities higher than those of DIPAMP in Rh-catalyzed asymmetric hydrogenation. These findings triggered the synthesis of structurally analogous but more rigid P-chiral phosphine ligands, and many highly efficient and practically useful ligands have since been reported (TangPhos, Trichickenfootphos, DuanPhos, QuinoxP\*, ZhangPhos, BenzP\*, etc.).

As mentioned above, many chiral phosphine ligands have been shown to exhibit excellent enantioselectivity and some outstanding ligands have been used in the industrial production of useful optically active compounds. However, there are no "omnipotent" ligands, and so the development of more efficient, operationally convenient, and widely applicable chiral phosphine ligands is still a vital research topic in the field of asymmetric catalysis.

### **3. Rhodium-catalyzed Asymmetric Hydrogenation**

### **3.1. General scope**

6 Hydrogenation

**Figure 1.** Representative chiral phosphine ligands

Rhodium-catalyzed hydrogenation is well suited to the enantioselective reduction of - and β-dehydroamino acid derivatives and enamides. Thus, chiral - and β-amino acids and secondary amine derivatives can be obtained in an enantiomerically pure or enriched form by the hydrogenation of amino-functionalized alkenes (Equations 1–3). The catalytic efficiency and enantioselectivity are largely dependent on the chiral ligands and substrates used. In general, electron-rich and structurally rigid ligands, such as DuPhos, DuanPhos, ZhangPhos, QuinoxP\*, and BenzP\*, provide the corresponding products in high to almostperfect enantioselectivity. Di- or tri-substituted alkenes are readily hydrogenated, but tetrasubstituted alkenes require higher hydrogen pressure, higher catalyst loading, and/or a higher reaction temperature to facilitate the hydrogenation reaction.

Rhodium catalysts are also used for the hydrogenation of itaconic acid derivatives, enol esters, and ethenephosphonates (Equations 4–6). As in the hydrogenation of dehydroamino acids and enamides, the oxygen functional groups capable of coordination to the rhodium atom play an important role in accelerating the reaction, as well as in the enantioselection.

### **3.2. Reaction mechanism**

Since the discovery of rhodium-catalyzed asymmetric hydrogenation, the reaction mechanism, including the catalytic cycle and the origin of the enantioselection process, has been studied extensively. Early studies using cationic rhodium complexes with *C*2 symmetric diphosphine ligands with two diaryl substituents at each phosphorus atom led to the so-called "unsaturated mechanism". This mechanism, proposed by Halpern and Brown, is based on the following experimental facts and considerations [25–28].


X

Asymmetric Hydrogenation 9

**Scheme 4.** Unsaturated mechanism: hydrogenation of MAC with Rh-(*S*,*S*)-DIPAMP leading to (*R*)-

*S R*

*k* major

*k* minor

7. A significant reduction in enantioselectivity is also observed when the reaction is performed under higher H2 pressure. This fact is interpreted by considering that the reaction of the less-reactive major isomer with dihydrogen is facilitated under high H2

2 : 98

*k* major = 600 *k* minor

Ph

NHCOMe

*Si*-coordinated

P

P

Ph

MeO

Minor diastereomer Unstable, More reactive

MeO2C

Rh<sup>+</sup>

Ph

OMe

CO2Me

H Ph

O

NH

Me

10 : 1

Solvate complex

P

Rh<sup>+</sup>

OMe

H

OMe H

Ph

OMe

P

Ph

MeO

The key points in this mechanism are illustrated in Scheme 4. This enantioselection mechanism is quite unique, differing from those of other asymmetric catalyses. It should be noted that this mechanism does not correspond to the "lock and key" principle, which is

In contrast, the development of electron-rich diphosphine ligands has revealed a new mechanistic aspect of rhodium-catalyzed asymmetric hydrogenation. It has been reported that rhodium catalysts with electron-rich phosphine ligands (DuPhos, BPE, BisP\*, MiniPHOS, Trichickenfootphos, TangPhos, DuanPhos, ZhangPhos, QuinoxP\*, BenzP\*, etc.) display very high to almost-perfect enantioselectivity in the hydrogenation of many dehydroamino acids and enamides. The origin of this exceedingly high enantioselectvity

widely invoked in stereoselective reactions catalyzed by enzymes.

phenylalanine methyl ester with 96% ee

NHCOMe

O

*Re*-coordinated Major diastereomer Stable, Less reactive

Rh<sup>+</sup>

Ph

OMe

P

P

Ph

MeO

H Ph

NH MeO2C

Me

CO2Me

pressure.

Ph


R1OOC

R1

R1

NHCOR3

NHCOR3

NHCOR<sup>3</sup>

R1OOC CO2R3 <sup>+</sup> H2

R1 R2

X

OAc

CO2R<sup>2</sup>

1. The solvate complex generated by the hydrogenation of a precatalyst reacts with a prochiral substrate, such as methyl (*Z*)--acetamidocinnamate (MAC), providing two diastereomeric catalyst–substrate complexes in a considerably high ratio. For example, the Rh-(*S*,*S*)-DIPAMP solvate complex binds to MAC to generate *Re*- and *Si*-

R1

H \* + <sup>2</sup> Rh-L\*

H \* + <sup>2</sup> Rh-L\*

H \* + <sup>2</sup> Rh-L\*

Rh-L\*

R<sup>2</sup> R1OOC

R2 R<sup>1</sup>

R<sup>2</sup> R2

NHCOR3

NHCOR3

<sup>R</sup>1OOC CO2R3 \*

Rh-L\* (5)

Rh-L\* (6)

X

OAc \*

R1 P(O)(OR2)2

R1 R2

R2

CO2R<sup>2</sup>

NHCOR3

R2

(1)

(2)

(3)

(4)

2. The configuration of the major isomer does not correspond to the configuration of the product if it is assumed that the oxidative addition of H2 occurs in an *endo*-manner and that the stereochemical integrity is maintained through to the final reductive elimination step. 3. At ambient temperatures, major and minor catalyst–substrate complexes are interconverted rapidly. The minor isomer is much more reactive with H2 than the major

isomer, and the reaction proceeds according to the Curtin–Hammett principle. 4. The oxidative addition of dihydrogen to the catalyst–substrate complex is ratedetermining and irreversible, and enantioselection is determined at this step. 5. The kinetic and equilibration data are consistent with the stereochemical outcome (*R*:*S* =

6. At low temperatures, enantioselectivity is significantly reduced. This fact is interpreted as reflecting that the interconversion between the major and minor isomers is very slow or almost in a frozen state at low temperatures. As a consequence, the major isomer competitively reacts with dihydrogen to generate the opposite enantiomeric product,

coordinated adducts in a ratio of about 10:1.

P(O)(OR2)2 <sup>+</sup> H2

X = OCOR, NHCOR

+ H2

R1 \*

resulting in lower enantioselectivity.

98:2; 96% ee).

**Scheme 4.** Unsaturated mechanism: hydrogenation of MAC with Rh-(*S*,*S*)-DIPAMP leading to (*R*) phenylalanine methyl ester with 96% ee

7. A significant reduction in enantioselectivity is also observed when the reaction is performed under higher H2 pressure. This fact is interpreted by considering that the reaction of the less-reactive major isomer with dihydrogen is facilitated under high H2 pressure.

The key points in this mechanism are illustrated in Scheme 4. This enantioselection mechanism is quite unique, differing from those of other asymmetric catalyses. It should be noted that this mechanism does not correspond to the "lock and key" principle, which is widely invoked in stereoselective reactions catalyzed by enzymes.

In contrast, the development of electron-rich diphosphine ligands has revealed a new mechanistic aspect of rhodium-catalyzed asymmetric hydrogenation. It has been reported that rhodium catalysts with electron-rich phosphine ligands (DuPhos, BPE, BisP\*, MiniPHOS, Trichickenfootphos, TangPhos, DuanPhos, ZhangPhos, QuinoxP\*, BenzP\*, etc.) display very high to almost-perfect enantioselectivity in the hydrogenation of many dehydroamino acids and enamides. The origin of this exceedingly high enantioselectvity

Asymmetric Hydrogenation 11

**Scheme 6.** Reaction pathway from catalyst–substrate complexes to (*R*)-*N*-acetylphenylalanine methyl

O

H

Rh+

Me

P

Bu*<sup>t</sup>*

Bu*<sup>t</sup>*

Me

Rh+

MeO2C

H2

S

NH

Ph CO2Me

O

NH

P

Bu*<sup>t</sup>*

Bu*<sup>t</sup>*

Me

P

Bu*<sup>t</sup>*

Ph

Me

Ph

H S

Ph

N H

H

Rh+

O

Me

NHCOMe

 *R*

CO2Me

CO2Me

H

P

CO2Me

Ph

P

Bu*<sup>t</sup>*

Bu*<sup>t</sup>*

Me

P

Bu*<sup>t</sup>*

Bu*<sup>t</sup>*

The origin of the enantioselection process has also been studied using MAC and Trichickenfootphos, a *C*1-symmetric three-hindered phosphine ligand [31,32]. In this case, two of the four possible diastereomeric catalyst–substrate complexes are thermodynamically stable and exist in a ratio of about 1:1. Remarkably, the respective complexes reacted with dihydrogen to yield the same (*R*)-product. NMR and computational studies have demonstrated that the complexes (**8***re* and **8***si*) dissociate the C=C double bond to generate nonchelating complex **9**, which in turn reacts with dihydrogen, with subsequent association

Recently, the hydrogenation mechanism has also been studied using [Rh((*R*,*R*)- BenzP\*)(nbd)]BF4 [33]. Low-temperature NMR and density functional theory (DFT) calculations have revealed more detailed aspects of the mechanism. DFT calculations showed the relative stability of each intermediate and the transition state energies. Consequently, the most reasonable reaction pathway from the solvate complex **10** to the product is proposed to be as shown in Scheme 7. The solvate complex **10** is readily hydrogenated to dihydride **12** via **11**, followed by the reaction of **12** with MAC to produce the nonchelating dihydride intermediate **15**. The nonchelating catalyst–substrate complex **13**

and migratory insertion, to yield the (*R*)-product (Scheme 6).

ester

P

Bu*<sup>t</sup>*

Bu*<sup>t</sup>*

Me

Rh+

H

MeO2C

O

H

NH

X Ph

X = CO2Me

H

Rh+

P

Bu*<sup>t</sup>*

Bu*<sup>t</sup>*

Me

P

Bu*<sup>t</sup>*

O

Me

NH

Me

Ph **ca. 1 : 1**

**8***re* **8***si*

P

Bu*<sup>t</sup>*

Bu*<sup>t</sup>*

Me

P

Bu*<sup>t</sup>*

O

S

**9**

Rh+

HN

Me

P

Bu*<sup>t</sup>*

**Scheme 5.** Mechanism of the asymmetric hydrogenation of MAC with Rh-(*S*,*S*)-*t*-Bu-BisP\*

cannot be explained well in terms of the "unsaturated mechanism" mentioned above. Gridnev and Imamoto et al. studied the hydrogenation mechanism using [Rh(*t*-Bu-BisP\*)(nbd)]BF4 (**1**) [29,30]. One of their notable findings was that the solvate complex [Rh(*t*-Bu-BisP\*)(CD3OD)2]BF4 (**2**) reacted with H2 at –90 °C to produce equilibrium amounts (ca. 20%) of rhodium dihydride complexes [RhH2(*t*-Bu-BisP\*)BF4 (**3a** and **3b**; dihydride diastereomers). The dihydride complexes reacted with MAC, even at very low temperatures (–100 °C), and were rapidly (within 3 min) converted to the monohydride intermediate **6** (Scheme 5). The reaction is considered to proceed through the associated intermediate **4** and monohydride **5**.

On the contrary, the hydrogenation of the catalysts–substrate complexes (**7***re* and **7***si* = ca. 10:1) was relatively slow. It required about 1 h at –80 °C to generate the same concentration of monohydride **6**. The reaction is considered to proceed through the solvate complex **2**, which is generated by the reversible dissociation of **7***re* and **7***si*, and to proceed via dihydrides **3a** and **3b**, **4**, and **5**. It is reasonable to infer that the enantioselection is determined at the migratory insertion step from **4** to **5**. There are eight possible diastereomers of **4**. Among them, complex **4** is energetically most stable, is preferentially formed, and undergoes migratory insertion via the lowest transition state, resulting in the formation of the (*R*)-hydrogenation product.

P P Bu*<sup>t</sup>*

Me

Me Bu*<sup>t</sup>*

O

X

P Bu*<sup>t</sup>*

Me

X = CO2Me

Me Bu*<sup>t</sup>*

Me

P Bu*<sup>t</sup>*

MAC

Me Bu*<sup>t</sup>*

Rh P H

H

+

S Rh P H

H

Rh(nbd)

+

BF4 – H2

Me

**4**

H

S

**1 2**

NH

Ph

**–100 °C, < 3 min**

Rh P P Bu*<sup>t</sup>*

S S

MAC

H Rh P H

S

S

Rh P P Bu*<sup>t</sup>*

Ph

OMe

O O

+ + +

H Ph

*R* NHCOMe

NH

Me

CO2Me

ca. 10 : 1

**7***re* **7***si*

Rh P P Bu*<sup>t</sup>*

H

OMe <sup>O</sup> NH

H2

**–80 °C**

**1 h**

Me O Ph

Me Bu*<sup>t</sup>*

Me

O Rh

**6**

+

Me CH2Ph

OMe

NH H O Me

P P Bu*<sup>t</sup>*

Me Bu*<sup>t</sup>*

**–50 °C**

Me Bu*<sup>t</sup>*

Me

P Bu*<sup>t</sup>*

Me

**3a 3b**

Me Bu*<sup>t</sup>*

Me Bu*<sup>t</sup>*

Me

H2 H2

<sup>+</sup> <sup>+</sup> <sup>+</sup>

**Scheme 5.** Mechanism of the asymmetric hydrogenation of MAC with Rh-(*S*,*S*)-*t*-Bu-BisP\*

is considered to proceed through the associated intermediate **4** and monohydride **5**.

formation of the (*R*)-hydrogenation product.

cannot be explained well in terms of the "unsaturated mechanism" mentioned above. Gridnev and Imamoto et al. studied the hydrogenation mechanism using [Rh(*t*-Bu-BisP\*)(nbd)]BF4 (**1**) [29,30]. One of their notable findings was that the solvate complex [Rh(*t*-Bu-BisP\*)(CD3OD)2]BF4 (**2**) reacted with H2 at –90 °C to produce equilibrium amounts (ca. 20%) of rhodium dihydride complexes [RhH2(*t*-Bu-BisP\*)BF4 (**3a** and **3b**; dihydride diastereomers). The dihydride complexes reacted with MAC, even at very low temperatures (–100 °C), and were rapidly (within 3 min) converted to the monohydride intermediate **6** (Scheme 5). The reaction

O NH

CH2Ph CO2Me

Me

**5**

Rh P S

H

+

P Bu*<sup>t</sup>*

Me

Me Bu*<sup>t</sup>*

On the contrary, the hydrogenation of the catalysts–substrate complexes (**7***re* and **7***si* = ca. 10:1) was relatively slow. It required about 1 h at –80 °C to generate the same concentration of monohydride **6**. The reaction is considered to proceed through the solvate complex **2**, which is generated by the reversible dissociation of **7***re* and **7***si*, and to proceed via dihydrides **3a** and **3b**, **4**, and **5**. It is reasonable to infer that the enantioselection is determined at the migratory insertion step from **4** to **5**. There are eight possible diastereomers of **4**. Among them, complex **4** is energetically most stable, is preferentially formed, and undergoes migratory insertion via the lowest transition state, resulting in the

**Scheme 6.** Reaction pathway from catalyst–substrate complexes to (*R*)-*N*-acetylphenylalanine methyl ester

The origin of the enantioselection process has also been studied using MAC and Trichickenfootphos, a *C*1-symmetric three-hindered phosphine ligand [31,32]. In this case, two of the four possible diastereomeric catalyst–substrate complexes are thermodynamically stable and exist in a ratio of about 1:1. Remarkably, the respective complexes reacted with dihydrogen to yield the same (*R*)-product. NMR and computational studies have demonstrated that the complexes (**8***re* and **8***si*) dissociate the C=C double bond to generate nonchelating complex **9**, which in turn reacts with dihydrogen, with subsequent association and migratory insertion, to yield the (*R*)-product (Scheme 6).

Recently, the hydrogenation mechanism has also been studied using [Rh((*R*,*R*)- BenzP\*)(nbd)]BF4 [33]. Low-temperature NMR and density functional theory (DFT) calculations have revealed more detailed aspects of the mechanism. DFT calculations showed the relative stability of each intermediate and the transition state energies. Consequently, the most reasonable reaction pathway from the solvate complex **10** to the product is proposed to be as shown in Scheme 7. The solvate complex **10** is readily hydrogenated to dihydride **12** via **11**, followed by the reaction of **12** with MAC to produce the nonchelating dihydride intermediate **15**. The nonchelating catalyst–substrate complex **13**

is also readily subjected to hydrogenation because dihydrogen is readily coordinated at the vacant site of the complex, leading to **15** via **14**. On the contrary, the hydrogenation of the chelating catalyst–substrate complex **16** requires a much higher activation energy, so the unsaturated pathway does not operate in this reaction system.

Asymmetric Hydrogenation 13

CO2Me

HN COPh

Ph

CO2Et

Cl

Ramipril

CO2H

HN

O

**23**: R = CONH2, 96% ee

O N

CF3

N H

O HN

H

Cl

Fe Taranabant: R = CN P(*t*-Bu)2

R

**Scheme 8.** Synthesis of ramipril via Rh-catalyzed asymmetric hydrogenation

CO2H

**Scheme 9.** Synthesis of taranabant via Rh-catalyzed asymmetric hydrogenation

Ligand =

CF3

process in the large-scale production of pregabalin [37].

Pregabalin, a kind of optically active -amino acid, is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures. This drug is marketed by Pfizer under the trade name Lyrica. A chemical synthesis of pregabalin is shown in Scheme 10, where the key intermediate **25** is obtained by the asymmetric hydrogenation of *tert*butylammonium (*Z*)-3-cyano-5-methyl-3-hexenoate (**24**) using a Rh-Trichickenfootphos catalyst. The very low catalyst loading (S/C =27,000), mild conditions (50 psi H2 pressure, room temperature), and high enantioselectivity (98% ee) indicate the potential utility of this

P(*o*-Tol)2

Rh–Ligand S/C = 2000

CF3CH2OH, 40 °C, 16 h, 100%

> Me H

H2 (150 psi)

chloride generates taranabant [35,36].

O

O N

HN

**22**

Cl

H2NOC

HN COPh

Cl

CO2Me

H2

H N H

**21**

H

Merck Research Laboratories identified taranabant, as a potential selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity. One of the synthetic routes to taranabant is shown in Scheme 9, and involves the rhodium-catalyzed asymmetric hydrogenation of a tetrasubstituted enamide **22**. The hydrogenation reaction to introduce two stereogenic centers is achieved with a JosiPhos-type ligand and trifluoroethanol as the solvent, to produce compound **23** with 96% ee, and one recrystallization of the product increases the ee value to > 99.5%. The final dehydration of the primary amide with cyanuric

[Rh((*S*C,*R*P)-DuanPhos)(cod)]BF4

**19 20**

S/C = 60000–80000 MeOH, 20–35 °C

Enantioselection occurs at a later stage. The recoordination of the double bond of complex **15** to the rhodium atom occurs readily in the non-hindered quadrant to form the chelated dihydride intermediate **17**. This undergoes migratory insertion to produce monohydride **18**, followed by reductive elimination to generate a product with the correct absolute configuration.

**Scheme 7.** The reaction pathway of the asymmetric hydrogenation of MAC catalyzed by the Rh-(*R*,*R*)- BenzP\* complex

### **3.3. Application to the synthesis of useful optically active compounds**

Rhodium complexes with chiral phosphine ligands have been widely used in academia and industry for the synthesis of the chiral building blocks of natural products, pharmaceuticals, and agrochemicals. Schemes 8–11 show representative examples.

Zhang et al. developed a new process for the production of ramipril, an angiotensinconverting enzyme inhibitor, used to treat high blood pressure and congestive heart failure (Scheme 8) [34]. The -dehydroamino acid methyl ester **19** was efficiently hydrogenated under mild conditions with a rhodium–DuanPhos complex to yield compound **20** with 99% ee. The hydrolysis of the vinyl chloride moiety of compound **20**, followed by its cyclization, generated bicyclic amino acid **21**, which was converted to ramipril.

**Scheme 8.** Synthesis of ramipril via Rh-catalyzed asymmetric hydrogenation

configuration.

P P Rh Bu*<sup>t</sup>* Me

> P P Rh O

**MAC**

MeO2C

**13**

P P Rh O Me

**16**

Me Bu*<sup>t</sup>*

S S

**H2**

NH

S

Ph

Ph

NH

CO2Me

Me

**H2**

BenzP\* complex

is also readily subjected to hydrogenation because dihydrogen is readily coordinated at the vacant site of the complex, leading to **15** via **14**. On the contrary, the hydrogenation of the chelating catalyst–substrate complex **16** requires a much higher activation energy, so the

Enantioselection occurs at a later stage. The recoordination of the double bond of complex **15** to the rhodium atom occurs readily in the non-hindered quadrant to form the chelated dihydride intermediate **17**. This undergoes migratory insertion to produce monohydride **18**, followed by reductive elimination to generate a product with the correct absolute

**Scheme 7.** The reaction pathway of the asymmetric hydrogenation of MAC catalyzed by the Rh-(*R*,*R*)-

Rhodium complexes with chiral phosphine ligands have been widely used in academia and industry for the synthesis of the chiral building blocks of natural products, pharmaceuticals,

Zhang et al. developed a new process for the production of ramipril, an angiotensinconverting enzyme inhibitor, used to treat high blood pressure and congestive heart failure (Scheme 8) [34]. The -dehydroamino acid methyl ester **19** was efficiently hydrogenated under mild conditions with a rhodium–DuanPhos complex to yield compound **20** with 99% ee. The hydrolysis of the vinyl chloride moiety of compound **20**, followed by its cyclization,

**3.3. Application to the synthesis of useful optically active compounds** 

and agrochemicals. Schemes 8–11 show representative examples.

generated bicyclic amino acid **21**, which was converted to ramipril.

unsaturated pathway does not operate in this reaction system.

P P Rh S

**10 12**

**11**

P P Rh O NH Me

MeO2C

**H**

**MAC MAC**

Ph

**H**

**H** P

**<sup>H</sup>** <sup>P</sup>

Ph

P Rh **<sup>H</sup>** <sup>S</sup> <sup>S</sup>

P Rh O NH Me

MeO2C

**14 15 17**

NHCOMe

CO2Me

S

Ph

**10**

P P Rh **<sup>H</sup> H**

X = CO2Me

P P Rh <sup>S</sup> **H**

**18**

O

X

Me

O

X

Me

NH

NH

**H**

Ph

Ph

**H H**

**H**

Merck Research Laboratories identified taranabant, as a potential selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity. One of the synthetic routes to taranabant is shown in Scheme 9, and involves the rhodium-catalyzed asymmetric hydrogenation of a tetrasubstituted enamide **22**. The hydrogenation reaction to introduce two stereogenic centers is achieved with a JosiPhos-type ligand and trifluoroethanol as the solvent, to produce compound **23** with 96% ee, and one recrystallization of the product increases the ee value to > 99.5%. The final dehydration of the primary amide with cyanuric chloride generates taranabant [35,36].

**Scheme 9.** Synthesis of taranabant via Rh-catalyzed asymmetric hydrogenation

Pregabalin, a kind of optically active -amino acid, is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures. This drug is marketed by Pfizer under the trade name Lyrica. A chemical synthesis of pregabalin is shown in Scheme 10, where the key intermediate **25** is obtained by the asymmetric hydrogenation of *tert*butylammonium (*Z*)-3-cyano-5-methyl-3-hexenoate (**24**) using a Rh-Trichickenfootphos catalyst. The very low catalyst loading (S/C =27,000), mild conditions (50 psi H2 pressure, room temperature), and high enantioselectivity (98% ee) indicate the potential utility of this process in the large-scale production of pregabalin [37].

Asymmetric Hydrogenation 15

96–99% ee

(*R*)-citronellol

96–99% ee

Ph2 P

Ru

O

O

O

R

O

R

P Ph2

(*R*)-BINAP-Ru(II)

(*S*)-citronellol

OH

subjected to hydrogenation with (*S*)-BINAP-Ru to produce (*R*)-citronellol and (*S*)-citronellol, respectively, and conversely, the use of (*R*)-BINAP-Ru produces the (*S*)- and (*R*)-products, respectively. Notably, the hydrogenation proceeds with a quite low catalyst loading (S/C = 50,000) to generate the products with a quantitative yield, with excellent enantioselectivities

OH OH

(*S*)-BINAP-Ru(II)

(*S*)-BINAP-Ru(II)

(*R*)-BINAP-Ru(II)

**Scheme 12.** Asymmetric hydrogenation of geraniol and nerol with BINAP-Ru(II) catalysts

**4.2. Hydrogenation of β-Keto esters and related substrates** 

enantioselectivities, up to > 99% [40].

The Ru(II) catalyst systems have been successfully applied to the enantioselective hydrogenation of ,β-unsaturated carboxylic acid esters, lactones, and ketones. Enamides are also efficiently hydrogenated with these catalysts. Using this catalyst system, isoquinoline alkaloids, morphine, and its artificial analogues can be prepared in an enantiopure form. A representative example, the synthesis of (*S*)-tetrahydropapaverine, is shown in Scheme 13 [39].

Optically active β-hydroxy carboxylic esters are an important class of compounds in the synthesis of naturally occurring and biologically active compounds. Noyori et al. demonstrated a useful method for the catalytic asymmetric synthesis of this class of compounds using BINAP-Ru(II) complexes as the catalysts. The BINAP-Ru dicarboxylate complexes, which proved to be highly efficient for the enantioselective hydrogenation of various olefins, were not effective in this transformation. Instead, halogen-containing complexes RuX2(binap) (X = Cl, Br, or I) were excellent catalyst precursors. The reactions with S/C > 1000 proceeded smoothly under 50–100 atm H2 pressure, with excellent

(96–99% ee) (Scheme 12) [38].

geraniol

nerol

OH

+ H2

+ H2

Ph2 P

Ru

O

O O

R

O

R

P Ph2

(*S*)-BINAP-Ru(II)

**Scheme 10.** Synthesis of a key intermediate in the production of pregabalin

Chiral β-amino acid derivatives are useful building blocks for the synthesis of β-peptides and β-lactam antibiotics. Asymmetric hydrogenation of β-dehydroamino acids with chiral rhodium catalysts is a useful method for the production of key chiral intermediates. An example of the preparation of a building block of the very late antigen-4 (VLA-4) antagonist S9059 is shown in Scheme 11. The hydrogenation of compound **26** in the presence of 0.1 mol % catalyst under 3 atm H2 pressure proceeded rapidly, to produce the corresponding product **27** with 97.7% ee [33].

**Scheme 11.** Asymmetric hydrogenation of a *N*-acetyl-β-dehydroamino acid ester

### **4. Ruthenium-catalyzed Asymmetric Hydrogenation**

### **4.1. Hydrogenation of functionalized alkenes**

The discovery of chiral ruthenium catalysts significantly expanded the scope of asymmetric hydrogenation. Noyori et al. made the first breakthrough in this area using BINAP-Ru(II) dicarboxylate complexes. These complexes catalyze the highly enantioselective hydrogenation of the carbon–carbon double bonds of the substrates, the asymmetric hydrogenation of which had been difficult to achieve with the rhodium catalysts reported until then. For example, geraniol and its geometric isomer nerol, a kind of allyl alcohol, are subjected to hydrogenation with (*S*)-BINAP-Ru to produce (*R*)-citronellol and (*S*)-citronellol, respectively, and conversely, the use of (*R*)-BINAP-Ru produces the (*S*)- and (*R*)-products, respectively. Notably, the hydrogenation proceeds with a quite low catalyst loading (S/C = 50,000) to generate the products with a quantitative yield, with excellent enantioselectivities (96–99% ee) (Scheme 12) [38].

14 Hydrogenation

*t*-BuNH3 +

MeO

MeO

product **27** with 97.7% ee [33].

CO2Et

**Scheme 10.** Synthesis of a key intermediate in the production of pregabalin

P P

S/C = 27000

Me

Bu-*<sup>t</sup> <sup>t</sup>*-Bu

Bu-*t*

–

Rh+ BF4

MeOH, 40 h –O2C

+ H2

CN

**Scheme 11.** Asymmetric hydrogenation of a *N*-acetyl-β-dehydroamino acid ester

MeO NHAc

MeO

**26 27**

MeO

Rh-(*R*,*R*)-QuinoxP\* S/C = 1000 MeOH, rt, 0.5 h

H2 (3 atm)

The discovery of chiral ruthenium catalysts significantly expanded the scope of asymmetric hydrogenation. Noyori et al. made the first breakthrough in this area using BINAP-Ru(II) dicarboxylate complexes. These complexes catalyze the highly enantioselective hydrogenation of the carbon–carbon double bonds of the substrates, the asymmetric hydrogenation of which had been difficult to achieve with the rhodium catalysts reported until then. For example, geraniol and its geometric isomer nerol, a kind of allyl alcohol, are

**4. Ruthenium-catalyzed Asymmetric Hydrogenation** 

**4.1. Hydrogenation of functionalized alkenes** 

Chiral β-amino acid derivatives are useful building blocks for the synthesis of β-peptides and β-lactam antibiotics. Asymmetric hydrogenation of β-dehydroamino acids with chiral rhodium catalysts is a useful method for the production of key chiral intermediates. An example of the preparation of a building block of the very late antigen-4 (VLA-4) antagonist S9059 is shown in Scheme 11. The hydrogenation of compound **26** in the presence of 0.1 mol % catalyst under 3 atm H2 pressure proceeded rapidly, to produce the corresponding

98% ee

CN

NHAc

CO2Et

N H

O

NHPh

97.7% ee

CO2H NH2

–O2C

MeO

H N

N

O

S9059; VLA-4 antagonist

N

O

HOOC <sup>O</sup>

*t*-BuNH3 +

**24 25** Pregabalin

**Scheme 12.** Asymmetric hydrogenation of geraniol and nerol with BINAP-Ru(II) catalysts

The Ru(II) catalyst systems have been successfully applied to the enantioselective hydrogenation of ,β-unsaturated carboxylic acid esters, lactones, and ketones. Enamides are also efficiently hydrogenated with these catalysts. Using this catalyst system, isoquinoline alkaloids, morphine, and its artificial analogues can be prepared in an enantiopure form. A representative example, the synthesis of (*S*)-tetrahydropapaverine, is shown in Scheme 13 [39].

### **4.2. Hydrogenation of β-Keto esters and related substrates**

Optically active β-hydroxy carboxylic esters are an important class of compounds in the synthesis of naturally occurring and biologically active compounds. Noyori et al. demonstrated a useful method for the catalytic asymmetric synthesis of this class of compounds using BINAP-Ru(II) complexes as the catalysts. The BINAP-Ru dicarboxylate complexes, which proved to be highly efficient for the enantioselective hydrogenation of various olefins, were not effective in this transformation. Instead, halogen-containing complexes RuX2(binap) (X = Cl, Br, or I) were excellent catalyst precursors. The reactions with S/C > 1000 proceeded smoothly under 50–100 atm H2 pressure, with excellent enantioselectivities, up to > 99% [40].

Asymmetric Hydrogenation 17

OH O

98% ee

**29**

SR

CO2H

N

Carbapenems

HO <sup>H</sup> <sup>H</sup>

O

P(OMe)2

**32** 98% ee

OMe

NHCOPh

O

Fosfomycin

H H

P O

OH OH

Me

*syn* : *anti* = 94 : 6

(DTBM-SEGPHOS = 5,5'-bis[di(3,5-di-*tert*-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3 benzodioxole) complex for this reaction yields **29** almost exclusively (98.6% diastereomeric

Ru–(*R*)-BINAP

**Scheme 15.** Industrial synthesis of a carbapenem intermediate with Ru-BINAP-catalyzed hydrogenation

Another example is shown in Scheme 16. Racemic dimethyl 1-bromo-2-oxopropylphosphonate (**31**) is hydrogenated in the presence of the (S)-BINAP-Ru complex to yield (1*R*,2*S*)-1-bromo-2 hydroxypropylphosphonate (**32**) with 98% ee. The product is converted into fosfomycin, a

OH

O

Br

The development of ruthenium catalysts containing enantiopure diphosphines and diamines has allowed the asymmetric hydrogenation of simple ketones to optically active secondary alcohols. After examining numerous chiral diamines, Noyori, Ohkuma, and their co-workers found that the most effective catalyst systems were BINAP–DPEN (DPEN = 1,2 diphenylethylenediamine) (**33**) and BINAP–DAIPEN (DAIPEN = 1,1-di-4-anisyl-2 isopropyl-1,2-ethylenediamine) (**34**) (Fig. 2) [16,17,47]. In particular, the latter catalytic system (**34**), which has sterically more demanding 3,5-xylyl moieties on the phosphorus atoms exhibited exceedingly high catalytic activities and enantioselectivities in the

excess, 99.4% ee) [45].

O O

+ –

**28**

*<sup>t</sup>*-BuMe2SiO <sup>H</sup>

OMe

NHCOPh

O

**30**

NH

OCOMe

+ H2 (100 atm)

clinically used antibiotic [46].

O

Br **31**

P(OMe)2

O

+ –

**Scheme 16.** Synthesis of fosfomycin via dynamic kinetic resolution

H2 (*S*)-BINAP–Ru(II) MeOH

**4.3. Hydrogenation of simple ketones** 

hydrogenation of a wide range of ketone substrates.

**Scheme 13.** Synthesis of (*S*)-tetrahydropapaverine via Ru-catalyzed asymmetric hydrogenation

The scope of this reaction was extensively expanded using various chiral phosphine ligands. As a result, a variety of β-keto esters, amides, and thiol esters with a functional group (R1 = ClCH2, alkoxymethyl, aryl, etc.) were hydrogenated in excellent enantioselectivities (Scheme 14). This method is currently used in academia and industry for the preparation of numerous chiral building blocks for the synthesis of biologically active compounds.

$$\begin{array}{ccccc}\text{\$\mathcal{O}\$} & \text{\$\mathcal{O}\$} & \text{\$\mathcal{O}\$} \\ \text{\$\mathcal{H}\$} & \text{\$\mathcal{O}\$} & \text{\$\mathcal{H}\$} \\ & & & \\ \text{\$\mathcal{H}\$}^{1} = \text{Me, ClCH}\_{2}, \text{Et, } \text{\$\mathcal{H}\$-Pr, \$n\$-Bu, \$\mathsf{PhCH}\_{2}\$, \$\mathsf{PhCH}\_{2}\$, \$\mathsf{PhCH}\_{2}\$\mathsf{CCH}\_{2}\$, \$\mathsf{H}\$} \\ & & & \\ \text{\$\mathcal{H}\$\mathcal{S}\$-Pr}\_{1} \text{S} \text{Cl} & \text{\$\mathcal{H}\$-Pr}\_{1} \text{H}\_{23} \text{, \$\mathsf{CH}\_{3}\$} \text{Cl} \text{(CH}\_{2})\_{11} \text{, \$\mathsf{CF}\_{3}\$, \$\mathsf{PhCO}\_{2}\$\mathsf{CH}\_{2}\$} \\ & & & \\ \text{\$\mathsf{PhSO}\$} 2\_{2}\text{CH}\_{2}, \text{C} \text{h} \text{N} \text{H} \text{CH}\_{2}, \text{Aryl, \$\mathsf{et}\$} \\ & & \mathbf{\mathsf{x}} \text{R}^{2} = \text{OMe, OEt, \$\mathsf{O} \text{Pr} \text{-}f\$}, \text{OMe} \text{-}t, \text{ NMe}\_{2}, \text{NPhMe}, \text{S} \text{Et} \\ \end{array}$$

**Scheme 14.** Ruthenium-catalyzed asymmetric hydrogenation of β-keto esters and related substrates

The hydrogenation of a β-keto ester bearing one substituent at the -position provides four possible stereoisomeric β-hydroxy esters. Because stereomutation at the -position of the βketo ester occurs readily, it should be possible to selectively hydrogenate one of the β-keto ester enantiomers to yield only one stereoisomer, if the reaction conditions and the chiral ligand are selected appropriately. Noyori et al. established this dynamic kinetic resolution process using BINAP-Ru complexes [41,42]. The great utility of this method has been demonstrated in the production of many enantiopure building blocks. A representative example of the production of carbapenems by Takasago International Corporation is shown in Scheme 15 [43,44]. The hydrogenation of racemic **28** occurs with full conversion to yield the (2*S*,3*R*) product **29** with high diastereo- and enantioselectivity, and the product is further converted to the key intermediate, azetidinone **30**. The use of the DTBM-SEGPHOS-Ru(II) (DTBM-SEGPHOS = 5,5'-bis[di(3,5-di-*tert*-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3 benzodioxole) complex for this reaction yields **29** almost exclusively (98.6% diastereomeric excess, 99.4% ee) [45].

**Scheme 15.** Industrial synthesis of a carbapenem intermediate with Ru-BINAP-catalyzed hydrogenation

Another example is shown in Scheme 16. Racemic dimethyl 1-bromo-2-oxopropylphosphonate (**31**) is hydrogenated in the presence of the (S)-BINAP-Ru complex to yield (1*R*,2*S*)-1-bromo-2 hydroxypropylphosphonate (**32**) with 98% ee. The product is converted into fosfomycin, a clinically used antibiotic [46].

**Scheme 16.** Synthesis of fosfomycin via dynamic kinetic resolution

#### **4.3. Hydrogenation of simple ketones**

16 Hydrogenation

MeO

MeO

NCHO

R1

O O

Ome

MeO

MeO

OMe

**Scheme 13.** Synthesis of (*S*)-tetrahydropapaverine via Ru-catalyzed asymmetric hydrogenation

(*S*)-Tetrahydropapaverine

NH

H2 (10~40 atm) (*S*)-BINAP-Ru

MeOH-CH2Cl2

chiral building blocks for the synthesis of biologically active compounds.

PhSO2CH2, CbzNHCH2, Aryl, etc

XR2 = OMe, OEt, OPr-*i*, OBu-*t*, NMe2, NHMe, SEt

The scope of this reaction was extensively expanded using various chiral phosphine ligands. As a result, a variety of β-keto esters, amides, and thiol esters with a functional group (R1 = ClCH2, alkoxymethyl, aryl, etc.) were hydrogenated in excellent enantioselectivities (Scheme 14). This method is currently used in academia and industry for the preparation of numerous

OMe

OMe

NCHO

>99.5% ee

OH O

95 – >99% ee

XR2 \*

Ome

OMe

MeO

MeO

**Scheme 14.** Ruthenium-catalyzed asymmetric hydrogenation of β-keto esters and related substrates

XR2 R1

R1 = Me, ClCH2, Et, *i*-Pr, *n*-Bu, PhCH2OCH2, PhCH2OCH2CH2, *i*-Pr3SiOCH2, *n*-C11H23, (CH3)2CH(CH2)11, CF3, PhCO2CH2,

Ru(II)–Ligand <sup>+</sup> H2

The hydrogenation of a β-keto ester bearing one substituent at the -position provides four possible stereoisomeric β-hydroxy esters. Because stereomutation at the -position of the βketo ester occurs readily, it should be possible to selectively hydrogenate one of the β-keto ester enantiomers to yield only one stereoisomer, if the reaction conditions and the chiral ligand are selected appropriately. Noyori et al. established this dynamic kinetic resolution process using BINAP-Ru complexes [41,42]. The great utility of this method has been demonstrated in the production of many enantiopure building blocks. A representative example of the production of carbapenems by Takasago International Corporation is shown in Scheme 15 [43,44]. The hydrogenation of racemic **28** occurs with full conversion to yield the (2*S*,3*R*) product **29** with high diastereo- and enantioselectivity, and the product is further converted to the key intermediate, azetidinone **30**. The use of the DTBM-SEGPHOS-Ru(II)

The development of ruthenium catalysts containing enantiopure diphosphines and diamines has allowed the asymmetric hydrogenation of simple ketones to optically active secondary alcohols. After examining numerous chiral diamines, Noyori, Ohkuma, and their co-workers found that the most effective catalyst systems were BINAP–DPEN (DPEN = 1,2 diphenylethylenediamine) (**33**) and BINAP–DAIPEN (DAIPEN = 1,1-di-4-anisyl-2 isopropyl-1,2-ethylenediamine) (**34**) (Fig. 2) [16,17,47]. In particular, the latter catalytic system (**34**), which has sterically more demanding 3,5-xylyl moieties on the phosphorus atoms exhibited exceedingly high catalytic activities and enantioselectivities in the hydrogenation of a wide range of ketone substrates.

Asymmetric Hydrogenation 19

OH

\*

OH

66% ee

NMe2

OH \*

96% ee

OH

\*

94% ee

S/C = 100,000 TOF = 35,000/min = 600/s

98% ee 93% ee

OMe

OH

N OH OH 100% ee

93% ee

\*

\*

OH CH3

MeO

\*

OH

Cl

\*

**Figure 3.** Representative examples of the ruthenium-catalyzed asymmetric hydrogenation of simple

OH

\*

97% ee

Ph Me HO H

>99% yield >99% ee

OMe

Ar = 3,5-Me2C6H3

97% ee

Ru-catalyst

11–35 °C 6 min

EtOH/*i*-PrOH (1:1)

Ar2 P

P Ar2

OH \*

99% ee 97% ee

O2N

OH

\* \* \*

*n* CF3 -C8H17

97% ee

OH

N 99.8% ee

99.8% ee

\* OH

OH

\*

\*

CF3

99% ee

OH \*

OH

S N

99% ee

\* \*

\*

96% ee

**Scheme 17.** Asymmetric hydrogenation of acetophenone catalyzed by a ruthenabicyclic complex

MeO

Ru

H2 <sup>N</sup> OTf H2 N H

without any direct interaction with the metal center.

which two hydrogen atoms effectively interact with the C+=O– dipole of the ketone, as shown in structure **40**. The reaction of the carbonyl group proceeds through a pericyclic sixmembered transition state (**41**). It should be noted that the reduction of the carbonyl group occurs in an outer coordination sphere of 18-electron Ru(H2)(diphosphine)(diamine),

ketones

OH

\*

OH

99.8% ee

Ph Me

O

OH

\* NCOPh Me

99.4% ee

OH \*

OMe

OH

O

OH

\*

99% ee

99% ee

OH

\*

O

+ H2 50 atm

Ru-catalyst =

94% ee

95% ee

**Figure 2.** Ru(II) complexes with BINAP and chiral diamine

Representative examples of compounds obtained with these catalysts are shown in Figure 3. Alkyl aryl ketones, unsymmetric diaryl ketones, heteroaromatic ketones, unsymmetric dialkyl ketones, fluoro ketones, amino ketones, and ,β-unsaturated ketones are hydrogenated with very high to almost-perfect enantioselectivities. High chemoselectivity is one of the characteristic features of this hydrogenation method. Therefore, only the carbonyl group is hydrogenated and the other functional groups, such as the carbon–carbon double bond and the nitro group, remain intact.

Recently, chiral ruthenabicylic complexes have been prepared and their exceedingly high catalytic performance has been demonstrated in the asymmetric hydrogenation of ketones [48]. Scheme 17 shows a typical example of the hydrogenation of acetophenone. The reaction under 50 atm H2 pressure in the presence of 0.001 mol% catalyst proceeds very rapidly and is completed within 6 min, producing 1-phenylethanol with an essentially quantitative yield and more than 99% ee. The exceedingly high turnover frequency (> 600/s) and almost-perfect enantioselectivity are the best so far reported for ketone hydrogenation. The catalyst has been successfully applied to the asymmetric hydrogenation of several ketones, which are difficult substrates to reduce with high efficiency using existing catalysts. These facts, together with the easy preparation of these catalysts, strongly predict the promising results in the hydrogenation of a wide range of ketone substrates.

### **4.4. Mechanism of ketone hydrogenation catalyzed by ruthenium complexes of diphosphine and diamine**

The mechanism of the Ru(II)-diphosphine/diamine-catalyzed asymmetric hydrogenation of ketones has been extensively studied by Noyori et al. [49]. The catalytic cycle demonstrated by them is shown in Scheme 18 [17,47,49].

The precatalyst **35** is converted via an induction process to the ruthenium hydride species **36**, which is equilibrated with other active species **37**, **38**, and **39**. The 18-electron Ru(II) hydride species **38** reacts with a ketone to produce a secondary alcohol and **39**. Complex **39** returns to **38** by the direct addition of H2 or via **36** and **37**, and again reacts with the ketone. The marked catalytic activity and enantioselectivity originate from a nonclassical metal–ligand bifunctional mechanism. Therefore, the active species **38** involves the H––Ru+–N––H+ quadrupole, in

**Figure 2.** Ru(II) complexes with BINAP and chiral diamine

Ar2 P

> Ru N H2

Cl

*trans*-RuCl2[(*S*)-binap][(*S*,*S*)-dpen]

H2 <sup>N</sup> Cl

P Ar2

bond and the nitro group, remain intact.

**diphosphine and diamine**

by them is shown in Scheme 18 [17,47,49].

Representative examples of compounds obtained with these catalysts are shown in Figure 3. Alkyl aryl ketones, unsymmetric diaryl ketones, heteroaromatic ketones, unsymmetric dialkyl ketones, fluoro ketones, amino ketones, and ,β-unsaturated ketones are hydrogenated with very high to almost-perfect enantioselectivities. High chemoselectivity is one of the characteristic features of this hydrogenation method. Therefore, only the carbonyl group is hydrogenated and the other functional groups, such as the carbon–carbon double

**33 34**

Ar2 P

> Ru N H2

Cl

H2 <sup>N</sup> Cl

OMe

OMe

*trans*-RuCl2[(*S*)-binap][(*S*)-daipen]

P Ar2

Recently, chiral ruthenabicylic complexes have been prepared and their exceedingly high catalytic performance has been demonstrated in the asymmetric hydrogenation of ketones [48]. Scheme 17 shows a typical example of the hydrogenation of acetophenone. The reaction under 50 atm H2 pressure in the presence of 0.001 mol% catalyst proceeds very rapidly and is completed within 6 min, producing 1-phenylethanol with an essentially quantitative yield and more than 99% ee. The exceedingly high turnover frequency (> 600/s) and almost-perfect enantioselectivity are the best so far reported for ketone hydrogenation. The catalyst has been successfully applied to the asymmetric hydrogenation of several ketones, which are difficult substrates to reduce with high efficiency using existing catalysts. These facts, together with the easy preparation of these catalysts, strongly predict the

promising results in the hydrogenation of a wide range of ketone substrates.

**4.4. Mechanism of ketone hydrogenation catalyzed by ruthenium complexes of** 

The mechanism of the Ru(II)-diphosphine/diamine-catalyzed asymmetric hydrogenation of ketones has been extensively studied by Noyori et al. [49]. The catalytic cycle demonstrated

The precatalyst **35** is converted via an induction process to the ruthenium hydride species **36**, which is equilibrated with other active species **37**, **38**, and **39**. The 18-electron Ru(II) hydride species **38** reacts with a ketone to produce a secondary alcohol and **39**. Complex **39** returns to **38** by the direct addition of H2 or via **36** and **37**, and again reacts with the ketone. The marked catalytic activity and enantioselectivity originate from a nonclassical metal–ligand bifunctional mechanism. Therefore, the active species **38** involves the H––Ru+–N––H+ quadrupole, in

**Figure 3.** Representative examples of the ruthenium-catalyzed asymmetric hydrogenation of simple ketones

**Scheme 17.** Asymmetric hydrogenation of acetophenone catalyzed by a ruthenabicyclic complex

which two hydrogen atoms effectively interact with the C+=O– dipole of the ketone, as shown in structure **40**. The reaction of the carbonyl group proceeds through a pericyclic sixmembered transition state (**41**). It should be noted that the reduction of the carbonyl group occurs in an outer coordination sphere of 18-electron Ru(H2)(diphosphine)(diamine), without any direct interaction with the metal center.

Asymmetric Hydrogenation 21

CF3

CF3 <sup>4</sup>

[Ir(phox)(cod)]+[PF6]– yielded high enantioselectivities of up to 98% ee in the hydrogenation of model substrates, but the turnover numbers were not large. The low activity of the catalysts was attributed to their deactivation during the hydrogenation reaction, and further experiments led them to the discovery of dramatic counterion effects. The replacement of the PF6– anion with a bulky, apolar, and weakly coordinating anion BARF (tetrakis[3,5 bis(trifluoromethyl)phenyl]borate) (BArF–) markedly improved the catalytic activity,

<sup>+</sup> X–

X = PF6

X = BArF = B

O

Bu-*t*

X = PF6: 1 mol% ~ 50% conv. 97% ee TOF = 2400 h– X = BArF: 0.02 mol% 100% conv. 98% ee TOF > 5000 h–

These successful results have significantly advanced this area of research with the development of numerous chiral P,N-ligands [13,54–58]. Representatives of the chiral iridium complexes so far reported are shown in Fig. 4. It should be noted that iridium complex **54**, with an *N*-heterocyclic carbene oxazoline ligand, is also effective in this kind of

Figure 5 shows some representative results for the asymmetric hydrogenation of unfunctionalized alkenes. Many rationally designed ligands display very high enantioselectivity (usually 99% ee) in the hydrogenation of a standard model substrate, (*E*)- -methylstilbene. Purely alkyl-substituted alkenes are also reduced with high enantioselectivity. In the hydrogenation of 1,1-diarylethenes, two different aryl groups are effectively distinguished to produce the corresponding alkanes with good to excellent enantioselectivity. Notably, even tetrasubstituted alkenes are subject to hydrogenation, although the enantioselectivity depends largely on the substrate and the ligand structure.

Pfaltz et al. have demonstrated the practical utility of this methodology in the hydrogenation of -tocotrienyl acetate **55** to produce -tocopheryl acetate **56**, a precursor of -tocopherol, which is a component of vitamin E. The two prochiral (*E*)-configured C=C bonds of **55** are enantioselectively reduced under the conditions shown in Scheme 20 to generate the (*R*,*R*,*R*)-configuration product **56** with 98% purity [60]. This method provides a highly effective stereoselective route to this class of compounds and has great advantages over previous strategies, which used a stepwise approach to introduce the stereogenic

allowing the use of catalyst loadings as low as 0.02 mol% (Scheme 19) [50,53].

(*o*-tol)2P N

Ir

**Scheme 19.** Anion effect on the hydrogenation of (*E*)--methylstilbene

+ H2 (10 atm)

asymmetric hydrogenation [59].

centers into the side chain.

**Scheme 18.** Mechanism of ketone hydrogenation catalyzed by Ru(II)-diphosphine/diamine catalysts

### **5. Iridium-catalyzed Asymmetric Hydrogenation**

### **5.1. Hydrogenation of unfunctionalized alkenes**

Chiral rhodium and ruthenium catalysts are frequently used as the most versatile catalysts for the asymmetric hydrogenation of alkenes. However, the range of the substrates used is limited to alkenes with a coordinating functional group adjacent to the C=C double bond, except for several examples. The high enantioselectivities obtained by using rhodium or ruthenium catalysts are responsible for the coordination of the functional group to the metal center and the alkene -bonding. In contrast, alkenes lacking coordinating groups have long been notoriously difficult to hydrogenate with high enantioselectivity. This difficulty was overcome by Pfaltz et al. in 1998 by using iridium complexes bearing chiral P,N-ligands [50]. Thus, they used Ir–PHOX complexes, which seemed to be the chiral analogues of Crabtree's catalyst [Ir(cod)(PCy3)(pyridine)]+[PF6]– (Cy = cyclohexyl) [51,52]. Their initial study using [Ir(phox)(cod)]+[PF6]– yielded high enantioselectivities of up to 98% ee in the hydrogenation of model substrates, but the turnover numbers were not large. The low activity of the catalysts was attributed to their deactivation during the hydrogenation reaction, and further experiments led them to the discovery of dramatic counterion effects. The replacement of the PF6– anion with a bulky, apolar, and weakly coordinating anion BARF (tetrakis[3,5 bis(trifluoromethyl)phenyl]borate) (BArF–) markedly improved the catalytic activity, allowing the use of catalyst loadings as low as 0.02 mol% (Scheme 19) [50,53].

**Scheme 19.** Anion effect on the hydrogenation of (*E*)--methylstilbene

20 Hydrogenation

**Scheme 18.** Mechanism of ketone hydrogenation catalyzed by Ru(II)-diphosphine/diamine catalysts

H2

H2 N

N H2

H2 N

induction process

+

H N N

H

–

–

+

H

N H2

P

C

H

P

Ru

H

–

+

C + O

H

O

**40**

Ru

transition state

**41**

N

H

N H2

H OH

P

O

P

H+

Ru

H

**39**

N H2

> H2 N

> N H2

P

P

H2 N

+

H+

H2

N H2

P

P

Ru

H H

H

**37**

P

P

Ru

Y

**35**

Ru

H

**36**

X

Chiral rhodium and ruthenium catalysts are frequently used as the most versatile catalysts for the asymmetric hydrogenation of alkenes. However, the range of the substrates used is limited to alkenes with a coordinating functional group adjacent to the C=C double bond, except for several examples. The high enantioselectivities obtained by using rhodium or ruthenium catalysts are responsible for the coordination of the functional group to the metal center and the alkene -bonding. In contrast, alkenes lacking coordinating groups have long been notoriously difficult to hydrogenate with high enantioselectivity. This difficulty was overcome by Pfaltz et al. in 1998 by using iridium complexes bearing chiral P,N-ligands [50]. Thus, they used Ir–PHOX complexes, which seemed to be the chiral analogues of Crabtree's catalyst [Ir(cod)(PCy3)(pyridine)]+[PF6]– (Cy = cyclohexyl) [51,52]. Their initial study using

**5. Iridium-catalyzed Asymmetric Hydrogenation** 

**5.1. Hydrogenation of unfunctionalized alkenes** 

P

P

Ru

H

H

**38**

These successful results have significantly advanced this area of research with the development of numerous chiral P,N-ligands [13,54–58]. Representatives of the chiral iridium complexes so far reported are shown in Fig. 4. It should be noted that iridium complex **54**, with an *N*-heterocyclic carbene oxazoline ligand, is also effective in this kind of asymmetric hydrogenation [59].

Figure 5 shows some representative results for the asymmetric hydrogenation of unfunctionalized alkenes. Many rationally designed ligands display very high enantioselectivity (usually 99% ee) in the hydrogenation of a standard model substrate, (*E*)- -methylstilbene. Purely alkyl-substituted alkenes are also reduced with high enantioselectivity. In the hydrogenation of 1,1-diarylethenes, two different aryl groups are effectively distinguished to produce the corresponding alkanes with good to excellent enantioselectivity. Notably, even tetrasubstituted alkenes are subject to hydrogenation, although the enantioselectivity depends largely on the substrate and the ligand structure.

Pfaltz et al. have demonstrated the practical utility of this methodology in the hydrogenation of -tocotrienyl acetate **55** to produce -tocopheryl acetate **56**, a precursor of -tocopherol, which is a component of vitamin E. The two prochiral (*E*)-configured C=C bonds of **55** are enantioselectively reduced under the conditions shown in Scheme 20 to generate the (*R*,*R*,*R*)-configuration product **56** with 98% purity [60]. This method provides a highly effective stereoselective route to this class of compounds and has great advantages over previous strategies, which used a stepwise approach to introduce the stereogenic centers into the side chain.

Asymmetric Hydrogenation 23

**Scheme 20.** Asymmetric hydrogenation of -tocotrienyl acetate

OH Ph \* OH

cat. **45**: 98% ee cat. **53**: 93% ee

cat. **43**: 96.5% ee NHAc Ph CO2Me

\*

cat. **45**: 93% ee Ph CO2Et

\*

\*

Ph

cat. **47**: 99% ee

B Ph O

cat. **48**: 98% ee

AcO P(O)Ph2 AcO P(O)Ph2

Ph

B Ph O O

<sup>+</sup> BArF –

**55**

1 mol%

O

(*o*-Tol)2P N Ir

NHAc Ph CO2Me

Ph CO2Et

*R*

Ph

CH2Cl2, 23 °C, >99% conv.

AcO

**Figure 6.** Representative examples of Ir-catalyzed asymmetric hydrogenation of functionalized alkenes

O

*R R R*

+ 3 H2

50 atm

*R*,*R*,*R*: >98%

O

Ph Ph O

<sup>O</sup> \* NEt Ph <sup>2</sup> NEt Ph <sup>2</sup>

CO2H

<sup>F</sup> Ph <sup>O</sup>

CO2H

<sup>F</sup> Ph cat. **52**: 99.2% ee

\*

cat. **48**: 99% ee

\*

OP(O)Ph2 OP(O)Ph2

cat. **48**: 84% ee

Ph Ph O \* \*

cat. **49**: 93% ee

cat. **50**: > 99% ee

\*

**56**

AcO

<sup>O</sup> CO2Et <sup>O</sup> CO2Et \* Ph

**Figure 4.** Representative chiral iridium complexes for asymmetric hydrogenation, X = BArF

**Figure 5.** Representative examples of Ir-catalyzed largely unfunctionalized alkenes

### **5.2. Hydrogenation of functionalized alkenes**

Recent studies of iridium-catalyzed asymmetric hydrogenation have significantly broadened its substrate spectrum. Therefore, not only unfuctionalized alkenes but also alkenes with functional groups connected to their C=C double bonds have been hydrogenated with high to excellent enantioselectivity. Figure 6 shows examples of the

Ar2P N

Ir (cod)

> N P Ar Ar

Me

P Ir N O

EtO2C

Ph

cat. **49**: 95% ee

(cod)

**51**

cat. **42**: 99% ee cat. **44**: 99% ee cat. **45**: 99% ee cat. **54**: 99% ee

R1 R1 O

S N

R2

Ph

Ph

+ X–

Ir+(cod) X–

<sup>+</sup> X–

**Figure 4.** Representative chiral iridium complexes for asymmetric hydrogenation, X = BArF

*t*-Bu

**47 48 49 50**

R O

P

Ph Ph

N R1

N

P N O

cat. **49**: 97% ee

Ar Ar

R Ir+(cod) X–

Ir+(cod) X–

R2

Ar Ar

N Ir+(cod) X– <sup>P</sup>

R

O

R1 R1

O P N

Ir (cod)

**42 43 44 45 46**

O

+ X–

R2

O P

R2 R2 N

O

O O

Bu-*t*

*t*-Bu

**52 53 54**

cat. **53**: 99% ee

cat. **45**: 37% ee

P N <sup>O</sup>

Bu-*t*

Ir (cod)

R

+ X–

Ir (cod)

R1

n

N

<sup>+</sup> X–

Ph

S N

<sup>+</sup> <sup>X</sup>–

Ph

<sup>+</sup> <sup>X</sup>–

Ir+(cod) X–

P Ar Ar

P Ir N

O

(cod)

Ir

*i*-Pr

cat. **53**: 65% ee F3C OMe

<sup>O</sup> <sup>N</sup> <sup>N</sup>

N

(cod) Pr-*i*

cat. **51**: 96% ee

Ph Ph

Ir+(cod) X–

<sup>O</sup> <sup>P</sup> Ar Ar

**Figure 5.** Representative examples of Ir-catalyzed largely unfunctionalized alkenes

cat. **46**: 99% ee

Ph

Ph

Recent studies of iridium-catalyzed asymmetric hydrogenation have significantly broadened its substrate spectrum. Therefore, not only unfuctionalized alkenes but also alkenes with functional groups connected to their C=C double bonds have been hydrogenated with high to excellent enantioselectivity. Figure 6 shows examples of the

MeO

**5.2. Hydrogenation of functionalized alkenes** 

Me

**Figure 6.** Representative examples of Ir-catalyzed asymmetric hydrogenation of functionalized alkenes

hydrogenation of allyl alcohols [61], furan rings [62], -dehydroamino acid derivatives [63], ,β-unsaturated ketones [64],,β-unsaturated carboxylic acid esters [61], -alkoxy ,βunsaturated acids [65], vinylphosphine oxides [66], enol phosphinates [67], vinyl boronates [68], and enamines [69,70]. Notably, substituted furans, vinyl boronates, and even enamines are hydrogenated with full conversion in high to excellent enantioselectivity.

Asymmetric Hydrogenation 25

Chiral complexes of titanium, zirconium, and lanthanides exhibit unique asymmetric hydrogenation properties, although at present, their practical use is limited to some special cases. Some late transition metals, such as palladium, cobalt, iron, and copper, are known to have potential utility in homogeneous asymmetric hydrogenation. The use of inexpensive metal complexes is clearly attractive for the manufacture of useful optically active

Asymmetric hydrogenation is a perfect atom-economic reaction, is usually carried out under mild conditions, and proceeds with an essentially quantitative yield. Undoubtedly, it is one of the most environmentally benign reactions and hence further investigations, using a variety of chiral metal catalysts, should allow the development of much more efficient and

[1] Akahori, S.; Sakurai, S.; Izumi, Y. & Fujii, Y. (1956), An Asymmetric Catalyst, *Nature*,

[2] Knowles, W.S. & Sabacky, M.J. (1968), Catalytic Asymmetric Hydrogenation Employing a Soluble Optically Active Rhodium Complex, *Chemical Comunications*, Vol.1968, pp.

[3] Horner, L.; Siegel, H. & Büthe, H. (1968), Asymmetric Catalytic Hydrogenation with an Optically Active Phosphinerhodium Complex in Homogeneous Solution, *Angewandte* 

[4] Dang, T.P. & Kagan, H.B. (1971), Asymmetric Synthesis of Hydratropic Acid and Amino Acids by Homogeneous Catalytic Hydrogenation, *Chemical Communications,* Vol.1971, p.

[5] Kagan, H.B. & Dang, T.P. (1972), Asymmetric Catalytic Reduction with Transition Metal Complexes. I. Catalytic System of Rhodium(I) with (–)-2,3-*O*-Isopropylidene-2,3 dihydroxy-1,4-bis-(diphenylphosphino)butane, a New Chiral Diphosphine, *Journal of* 

[6] Knowles, W.S.; Sabacky, M.J.; Vineyard, B.D. & Weinkauff, D.J. (1975), Asymmetric Hydrogenation with a Complex of Rhodium and a Chiral Bisphosphine, *Journal of the* 

[7] Knowles, W.S. (2002), Asymmetric Hydrogenations, *Angewandte Chemie International* 

[8] Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T. & Noyori, R. (1980), Synthesis of 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), an Atropisomeric Chiral Bis(triaryl)phosphine, and Its Use in the Rhodium(I)-Catalyzed Asymmetric

convenient methodologies for the preparation of optically active compounds.

*Nippon Chemical Industrial Co., Ltd. and Chiba University, Japan* 

*Chemie International Edition in English*, Vol.7, p. 942

*the American Chemical Society*, Vol.94, pp. 6429-6433

*American Chemical Society*, Vol.97, pp. 2567-2568

*Edition*, Vol.41, pp. 1998-2007.

compounds by asymmetric hydrogenation.

**Author details** 

Tsuneo Imamoto

**7. References** 

Vol.178, p. 323

1445-1446

481

### **5.3. Hydrogenation of simple ketones**

It is well known that chiral iridium catalysts are applicable to the enantioselective hydrogenation of imines [71]. Recently, it has been shown that ketones, including ,βunsaturated ketones, are also efficiently hydrogenated when iridium catalysts are used with P,N-ligands [72,73]. In contrast to the iridium complexes used with bidentate P,N-ligands, which tend to lose their activity under hydrogenation conditions, the complexes used with tridentate complexes resist deactivation and eventually exhibit high catalytic activity [73]. A typical example obtained by the use of catalyst **57** is shown in Scheme 20. The exceedingly high turnover number (TON), turnover frequency (TOF), and excellent enantioselectivity are comparable to those of chiral ruthenium complexes and indicate their great potential utility in the production of chiral secondary alcohols from ketones.

**Scheme 21.** Ir-catalyzed asymmetric hydrogenation of acetophenone

### **6. Conclusion**

Since the discovery of homogeneous asymmetric hydrogenation, this area has progressed significantly over the past four decades. A variety of alkenes, including unfunctionalized alkenes, are hydrogenated enantioselectively using transition metal complexes with chiral ligands. Rhodium, ruthenium, and iridium are most frequently used as the center metals of these complexes, and the methods involving these complexes have become common processes in the efficient preparation of the chiral building blocks of natural products, pharmaceuticals, agrochemicals, and flavors.

Chiral complexes of titanium, zirconium, and lanthanides exhibit unique asymmetric hydrogenation properties, although at present, their practical use is limited to some special cases. Some late transition metals, such as palladium, cobalt, iron, and copper, are known to have potential utility in homogeneous asymmetric hydrogenation. The use of inexpensive metal complexes is clearly attractive for the manufacture of useful optically active compounds by asymmetric hydrogenation.

Asymmetric hydrogenation is a perfect atom-economic reaction, is usually carried out under mild conditions, and proceeds with an essentially quantitative yield. Undoubtedly, it is one of the most environmentally benign reactions and hence further investigations, using a variety of chiral metal catalysts, should allow the development of much more efficient and convenient methodologies for the preparation of optically active compounds.

### **Author details**

24 Hydrogenation

hydrogenation of allyl alcohols [61], furan rings [62], -dehydroamino acid derivatives [63], ,β-unsaturated ketones [64],,β-unsaturated carboxylic acid esters [61], -alkoxy ,βunsaturated acids [65], vinylphosphine oxides [66], enol phosphinates [67], vinyl boronates [68], and enamines [69,70]. Notably, substituted furans, vinyl boronates, and even enamines

It is well known that chiral iridium catalysts are applicable to the enantioselective hydrogenation of imines [71]. Recently, it has been shown that ketones, including ,βunsaturated ketones, are also efficiently hydrogenated when iridium catalysts are used with P,N-ligands [72,73]. In contrast to the iridium complexes used with bidentate P,N-ligands, which tend to lose their activity under hydrogenation conditions, the complexes used with tridentate complexes resist deactivation and eventually exhibit high catalytic activity [73]. A typical example obtained by the use of catalyst **57** is shown in Scheme 20. The exceedingly high turnover number (TON), turnover frequency (TOF), and excellent enantioselectivity are comparable to those of chiral ruthenium complexes and indicate their great potential

Ph Me

91% yield 98% ee

<sup>N</sup> <sup>N</sup> Ar = 3,5-(*t*-Bu)2C6H3

H OH

S/C = 5,000,000 TON = 4,550,000 TOF = 12,600/h

Since the discovery of homogeneous asymmetric hydrogenation, this area has progressed significantly over the past four decades. A variety of alkenes, including unfunctionalized alkenes, are hydrogenated enantioselectively using transition metal complexes with chiral ligands. Rhodium, ruthenium, and iridium are most frequently used as the center metals of these complexes, and the methods involving these complexes have become common processes in the efficient preparation of the chiral building blocks of natural products,

Me

are hydrogenated with full conversion in high to excellent enantioselectivity.

utility in the production of chiral secondary alcohols from ketones.

Ir-catalyst

EtOH, *t*-BuOK 15 days

> Ar2 P

> > **57**

Ir Cl H

H H

**Scheme 21.** Ir-catalyzed asymmetric hydrogenation of acetophenone

pharmaceuticals, agrochemicals, and flavors.

**6. Conclusion** 

Ph Me

+ H2

100–60 atm

Ir-catalyst =

O

**5.3. Hydrogenation of simple ketones**

Tsuneo Imamoto *Nippon Chemical Industrial Co., Ltd. and Chiba University, Japan* 

### **7. References**


Hydrogenation of -(Acylamino)acrylic Acids, *Journal of the American Chemical Society*, Vol.102, pp. 7932-7934

Asymmetric Hydrogenation 27

Highly Enantioselective Hydrogenation Reactions, *Journal of the American Chemical* 

[24] Yamanoi, Y. & Imamoto, T. (1999), Methylene-Bridged P-Chiral Diphosphines in Highly Enantioselective Reactions, *Journal of Organic Chemistry*, Vol.64, pp. 2988-2989 [25] Halpern, J. (1982), Mechanism and Stereoselectivity of Asymmetric Hydrogenation,

[26] Halpern, J. (1985), Asymmetric Catalytic Hydrogenation: Mechanism and Origin of Enantioselection, In: *Asymmetric Synthesis*, J.D. Morrison (Ed.), Vol.5, Chapter 2, pp. 41-

[27] Brown, J.M. (1999), Hydrogenation of Functionalized Carbon-Carbon Double Bonds, In: *Comprehensive Asymmetric Catalysis*, Vol. 2, E.N. Jacobsen, A. Pfaltz & H. Yamamoto

[28] Brown, J.M. (2007), Mechanism of Enantioselective Hydrogenation, In: *Handbook of Homogeneous Hydrogenation*, Vol.3, J.G. de Vries & C.J. Elsevier (Eds.), pp. 1073-1103,

[29] Gridnev, I.D.; Higashi, N.; Asakura, K. & Imamoto, T. (2000), Mechanism of Asymmetric Hydrogenation Catalyzed by a Rhodium Complex of (*S*,*S*)-1,2-Bis(*tert*butylmethylphosphino)ethane. Dihydride Mechanism of Asymmetric Hydrogenation,

[30] Gridnev, I.D. & Imamoto, T. (2004), On the Mechanism of Stereoselection in Rh-Catalyzed Asymmetric Hydrogenation: A General Approach for Predicting the Sense of

[31] Gridnev, I.D.; Imamoto, T.; Hoge, G.; Kouchi, M. & Takahashi, H. (2008), Asymmetric Hydrogenation Catalyzed by a Rhodium Complex of (*R*)-(*tert*-Butylmethylphosphino)(di-*tert*-butylphosphino)methane: Scope of Enantioselectivity and Mechanistic Study, *Journal of the American Chemical Society*, Vol.130, No.8, pp. 2560-

[32] Gridnev, I.D. & Imamoto, T. (2009), Mechanism of Enantioselection in Rh-Catalyzed Asymmetric Hydrogenation. The Origin of Utmost Catalytic Performance, *Chemical* 

[33] Imamoto, T.; Tamura, K.; Zhang, Z.; Horiuchi, Y.; Sugiya, M.; Yoshida, K.; Yanagisawa, A. & Gridnev, I.D. (2012). Rigid P-Chiral Phosphine Ligands with *tert*-Butylmethylphosphino Groups for Rhodium-Catalyzed Asymmetric Hydrogenation of Functionalized Alkenes, *Journal of the American Chemical Society*, Vol.134, pp. 1754-1769 [34] Liu, Z.; Lin, S.; Li, W.; Zhu, J.; Liu, X.; Zhang, X.; Lu, H.; Xiong, F. & Tian, Z. (2011), Enantioselective Synthesis of Cycloalkenyl-Substituted Alanines, U.S. Pat. Appl. Publ.,

[35] Wallace, D.J.; Campos, K.R.; Shultz, C.S.; Klapars, A.; Zewge, D.; Crump, B.R.; Phenix, B.D.; McWilliams, C.; Krska, S.; Sun, Y.; Chen, C. & Spindler, F. (2009), New Efficient Asymmetric Synthesis of Taranabant, a CB1R Inverse Agonist for the Treatment of

[36] Sun, Y.; Krska, S.; Shultz, C.S.; & Tellers, D.M. (2010), Enabling Asymmetric Hydrogenation for the Design of Efficient Synthesis of Drug Substances, In: *Asymmetric* 

Obesity, *Organic Process Research & Development*, Vol.13, pp. 84-90

(Eds.), pp. 121-182, ISBN 3-540-64336-2, Springer-Verlag, Berlin, Germany

ISBN: 978-3-527-31161-3, Wiley-VCH; Weinheim, Germany

*Journal of the American Chemical Society*, Vol.122, pp. 7183-7194

Enantioselectivity, *Accounts of Chemical Research*, Vol. 37, pp. 633-644

*Society*, Vol.120, pp. 1635-1636

*Science*, Vol.217, pp. 401-407

2572

69, Academic Press, New York, USA

*Communications*, No.48, pp. 7447-7464

US 20110257408 A1 20111020


Highly Enantioselective Hydrogenation Reactions, *Journal of the American Chemical Society*, Vol.120, pp. 1635-1636

[24] Yamanoi, Y. & Imamoto, T. (1999), Methylene-Bridged P-Chiral Diphosphines in Highly Enantioselective Reactions, *Journal of Organic Chemistry*, Vol.64, pp. 2988-2989

26 Hydrogenation

Vol.102, pp. 7932-7934

*Letter*, Vol.34, pp. 3149-3150

VCH; Weinheim, Germany

436, Wiley, ISBN 978-0-470-17577-4

527-32704-1, Weinheim, Germany

3-527-31746-2, Weinheim, Germany

*Chemical Society*, Vol.112, pp. 5244-5252

New York, USA

1049-1072, ISBN: 978-3-527-31161-3

*International Edition*, Vol.41, No.12, pp. 2008-2022.

*International Edition in English*, Vol.32, pp. 566-568

Hydrogenation of -(Acylamino)acrylic Acids, *Journal of the American Chemical Society*,

[9] Noyori, R. (2002), Asymmetric Catalysis: Science and Opportunities, *Angewandte Chemie* 

[10] Matt, P.V. & Pfaltz, A. (1993), Chiral Phosphinoaryldihydrooxazoles as Ligands in Asymmetric Catalysis: Pd-Catalyzed Allylic Substitution, *Angewandte Chemie* 

[11] Sprinz, J. & Helmchem, G. (1993), Phosphinoaryl- and Phosphinoalkyloxazolines as New Chiral Ligands for Enantioselective Catalysis: Very High Enantioselectivity in Palladium Catalyzed Allylic Substitutions, *Tetrahedron Letters*, Vol.34, pp. 1769-1772 [12] Dawson, G.J.; Frost, C.G. & Williams, J.M.J. (1993), Asymmetric Palladium Catalyzed Allylic Substitution Using Phosphorus Containing Oxazoline Ligands, *Tetrahedron* 

[13] Pfaltz, A. & Bell, S. (2007) Enantioselective Hydrogenation of Unfunctionalized Alkenes, In: *Handbook of Homogeneous Hydrogenation*, Vol.3, J.G. de Vries & C.J. Elsevier (Eds.), pp.

[14] Woodmansee, D.H. & Pfaltz, A. (2011), Asymmetric Hydrogenation of Alkenes Lacking

[15] Noyori, R. (1994). *Asymmetric Catalysis in Organic Synthesis*, Wiley, ISBN 0-471-57267-5,

[16] Noyori, R. & Ohkuma, T. (2001), Asymmetric Catalysis by Architectural and Functional Molecular Engineering: Practical Chemo- and Stereoselective Hydrogenation of

[17] Ohkuma, T. & Noyori, R. (2007), Enantioselective Ketone and β-Keto Ester Hydrogenations (Including Mechanisms), In: *Handbook of Homogeneous Hydrogenation*, Vol.3, J.G. de Vries & C.J. Elsevier (Eds.), pp. 1105-1163, ISBN: 978-3-527-31161-3, Wiley-

[18] Shang, G.; Li, W. & Zhang, X. (2010). Transition Metal-Catalyzed Homogeneous Asymmetric Hydrogenation, In: *Catalytic Asymmetric Synthesis*, I. Ojima, (Ed.), pp. 343-

[19] Tang, W. & Zhang, X. (2003). New Chiral Phosphorus Ligands for Enantioselective

[20] Zhou, Q.-L. (Ed.) (2011) *Privileged Chiral Ligands and Catalysts*, Wiley-VCH, ISBN 978-3-

[21] Börner, A. Ed. (2008). *Phosphorus Ligands in Asymmetric Catalysis*, Wiley VCH, ISBN 978-

[22] Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T. & Sato, K. (1990), Synthesis and Reactions of Phosphine–Boranes. Synthesis of New Bidentate Ligands with Homochiral Phosphine Centers via Optically Pure Phosphine–Boranes, *Journal of the American* 

[23] Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta, H.; Matsukawa, S. & Yamaguchi, K. (1998), P-Chiral Bis(trialkylphosphine) Ligands and Their Use in

Coordinating Groups, *Chemical Communications*, Vol.47, pp. 7912-7916

Ketones, *Angewandte Chemie International Edition*, Vol.40, pp. 40-73

Hydrogenation, *Chemical Reviews*, Vol.103, pp. 3029-3069


*Catalysis on Industrial Scale*, Second Ed., H.-U. Blaser & H.-J. Federsel (Eds.), pp. 333-376, ISBN: 978-3-527-32489-7

Asymmetric Hydrogenation 29

[49] Sandoval, C.A.; Ohkuma, T.; Muniz, K. & Noyori, R. (2003), Mechanism of Asymmetric Hydrogenation of Ketones Catalyzed by BINAP/1,2-Diamine-Ruthenium(II)

[50] Lightfoot, A.; Schnider, P. & Pfaltz, A. (1998), Enantioselective Hydrogenation of Olefins with Iridium–Phosphanodihydrooxazole Catalysts, *Angewandte Chemie International* 

[51] Crabtree, R.H.; Felkin, H. & Morris, G.E. (1977), Cationic Iridium Diolefin Complexes as Alkene Hydrogenation Catalysts and the Isolation of Some Related Hydrido

[52] Crabtree, R.H. (1979), Iridium Compounds in Catalysis, *Accounts of Chemical Research*,

[53] Smidt, S.P.; Zimmermann, N.; Studer, M. & Pfaltz, A. (2004), Enantioselective Hydrogenation of Alkenes with Iridium-PHOX Catalysts: A Kinetic Study of Anion

[54] Roseblade, S.J. & Pfaltz, A. (2007), Iridium-Catalyzed Asymmetric Hydrogenation of

[55] Woodmansee, D. H. & Pfaltz, A. (2011), Asymmetric Hydrogenation of Alkenes Lacking

[56] Church, T.L. & Andersson, P.G. (2008), Iridium Catalysts for the Asymmetric Hydrogenation of Olefins with Nontraditional Functional Substituents, *Coordination* 

[57] Pamies, O.; Andersson, P.G. & Diéguez, M. (2010), Asymmetric Hydrogenation of Minimally Functionalised Terminal Olefins: An Alternative Sustainable and Direct Strategy for Preparing Enantioenriched Hydrocarbons, *Chemistry: A European Journal*,

[58] Cui, X. & Burgess, K. (2005), Catalytic Homogeneous Asymmetric Hydrogenation of

[59] Perry, M.C.; Cui, X.; Powell, M.T.; Hou, D.-R.; Reibenspies, J.H. & Burgess, K. (2003), Optically Active Iridium Imidazol-2-ylidene-oxazoline Complexes: Preparation and Use in Asymmetric Hydrogenation of Arylalkanes, *Journal of the American Chemical Society*,

[60] Bell, S.; Wüstenberg, B.; Kaiser, S.; Menges, F.; Netscher, T. & Pfaltz, A. (2006), Asymmetric Hydrogenation of Unfunctionalized, Purely Alkyl-Substituted Olefins,

[61] Källström, K.; Hedberg, C.; Brandt, P.; Bayer, A. & Andersson, P.G. (2004), Rationally Designed Ligands for Asymmetric Iridium-Catalyzed Hydrogenation of Olefins, *Journal* 

[62] Kaiser, S.; Smidt, S.P. & Pfaltz, A. (2006), Iridium Catalysts with Bicyclic Pyridine-Phosphinite Ligands: Asymmetric Hydrogenation of Olefins and Furan Derivatives,

[63] Bunlaksananusorn, T.; Polborn, K. & Knochel, P. (2003), New P,N Ligands for Asymmetric Ir-Catalyzed Reactions, *Angewandte Chemie International Edition*, Vol.42, pp.

Largely Unfunctionalized Alkenes, *Chemical Reviews*, Vol.105, pp. 3272-3296

Complexes, *Journal of the American Chemical Society*, Vol.125, pp. 13490-13503

Complexes, *Journal of Organometallic Chemistry*, Vol.141, pp. 205-215

Effects, *Chemistry: A European Journal*, Vol.10, pp. 4685-4693

Olefins, *Accounts of Chemical Research*, Vol.40, pp. 1402-1411

*of the American Chemical Society*, Vol.126, pp. 14308-14309

*Angewandte Chemie International Edition*, Vol.45, pp. 5194-5197

*Chemistry Reviews*, Vol.252, pp. 513-531

Vol.16, pp. 14232-14240

Vol.125, pp. 113-123

3941-3943

*Science*, Vol.311, pp. 642-644

Coordinating Groups, *Chemical Communications*, Vol.47, pp. 7912-7916

*Edition*, Vol.37, pp. 2897-2899

Vol.12, pp. 331-337


[49] Sandoval, C.A.; Ohkuma, T.; Muniz, K. & Noyori, R. (2003), Mechanism of Asymmetric Hydrogenation of Ketones Catalyzed by BINAP/1,2-Diamine-Ruthenium(II) Complexes, *Journal of the American Chemical Society*, Vol.125, pp. 13490-13503

28 Hydrogenation

ISBN: 978-3-527-32489-7

Vol.111, pp. 9134-9135

Vol.117, pp. 2931-2932

Vol.86, pp. 202-219

10699

*Research*, Vol.40, pp. 1385-1393

110

*Catalysis on Industrial Scale*, Second Ed., H.-U. Blaser & H.-J. Federsel (Eds.), pp. 333-376,

[37] Hoge, G.; Wu, H.-P.; Kissel, W.S.; Pflum, D.A.; Greene, D.J. & Bao, J. (2004), Highly Selective Asymmetric Hydrogenation Using a Three Hindered Quadrant Bisphosphine

[39] Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya, H. & Noyori, R. (1994), General Asymmetric Synthesis of Isoquinoline Alkaloids. Enantioselective Hydrogenation of Enamides Catalyzed by BINAP-Ruthenium(II) Complexes, *The* 

[40] Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H. & Akutagawa, S. (1987), Asymmetric Hydrogenation of β-Keto Carboxylic Esters. A Practical, Purely Chemical Access to β-Hydroxy Esters in High Enantiomeric Purity,

[41] Kitamura, M.; Tokunaga, M. & Noyori, R. (1993), Quantitative Expression of Dynamic Kinetic Resolution of Chirally Labile Enantiomers: Stereoselective Hydrogenation of 2- Substituted 3-Oxo Carboxylic Esters Catalyzed by BINAP-Ruthenium(II) Complexes,

[42] Noyori, R.; Tokunaga, M. & Kitamura, M. (1995), Stereoselective Organic Synthesis via Dynamic Kinetic Resolution, *Bulletin of the Chemical Society of Japan*, Vol.68, pp. 36-56 [43] Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T. & Kumobayashi, H. (1989), Stereoselective Hydrogenation via Dynamic Kinetic Resolution, *Journal of the American Chemical Society*,

[44] Ohkuma, T.; Kitamura, M. & Noyori, R. (2000), Asymmetric Hydrogenation, in *Catalytic Asymmetric Synthesis*, 2nd edn (Ed. Ojima, I.), John Wiley & Sons, Inc., New York, pp. 1-

[45] Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N. & Saito, T. (2007), Developments in Asymmetric Hydrogenation from an Industrial Perspective, *Accounts of Chemical* 

[46] Kitamura, M.; Tokunaga, M. & Noyori, R. (1995), Asymmetric Hydrogenation of β-Keto Phosphonates: A Practical Way to Fosfomycin, *Journal of the American Chemical Society*,

[47] Ohkuma, T. (2010), Asymmetric Hydrogenation of Ketones: Tactics to Achieve High Reactivity, Enantioselectivity, and Wide Scope, *Proceedings of the Japan Academy, Ser. B*,

[48] Matsumura, K.; Arai, N.; Hori, K.; Saito, T.; Sayo, N.; Ohkuma, T. (2011), Chiral Ruthenabicyclic Complexes: Precatalysts for Rapid, Enantioselective, and Wide-Scope Hydrogenation of Ketones, *Journal of the American Chemical Society*, Vol.133, pp. 10696-

Rhodium Catalyst, *Journal of the American Chemical Society*, Vol.126, pp. 5966-5967 [38] Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; & Noyori, R. (1987), Enantioselective Hydrogenation of Allylic and Homoallylic

Alcohols, *Journal of the American Chemical Society*, Vol.109, pp. 1596-1597

*Journal of Organic Chemistry*, Vol.59, pp. 297-310

*Journal of the American Chemical Society*, Vol.109, pp. 5856-5858

*Journal of the American Chemical Society*, Vol.115, pp. 144-152


[64] Lu, W.-J.; Chen, Y.-W. & Hou, X.-L. (2008), Iridium-Catalyzed Highly Enantioselective Hydrogenation of the C=C Bond of ,β-Unsaturated Ketones, *Angewandte Chemie International Edition*, Vol.48, pp. 10133-10136

**Chapter 2** 

© 2012 Štefane and Požgan, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 Štefane and Požgan, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Asymmetric Hydrogenation and Transfer** 

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 stereo- and 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

**2. Homogenous, asymmetric hydrogenation and transfer hydrogenation** 

Since the application of very efficient, chiral BINAP-derived ruthenium complexes in the AH of functionalized ketones (β-keto esters) at a high enantioselectivity level in the homogenous phase (Noyori et al., 1987), the development of more robust and reactive molecular catalysts is still highly desirable. Furthermore, because of the structural and functional diversity of organic substrates, no universal catalysts exist. Ruthenium complexes bearing chiral ligands are among the most commonly used catalysts for AH and ATH,

**Hydrogenation of Ketones** 

Additional information is available at the end of the chapter

Bogdan Štefane and Franc Požgan

http://dx.doi.org/10.5772/47752

on the metal center of the catalyst.

**1. Introduction** 


**Chapter 2** 
