Privileged Chiral Ligands and Catalysts E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 603

Veröffentlichungsjahr: 2011

Beschreibung

Catalytic asymmetric synthesis has been one of the most active research areas in chemistry (Nobel Prize in 2001). The development of efficient chiral catalysts plays a crucial role in asymmetric catalysis. Although many chiral ligands/catalysts have been developed in the past decades, the most efficient catalysts are derived from a few core structures, called "privileged chiral catalysts". This ultimate "must have" and long awaited reference for every chemist working in the field of asymmetric catalysis starts with the core structure of the catalysts, explaining why a certain ligand or catalyst is so successful. It describes in detail the history, the basic structural characteristics, and the applications of these "privileged catalysts". This novel presentation provides readers with a much deeper insight into the topic and makes it a must-have for organic chemists, catalytic chemists, chemists working with/on organometallics, chemists in industry, and libraries.

From the contents:
* BINAP
* Bisphosphacycles - From DuPhos and BPE to a Diverse Set of Broadly Applied Ligands
* Josiphos Ligands: From Discovery to Technical Applications
* Chiral Spiro Ligands
* Chiral Bisoxazoline Ligands
* PHOX Ligands
* Chiral Salen Complexes
* BINOL
* TADDOLate Ligands
* Cinchona Alkaloids
* Proline Derivatives

Leseprobe

Contents

Preface

List of Contributors

Chapter 1: BINAP

1.1 Introduction: Structural Consideration

1.2 Hydrogenation of Olefins

1.3 Hydrogenation of Ketones

1.4 Isomerization of Allylamines and Allylalcohols

1.5 Hydroboration, Hydrosilylation, Hydroacylation, and Hydroamination

1.6 Allylic Alkylation

1.7 Heck Reaction

1.8 Aldol and Mannich-Type Reactions

1.9 Nucleophilic Additions to Carbonyl and Imino Compounds

1.10 α-Substitution Reactions of Carbonyl Compounds

1.11 Michael-Type Reactions

1.12 Conjugate Additions Using Organoboron and Grignard Reagents

1.13 Diels–Alder Reaction

1.14 Ene Reaction

1.15 Cyclization

1.16 Ring-Opening Reactions

1.17 Concluding Remarks

Chapter 2: Bisphosphacycles – From DuPhos and BPE to a Diverse Set of Broadly Applied Ligands

2.1 Introduction

2.2 Development of Bisphosphacycle Ligands

2.3 Applications of Bisphosphacycle Ligands

2.4 Concluding Remarks

Chapter 3: Josiphos Ligands: From Discovery to Technical Applications

3.1 Introduction and Background

3.2 Discovery and Development of the Josiphos Ligand Family

3.3 Why Are Josiphos Ligands So Effective?

3.4 Catalytic Profile of the Josiphos Ligand Family

3.5 Concluding Remarks

Chapter 4: Chiral Spiro Ligands

4.1 Introduction

4.2 Preparation of Chiral Spiro Ligands

4.3 Asymmetric Hydrogenation

4.4 Asymmetric Carbon–Carbon Bond Forming Reaction

4.5 Asymmetric Carbon–Heteroatom Bond Forming Reaction

4.6 Conclusion

Chapter 5: Chiral Bisoxazoline Ligands

5.1 Introduction

5.2 Enantioselective Carbon–Carbon Bond Formation

5.3 Enantioselective Carbon–Heteroatom Bond Formation

5.4 Enantioselective Cycloaddition Reactions

5.5 Conclusions

Chapter 6: PHOX Ligands

6.1 Introduction

6.2 Synthesis of PHOX Ligands

6.3 Nucleophilic Allylic Substitution

6.4 Decarboxylative Tsuji Allylations

6.5 Heck Reaction

6.6 Hydrogenation

6.7 Cycloadditions

6.8 Miscellaneous Reactions

6.9 Conclusion

Chapter 7: Chiral Salen Complexes

7.1 Introduction

7.2 Synthesis of Chiral Salen Complexes

7.3 Structural Properties of Chiral Salen Complexes

7.4 Asymmetric Reactions Catalyzed by Chiral Salen Complexes

7.5 Conclusion and Outlook

Chapter 8: BINOL

8.1 Introduction

8.2 Applications in Reduction and Oxidation

8.3 Metal/BINOL Chiral Lewis Acid Catalysts in Asymmetric C–C Bond Forming Reactions

8.4 Acid/Base Bifunctional Metal/BINOL Catalysts

8.5 BINOL in Organocatalysis

8.6 Summary

Chapter 9: TADDOLate Ligands

9.1 Introduction

9.2 Nucleophilic Additions to C=O Double Bonds

9.3 Nucleophilic Conjugate Additions to Electron-Deficient C=C Double Bonds

9.4 Nucleophilic Substitutions

9.5 Cycloaddition Reactions

9.6 Oxidation and Reduction Reactions

9.7 Miscellaneous Reactions

9.8 Conclusions

Chapter 10: Cinchona Alkaloids

10.1 Introduction

10.2 Metal Catalysis

10.3 Phase-Transfer Catalysis

10.4 Nucleophilic Catalysis

10.5 Base Catalysis

10.6 Cooperative and Multifunctional Catalysis

10.7 Conclusion

10.8 Acknowledgments

Chapter 11: Proline Derivatives

11.1 Introduction

11.2 Proline as Organocatalyst

11.3 Proline Analogs as Organocatalysts

11.4 5-Pyrrolidin-2-yltetrazole as Organocatalyst

11.5 Pyrrolidine-Based Sulfonamides as Organocatalysts

11.6 Pyrrolidine-Based Amides as Organocatalysts

11.7 Pyrrolidine Diamine Catalysts

11.8 Diarylprolinols or Diarylprolinol Ether Catalysts

11.9 Concluding Remarks

Index

The Editor

Prof. Qi-Lin Zhou

Nankai University

Institute of Elemento-Organic Chemistry

94 Weijin Road

Tianjin 300071

China

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2011 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

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Preface

Catalytic asymmetric synthesis has been one of the most active research areas in modern chemistry. Asymmetric catalyses with enzymes, chiral metal complexes, and chiral organic molecules have emerged as successful and powerful tools in asymmetric synthesis. Among the three catalytic asymmetric processes, artificial metal complex catalysis and organocatalysis have only a very short history compared to traditional biocatalysis but are now a predominant part of asymmetric synthesis in both research and application. The development of efficient synthetic chiral catalysts, including chiral metal complex catalysts modified with various chiral ligands and chiral organo-molecule catalysts, is at the center of research in asymmetric catalysis. Although numerous chiral ligands as well as chiral catalysts have been reported in past decades, only a handful of them, rooted in a very few core structures, can be regarded as truly successful in demonstrating proficiency in various mechanistically unrelated reactions. Researchers have designated chiral catalysts showing good enantioselectivity over a wide range of different reactions as “privileged chiral catalysts,” a term coined by Jacobsen. The essential feature that makes a catalyst “privileged” is its scaffold (core structure). To understand the relationship between the structure of a “privileged” catalyst and its catalytic features in reactions is the key to opening the door to designing more efficient catalysts. Furthermore, a deep insight into the structural characteristics of the most successful catalysts so far reported will facilitate the selection of appropriate catalysts in developing new asymmetric processes. However, available books on asymmetric synthesis have focused predominantly on asymmetric reactions, making it difficult to perceive the suite of chiral catalysts in terms of structural characteristics and catalytic abilities. This book, Privileged Chiral Ligands and Catalysts, tells the stories of these ligands and catalysts from the core structure point of view, a rarity in previous books. This book is a timely overview of a few popularly used chiral ligands and catalysts, focused on their structural aspects and the relationship between the structure of catalysts and their success in catalytic operations.

It is not the goal, and it would be an almost impossible undertaking, to provide a comprehensive book on chiral ligands and catalysts. To illustrate clearly the key points of “privileged” chiral ligands and catalysts in a 400-page book we have selected eleven ligands and catalysts as examples to discuss in detail, namely, BINAP, DuPhos, Josiphos, spiro ligands, BOX, PHOX, Salen complexes, BINOL, TADDOL, cinchona alkaloids, and proline, rather than examining all of the high-profile candidates. Among the eleven, BINAP, DuPhos, Josiphos, spiro ligands, BOX, and PHOX are chiral ligands in metal catalysts; Salen complexes are chiral metal catalysts, and cinchona alkaloids and proline are generally used as organocatalysts. BINOL and TADDOL were used as chiral ligands in Lewis acid catalysts in earlier studies but recently they have also been used as organocatalysts in various reactions. The editor, based solely on personal taste, has sought to arrange the presentation of the eleven ligands or catalysts by starting with ligands, then addressing metal catalysts and organocatalysts. Although the selection is subjective we believe that the important ligands and catalysts in the field of asymmetric synthesis are included and that the general aspects of ligand and catalyst design will thus be fully exhibited through these eleven examples.

The eleven selected ligands or catalysts are independent of each other and so, as a result, each chapter in this book provides an individual overview of each one. Although the authors responsible for each chapter were given sufficient freedom to organize their material, we encouraged them to provide a short discussion of the family of ligands or catalysts to which the individual ligand or catalyst belongs. It is beneficial to readers to see the full spectrum of the ligands or catalysts rooted on the same scaffolds. Each chapter also emphasizes the chiral-inducing models of metal catalysts or organocatalysts to illustrate the transfer of chirality from catalysts to substrates in different reactions. The most successful applications, especially the latest identified reactions of these ligands or catalysts, have been described to support their designation as “privileged” catalytic properties. In contrast, well-known classic applications are discussed only briefly.

The editor believes that the authors have described the most important features of these specific ligands or catalysts discussed in this book. The reader can find the design principle of the chiral ligands and catalysts readily in each chapter. Because many common principles have been considered during the development of the most successful ligands or catalysts, some overlap of these principles inevitably occurs among the chapters. For instance, the features of high chemical robustness and ease of modification can be found in all eleven selected ligands or catalysts. Further, it is generally accepted that the high scaffold rigidity of the ligand or catalyst plays a crucial role in making it “privileged.” Accordingly, the reader may readily notice that almost all of the successful ligands or catalysts contain five- or six-membered rings. In addition to the structural properties of each ligand or catalyst, an easily available starting material is also important. At least three selected ligands and catalysts – proline, cinchona alkaloids, and TADDOL – are derived directly from a “chiral pool.” The chiral moiety of the ligands BOX and PHOX are chiral amino alcohols, derived from natural amino acids. The coordinating atom is another important aspect of ligand design, and the most successful ligands all have phosphorus or nitrogen as the coordinating atom. In addition, the dentate number of chiral ligands and the chelating ring size of catalysts are crucial features for obtaining satisfactory chiral induction.

It is our hope that the new descriptive model in this book will lead readers to constructive thinking about what makes chiral catalysts “privileged” and encourage more creative work for the development of “privileged ligands and catalysts.” If this book is helpful to our colleagues in the chemistry community in their design of chiral ligands or catalysts, selection of appropriate catalysts in their chiral synthesis, or other aspects of their research we believe our goal will have been met.

I am deeply indebted to all chapter authors for their significant contributions to the book. I am grateful to Dr. Elke Maase of Wiley-VCH, who initiated the project of editing this book, and to Lesley Belfit for her support during the editing process. I also thank my colleague Dr. Shou-Fei Zhu for his constructive suggestions in editing this book.

Qi-Lin Zhou

Nankai University

Tianjin, China

List of Contributors

Cory Bausch

University of Basel

Department of Chemistry

St. Johanns-Ring 19 4056 Basel

4056 Basel

Switzerland

Hans-Ulrich Blaser

Solvias AG

P.O. Box

Switzerland

4002 Basel

Yonggang Chen

Brandeis University

Department of Chemistry

415 South St., Waltham

MA 024543

USA

Li Deng

Brandeis University

Department of Chemistry

415 South St., Waltham

MA 024543

USA

Nobuhito Kurono

Hokkaido University, Graduate School of Engineering

Division of Chemical Process Engineering, Laboratory of Organic Synthesis

Sapporo 060- 8628

Japan

Hongming Li

Brandeis University

Department of Chemistry

415 South St., Waltham

MA 024543

USA

Xiao-Bing Lu

Dalian University of Technology

State Key Laboratory of Fine Chemicals

No. 2 Linggong Road

Dalian

Liaoning 116024

China

Shigeki Matsunaga

The University of Tokyo

Graduate School of Pharmaceutical Sciences

Tokyo 113-0033

Japan

Esteban Mejía

ETH Zürich

Laboratorium für Anorganische Chemie

Wolfgang-Pauli-Str. 10

8093 Zürich

Switzerland

Takeshi Ohkuma

Hokkaido University, Graduate School of Engineering

Division of Chemical Process Engineering, Laboratory of Organic Synthesis

Sapporo 060- 8628

Japan

Hélène Pellissier

Université Paul Cézanne – Aix-Marseille III

Institut Sciences Moléculaires de Marseille

Avenue Esc. Normandie-Niemen

13397 Marseille

France

Andreas Pfaltz

University of Basel

Department of Chemistry

St. Johanns-Ring 19

4056 Basel

Switzerland

Benoît Pugin

Solvias AG

P.O. Box

4002 Basel

Switzerland

Masakatsu Shibasaki

The University of Tokyo

Graduate School of Pharmaceutical Sciences

Tokyo 113-0033

Japan

Mukund P. Sibi

North Dakota State University

Department of Chemistry and Molecular Biology

1231 Albrecht Boulevard

Fargo

USA

Felix Spindler

Solvias AG

P.O. Box

4002 Basel

Switzerland

Levi M. Stanley

University of Illinois at Urbana-Champaign

Department of Chemistry

Urbana

USA

Antonio Togni

ETH Zürich

Laboratorium für Anorganische Chemie

Wolfgang-Pauli-Str. 10

8093 Zürich

Switzerland

Wei Wang

University of New Mexico

Department of Chemistry and Chemical Biology

Albuquerque

NM 87131-0001

USA

and

Chinese Academy of Sciences

Shanghai Institute of Materia Medica

Shanghai 201203

China

Shilei Zhang

University of New Mexico

Department of Chemistry and Chemical Biology

Albuquerque

NM 87131-0001

USA

Weicheng Zhang

Nankai University

College of Pharmacy

94 Weijin Road

Tianjin 300071

China

Wen-Zhen Zhang

Dalian University of Technology

State Key Laboratory of Fine Chemicals

No. 2 Linggong Road

Dalian

Liaoning 116024

China

Xumu Zhang

Rutgers, The State University of New Jersey

Department of Chemistry and Chemical Biology

610 Taylor Road

Piscataway

NJ 08854

USA

Qi-Lin Zhou

Nankai University

Institute of Elemento-organic Chemistry

94 Weijin Road

Tianjin 300071

China

Shou-Fei Zhu

Nankai University

Institute of Elemento-organic Chemistry

94 Weijin Road

Tianjin 300071

China

Chapter 1

BINAP

Takeshi Ohkuma and Nobuhito Kurono

1.1 Introduction: Structural Consideration

BINAP (2,2′-diphenylphosphino-1,1′-binaphthyl), which was devised by Ryoji Noyori (winner of the Nobel Prize in Chemistry 2001), is typical among chiral diphosphine ligands [1–3]. BINAP chemistry has contributed notably the development of the field of asymmetric catalysis [1, 4]. This ligand with transition metallic elements forms C2-symmetric chelate complexes. Figure 1.1 indicates the chiral structure created by an (R)-BINAP–transition metal complex. The naphthalene rings of BINAP are omitted in the side view (right-hand side) for clarity. As illustrated in the top view, the axial-chirality information of the binaphthyl backbone is transferred through the P-phenyl rings to the four coordination sites shown by and . The coordination sites placed in the P1–M–P2 plane are sterically influenced by the “equatorial” phenyl rings, whereas the out-of-plane coordination sites, , are affected by the “axial” phenyl groups (side view). Consequently, the two kinds of quadrant of the chiral structure (first and third versus second and forth in the side view) are clearly discriminated spatially, where the second and fourth quadrants are sterically crowded, while the first and third ones are open for approach of substrates and reagents. This chiral structure realizes excellent enantiodifferentiation in various asymmetric catalytic reactions. The flexibility of the binaphthyl backbone appears to enable a wide scope of substrate.

Figure 1.1 Molecular models of an (R)-BINAP–transition metal complex.

The great success of BINAP chemistry has encouraged researchers to develop BINAP derivatives and related chiral biaryl diphosphines [5]. Figure 1.2 illustrates representative examples. As shown in Figure 1.1, substitution manner of P-aryl rings of BINAP ligands obviously affects the chiral structure of metal complexes. TolBINAP, which has P-4-tolyl groups, shows similar enantioselective features to those of BINAP, although the solubility of the metal complexes in organic solvents is increased [6]. XylBINAP and DTBM-BINAP bearing 3,5-dialkyl groups on the P-phenyl rings give better enantioselectivity than that with the original ligand in some cases [6]. The bulkier P-aryl groups seem to make the contrast of congestion in the chiral structure clearer. Diphosphines with a relatively small P1–M–P2 angle in the complexes, that is, MeO-BIPHEP [7], SEGPHOS [8], SYNPHOS (BisbenzodioxanPhos) [9], P-Phos [10], and Difluorphos [11], place the “equatorial” phenyl groups in forward regions, providing highly contrasted chiral structures. The chiral structures are varied by the size of the P1–M–P2 angle. CnTunaphos (n = 1–6) can control the angle by changing the number of CH2 moieties [12]. H8-BINAP [13] and BIPHEMP [14], which are alkylated biphenyl diphosphines, exhibit some unique stereoselective characters. Heteroaromatic biaryl ligands, Bitianp [15] and P-Phos, as well as fluorinated diphosphine, Difluorphos, are expected to add some electronic perturbation in the catalytic systems.

Figure 1.2(R)-BINAP and selected chiral biaryl diphosphines.

In this chapter we introduce typical, but not comprehensive, asymmetric reactions catalyzed by the BINAP–metal complexes, achieving excellent enantioselectivity. Mechanistic considerations for some reactions are commented on with molecular models.

1.2 Hydrogenation of Olefins

In 1980, highly enantioselective hydrogenation of α-(acylamino)acrylic acids and esters catalyzed by the cationic BINAP–Rh(I) complexes was reported [16–18]. For example, (Z)-α-(benzamido)cinnamic acid is hydrogenated with [Rh{(R)-binap}(CH3OH)2]ClO4 to afford (S)-N-benzoylphenylalanine in 100% enantiomeric excess (ee) and 97% yield [substrate/catalyst molar ratio (S/C) = 100, 4 atm H2, room temperature), 48 h, in C2H5OH] (Scheme 1.1). In terms of enantioselectivity this hydrogenation appears to be excellent; however, very careful choice of reaction parameters, such as low substrate concentration and low hydrogen pressure, is required [19–22]. The scope of the olefinic substrates is insufficiently wide.

Scheme 1.1 Hydrogenation of (Z)-α-(benzamido)cinnamic acid with a BINAP–Rh catalyst.

BINAP–Ru(II) catalysis resolved the above problems. Methyl (Z)-α-(acetamido)cinnamate is hydrogenated in the presence of Ru(OCOCH3)2[(R)-binap] (S/C = 200) in CH3OH (1 atm H2, 30 °C, 24 h) to give methyl (R)-α-(acetamido)cinnamate in 92% ee and 100% yield (Scheme 1.2) [17, 23, 24]. Various olefinic substrates, including enamides, α,β- and β,γ-unsaturated carboxylic acids, and allylic and homoallylic alcohols, are converted into the desired products in high ee [25]. About 300 tons per year of optically active citronellol is produced by this hydrogenation [26]. The citronellol synthesis, by the use of a Ru(II) catalyst with a MeO-BIPHEP derivative, is applied to the production of vitamin E [27]. The H8-BINAP–Ru(II) catalyst reduces α,β-unsaturated carboxylic acids with even higher enantioselectivity [28].

Scheme 1.2 Hydrogenation of functionalized olefins catalyzed by BINAP–Ru complexes.

Figure 1.3 illustrates a mechanism for the hydrogenation of methyl (Z)-α-acetamidocinnamate catalyzed by the BINAP–Ru(II) complex [19, 20, 23]. Precatalyst Ru(OCOCH3)2[(R)-binap] [(R)-1] was converted into the RuH(OCOCH3) complex 2, which is an active species, under a H2 atmosphere with release of CH3CO2H. The enamide substrate reversibly coordinates to the Ru center in bidentate fashion, forming 3. Migratory insertion gives 4, followed by Ru–C bond cleavage largely by H2, but also by CH3OH solvent to some extent, resulting in the chiral product and regenerating the catalytic species 2. The stereochemistry of the product is determined at the irreversible step (4→2). Because the reactivities of the two diastereomers of 4 are similar, the enantioselectivity of the product corresponds well to the relative stability (population) of the diastereomeric enamide–RuH(OCOCH3) intermediates [not transition states (TSs)], Si-3 and Re-3 (Figure 1.4). The Si-3 is more favored over the diastereomeric isomer Re-3, because the latter suffers nonbonded repulsion between an equatorial phenyl ring of the (R)-BINAP and the methoxycarbonyl group of substrate. Therefore, the major (favored) intermediate Si-3 is converted into the (R) hydrogenation product via 4.

Figure 1.3 Catalytic cycle of BINAP–Ru catalyzed hydrogenation of methyl (Z)-α-acetamidocinnamate. (For clarity the β-substituents in the substrates are omitted.)

Figure 1.4 Molecular models of diastereomeric (R)-BINAP/enamide Ru complexes 3 (not transition state).

1.3 Hydrogenation of Ketones

1.3.1 Functionalized Ketones

Ru(OCOCH3)2(binap) is feebly active for the hydrogenation of ketones, although it shows remarkable catalytic efficiency for the reaction of functionalized olefins. This problem is resolved simply by replacing the carboxylate ligands with halides. For instance, β-keto esters (R = alkyl) are hydrogenated with RuCl2(binap) (polymeric form; S/C = 2000) in CH3OH (100 atm H2, 30 °C, 36 h) to give the β-hydroxy esters in >99% ee quantitatively (Scheme 1.3) [29, 30]. A turnover number (TON) of 10 000 is achieved in the best cases. Several related complexes exhibit comparable catalytic efficiency, including RuCl2(binap)(dmf)n (oligomeric form) [31], [RuCl(binap)(arene)]Cl [6, 32], [NH2(C2H5)2][{RuCl(binap)}2(μ-Cl)3] [24, 33], and other in situ prepared halogen-containing BINAP–Ru complexes [34]. A range of α-, β-, and γ-hetero substituted ketones as well as difunctionalized ketones and diketones is converted into the chiral alcohols in high ee (Scheme 1.3) [17, 35, 36]. Ruthenium(II) complexes with biaryldiphosphines that have smaller dihedral angles (MeO-BIPHEP [37], P-Phos [10], SEGPHOS [8], and SYNPHOS [9]) hydrogenate an aromatic β-keto ester (R = C6H5) in high stereoselectivity [38]. For the reaction of an analogue with trifluoromethyl group (R = CF3), the Difluorphos–Ru(II) complex exhibits fine enantioselectivity [11]. The electronic deficient character of this ligand is supposed to be important.

Scheme 1.3 Hydrogenation of functionalized ketones catalyzed by BINAP–Ru complexes.

Figure 1.5 shows a plausible catalytic cycle of hydrogenation of β-keto esters mediated by BINAP–Ru(II) complexes [19, 20]. The (R)-BINAP–RuCl2 precatalyst [(R)-5] and H2 generate the active catalytic RuHCl species 6 with release of HCl. The β-keto ester reversibly coordinates to the Ru center of 6, forming the σ-type chelate complex 7. Protonation at the carbonyl oxygen of the substrate increases electrophilic ability of the carbonyl carbon, and induces a change in chelate fashion from σ to π. Therefore, the subsequent migration of hydride on the Ru to the keto-ester carbonyl carbon occurs smoothly, resulting in the hydroxy-ester complex 8. Replacement of the (R) hydroxy ester with solvent molecules gives the cationic species 9. Heterolytic cleavage of H2 by 9 regenerates 6 along with proton. Enantioface selection of the substrate occurs in the first irreversible hydride migration step, 7→8. Protonation of the carbonyl oxygen with a strong acid (HCl) in 7 is crucial for conversion into 8. Hydrogenation with the BINAP–Ru(OCOCH3)2 complex releases CH3CO2H instead of HCl, however, the acidity of CH3CO2H is insufficient to activate the keto-ester substrate.

Figure 1.5 Catalytic cycle of BINAP–Ru catalyzed hydrogenation of β-keto esters.

Figure 1.6 illustrates molecular models of diastereomeric TSs, Si-10 and Re-10, in the hydride transfer step (7→8 in Figure 1.5) in the hydrogenation of β-keto esters catalyzed by the (R)-BINAP–Ru(II) complex [19, 20]. The protonated carbonyl moiety of substrate, C=O+H, coordinates parallel to the H−Ru bond in a π fashion. Thus, the “R” group connecting to the carbonyl is placed close to the P-phenyl group of the (R)-BINAP ligand. The TS Re-10 producing the (S) alcohol is disfavored due to the notable R/Ph repulsion in the crowded region of the fourth quadrant. Therefore, the (R) product is predominantly obtained via the TS Si-10.

Figure 1.6 Molecular models of diastereomeric transition states in (R)-BINAP–Ru catalyzed hydrogenation of β-keto esters.

BINAP–Ru(II) catalyzed hydrogenation of functionalized ketones is used for the production of useful chiral compounds in the chemical industry. Scheme 1.4 shows an example for the synthesis of carbapenems, a class of β-lactam antibiotics (>100 tons per year) [1, 17]. The racemic α-substituted β-keto ester is hydrogenated in the presence of BINAP–Ru catalyst with a stereo-mutation at the α position [39]. The chiral structure of the BINAP complex as well as intramolecular asymmetric induction of the substrate efficiently control the contiguous two chiral centers of the product. Therefore, the (2S,3R) alcoholic product is obtained selectively among four possible stereoisomers through the dynamic kinetic resolution [40]. The use of DTBM-SEGPHOS–Ru(II) complex for this reaction affords exclusively the (2S,3R) product [8].

Scheme 1.4 Synthesis of a carbapenem intermediate by BINAP–Ru catalyzed hydrogenation of an α-substituted β-keto ester.

1.3.2 Simple Ketones

The BINAP–RuCl2 catalyst hydrogenates functionalized ketones with high enantioselectivity through TSs stabilized by the substrate–Ru chelate structure (Figure 1.6). However, this catalyst is totally inert in hydrogenation of simple (unfunctionalized) ketones, because the chelate-stabilization in the TS is not available. High reactivity and enantioselectivity for this reaction is achieved by the use of a combined catalyst system of RuCl2(xylbinap)(daipen) and alkaline base or RuH(η1-BH4)(xylbinap)(dpen) with or without a base (Scheme 1.5) [41, 42]. For example, hydrogenation of acetophenone with RuH(η1-BH4)[(S)-xylbinap][(S,S)-dpen] at an S/C of 100 000 (8 atm H2, 45 °C) in t-C4H9OK (0.014 M, 400 equiv to Ru) containing 2-propanol is completed in 45 min to afford (R)-1-phenylethnol in 99% ee. The average turnover frequency (TOFav = TON min−1) is about 2200. The ee value is decreased to 80–82% when BINAP or TolBINAP is used instead of XylBINAP [43]. A series of simple ketones, including alkyl aryl ketones, unsymmetrical benzophenones, hetero-aromatic ketones, α,β-unsaturated ketones, α-amino ketones, and some aliphatic ketones, is hydrogenated in high enantioselectivity [44, 45]. The analogous catalyst systems using chiral biaryl diphosphines with P-3,5-xylyl groups exhibit similar efficiency [30, 46].

Scheme 1.5 Hydrogenation of simple ketones catalyzed by XylBINAP/1,2-dimaine–Ru complexes.

Figure 1.7 illustrates a proposed catalytic cycle for the hydrogenation of simple ketones with the (S)-TolBINAP/(S,S)-DPEN–Ru(II) complex [42, 47]. The precatalyst 11 (X, Y = Cl, Cl or η1-BH4, H) is converted into the cationic complex 12 in 2-propanol under reductive conditions with or without base. Species 12 and H2 reversibly forms the molecular hydrogen complex 13, followed by deprotonation to give the active RuH2 complex 14. A ketone is readily reduced by 14, affording the alcoholic product and the 16-electron Ru–amide complex 15. The cationic complex 12 is promptly regenerated by protonation of 15 in an alcoholic medium; 15 is partly converted into 14 by the addition of H2. The reaction of RuH2 species 14 and a ketonic substrate proceeds thorough the pericyclic six-membered TS 16. The Hδ−–Ruδ+–Nδ−–Hδ+ quadrupole on the catalyst and the Cδ+=Oδ− dipole of the substrate effectively interact to reduce the activation energy. Therefore, presence of an “NH” moiety on the diamine ligand is crucial to achieve high catalytic activity.

Figure 1.7 Catalytic cycle of TolBINAP/DPEN–Ru catalyzed hydrogenation of simple ketones.

The mode of enantioface-selection is explained by the use of TS molecular models shown in Figure 1.8 [42, 47]. These are completely different from the TSs in the hydrogenation of β-keto esters catalyzed by the BINAP–Ru(II) complex without diamine ligand (Figure 1.6). The (S)-TolBINAP/(S,S)-DPEN–RuH2 complex 14 has a C2-symmetric structure, in which the skewed five-membered DPEN chelate-ring appropriately arranges the amino protons. The axially directed proton, Hax, is more reactive than the equatorial one (Heq), because the Hδ−–Ruδ+–Nδ−–Haxδ+ quadrupole forming a smaller dihedral angle preferentially interacts with the Cδ+=Oδ− dipole of the ketone. Acetophenone approaches the reaction site with the Si-face (Si-17) or Re-face (Re-17) forming the pericyclic TS. The TS Re-17 suffers significant nonbonded repulsive interaction between the phenyl ring of substrate and the aromatic groups of the (S)-TolBINAP. Therefore, the reaction selectively proceeds via the TS Si-17 to give the (R) product. The secondary NH/π attractive interaction between the NHeq and the phenyl of acetophenone appears to further stabilize the TS Si-17. This interpretation is supported by the result that the catalyst with the sterically more demanding XylBINAP instead of TolBINAP exhibits higher enantioselectivity (Scheme 1.5).

Figure 1.8(S)-TolBINAP/(S,S)-DPEN–RuH2 species (left) and diastereomeric transition states in the hydrogenation of acetophenone. (For clarity the equatorially oriented phenyl substituents in the DPEN ligands are omitted in the molecular models.)

The chiral environment of the BINAP/diamine–Ru(II) complexes is readily modified by changing the combination of the diphosphine and diamine ligands (Figure 1.9). For example, the (S)-TolBINAP/(R)-DMAPEN–Ru(II) catalyst hydrogenates phenylglyoxal diethyl acetal and (E)-chalcone to afford the corresponding alcohols in 96% and 97% ee [48]. The same products in only 36% and 45% ee, respectively, are obtained by the use of the (S)-XylBINAP/(S)-DAIPEN–Ru(II) catalyst, which gives the highest ee (99%) of product in the reaction of acetophenone (Scheme 1.5). The combination of (S)-TolBINAP and (R)-IPHAN, a chiral 1,4-diamine, achieves high reactivity and enantioselectivity in the hydrogenation of 1-tetralones, a class of cyclic aromatic ketones, and substituted 2-cyclohexenones [49]. With the use of TolBINAP/PICA–Ru(II) catalyst, sterically very crowded tert-alkyl ketones and acyl silanes are smoothly hydrogenated to quantitatively afford the chiral products in high ee [50]. Custom catalyst design notably expands the scope of substrates. This method is utilized in chemical industries on a productive scale [51, 52].

Figure 1.9 TolBINAP/amine ligand–Ru complexes and alcoholic products.

1.4 Isomerization of Allylamines and Allylalcohols

Asymmetric isomerization of allylamines is a simple and atom-economical reaction by which to obtain optically active enamines [53]. Scheme 1.6 shows a representative example for the BINAP–Rh(I) catalyzed isomerization of diethylgeranylamine to citronellal diethylenamine. [Rh{(S)-binap}(cod)]ClO4 promotes the reaction in THF (60–120 °C) to afford the chiral enamine in 96–99% ee [54]. The TON approaches 8000 within 7 h. The catalyst can be recycled, so that the total chiral-multiplication number reaches 400 000. [Rh(binap)2]ClO4 acts at higher reaction temperature, but the robustness of this complex leads to its preferred practical use. More than 1500 tons of (–)-menthol are produced per year by this method [53]. Several allylamine substrates with different N-substituents, alkoxy alkyl groups, aromatic moieties, and cyclic skeletons are also converted into the desired compounds in high ee.

Scheme 1.6 Isomerization of allylamines catalyzed by BINAP–Rh complexes and the industrial application to the synthesis of (–)-menthol.

The BINAP–Rh(I) catalyzed isomerization of allylalcohols is less successful in terms of enantioselectivity. Nevertheless, some useful reactions are reported [53]. When racemic 4-hydroxy-2-cyclopentenone is subjected to isomerization conditions in the presence of [Rh{(R)-binap}(CH3OH)2]ClO4 (S/C = 200, 0 °C, 14 days), the (R)-hydroxy enone in 91% ee is recovered at 72% conversion (Scheme 1.7) [55]. The relative reaction rate between the two enantiomers (kf/ks) is calculated to be 5. The (R) product can be optically purified by recrystallization after conversion into the tert-butyldimethylsilyl ether. Desymmetrization of meso allylic 1,4-enediol di-triethylsilyl ether by enantioselective isomerization is achieved by the use of [Rh{(S)-binap}(cod)]ClO4 (S/C = 50, CH2ClCH2Cl reflux, 16 h) [56]. The desired (R)-mono-silyloxy-ketone is obtained in 97.5% ee and 85.8% yield.

Scheme 1.7 Isomerization of allylic alcohol and allylic ether catalyzed by BINAP–Rh complexes.

1.5 Hydroboration, Hydrosilylation, Hydroacylation, and Hydroamination

Enantioselective hydroboration of olefins is a reliable procedure for the synthesis of chiral alcohols in combination with an oxidation procedure [57]. Styrene and catechol borate (1.1 equiv) react in DME with an in situ prepared catalyst from [Rh(cod)2]BF4 and (R)-BINAP (S/C = 50, −78 °C, 2 h), followed by a treatment with H2O2 under basic conditions, to give (R)-1-phenylethanol in 96% ee and 91% yield (Scheme 1.8) [58]. The regioisomeric 2-phenylethanol, which is a major isomer in the reaction without a catalyst, is not detected. Aromatic substituted styrenes also react with high stereoselectivity. The reactivity and enantioselectivity are decreased in the hydroboration of α- or β-substituted styrenes.

Scheme 1.8 Hydroboration of styrenes with a BINAP–Rh catalyst.

The BINAP–Rh complex efficiently catalyzes asymmetric intramolecular hydrosilylation of allylic alcohol silylethers [59]. As shown in Scheme 1.9, a cinnamyl alcohol silylether (18) is converted into the cyclic silylether 19 in acetone with [Rh{(S)-binap}(nbd)]ClO4 (S/C = 50, 25 °C, 5 min) [60]. The competitive intermolecular reaction is observed at less than 1%. Treatment of 19 under oxidative conditions afforded (R)-1-phenyl-1,3-propanediol in 97% ee and 75% yield. The cyclic silane structure of 18 is crucial for efficient enantioselection. Several 2- and 3-substituted compounds are converted into the desired products in high ee. Enantioselective 1,4-disilylation of 4′-methoxybenzalacetone using Cl2(C6H5)SiSi(CH3)3 (1.5–2 equiv) as a reagent catalyzed by PdCl2[(R)-binap] (S/C = 200, 80 °C, 0.5 h) gives the silylation compound 20, which is converted into the β-hydroxy ketone 21 in 92% ee through treatment with CH3Li, acidic hydrolysis, and oxidative cleavage of the C−Si bond [61]. The symmetric disilane reagents do not react with the enone. Aliphatic and aromatic enones react with good to high enantioselectivity.

Scheme 1.9 Enantioselective hydrosilylation of olefins and disilylation of enones.

Enantioselective hydrosilylation of α,β-unsaturated ketones catalyzed by Cu(I) complexes with TolBINAP and DTBM-SEGPHOS affords the chiral β-substituted ketones in high ee. Scheme 1.10 illustrates an example using the DTBM-SEGPHOS–Cu(I) system [62]. The safe and inexpensive polymethylhydrosiloxane (PMHS) is used as a reducing agent. The reaction of isophorone is carried out with an in situ prepared catalyst from CuCl (S/C = 100), the (R) ligand (S/ligand = 275 000), and t-C4H9OK in toluene (−35 °C, 3 days) to give the (R) ketone in 98.5% ee and 88% yield after hydrolysis. The chiral multiplicity is remarkably high. In a similar manner, α,β-unsaturated esters [63], aromatic ketones [64], and aromatic imines [65] are also reduced with high levels of enantioselection. The use of tetramethyldisiloxane (TMDS) under modified conditions gives better stereoselectivity for the reaction of imines. Hydrosilylation of ketones with an air-stable BINAP–CuF2 catalyst system is also reported [66].

Scheme 1.10 Asymmetric hydrosilylation of enones, ketones, and imines with DTBM-SEGPHOS–Cu catalysts.

Intramolecular hydroacylation of 4-tert-butyl-4-pentenal catalyzed by the cationic (S)-BINAP–Rh(I) complex (S/C = 20–25) in CH2Cl2 (25 °C, 2–4 h) gives (S)-3-tert-butylpentanone in >99% ee in high yield (Scheme 1.11) [67]. Desymmetrization of a meso 3,3-dialkynylpropanal 22 by hydroacylation with the TolBINAP–Rh(I) catalyst (S/C = 10, 10 °C, 2 h) gives the 2-cyclopentenone with a quaternary carbon center at the 4 position of 23 in 92% ee [68]. A keto aldehyde 24 is quantitatively converted into the seven-membered lactonic compound (S)-25 in >99% ee by the DTBM-SEGPHOS–Rh(I) catalyzed hydroacylation (S/C = 20, room temperature, 2 days) [69]. A series of substrates with aliphatic and aromatic moieties reacts with high enantioselectivity.

Scheme 1.11 Chiral diphosphine–Rh catalyzed intramolecular hydroacylation.

A catalyst system consisting of [IrCl{(S)-binap}]2 and a fluoride source (F/C = 4) effects the asymmetric reaction of norbornene and aniline without solvent (S/C = 50, 75 °C, 72 h), leading to the hydroamination product (R)-26 in 95% ee and 22% yield (Scheme 1.12) [70]. Fluoride appears to act as a π-donating anionic ligand accelerating the N–H oxidative addition to Ir. Intramolecular hydroamination of an N-tosyl allenic compound (27) is carried out in CH2ClCH2Cl with (AuOpnb)2[(R)-xylbinap], a unique bimetallic complex (S/C = 33, 23 °C, 15 h), to quantitatively yield the cyclic amine product (S)-28 in 99% ee [71]. Choice of p-nitrobenzoate as an anionic ligand is crucial to achieve a high yield and ee of the product. A range of substrates with linear and cyclic alkyl substituents at the allenic moiety gives the desired products in equally high ee. The BINAP–Pd catalyzed reaction of styrenes and anilines has also been reported [72].

Scheme 1.12 Enantioselective hydroamination of olefins and allenes.

1.6 Allylic Alkylation

Allylic alkylation of 3-acetoxy-1,3-diphenyl-1-propene with the sodium salt of dimethyl 2-acetamidomalonate (29a) in the presence of a catalyst formed in situ from [Pd(η3-C3H5)Cl]2 and (S)-BINAP (S/C = 100, 25 °C, 120 h) affords the (S) adduct (S)-30a in 95% ee and 92% yield (Scheme 1.13) [73, 74]. When this reaction is conducted with the sodium salt of simple dimethyl malonate 29b the enantioselectivity is decreased drastically. This problem is solved by using Zn(C2H5)2 as a base to generate the malonate [75]. The desired product 30b is obtained in 99% ee (S/C = 25, room temperature, 20 h). The reaction of a prochiral nucleophile prepared from an α-acetamide-β-keto ester 31 and t-C4H9OK with cinnamyl acetate in the presence of the (R)-BINAP–Pd(II) complex (S/C = 50, −30 °C, 48 h) gives the (R) adduct (R)-32 in 95% ee [76]. The bulky γ substituent of the allylic acetate (C6H5 in this case) is crucial to achieve high enantioselectivity.

Scheme 1.13 Enantioselective allylic substitution with BINAP–Pd catalyst.

1.7 Heck Reaction

1.7.1 Intramolecular Reaction

Asymmetric Heck-type cyclization of various vinyl halides and enol triflates is catalyzed by BINAP–Pd complexes [77]. Synthetically useful chiral cyclic compounds with functionalities are produced by this reaction. For example, a prochiral enol triflate 33 is cyclized with Pd(OCOCH3)2, (R)-BINAP, and K2CO3 in toluene (S/C = 20, 60 °C, 27 h) to afford (S,S)-34 in 91% ee and 60% yield (Scheme 1.14) [78]. Spirooxindols 36 are prepared from the aryl iodide 35 in up to 95% ee [79]. Both enantiomers of 36 can be selectively synthesized from the single enantiomer of the catalyst. Thus, 35 reacts with the (R)-BINAP–Pd catalyst in the presence of Ag3PO4 (2 equiv) in N-methylpyrrolidine (NMP) (S/C = 10, 60 °C, 25 h) to afford (S)-36 in 80% ee. When the reaction is conducted with the (R)-BINAP–Pd catalyst and 1,2,2,6,6-pentamethylpiperidine (PMP; 5 equiv) in N,N-dimethylacetamide (DMA) (S/C = 10, 100 °C, 1.5 h), the (R) product is selectively obtained. These results suggest that the reaction mechanism with a cationic Pd catalyst is different from that catalyzed by the neutral species.

Scheme 1.14 Intramolecular Heck reaction with BINAP–Pd catalysts.

1.7.2 Intermolecular Reaction

The BINAP–Pd catalyst exhibits high enantioselectivity in the intermolecular Heck reaction [77a, d]. When phenyl triflate reacts with 2,3-dihydrofuran (5 equiv) in the presence of an in situ formed (R)-BINAP–Pd complex and 1,8-bis(dimethylamino)naphthalene (proton sponge; 3 equiv) in benzene (S/C = 33, 40 °C, 9 days), (R)-2-phenyl-2,3-dihydrofuran [(R)-37] in >96% ee and (S)-2-phenyl-2,5-dihydrofuran [(S)-38] in 17% ee are obtained in a 71 : 29 ratio (Scheme 1.15) [80]. The choice of base is important to attain high enantioselectivity. The high basicity and bulkiness of the proton sponge appears to fit with the reaction. Several substituted phenyl triflates and 2-naphthyl triflates have been used successfully under the optimized conditions. When the reaction of phenyl triflate and 2,3-dihydrofuran is carried out with the DTB-MeO-BIPHEP–Pd catalyst (DTB; see Figure 1.2) using N(C2H5)(i-C3H7)2 as a base, 37 is obtained in 99% ee and 70% yield [81]. The BITIANP–Pd catalyzed reaction gives exclusively 37 in 91% ee [82].

Scheme 1.15 Intermolecular Heck-type arylation and alkenylation with BINAP–Pd catalysts.

The Heck-type alkenylation of olefins is also catalyzed by the BINAP–Pd complex. The reaction of 2-ethoxycarbonyl-1-cyclohexenyl triflate (39) and 2,3-dihydrofuran (4 equiv) in the presence of Pd(binap)2 (S/C = 33) and proton sponge (2 equiv) in benzene (40 °C, 56 h) affords the chiral product 40 (X = O) in >96% ee [83]. The use of preformed complex Pd(binap)2 restrains formation of the regioisomeric products. When the reaction is conducted using 1-methoxycarbonyl-2-pyrroline instead of dihydrofuran (S/C = 33, 60 °C, 20 h), the desired product 40 (X = NCO2CH3) is obtained in >99% ee and 95% yield. The BITIANP–Pd catalyst exhibits similar efficiency [84].

1.8 Aldol and Mannich-Type Reactions

1.8.1 Aldol Reaction

The asymmetric aldol reaction is a reliable method to produce synthetically useful chiral β-hydroxy carbonyl compounds [85]. Benzaldehyde and a silyl enolate of acetophenone (41) (1.5 equiv) react with [Pd{(R)-binap}(H2O)2](BF4)2 (S/C = 20) in 1,1,3,3-tetramethylurea (TMU) (0 °C, 24 h) to afford (R)-3-hydroxy-1,3-diphenyl-1-propanone [(R)-42] in 89% ee and 92% yield (Scheme 1.16) [86]. The structure of the BINAP–Pd(II) complex has been determined by a X-ray crystallographic analysis. A chelating acyl Pt(II) complex Pt(3,5-dtbs)[(R)-binap] that can be handled in the open air is activated as a catalyst by treatment with p-toluenesulfonic acid (acid : Pt = 1 : 1) [87]. The BINAP–Pt species catalyzes the aldol reaction of 3-phenylpropanal and a ketene silyl acetal (43) (1.5 equiv) with 2,6-lutidine (amine : Pt = 1 : 1) in CH2Cl2 (S/C = 20, −25 °C, 168 h) to give the chiral product 44 in 95% ee. Primary alkyl aldehydes react with high enantioselectivity. Aromatic aldehydes show higher reactivity, but the ee of the products is significantly lower. A Pt cationic complex appears to be the active species.

Scheme 1.16 Asymmetric aldol reaction catalyzed by BINAP–Pd and BINAP–Pt complexes.

An in situ prepared complex from AgF and (R)-BINAP in a 1 : 1 ratio catalyzes the asymmetric aldol reaction of trimethoxysilyl enolates and aromatic aldehydes (Scheme 1.17) [88]. When the silyl enolate of tert-butyl ethenyl ketone 45 reacts with benzaldehyde in the presence of the BINAP–Ag catalyst in CH3OH (S/C = 10, −78 to −20 °C, 6 h), the aldol product 46 is obtained in 97% ee (syn : anti = >99 : 1) [89]. Regardless of (E/Z) stereochemistry of the enolate the syn diastereo isomer is preferably formed. The reactivity is significantly decreased in the reaction with aliphatic aldehydes. The related catalyst prepared from AgOTf and BINAP promotes the aldol reaction of aldehydes with tributyltin enolates [90]. An enantioselective nitroso aldol reaction has been achieved by the use of the BINAP–Ag chemistry. The reaction of the trimethyltin enolate of cyclohexanone (47) and nitrosobenzene (1 equiv) with Ag(OTf)[(R)-tolbinap] (S/C = 10) in THF (−78 °C, 2 h) gives exclusively the (R) O-adduct (R)-48 in 99% ee [91]. In contrast, the tributyltin enolate and nitrosobenzene react in the presence of a bimetallic complex [Ag(OTf)]2[(R)-tolbinap] (S/C = 25) in ethylene glycol diethyl ether (−78 °C, 2 h) to afford selectively the N-adduct 49 in >99% ee. Thus, a series of N- and O-nitroso aldol products is synthesized in high chemo- and enantioselectivity.

Scheme 1.17 BINAP–Ag catalyzed aldol reactions.

Asymmetric addition of silyl dienolates to aldehydes can be performed with the BINAP–Cu catalyst. For example, thiophene-2-carbaldehyde reacts with 50 catalyzed by a species formed in situ from Cu(OTf )2, (S)-TolBINAP, and [(n-C4H9)4N](C6H5)2SiF2 (TBAT) (S/C = 50) in THF (−78 °C, 6–8 h) to afford the (R)-adduct (R)-51 in 95% ee almost quantitatively (Scheme 1.18) [92]. A range of aromatic and α,β-unsaturated aldehydes reacts with high enantioselectivity. The Cu(I) dienolate prepared in this system appears to be a catalytic cycle species. Usually, the aldol reaction of ketones is difficult because of their lower reactivity than that of aldehydes. However, the reaction of methyl primary alkyl ketones and a silyl dienolate (52) is successfully catalyzed by a ternary system consisting of Cu(OTf)2, TolBINAP, and TBAT (S/C = 10) at ambient temperature to give the cyclized product 53 in 90% ee and 81% yield [93]. Aryl methyl ketones also react with medium to high enantioselectivity.

Scheme 1.18 BINAP–Cu catalyzed aldol reactions with silyl dienolates.

1.8.2 Mannich-Type Reaction

The Mannich-type reaction of a β-keto ester 54 and N-Boc-protected imine of benzaldehyde 55 is catalyzed by [Pd{(R)-binap}(H2O)2](OTf)2 (S/C = 20) in THF (0 °C, 5 h) to afford the adduct (R,S)-56 (syn : anti = 88 : 12) in 99% ee and 93% yield (Scheme 1.19) [94]. The reaction appears to proceed through the cationic Pd enolate 57, illustrated in the scheme, with release of H2O and TfOH from the precatalyst. The bulky tert-butyl group of the enolate preferably locates in the first quadrant to avoid the crowded second quadrant with the equatorial P-phenyl ring of (R)-BINAP (see side view); the tert-butyl group then shields the Si-face of the enolate. Therefore, the enolate predominantly reacts with the electrophile at the Re-face to give the desired enantiomer of product. The chiral structure of BINAP indirectly controls the approach of the electrophile. The in situ formed protic acid, TfOH, is presumed to activate the imino substrate. A series of aromatic and α,β-unsaturated imines as well as α-imino esters reacts with high enantioselectivity.

Scheme 1.19 Mannich-type reaction catalyzed by BINAP–Pd complex, and molecular models of the Pd-enolate intermediate.

1.9 Nucleophilic Additions to Carbonyl and Imino Compounds

1.9.1 Allylation

Enantioselective addition of allyltrimethoxysilane (58) to aldehydes is performed by the use of BINAP–Ag catalysts (Scheme 1.20) [88, 95]. When benzaldehyde reacts with 58 (1.5 equiv) in the presence of a complex formed in situ from AgF and (R)-TolBINAP (S/C = 33) in CH3OH (−20 °C, 4 h), the homoallylic alcohol (R)-59 is obtained in 94% ee and 80% yield [96]. Several aromatic and α,β-unsaturated aldehydes react with good to high enantioselectivity. The allylation of ketones is catalyzed by the chiral Ag complex. Thus, 2-chloro-2-cyclohexenone and 58 (2 equiv) react with the (R)-Difluorphos–AgF catalyst (S/C = 20) and CH3OH (1 equiv) in THF (−78 °C, 12 h) to produce predominantly the 1,2-addition product 60 in 96% ee and 97% yield [97]. This reaction does not proceed in CH3OH solution, while a stoichiometric amount of CH3OH in THF improves the product yield. This is because the protonation of a Ag-alkoxide intermediate with CH3OH occurs smoothly. The reaction of cyclic and acyclic aromatic ketones also proceeds with high enantioselectivity.

Scheme 1.20 Addition of allyltrimethoxysilane to aldehydes and ketones with chiral Ag catalysts.

1.9.2 Alkenylation and Arylation

A chiral catalyst generated in situ from CuF2 and (R)-DTBM-SEGPHOS (ligand and also reductant) effects asymmetric vinylation and arylation to aldehydes (Scheme 1.21). The reaction of 4-chlorobenzaldehyde and trimethoxyvinylsilane (61a; R = CH2=CH, X = OCH3; 2 equiv) with the (R)-DTBM-SEGPHOS–Cu catalyst (S/C = 33) in DMF (40 °C, 2 h) affords quantitatively the allylic alcohol (S)-62a (R = CH2=CH) in 97% ee [98]. Several aromatic, aliphatic, and α,β-unsaturated aldehydes react with good to excellent levels of enantioselectivity. When the reaction is carried out using dimethoxydiphenylsilane (61b; R = X = C6H5) (S/C = 33, 40 °C, 1 h), the diaryl methanol (S)-62b (R = C6H5) is obtained in 92% ee. The asymmetric Friedel–Crafts type arylation of imines is catalyzed by a complex prepared in situ from CuPF6 and (R)-TolBINAP. An N-protected α-imino ester (63) reacts with N,N-dimethylaniline in the presence of the (R)-TolBINAP–Cu catalyst (S/C = 20) in THF at −78 °C to afford the aromatic α-amino-acid derivative 64 in 96% ee [99]. Only the para-substituted compound is detected. A series of aniline analogues can be converted into the desired products in high regio- and enantioselectivity.

Scheme 1.21 Vinylation and arylation to aldehydes and α-imino esters with chiral Cu catalysts.

1.9.3 Dienylation

The carbonyl dienylation using acetylene and hydrogen gas is achieved with a cationic Rh catalyst (Scheme 1.22) [100]. Thus, an α-substituted aldehyde 65, acetylene (1 atm), and H2 (1 atm) react with a complex formed in situ from [Rh(cod)2]BARF (BARF = B[3,5-(CF3)2C6H3]4) and (R)-MeO-BIPHEP (S/C = 20) in the presence of triphenylacetic acid (7.5 mol%) and Na2SO4 (2 equiv) in CH2ClCH2Cl (25 °C, 72 h) to exclusively afford the (Z)-dienylation product 66 in 88% ee and 85% yield [101]. This reaction is suggested to proceed through the carbonyl insertion of a rhodacyclopentadiene that is formed by acetylene dimerization. When 6-bromopyridine-2-carboxaldehyde (67) reacts with an enyne 68 (2 equiv) and H2 (1 atm) in the presence of the (R)-TolBINAP–[Rh(cod)2]OTf complex (S/C = 25) and triphenylacetic acid (2 mol%) at 40 °C, the (E)-dienylation product 69 is obtained in 99% ee [102]. Many heterocyclic aromatic aldehydes as well as ketones are converted into the desired products in high ee.

Scheme 1.22 Dienylation of aldehydes catalyzed by chiral Rh complexes.

1.9.4 Cyanation

The combined catalyst system of Ru[(S)-phgly]2[(S)-binap] (phgly = phenylglycinate) and Li2CO3 in a 1 : 1 ratio effects asymmetric cyanosilylation of aldehydes (Scheme 1.23). The reaction of benzaldehyde and (CH3)3SiCN (1.2 equiv) with the Ru[(S)-phgly]2[(S)-binap]–Li2CO3 system (S/C = 10 000) in diethyl ether (−78 °C, 12 h) affords the cyanohydrin product (R)-70 quantitatively with 97% ee [103]. The Ru complex alone does not show substantial reactivity. The combined system can complete the reaction with an S/C of 100 000 at −40 °C to give 70 in 90% ee. A series of aromatic, heteroaromatic, and α,β-unsaturated aldehydes reacts with high enantioselectivity. Methyl benzoylformate reacts with (CH3)3SiCN (2 equiv) catalyzed by the Ru[(S)-phgly]2[(S)-binap]–C6H5OLi system (S/C = 1000) in t-C4H9OCH3 (−60 °C, 18 h) to give the adduct (R)-71 quantitatively with 99% ee [104]. The reaction is completed with an S/C of 10 000 at −50 °C to afford the product in 98% ee. A range of aromatic, aliphatic, and α,β-unsaturated keto esters can be converted into the silylated products with high enantioselectivity.

Scheme 1.23 Cyanosilylation of aldehydes and α-keto esters with a chiral Ru · Li catalyst.

1.10 α-Substitution Reactions of Carbonyl Compounds

1.10.1 Fluorination and Amination

The α-fluorination of 1,3-dicarbonyl compounds is successfully catalyzed by the XylBINAP– and DTBM-SEGPHOS–Pd complexes [105]. For example, β-keto ester 72 reacts with N-fluorobenzenesulfonimide (NFSI; 1.5 equiv) in the presence of [Pd{(R)-xylbinap}(OH)2](BF4)2 (S/C = 40) in C2H5OH (−10 °C, 20 h) to afford the α-fluorinated product (R)-73 in 94% ee and 91% yield (Scheme 1.24) [106]. The mode of enantioface selection is similar to that of the BINAP–Pd catalyzed Mannich-type reaction (Scheme 1.19). The more stereo-demanding XylBINAP is preferable for this reaction. C2H5OH is the solvent of choice, because the alcohol appears to facilitate the formation of a Pd-enolate intermediate. This chemistry is applicable to the reaction of β-keto phosphonates and α-tert-butoxycarbonyl lactones and lactams as well as N-(tert-butoxycarbonyl)oxindols [107].

Scheme 1.24 α-Fluorination of carbonyl compounds with chiral Pd catalysts.

The BINAP–Pd catalyst effects the asymmetric reaction of β-keto esters and azodicarboxylates (Scheme 1.25). Thus, cyclic β-keto ester 74 reacts with diisopropyl azodicarboxylate using [Pd{(R)-binap}(CH3CN)(H2O)](PF6)2 (S/C = 1000) in acetone (room temperature, 70 h) to give the α adduct (S)-75 in 97% ee and 96% yield [108]. The mechanism is closely related to that of α fluorination. α-Cyanoketones can also be used as substrates [109].

Scheme 1.25 α-Amination of β-keto esters catalyzed by BINAP–Pd complex.

1.10.2 Arylation and Orthoester Alkylation

Asymmetric α-arylation of substituted carbonyl compounds has been developed for the construction of all-carbon chiral quaternary centers. The chiral catalyst formed from Pd(OCOCH3)2 and (S)-BINAP (S/C = 5) promotes the reaction of an α-methyl ketone (76) and 4-tert-butylbromobenzene (2 equiv) in the presence of t-C4H9ONa (2 equiv) at 100 °C to afford the arylation product 77 in 98% ee and 75% yield (Scheme 1.26) [110]. Some specific substrates react with high stereoselectivity. The BINAP–Ni complex effectively catalyzes asymmetric arylation of α-substituted γ-butyrolactones. For example, the reaction of α-methyl-γ-butyrolactone and chlorobenzene (1 equiv) is catalyzed by the (S)-BINAP–Ni(cod)2 system (S/C = 20) with NaHMDS (2.3 equiv) and ZnBr2 (15 mol%) in a toluene–THF mixture (60 °C, 17–20 h) to produce the α phenylation product (S)-78 in >97% ee [111]. Addition of the Zn salt significantly increases the reaction rate and yield of products. A range of optically active α-alkyl α-aryl γ-butyrolactones can be synthesized by this method.

Scheme 1.26 α-Arylation of carbonyl compounds with BINAP–Pd and –Ni catalysts.

Asymmetric α alkylation of carbonyl compounds is difficult. However, the reaction of N-propionylthiazolidinethione (79) and trimethyl orthoformate (3 equiv) is catalyzed by [Ni{(R)-tolbinap}](OTf)2 (S/C = 20) with 2,6-lutidine (3 equiv) and BF3 · O(C2H5)2 (3 equiv) in CH2Cl2 (−78 °C, 0.5 h) to afford the α adduct (S)-80 in 97% ee and 73% yield (Scheme 1.27) [112]. A series of acyl derivatives of 79 reacts with high enantioselectivity. The corresponding oxazolidinone does not give the desired product. This addition reaction is suggested to proceed via a Ni-enolate intermediate (81), the conformation of which is fixed by the S–Ni–O chelate structure. The electrophile (CH3O+ =CHOCH3) approaches the α-carbon of the enolate from the α-Re-face side or α-Si-face side (see the side view in Scheme 1.27). The C–C bond formation predominantly occurs at the side of α-Re-face [first quadrant of (R)-BINAP–Ni complex], because the α-Si-face of the enolate is covered by the equatorial P-phenyl ring of (R)-BINAP at the fourth quadrant. Thus, the (S) addition product is obtained in high ee.

Scheme 1.27 α-Orthoester alkylation catalyzed by TolBINAP–Ni complex, and molecular models of the Ni enolate intermediate.

1.11 Michael-Type Reactions

1.11.1 Michael Reaction

The asymmetric Michael reaction [113] of 1,3-dicarbonyl compounds with α,β-unsaturated ketones proceeds without addition of strong acid or base when [Pd(binap)(H2O)2](OTf)2 is used as the catalyst (Scheme 1.28). For instance, cyclic β-keto ester 82 reacts with 3-penten-2-one using the (R)-BINAP–Pd aqua complex (S/C = 20) in THF (−20 °C, 24 h) to afford the conjugate addition product 83 in 89% yield (diastereomer ratio = 8 : 1) [114]. The ee value of the major diastereomer is 99%. The aqua Pd complex appears to be in equilibrium among three species: 84 (a dimer), 85 (a hydroxo complex), and 86 (an aqua complex). Species 85, which includes a Lewis acidic Pd center and a Brønsted basic OH, is suggested to behave as the catalyst. The acid–base bifunctionality cooperatively forms the Pd-enolate intermediate. The enone substrate is activated by a protonation with TfOH formed in this system. The enantioselective manner is similar to that shown in Section 1.8.2 (Mannich-type reaction) (Scheme 1.19).

Scheme 1.28 Michael reaction catalyzed by BINAP–Pd complex.

The addition reaction of a fumarate derivative of thiazolidinethione (87) and tert-butyl 3-oxobutanoate (1.5 equiv) is catalyzed by [Ni{(S)-tolbinap}](BF4)2 (S/C = 10) in ethyl acetate (0 °C, 12 h) to give the Michael product 88 in 87% yield (Scheme 1.29) [115]. Treatment of 88 with DBU (0.05 equiv) affords quantitatively the dihydropyrone (R)-89 in 97% ee. The nickel catalyst is presumed to activate both the thione Michael acceptor 87 and the nucleophilic β-keto ester.

Scheme 1.29 Michael reaction catalyzed by TolBINAP–Ni complex.

1.11.2 Aza-Michael Reaction

Conjugate addition of primary aromatic amines to N-alkenoyl carbamates is catalyzed by the BINAP–Pd complex (Scheme 1.30). The reaction of 4-chloroaniline and a tert-butyl alkenoyl carbamate 90 (1.5 equiv) with [Pd{(R)-binap}(CH3CN)]-(OTf)2 (S/C = 50) proceeds in toluene (25 °C, 18 h) to give the amination product 91 in >99% ee quantitatively [116]. The reactivity and enantioselectivity depend on the electronic character of the anilines. Alkenoyl oxazolidinone 92 reacts with a salt of 4-methoxyaniline and TfOH (1.5 equiv) in the presence of [PdOH{(R)-binap}]2(OTf)2 (S/C = 50) in THF (room temperature, 12 h) to afford the β-amination product 93 in 98% ee and 92% yield [117]. A catalytic amount of the basic PdOH complex reacts with the aniline salt to generate the appropriate amount of the free amine, so that the uncatalyzed addition reaction with the aniline is inhibited. The reaction using aniline analogues substituted by electron-rich and -deficient groups also shows high enantioselectivity.

Scheme 1.30 Aza-Michael reactions catalyzed by BINAP–Pd complexes.

1.12 Conjugate Additions Using Organoboron and Grignard Reagents

Asymmetric 1,4-addition reactions of α,β-unsaturated carbonyl compounds are versatile procedures for the synthesis of useful chiral β-substituted carbonyl compounds [118, 119]. The reaction of 2-cyclohexenone and phenylboroxine (2.5 equiv) is catalyzed by [RhOH{(R)-binap}]2 (S/C = 33) in a 10 : 1 mixture of dioxane and H2O (35 °C, 3 h) to afford (R)-3-phenylcyclohexanone in 99% ee quantitatively (Scheme 1.31) [120]. Under the same conditions 3-nonen-2-one, an acyclic enone, is converted into the (R) phenylation product in 98% ee. This method is applied to various cyclic and acyclic esters and amides as well as 1-alkenylphosphonates and nitroalkenes by appropriate use of the borane reagents, such as arylboronic acids, LiBAr(OCH3)3, and ArBF3K [121]. Arylsiloxanes are also used for this reaction [122].

Scheme 1.31 Conjugate addition reactions using arylboron reagents catalyzed by BINAP–Rh complexes.

Figure 1.10a illustrates a plausible reaction mechanism for the 1,4-addition of aryl boronic acids to α,β-unsaturated carbonyl compounds catalyzed by the (R)-BINAP–Rh complex [120]. The [Rh]OH complex 94 is converted into the [Rh]Ar species 95 by transmetallation of an aryl group from boron to rhodium. An enone substrate is inserted into the Rh–Ar bond to form an oxa-π-allyl-rhodium intermediate 96. Hydrolysis of 96 by H2O releases the arylation product along with regeneration of the catalyst species 94. Therefore, an addition of H2O in the reaction media is necessary. The configuration of the products is determined at the insertion of the enone into the Rh–Ar bond (95→96). At this step an enone substrate (e.g., 2-cyclohexenone) coordinates with the α-Re-face to avoid steric hindrance caused by an equatorial P-phenyl ring of the (R)-BINAP at the second quadrant (Figure 1.10b; 97). Therefore, migration of an Ar group from the Rh center to the β-carbon of 2-cyclohexenone forms the β-(R) configuration in the intermediate 96.

Figure 1.10 (a) Plausible 1,4-addition reaction mechanism catalyzed by (R)-BINAP–Rh complex; (b) molecular models of the stereo-determining step.

The BINAP–Rh complexes also catalyze the asymmetric 1,4-addition of alkenyl groups (Scheme 1.32). 2-Cyclohexenone reacts with an alkenylcatecholborane 98 (5 equiv) using the (S)-BINAP–Rh(acac)(CH2=CH2) system as a catalyst (S/C = 33) and (C2H5)3N (10 equiv) (100 °C, 3 h) to furnish the alkenylation product (S)-99 in 96% ee and 92% yield [123]. Addition of a base is necessary to trap acidic alkenylboronic acid and catechol generated during the reaction. The conjugate alkenylation of 2-cyclohexenone with an alkenyl Zr reagent (100) (1.2 equiv), which is prepared by hydrozirconation of 1-heptyne with Cp2ZrHCl (room temperature, 0.5 h), can be carried out with the (S)-BINAP–[Rh(cod)-(CH3CN)2]BF4 system (S/C = 20) in an aprotic media (room temperature, 5 h) to give the adduct 99 in 99% ee and 96% yield after usual workup [124]. The enantioselectivity is somewhat decreased in the reaction of acyclic enones.

Scheme 1.32 Conjugate addition reactions using alkenyl metal reagents catalyzed by BINAP–Rh complexes.

Asymmetric 1,4-addition of alkyl groups by Grignard reagents to α,β-unsaturated esters is catalyzed by the BINAP–Cu complex. For example, unsaturated ester 101 and C2H5MgBr (5 equiv) react with the (R)-TolBINAP–CuI system (S/C = 100) in t-C4H9OCH3 (−40 °C, 2–3 h) to afford the β-substituted ester (S)-102 in 95% ee and 90% yield (Scheme 1.33) [125]. The absolute configuration of product is reversed by using the geometrical isomer. Thus, methyl (E)-5-phenyl-2-pentenoate [(E)-103] is converted into the (R) product (R)-104 in 93% ee with the (R)-TolBINAP–Cu catalyst. On the other hand, the reaction of (Z)-103 results in the (S) adduct (S)-104 in 94% ee catalyzed by the same complex.

Scheme 1.33 1,4-Addition of alkyl groups using Grignard reagents catalyzed by TolBINAP–Cu complex.

1.13 Diels–Alder Reaction

A dicationic BINAP–Pd complex acts as an efficient Lewis-acidic catalyst for asymmetric Diels–Alder cyclization [126]. The reaction of N-acryloyloxazolidinone (105) and cyclopentadiene (5 equiv) with [Pd{(R)-binap}(C6H5CN)](BF4)2 (S/C = 10) in CH2Cl2 (−50 °C, 24 h) affords the cyclization product (S)-106 in 99% ee and 95% yield (endo : exo = 95 : 5) (Scheme 1.34) [127]. The enantioselectivity depends on the nature of the counter anion (77% ee with the PF6− complex). The reaction appears to proceed through the intermediate 107, which has a six-membered Pd–105 chelate-ring structure. The diene approaches the dienophile from the side of α-Re-face to avoid repulsive interaction with the (R)-BINAP’s equatorial P-phenyl ring at the fourth quadrant (see the side view of 107), exclusively forming the (S) chiral center.

Scheme 1.34 Diels–Alder reaction catalyzed by BINAP–Pd complex, and molecular models of the reaction intermediate.

The BINAP–Pd has been applied successfully to the asymmetric hetero-Diels–Alder reaction [128]. Thus, phenylglyoxal reacts with 2,3-dimethyl-1,3-butadiene (1.5 equiv) in the presence of [Pd{(S)-binap}(C6H5CN)](BF4)2 (S/C = 50) in CH3Cl (0 °C, 24 h) to give the cycloadduct (R)-108 in 99% ee and 67% yield (Scheme 1.35) [129]. An addition of MS-3A increases the enantioselectivity. A trace amount of H2O existing in the reaction system may react with the Pd complex to generate acidic impurities, causing an achiral pathway of the reaction. The corresponding Pt complex under the same conditions also exhibits high enantioselectivity [130]. The Pd-catalyzed asymmetric 1,3-dipolar cyclization of nitrones and N-alkenoyloxazolidinones is also studied [131]. The asymmetric cyclization of a kind of Danishefsky’s diene (109) and an N-tosyl-α-imino ester 110 (1.25 equiv) with the (S)-TolBINAP–CuClO4 · 4CH3CN system (S/C = 100) in THF at −78 °C produces the aza-cyclization product 111 in 96% ee and 70% yield (trans : cis = 10 : 1) [132]. The use of several other solvents decreases both diastereoselectivity and enantioselectivity. The SEGPHOS–Cu catalyzed nitroso Diels–Alder reaction proceeds in a highly diastereo- and enantioselective manner. Thus, 6-methylnitrosopyridine (113) and a diene (112) (1.2 equiv) react with the (R)-SEGPHOS–[Cu(CH3CN)4]PF6 system (S/C = 10) in CH2Cl2 (−85 to −20 °C, 6 h) to afford quantitatively the adduct 114 in 97% ee as a single diastereomer [133]. A methyl group at the 6 position of nitrosopyridine is essential to attain high enantioselectivity. The reaction is supposed to proceed through a tetrahedral intermediate (115) with a Cu–113 chelate ring. The diene horizontally approaches the nitroso N=O from the Re-face direction at the first quadrant, because the opposite side is blocked by the equatorial P-phenyl ring of (R)-SEGPHOS at the second quadrant, resulting in 114 predominantly.

Scheme 1.35 Hetero-Diels–Alder reactions and a molecular model of the reaction intermediate with (R)-SEGPHOS–Cu catalyst.

1.14 Ene Reaction

Under appropriate Lewis-acidic conditions alkenes react with imino and carbonyl compounds [134]. An N-toluenesulfonyl-α-imino ester (116) and α-methylstyrene (2 equiv) react with the (R)-TolBINAP–[Cu(CH3CN)4]ClO4 system (S/C = 20) in benzotrifluoride, a polar aromatic solvent, (room temperature, 18 h) to afford the α-amino ester (S)-117 in 99% ee and 92% yield (Scheme 1.36) [135]. Hetero-substituted alkenes are applicable to this reaction. A carbonyl-ene reaction is carried out with the SEGPHOS–Pd catalyst. Thus, methylenecyclopentane and ethyl trifluoropyruvate (118; 1.5 equiv) react, using a dicationic catalyst prepared