Asymmetric Cyclization Reactions Through an Enamine/Acid Cooperative Approach

MIAMI UNIVERSITY

The Graduate School

Certificate for Approving the Dissertation

We hereby approve the Dissertation

Yongming Deng

Candidate for the Degree:

Doctor of Philosophy

Hong Wang, Advisor

Michael Novak, Committee Chair

Scott Hartley, Reader

Shouzhong Zou, Reader

Annette Bollmann, Graduate School Representative ABSTRACT

ASYMMETRIC CYCLIZATION REACTIONS THROUGH AN ENAMINE/ACID COOPERATIVE APPROACH. SYNTHESIS OF UNSYMMETRICALLY FUNCTIONALIZED BENZOPORPHYRINS by Yongming Deng

The combination of enamine catalysis with metal catalysis, aiming to achieve organic transformations that cannot be accessed by enamine catalysis or metal catalysis independently, promises huge potential. The major obstacle in the development of enamine/metal Lewis acid combining catalysis is the incompatibility of the catalysts. The goal of this research is to solve this long lasting challenge and develop powerful asymmetric catalysts.

Chapter one will provide a brief introduction to asymmetric catalysis and combing catalysis of enamine catalysis with transition metal catalysis.

In Chapter two, the first application of arylamines in enamine catalysis is presented. The incompatibility of enamine catalysts and metal Lewis acid is solved by applying arylamines/acids cooperative catalysis. Through combination with either a metal Lewis acid or a chiral phosphoric acid, arylamines successfully catalyzed the asymmetric aldol reaction of cyclohexanone with both isatin and enones. Additionally, a highly chemo- and enantioselective three-component aza-Diels-Alder reaction was developed by combining arylamines with metal Lewis acids.

In Chapter three, we devise a new type of chiral Lewis-acid-assisted Lewis acid catalyst formed from a metal Lewis acid and a chiral metal phosphate (MLA/M[P]3-LLA). A highly chemo- and enantioselective three-component aza-Diels-Alder reaction of cylic ketones (5, 6, and 7 membered) was successfully achieved by in situ prepared

MLA/M[P]3-LLA. Preliminary structural studies have revealed that these LLA catalysts have a bimetallic center with bridging phosphate ligands. The Lewis acidity and stereoselectivity of the MLA/M[P]3-LLA catalysts can be easily tuned by changing either the Lewis acid co-catalyst or the chiral metal phosphate component, forming either homobimetallic or heterobimetallic catalysts.

In Chapter four, a trio catalysis system involving arylamines, BINOL-phosphoric acids, and metal Lewis acids is first disclosed. By using this trio catalyst, a series of optically active functionalized dihydropyridines was successfully synthesized through a highly chemo- and enantioselective three-component aza-Diels-Alder reaction of substituted cinnamaldehyde, cyclic ketone, and arylamine.

In Chapter five, a series of unsymmetrically functionalized benzoporphyrins was successfully synthesized.

ASYMMETRIC CYCLIZATION REACTIONS THROUGH AN ENAMINE/ ACID COOPERATIVE APPROACH. SYNTHESIS OF UNSYMMETRICALLY FUNCTIONALIZED BENZOPORPHYRINS A DISSERTATION

Submitted to the Faculty of

Miami University in partial

fulfillment of the requirements

for the degree of

Doctor of Philosophy

Department of Chemistry and Biochemistry

Yongming Deng

Miami University

Oxford, Ohio

2014

Dissertation Director: Hong Wang

Table of Contents

Chapter 1: Introduction ...... 1

1.1 Synthetic Approaches to Enantiopure Compounds ...... 1

1.1.1 Resolution ...... 2

1.1.2 Chiral Pool ...... 2

1.1.3 Chiral Auxiliary ...... 3

1.1.4 Asymmetric Catalysis ...... 3

1.1.4.1 Biocatalysis in Asymmetric Catalysis ...... 4

1.1.4.2 Metallic Catalysis in Asymmetric Catalysis ...... 4

1.1.4.3 Organocatalysis ...... 5

1.2 Cooperative Enamine-Transition Metal Catalysis ...... 10

1.2.1 Combination of an Aliphatic Amine with a Soft Metal: Soft/Hard Approach 11

1.2.1.1 Combination of an Aliphatic Amine with Pd(0 or II) ...... 11

1.2.1.2 Combination of an Aliphatic Amine with Au(I) ...... 13

1.2.1.3 Combination of an Aliphatic Amine with Cu( I) ...... 14

1.2.1.4 Combination of an Aliphatic Amine with Ir( II) ...... 15

1.2.2 Bifunctional Amine/Metal Lewis Acid Catalysts ...... 16

1.3 Summary ...... 18

Acknowledgement: ...... 19

Reference: ...... 19

Chapter 2: Arylamines Catalyze Enamine Formation: A New Tool for Cooperative Organo-Aminocatalysis and Acid Catalysis ...... 22

Acknowledgement: ...... 22

2.1 Introduction ...... 23

2.2 Concept Design ...... 24

2.3 Results and Discussion ...... 24

2.3.1 Arylamine/Acid Catalyzed Asymmetric Aldol Reaction ...... 24

2.3.1.1 Arylamine/Acid Catalyzed Asymmetric Aldol Reaction of Isatin and Cyclohexanone ...... 24

2.3.1.2 Arylamine/Acid Catalyzed Asymmetric Aldol Reaction of Enone and Cyclic Ketones ...... 27

2.3.2 Three-Component Aza-Diels-Alder Reaction (ADAR) of Enones, Cyclic Ketones, and Arylamines ...... 30

2.3.2.1 Racemic Three-Component ADAR of Enones, Cyclic Ketones, and Arylamines ...... 32

2.3.2.2 Asymmetric Three-Component ADAR of Enones, Cyclic Ketones, and Arylamines ...... 33

2.3.2.3 Study of Catalytic Role of Arylamine ...... 40

2.4 Conclusion ...... 41

2.5 Experiment Section ...... 42

2.5.1 Reaction Set Up ...... 42

2.5.2 Characterization Data and HPLC Conditions ...... 45

Reference: ...... 59

Chapter 3: Enantioselective Lewis-Acid-Assisted Lewis Acid Catalysts Derived from Chiral Metal Phosphates: Three-Component Asymmetric ADARs of Cyclic Ketones ... 61

3.1 Introduction to Lewis Acid Assisted Lewis Aicd ...... 62

3.2 Results and Discussion ...... 63

3.2.1 Development of Metal Lewis Acid-Assisted Metal Lewis Acid Catalysts

(MCl3/M[P]3-LLA) ...... 64

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3.2.2 M(OTf)3/M[P]3-LLA: Asymmetric Three-Component ADARs of Cyclopentanone and Cycloheptanone...... 69

3.2.3 Further Investigation of Metal Lewis Acid/Chiral Metal Phosphate LLA...... 74

3.2.3.1 The Effects of Metal Phosphate and Y2BINOL3 on Bimetallic LLA Catalytic System...... 74

1 31 3.2.3.2 H and P NMR Spectroscopic Analysis of Y(OTf)3/Y[P]3-LLA Catalyst...... 76

3.2.3.3 Preliminary Crystal Structure and MALDI-TOF Spectrometry of

Y(OTf)3/Y[P]3-LLA...... 80

3.3 Conclusion ...... 81

3.4 Experiment Section ...... 82

3.4.1 Reaction Set Up ...... 82

3.4.2 Characterization Data and HPLC Conditions ...... 84

Reference: ...... 103

Chapter 4: Trio Catalysis of Arylamine, BINOL-phosphoric Acid, and Metal Lewis Acid: Asymmetric Three-component Aza-Diels Alder Reaction of Substituted Cinnamaldehyde, Cyclic Ketone, and Arylamine ...... 106

4.1 Introduction ...... 107

4.2 Design Plan ...... 108

4.3.1 Conditions Screening and Reaction Optimization ...... 110

4.3.2 Substrate Scope of Three-Component ADAR of Substituted Cinnamaldehyde, Cyclic Ketone, and Arylamine ...... 114

4.4 Conclusion ...... 118

4.5 Experimental Section ...... 119

4.5.1 Reaction Set Up ...... 119

4.5.2 Characterization Data and HPLC Conditons ...... 120

Reference ...... 133

Chapter 5: Synthesis of Unsymmetrically Functionalized Benzoporphyrins ...... 135

5.1 Introduction ...... 136

5.2 Results and Discussion ...... 136

5.3 Experimental Section ...... 137

5.3.1 Reaction Set Up ...... 137

5.3.2 Characterization Data ...... 140

Reference ...... 142

Chapter 6: Conclusions ...... 143

6.1 Cooperative Catalysis with Arylamines and Acids ...... 143

6.2 Lewis-Acid-Assisted Lewis Acid Catalysts Derived from Chiral Metal Phosphates...... 144

Reference ...... 144

List of Tables Table 2.1 Condition screening for asymmetric aldol reactions of isatin and cyclohexanone ...... 25 Table 2.2 Condition screening of asymmetric aldol reaction of isatin and cyclohexanone ...... 26 Table 2.3 Condition screening for direct aldol reaction of enone and cyclohexanone ..... 28 Table 2.4 Condition screening of asymmetric aldol reaction of enone and cyclohexanone ...... 29 Table 2.5 Substrate scope of asymmetric aldol reaction of enone 1 and cyclic ketone .... 30 Table 2.6 Metal screening of the three-component ADAR ...... 33 Table 2.7 Chiral ligand screening for asymmetric three-component ADAR ...... 34 Table 2.8 Screening of metals for asymmetric three-component ADARs using chiral metal phosphate complex ...... 36 Table 2.9 Screening of solvents for asymmetric three-component ADARs using chiral metal phosphate complex ...... 36 Table 2.10 Further condition optimization of asymmetric three-component ADARs using chiral metal phosphate complex ...... 37 Table 2.11 Scope of asymmetric three-component inverse-electron-demand ADARs .... 38 Table 3.1 Condition optimization of asymmetric ADARs of cyclohexanone, p- methoxyaniline and 1a ...... 65 Table 3.2 Further condition optimization of asymmetric ADARs of cyclohexanone, p- methoxyaniline and 1a ...... 67 Table 3.3 Substrate scope of asymmetric three-component ADAR of cyclohexanone catalyzed by YCl3/Y[P]3-LLA ...... 69 Table 3.4 Condition optimization of asymmetric ADAR of cyclopentanone, p- methoxyaniline and 1a ...... 71 Table 3.5 Substrate scope of asymmetric three-component ADAR of cyclopentanone catalyzed by Yb(OTf)3/Y[P]3-LLA ...... 72 Table 3.6 Substrate scope of asymmetric three-component ADAR of cycloheptanone catalyzed by Yb(OTf)3/Y[P]3-LLA ...... 73

Table 3.7 Metal phosphate effects on Yb(OTf)3/M[P]3-LLA catalysts for ADAR ...... 75

Table 3.8 The combination of Y2BINOL3 with metal Lewis acid for ADAR ...... 76 Table 3.9 1H NMR and 31P NMR data for select compounds(a) ...... 78 Table 4.1 Catalysts screening for three-component ADAR of 1a, 2a, and 3a ...... 111 Table 4.2 Solvent screening for three-component ADAR of 1a, 2a, and 3a ...... 112

Table 4.3 Ratio study of 5b to Y(OTf)3 in binary acid catalyst for ADAR ...... 114 Table 4.4 Three component reactions of α-ethyl, butyl, and bromo-cinnamaldehydes .. 117

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List of Figures

Figure 1.1 Resolution of racemic compounds to enantiopure compounds ...... 2 Figure 1.2. Asymmetric synthesis through chiral pool approach ...... 2 Figure 1.3. Chiral auxiliary in asymmetric synthesis ...... 3 Figure 1.4. Sharpless epoxidation ...... 4 Figure 1.5. Yeast catalyzed asymmetric reduction of ketone ...... 4 Figure 1.6. Chiral ligands...... 5 Figure 1.7. Asymmetric aldol reaction by chiral metal complex ...... 5 Figure 1.8. Examples of activation mode of organocatalysts ...... 6 Figure 1.9. List and Barba's intermolecular aldol reaction by (S)-proline ...... 7 Figure 1.10. General catalytic cycle of enamine catalysis ...... 7 Figure 1.11. MacMillan's asymmetric Diels-Alder reaction by iminium catalysis ...... 8 Figure 1.12.General iminium catalysis: LUMO–lowering ...... 8 Figure 1.13. Examples of chiral hydrogen-bond catalysts ...... 9 Figure 1.14. Asymmetric Strecker reactions by Jacobsen thiourea catalyst ...... 9 Figure 1.15. Chiral diols as enantioselective H-bonding catalysts ...... 10 Figure 1.16. Cόrdova's direct α-allylic alkylation of aldehydes and cyclic ketones ...... 11 Figure 1.17. Pd/proline-catalyzed α-allylation reaction with allylic alcohols ...... 12 Figure 1.18. Asymmetric α-allylation of different aldehydes with allylic alcohols ...... 12 Figure 1.19. α-Allylation of aldehydes with alcohols by Au(I)/amine catalyst ...... 13 Figure 1.20. 5-exo-dig Cyclization of formyl alkyne catalyzed by combined gold(I)/amine catalysts ...... 14 Figure 1.21. Direct asymmetric cross aldol reaction of ynal and aldehyde by cooperative prolinol ether-CuI-Brønsted acid catalysis ...... 14 Figure 1.22. Enamine/Cu(I) catalysis for asymmetric propargylic alkylation of aldehydes with propargylic esters ...... 15 Figure 1.23. Asymmetric α-allylation of branched aldehydes with allylic alcohols with Ir(II)/amine ...... 16 Figure 1.24. Bifunctional amine/metal Lewis acid catalyzed asymmetric direct cross aldol reaction of ketones and aldehydes ...... 17

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Figure 1.25. Bifunctional amine/metal Lewis acid catalyzed asymmetric inverse-electron- demand hetero-Diels-Alder reaction of cyclic ketones ...... 17 Figure 1.26. Bifunctional amine/metal Lewis acid catalyzed asymmetric Michael addition of ketones to alkylidene malonates and allylidene malonates ...... 18 Figure 2.1 Combination of enamine catalysis with metal catalysis ...... 23 Figure 2.2 Direct aldol reaction of isatin 1 and cyclohexanone by arylamine/metal Lewis acid ...... 25 Figure 2.3 Chen's inverse-electron-demand ADAR of carbonyl compounds ...... 31 Figure 2.4 Proposed inverse-electron-demand aza-Diels-Alder reaction ...... 32 Figure 2.5 Preparation of chiral silver phosphate ...... 35 Figure 2.6 Reduction of compound 4d ...... 39 Figure 2.7 Compatibility study of arylamines with metal Lewis acids ...... 40 Figure 2.8 Two-component ADAR reaction...... 41 Figure 3.1 Asymmetric three-component inverse-electron-demand ADAR of cyclic ketones through the combination of enamine and metal Lewis acid catalysis ...... 63

Figure 3.2 Different methods for preparation of Y[P]3 ...... 65

Figure 3.3 Protons assignment for HCPA and Y(OTf)3/Y[P]3-LLA (1,4-dioxane-d8) ..... 77 1 Figure 3.4 H NMR spectra of HCPA, Y[P]3, and Y(OTf)3/Y[P]3-LLA in 1,4-dioxane-d8 ...... 78 31 Figure 3.5 P NMR spectra of HCPA, Y[P]3, and Y(OTf)3/Y[P]3-LLA in 1,4-dioxane-d8...... 79

Figure 3.6 In situ formation of Y(OTf)3/Y[P]3-LLA. View on the right side of preliminary crystal structure of Y(OTf)3/Y[P]3-LLA. All hydrogen atoms and solvent molecules are omitted for clarity. (The gray-, red-, orange- and blue-colored spheres represent carbon, oxygen, phosphorus, and yttrium atoms, respectively) ...... 80 Figure 3.7 MALDI-TOF spectra of Y(OTf) /Y[P] -LLA ...... 84 3 3 Figure 4.1 Concept of trio catalysis with metal Lewis acid, BINOL-phosphoric acid and arylmine ...... 108 Figure 4.2 Top: previous reported Mannich reactions of aldehydes, ketones, and amines. Bottom: proposed three-component ADAR of substituted cinnamaldehyde, cyclic ketone, and arylamine catalyzed by a trio catalyst...... 110

Figure 4.3 Substrate scope of three-component ADAR of cinnamaldehyde, cyclic ketone, and arylamine ...... 116 Figure 4.4 ADARs of enal 1h ...... 117 Figure 4.5 Preparation of 6 and crystal structure of 6 ...... 118 Figure 5.1 Preparation of unsymmetrically functionalized benzoporphyrins ...... 137

List of Abbreviations

ACDC: Asymmetric counteranion-directed catalysis ADAR: Aza-Diels-Alder Reaction BINOL: 1,1'-Bi-2-naphthol BOX: Bis(oxazoline) ligands CAC: Combined acid catalysis CCDC: Cambridge Crystallographic Data Centre COSY: Correlation spectroscopy DCM: Dichloromethane DEPT: Distortionless enhancement by polarization transfer DHPs: dihydropyridines DMF: Dimethylformamide DNA: Deoxyribonucleic acid dr: Diastereomeric ratio ee: Enantiomeric excess ESI: Electrospray ionization HCPA: (R)-(−)-1,1′-Binaphthalene-2,2′-diyl hydrogen phosphate HOMO: Highest occupied molecular orbital HPLC: High-performance liquid chromatography HRMS: High-resolution mass spectrometry HSQC: Heteronuclear single quantum coherence spectroscopy IED-HDA: Inverse electron-demand hetero-Diels-Alder LLA: Lewis acid assisted Lewis acid catalyst LUMO: Lowest unoccupied molecular orbital MALDI-Tof: Matrix-assisted laser deporption ionization-time of fly mass spectrometry MeOH: Methanol MS: Mass spectrometry NMR: Nuclear magnetic resonance OTf: triflate

PNNP: chiral tetradentate ligands with a P2N2 ligand set

PyBOX: Pyridine bis(oxazoline) ligands RNA: Ribonucleic acid THF: Tetrahydrofuran TLC: Thin-layer chromatography TRIP: 3,3 ′ -Bis(2,4,6-triisopropylphenyl)-1,1 ′ -binaphthyl-2,2 ′ -diyl hydrogenphosphate UV-Visble: Ultraviolet visible spectroscopy

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DEDICATED TO MY PARENTS

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Acknowledgement

My deepest gratitude goes to my advisor, Dr. Hong Wang, for her guidance, support, patience, and encouragement throughout my graduate study. I have been amazingly fortunate to have Dr. Wang not only as my advisor in research, but also as a mentor in my career. Besides all the research techniques, abilities, she taught me to open to criticism, to be open-minded, and so many great qualities. She is an outstanding role model not only as a chemist with a strong work ethic, but also as a person with a great personality. Her generous support helped me overcome the roadblocks both in my research and life. I know all I have learned from her will benefit me throughout my whole career and life.

Many thanks go to my committee members: Dr. Novak, Dr. Hartley, Dr. Zou, and Dr. Bollmann for their time, patience, and their insightful suggestions to this dissertation.

I am grateful to all the past and current Wang group members, Dr. Zhenghu Xue, Dr. Lu Liu, Dr. Lin Jiang, Dr. Philias Daka, Rohit Deshpande, Alex Matus, Erika Csatary, Ryan Sharkisian, Siddhartha Kumar, Dr. Waruna. In particular, I must thank the postdocs, Dr. Zhenghu Xu for his help and basic training to me during my early years in the Wang lab. Great appreciation goes to Dr. Lu Liu, for his many useful suggestions and discussions regarding my research projects, especially for the research in Chapter 2. Special thanks go to Dr. Hartley and again to Dr. Wang for providing the great opportunity of joint group meetings, from which I learned a lot more than only asymmetric catalysis in the past five years.

I would like to thank our collaborators, Dr. Kraig Wheeler at Eastern Illinois University for his wonderful work to solve crystal structures involved in my research projects, and Dr. David Tierney for his great help with EPR studies.

I would also like to thank Miami University and Department of Chemistry and Biochemistry for providing great opportunities to study and meet all the good people. Thanks to NSF for providing financial support for my research.

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Many thanks go to all my friends in Oxford, Dr. Yongan Tang, Dr. Min Li, Dr. Lin Dai, Jie Wang, et al. Without them, I cannot overcome the crisis situations in the past five years.

Most importantly, none of this would have been possible without the love and patience from my family. Any word cannot express my gratitude to my parents, Mr. Tiancheng Deng and Ms. Xiuyun Guan. Their enormous love, support and encouragement throughout my life make me the person I am today. They give me the strength and courage to face any challenge in my life.

Last, but not least, my gratitude goes to my beautiful wife, Fengfeng Ren. Without her unconditional love, support, encouragement, and understanding, I would never have accomplished what I have. She makes me a better man. Her continuous love supported me to attain my Doctoral degree and will continue being the driving force in my whole career and life.

Chapter 1: Introduction The incompatibility of catalysts is the major challenge in the development of combined catalytic systems. In particular, the acid-base quenching reaction is a critical problem in the incorporation of enamine catalysis with hard metal Lewis acid catalysis. One of the main goals of our research group is to solve this long-lasting challenge. In this dissertation, the concept of an arylamine serving as efficient amine catalyst in combination with a hard metal Lewis acid or a Brønsted acid is introduced. Before the research details, a brief introduction is presented in this chapter. This chapter starts with the significance of chiral compounds, followed by different approaches to synthesizing chiral compounds; asymmetric catalysis is then introduced with the extension to the introduction of cooperative enamine/ transition metal catalysis.

1.1 Synthetic Approaches to Enantiopure Compounds The phenomenon of handedness, “chirality,” is one of the most important features of natural existence. Importantly, in nature, usually only one form of chiral molecules is dominated and useful.1 For example, in metabolic pathways, only D sugars in DNA and RNA naturally exist in life, while all amino acids in proteins are in L form.2-3 In order to match the chiral molecules in our cells, most prescription drugs are produced as chiral molecules, mainly as single enantiomers. It happens often that only one of the two enantiomers is effective; the other form may even be harmful, for instance the Thalidomide tragedy in the 1960s.4 This means that it is vital to be able to synthesize enantiopure molecules effectively in pharmaceutical industry.5-10 However, it is not only for bio-related applications,11 materials science also have great demand for enantiopure compounds, for example in the development of liquid crystals and chiral polymers.8,12 The extensive demand for enantiopure molecules has been driving chemists to develop effective methodologies to synthesize optically active compounds.13-17

There are different methods to obtain enantiopure compounds including resolution, chiral pool, chiral auxiliary and asymmetric catalysis, all of which will be discussed in the following sections.

1.1.1 Resolution Until 1970s, resolution of racemic compounds dominated in acquiring optically active compounds.18-20 In resolution, enantiopure compounds were obtained by separating racemates through using recrystallization,21 chiral resolving agents,17 or chiral column chromatography22-23. The obvious drawback of racemic resolution is that only up to 50% yield of the desired enantiomer could be attained.

Figure 1.1 Resolution of racemic compounds to enantiopure compounds 1.1.2 Chiral Pool In chiral pool synthesis, the asymmetric synthesis starts with readily available enantiopure starting materials, usually enantiopure natural products, such as monosaccharides and amino acids.24-25 The inherent enantiopurity from the substances is retained in the synthesis sequence (Figure 1.2). Apparently, this method relies on available enantiomerically enriched precursors. However, sometimes, it may be challenging to find suitable enantiomerically pure starting materials bearing similar structural components as the desired final product.

Figure 1.2. Asymmetric synthesis through chiral pool approach

1.1.3 Chiral Auxiliary Chiral auxiliaries are chiral moieties that can temporarily be incorporated to the starting materials generating new chiral selectivity in the reaction sequence.26-27 In asymmetric synthesis utilizing chiral auxiliaries, several key steps are usually included, as shown in Figure 1.3: a). incorporation of prochiral substrates with chiral auxiliary; b). diastereoselective transformation; c). separation of diastereoisomers; d) at last, auxiliary cleavage and generation of the desired enantiomerically pure product. Today numerous well-known chiral auxiliaries have been developed and utilized for a number of reactions. However, stoichiometric quantities of the chiral auxiliaries are needed. This makes this method not efficient when suitable chiral auxiliary is difficult to access.

Figure 1.3. Chiral auxiliary in asymmetric synthesis 1.1.4 Asymmetric Catalysis In reactions catalyzed by asymmetric catalysts, one molecule of chiral catalyst can help produce many chiral products by continuing regeneration. This key feature makes this method well suited for industrial synthesis. In addition, asymmetric catalysis has a broader range of applications in many organic transformations than any of the previous discussed approaches to produce enantiomerically pure compounds.15,28-30 Back in the 1970s to 1980s, breakthroughs in asymmetric catalysis were made by William Knowles,31-32 Ryoji Noyori33-34 on the asymmetric hydrogenation reactions, and K. Barry Sharpless35 on chirally catalyzed oxidation reactions (Figure 1.4). Since then, the

3 investigation of asymmetric catalysts has drawn intense interests both in academic research and industry.

Figure 1.4. Sharpless epoxidation Depending on the nature of the chiral catalysts, in asymmetric catalysis there are three major classes: biocatalysis, metal catalysis and organocatalysis.

1.1.4.1 Biocatalysis in Asymmetric Catalysis In biocatalysis, natural catalysts, such as enzymes, are utilized to catalyzed chemical transformations.36-37 Almost all enzymes carry chirality, from their building blocks, L-amino acids. For example, in the reduction of ketones, Yeast can act as a chiral catalyst to produce enantiomerically enriched alcohol (Figure 1.5).38 However, the development of biocatalysis is still slow owing to several limitations, such as limited operating regents and limited available enzymes.

Figure 1.5. Yeast catalyzed asymmetric reduction of ketone 1.1.4.2 Metallic Catalysis in Asymmetric Catalysis Metallic, as the most applied and developed catalysts in synthetic chemistry, has also been deeply investigated in asymmetric catalysis.39 In metallic asymmetric catalysis, usually chiral coordination metal complexes are utilized as catalysts. In the chiral metal

4 complexes, the chirality is typically introduced by a heteroatom-containing organic ligand. Since the first application of chiral phosphine ligand in rhodium complexes catalyzed asymmetric hydrogenation reactions, a number of effective chiral ligands have been synthesized and applied in many asymmetric reactions (Figure 1.6 and 1.7).40-41

Figure 1.6. Chiral ligands

Figure 1.7. Asymmetric aldol reaction by chiral metal complex 1.1.4.3 Organocatalysis In organocatalysis, the organic molecules, which contain no metal elements, serve as catalysts in chemical transformations. The rapid growth in this field over the last decade has dramatically changed the profile of asymmetric catalysis.42-46 Organocatalysts are often easy to handle because they are insensitive to air and moisture and non-toxic. In addition, a large chiral pool of organocatalysts is available, making organocatalysts readily manipulable to achieve high stereoselectivity in a reaction.

In many cases, referring to the activation mode of organocatalysts in organic transformations, organocatalysis can be divided into two major classes: a). covalent bonding organocatalysts: e.g. enamine/iminium ion activation by Lewis basic secondary or primary amines; b). non-covalent catalysis, such as ureas and thioureas, diols, etc. The activation modes showed in Figure 1.8 cover a major portion of organocatalysis landscape.

Figure 1.8. Examples of activation mode of organocatalysts 1.1.4.3.1 Asymmetric Enamine Catalysis and Iminium Catalysis The use of small amino acids as chiral catalysts in organic transformations can be tracked back to the 1970s. An intermolecular aldol reaction was discovered to be catalyzed by proline, known as Hajos–Parrish–Eder–Sauer–Wiechert reaction.47 However, before 2000, these studies were considered just unique chemical reactions, not as part of a larger, interconnected research field or new concept in catalysis.

Asymmetric enamine catalysis

In 2000, the first amine-catalyzed intermolecular aldol reaction was developed by List, Barbas, et. al. etc.48 In this transformation, catalytic amount of (S)-proline (20-30 mol%) was found to catalyze the asymmetric intermolecular aldol reaction of excess acetone with some aromatic and α-branched aldehydes successfully (Figure 1.9). The basis of this transformation is the reversible generation of enamines from catalytic amount of (S)-proline and ketones.

Figure 1.9. List and Barba's intermolecular aldol reaction by (S)-proline Since then, a number of organic transformations have been realized by enamine catalysis of proline derivatives and other aliphatic amines. In these reactions, they share similar catalytic cycles (Figure 1.10). a). Under dehydration conditions, the enamine intermediate is generated from an amine catalyst and the carbonyl compound; b). electrophilic attack to the enamine leads to the formation of iminium ion intermediate; c) at last, the final product is produced by hydroxylation of iminium ion.46 The key feature here is the HOMO activation from the enamine formation, and the chirality can be introduced to the carbon scaffold of amine catalysts.46,49

Figure 1.10. General catalytic cycle of enamine catalysis Asymmetric iminium catalysis

Regarding iminium catalysis, one of the most important developed catalysts is MacMillan’s imidazolidinone-based organocatalysts.50-51 In 2000, MacMillan disclosed the first enantioselective organocatalytic Diels-Alder reaction through iminium catalysis (Figure 1.11). In this report, a more general catalysis strategy of iminium catalysis was illustrated.51

Figure 1.11. MacMillan's asymmetric Diels-Alder reaction by iminium catalysis Inspired by this seminal work, the development of iminium catalysis dramatically influenced asymmetric catalysis in the following decade. Many transformations have been achieved by this “LUMO-lowering catalysis” (Figure 1.12), including Diels-Alder reactions,51 1,3-dipolar cycloaddition reactions,52 Friedel-Crafts alkylation reactions,53 etc.

Figure 1.12.General iminium catalysis: LUMO–lowering 1.1.4.3.1 Hydrogen-Bond Catalysis in Asymmetric Organocatalysis Another main category in asymmetric organocatalysis is hydrogen-bond activation.54 In biocatalysis, hydrogen-bond activation is the dominant mechanism. In the gold rush of organocatalysis, asymmetric hydrogen-bond catalysis also achieved

8 significant progress. In Figure 1.13, several asymmetric H-bond catalysts are listed (Figure 1.13).

Figure 1.13. Examples of chiral hydrogen-bond catalysts Among the number of hydrogen-bond catalysts, the most efficient and broadly used scaffold is Jacobsen ureas and thioureas. In the transformations promoted by ureas and thioureas, a double hydrogen-bond activation mode usually accounts for the catalytic activity. A Jacobsen thiourea catalyzed aymmetric Stecker reaction is shown in Figure 1.14.55-56

Figure 1.14. Asymmetric Strecker reactions by Jacobsen thiourea catalyst Application of chiral diols and biphenols in hydrogen-bond catalysis is very recent. The first successful application of chiral diols as enantioselective H-bonding catalysts was accomplished by Rawal and co-workers for an asymmetric hetero-Diels- Alder reaction of aminodienes with aromatic and aliphatic aldehydes (Figure 1.15).57

Figure 1.15. Chiral diols as enantioselective H-bonding catalysts

As shown in this section, organocatalysis has rapidly grown into the third pillar in asymmetric catalysis, along with metal catalysis and biocatalysis. Other important areas in asymmetric catalysis, such as Lewis base catalysis, Brønsted acid catalysis, counterion catalysis and heterocyclic carbene catalysis, can also be included in organocatalysis.

1.2 Cooperative Enamine-Transition Metal Catalysis In recent years, a new research area, the combination of organocatalysis with metal catalysis, has emerged, aiming to achieve organic transformations that cannot be 58-62 accessed by organocatalysis or metal catalysis independently. Given the rich chemistry established in both organometallic catalysis and organocatalysis, this new concept offers tremendous possibilities. Although the merging of enamine catalysis with transition metal catalysis promises huge potential, this research area has grown relatively slowly. The major challenge lies in the incompatibility of the catalysts;63-64 in particular, the combination of an amine catalyst with a hard metal Lewis acid is very difficult.

As discussed in the preceding sections, in enamine catalysis, a chiral aliphatic primary or secondary amine, which is a Lewis base, acts as the catalyst. When an amine catalyst is mixed with a metal Lewis acid, an acid-base quenching reaction will occur, thus causing catalyst deactivation. In order to solve the incompatibility problems, the soft/hard approach, in which a hard base is employed with a soft acid, is the general way investigated. Our group also disclosed the utilization of a chelating ligand to avoid the acid-base interaction.

1.2.1 Combination of an Aliphatic Amine with a Soft Metal: Soft/Hard Approach The soft/hard approach is a general and effective strategy in combining enamine catalysis with transition metal catalysis. Using this strategy, aliphatic amine catalysts has been successfully combined with soft metal catalysts, such as Pd(0 or II), Au(I), Ir(II), Cu(I), and Ag(I).

1.2.1.1 Combination of an Aliphatic Amine with Pd(0 or II) The direct intermolecular -alkylation of aldehydes and cyclic ketones was not achieved until 2006 by the Cόrdova group through the combination of enamine catalysis with Pd(0) catalysis (Figure 1.16).65 The authors proposed that two powerful catalytic cycles were merged in this transformation, enabling both electrophilic and nucleophilic activation (Figure 1.16): 1) Activated enamine intermediates were in situ formed from aldehydes or ketones with pyrrolidine; 2) Electrophilic Tsuji–Trost palladium π-allyl complexes66-67 were catalytically generated in the other catalytic cycle; 3) Nucleophilic attack of enamine intermediates to palladium π-allyl electrophiles followed by reductive elimination leading to iminium intermediate and Pd0; 4) Subsequent hydrolysis of the iminium intermediate afforded -allylic alkylated aldehydes or ketones and regenerated the secondary amine catalyst.

Figure 1.16. Cόrdova's direct α-allylic alkylation of aldehydes and cyclic ketones

Using a similar approach, Saicic and co-workers reported the construction of five and six-membered rings through direct intramolecular -allylic alkylation of aldehydes in 2007.68 In 2009, Breit and co-workers reported a dual Pd/proline-catalyzed -allylation reaction of aldehydes and ketones using allylic alcohols directly (Figure 1.17).69 Under optimized conditions, up to 96 % yield of direct intermolecular allylation products were obtained.

Figure 1.17. Pd/proline-catalyzed α-allylation reaction with allylic alcohols

The first examples of asymmetric Tsuji–Trost-type -allylation of carbonyl compounds with allylic alcohols were achieved by the List group in 2011 through the concerted action of three different species, [Pd(PPh3)4], benzhydrylamine, and TRIP, generating all-carbon quaternary stereogenic centers in high yields (up to 98%) and enantioselectivity (up to >99% ee) (Figure 1.18).70 The high enantioselectivity of this reaction was enabled by asymmetric counteranion-directed catalysis (ACDC).71-72

Figure 1.18. Asymmetric α-allylation of different aldehydes with allylic alcohols

1.2.1.2 Combination of an Aliphatic Amine with Au(I) Recently, Bandini demonstrated the feasibility of the addition of enamines to gold(I) activated -allyl electrophiles for an intramolecular -allylic alkylation of aldehydes with alcohols (Figure 1.19).73 Substrates bearing aminosulfonyl groups, benzyl carbamate groups, and malonyl tethers were all tolerated in this catalysis system leading to desired products with moderate to high yields and high enantioselectivities.

Figure 1.19. α-Allylation of aldehydes with alcohols by Au(I)/amine catalyst Homogeneous gold (I) complexes have shown to be efficient carbophilic Lewis acid catalysts for the construction of complex carbocycles.74-76 In 2008, the Kirsch group demonstrated for the first time the direct carbocyclization of aldehydes with alkynes through cooperative enamine catalysis/Au (I) catalysis (Figure 1.20).77 The cyclization of secondary formyl alkyne gave the desired 5-exo-dig cyclization product (Figure 1.20 up equation) bearing an all-carbon quaternary stereocenter in good yields. Reaction of - unbranched aldehydes resulted in 5-exo-dig cyclization products followed by immediate double bond migration (Figure 1.20 bottom equation).

Figure 1.20. 5-exo-dig Cyclization of formyl alkyne catalyzed by combined gold(I)/amine catalysts 1.2.1.3 Combination of an Aliphatic Amine with Cu( I) In 2013, the Palomo group reported a highly stereocontrolled synthesis of functionalized propargylic alcohols via asymmetric direct aldol reaction of aldehydes and ynals. This reaction was catalyzed by a ternary catalyst system comprised of a chiral prolinol ether, CuI, and benzoic acid (Figure 12.1).78 Good yields, excellent diastereoselectivities (over 20/1 dr (anti/syn)), and excellent enantioselectivities (up to 99% ee) were achieved. It was suggested that the high diastereoselectivities might arise from the steric inflation of the alkyne moiety as a consequence of metal–alkyne association. This ternary catalyst system was well compatible with a broad substrate scope of ynals and aldehydes bearing both linear and branched alkyl chains with various functional groups including alkene, carbamate, ester, ether, and acetal.

Figure 1.21. Direct asymmetric cross aldol reaction of ynal and aldehyde by cooperative prolinol ether-CuI-Brønsted acid catalysis Later on, a new catalytic system for the asymmetric propargylic alkylation of aldehydes using CuOTf and a chiral pyrrolidine (Figure 1.22) was developed by

Nishibayashi group.79 It was suggested that the reaction occurred through the nucleophilic addition of the enamine generated in situ from the aldehydes and pyrrolidine to the Cu(I)-allenylidene complex formed from propargyl alcohol and Cu(I).

Figure 1.22. Enamine/Cu(I) catalysis for asymmetric propargylic alkylation of aldehydes with propargylic esters 1.2.1.4 Combination of an Aliphatic Amine with Ir( II) Recently the Carreira group accomplished an asymmetric -allylation of branched aldehydes with allylic alcohols (Figure 1.23).80 In this reaction, an allyliridium intermediate similar to Tsuji–Trost palladium -allyl electrophiles was formed acting as the electrophile. It is notable that ,-unsaturated aldehydes bearing vicinal quaternary/tertiary stereogenic centers were generated in this reaction in good yields and excellent selectivities with wide substrate scope. This difficult asymmetric organic transformation was achieved through a novel stereodivergent dual catalysis, engaging both a chiral iridium catalyst and a chiral amine catalyst, which activate the allylic alcohol and aldehyde substrates, respectively.

Figure 1.23. Asymmetric α-allylation of branched aldehydes with allylic alcohols with Ir(II)/amine 1.2.2 Bifunctional Amine/Metal Lewis Acid Catalysts In order to solve the acid-base quenching problem, our group designed and developed a class of bifunctional amine/metal Lewis acid catalysts for cooperatively incorporating enamine catalysis with metal Lewis acid catalysis (Figure 1.24). In these bifunctional catalysts, the Lewis base (primary or secondary amine) is tethered to a chelating ligand, which serves as a “trap” for the incoming metal. In this way, the base and the metal Lewis acid are brought into close proximity without interacting with each other. These bifunctional catalysts were evaluated in asymmetric direct aldol reactions.81- 83 In combining with the ligands, Cu(II) salts turned out to be most active catalysts affording the aldol products in high yields, high diastereoselectivities and high enantioselectivities. It is notable that the activities of these catalysts in aldol reactions are much enhanced relative to those of organocatalysts.

Figure 1.24. Bifunctional amine/metal Lewis acid catalyzed asymmetric direct cross aldol reaction of ketones and aldehydes Using these bifunctional amine/metal Lewis acid catalysts, a difficult inverse electron-demand hetero-Diels-Alder (IED-HDA) reaction of cyclic ketones and ,- unsaturated--ketoesters was also achieved (Figure 1.25).84

Figure 1.25. Bifunctional amine/metal Lewis acid catalyzed asymmetric inverse-electron-demand hetero-Diels-Alder reaction of cyclic ketones By using the enamine-metal Lewis acid bifunctional catalysis, a difficult asymmetric Michael addition of ketones to akylidene malonates and allylidene malonates was accompolished recently (Figure 1.26).85

Figure 1.26. Bifunctional amine/metal Lewis acid catalyzed asymmetric Michael addition of ketones to alkylidene malonates and allylidene malonates 1.3 Summary Since the realization of the first combination of enamine catalysis with transition metal catalysis in 2006 by the Cόrdova group, considerable progress has been made on cooperative enamine/transition metal catalysis. In particular, significant advances have been achieved in direct α-allylation and α-propargylation of aldehydes in the past several years. Despite these advances, this research area is still in its infancy, the potential of which is far from fully explored. The foreseeable problems in developing cooperative enamine/metal catalysis still lie in catalyst incompatibility arising mainly from acid–base quenching reactions. Although perceivable problems exist, several strategies, including soft metal Lewis acid/hard Lewis base combination, the utilization of a chelating ligand, as well as mixing an ammonium salt with a Lewis acid, have been developed to overcome these problems.

As continuous work in our group to solve catalyst incompatibility problem in the development of cooperative enamine/metal catalysis, in this dissertation, the first application of arylamines in enamine catalysis is presented. The incompatibility of enamine catalysts and metal Lewis acids is solved by applying arylamines/acids cooperative catalysis. In addition, a highly chemo- and enantioselective three-component aza-Diels-Alder reaction of cyclic ketones with enones was developed through the combination of an arylamine with a stronger metal Lewis acid. In Chapter 3, a new type of chiral Lewis-acid-assisted Lewis acid catalyst formed from a metal Lewis acid and a chiral metal phosphate (MLA/M[P]3-LLA) was disclosed. A highly chemo- and enantioselective three-component aza-Diels-Alder reaction of cylic ketones (5, 6, and 7 membered) was successfully achieved by in situ prepared MLA/M[P]3-LLA. In Chapter

4, a trio catalysis system from arylamines, BINOL-phosphoric acids, and metal Lewis acids was developed. By using this trio catalyst, a highly chemo- and enantioselective three-component aza-Diels-Alder reaction of substituted cinnamaldehydes, cyclic ketones, and arylamines was successfully achieved.

Acknowledgement: [Chem. Commun., 2014, 50, 4272-4284] - Reproduced by permission of The Royal Society of Chemistry. http://pubs.rsc.org/en/content/articlepdf/2014/cc/c4cc00072b

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Chapter 2: Arylamines Catalyze Enamine Formation: A New Tool for Cooperative Organo-Aminocatalysis and Acid Catalysis

Abstract

A new concept of using arylamines as enamine catalysts was introduced. Arylamines and metal Lewis acids are used as catalysts in the highly chemo- and enantioselective three-component inverse-electron-demand aza-Diels–Alder reaction of cyclic ketones with enones (86-96% ee, 68-90% yield). The enantioselectivity is introduced by a simple chiral metal phosphate complex. Arylamines can also serve as effective enamine catalysts in combination with either a metal Lewis acid or a Brønsted acid.

Paper published from the work in this chapter:

Deng, Y.; Liu, L.; Sarkisian, R. G.; Wheeler, K.; Wang, H.; Xu, Z. Angew. Chem. Int. Ed. Engl. 2013, 52, 3663-3667.

Acknowledgement: Deng, Y.; Liu, L.; Sarkisian, R. G.; Wheeler, K.; Wang, H.; Xu, Z.: Arylamine-catalyzed enamine formation: cooperative catalysis with arylamines and acids. Angew. Chem. Int. Ed. Engl. 2013, 52, 3663-3667. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission. http://onlinelibrary.wiley.com/doi/10.1002/anie.201209268/pd

2.1 Introduction As presented in Chapter 1, the explosive growth of organocatalysis has made huge impact on asymmetric catalysis in the past decade.1-5 Transition metal catalysis, on the other hand, has long been established as one of the most powerful tools in organic synthesis.6 The combination of the organo-aminocatalysis with the more traditional metal Lewis acid catalysis has emerged, aiming to deliver organic transformations that cannot be accomplished by organocatalysis or metal catalysis independently.7-10 The first combination of organo-enamine catalysis with metal catalysis was achieved in 2006 by the Cordova group.11 Since then, considerable progress has been made on the combination of enamine catalysis with metal Lewis acid catalysis leading to a series of exciting discoveries.7,12-15

Figure 2.1 Combination of enamine catalysis with metal catalysis Although promised huge potential, this research area has been growing slowly. The major challenge lies in the catalyst incompatibility; in particular, the incorporation of enamine catalysis with harder metal Lewis acid is very difficult. Combining enamine catalysis with harder metal Lewis acid catalysis (Figure 2.1, C) has turned out to be a very challenging problem that lies in acid-base self-quenching reactions, rendering catalyst-inactivation.16 In asymmetric aminocatalysis involving either enamine or iminium catalysis, a chiral aliphatic secondary or primary amine serves as the amine catalyst. Aliphatic amines are hard bases, and are likely compatible with softer metals based on the soft/hard approach, but less likely with harder metals. Given the huge number of substrates that can be activated by the large variety of metal Lewis acids, circumventing such problem represents an important breakthrough.

2.2 Concept Design We hoped to find an amine catalyst that can be compatible with a large variety of metal Lewis acids to significantly extend the scope of enamine-metal Lewis acid catalysis, and to open up a new research area of iminium-metal Lewis acid catalysis. We considered arylamines such as aniline. Arylamines have much lower pKa (4-6) than aliphatic amines (pKa, 9-11), and should be much softer due to the delocalization of the lone pair to the aromatic -system. It appeared to us that arylamines are ideal candidates to combine with harder metal Lewis acids.

Despite long existence in organic chemistry, aromatic amines have never been used as enamine catalysts.17 This may be mainly due to the general understanding of the much lower nucleophilicity of aromatic amines. However, aromatic amines forming enamine intermediate and reacting in subsequent reactions have been suggested by the List group in an organocatalytic cascade reaction.18 In a recent work, the Gong group also suggested that an achiral aromatic amine played a crucial role in controlling the stereochemistry of a Friedländer condensation by forming an enamine intermediate.19

We speculate that aromatic amines might be suitable to serve as an efficient enamine catalyst in conjunction with a stronger metal Lewis acid. The lower nucleophilicity of the enamines can be compensated by the following factors: 1) facilitated formation of enamine in the presence of a metal Lewis acid; 2) higher activation of the electrophiles by a metal Lewis acid.

2.3 Results and Discussion

2.3.1 Arylamine/Acid Catalyzed Asymmetric Aldol Reaction

2.3.1.1 Arylamine/Acid Catalyzed Asymmetric Aldol Reaction of Isatin and Cyclohexanone To test the feasibility of our plan, the direct aldol reaction of isatin and cyclohexanone was carried out first. It is proposed that in the presence of a hard metal Lewis acid, cyclic ketone can be activated by formation of enamine intermediate with an

24 arylamine. Following nucleophilic addition to isatin, sequential transformations will lead to the aldol product.

Figure 2.2 Direct aldol reaction of isatin 1 and cyclohexanone by arylamine/metal Lewis acid As indicated in Table 2.1, the reaction could not be catalyzed by a metal Lewis acid or aniline alone (entries 1 and 2). But when catalytic amount of aniline was combined with a metal Lewis acid (Y(OTf)3), the reaction proceeded smoothly to give the desired aldol products with 80% yield in 6 hours (entry 3), indicating the power of the combination. It should be mentioned that when an alkylamine (hexylamine) was combined with Y(OTf)3 for the aldol reaction of isatin, no reaction occurred, again illustrating the much better compatibility of arylamines with harder metal Lewis acids (entry 5).

Table 2.1 Condition screening for asymmetric aldol reactions of isatin and cyclohexanone

catalyst yield(a) entry amine (mol%) solvent time [h] (mol%) (%)

1 Y(OTf)3 (10) - THF 48 0

2 - aniline (10) THF 24 trace

3 Y(OTf)3 (10) aniline (10) THF 6 80

4 - hexylamine (10) THF 24 10

5 Y(OTf)3 (10) hexylamine (10) THF 24 0

The reactions were performed with 0.1 mmol of isatin and 0.05 ml of cyclic ketone in 1 ml solvent. (a) The yields were determined by 1H NMR analysis of crude reaction mixtures.

After achieving the direct aldol reaction of isatin catalyzed by combing catalyst of arylamine and Y(OTf)3. The asymmetric version of this reaction was performed. As shown in Table 2.2, after screening different chiral ligands to combine with Y(OTf)3, only 8 % ee can be obtained with very low activity (entry 2). Then a chrial aylamine was combined with Y(OTf)3 to catalyze this aldol reaction. To our delight, combination of the chiral arylamine with Y(OTf)3 gave excellent enantioselectivity for the aldol reaction of isatin (95% ee, entry 7). These data strongly suggest that an arylamine can serve as an amine catalyst in conjunction with a metal Lewis acid. The stereoselectivity can be introduced through a chiral amine.

Table 2.2 Condition screening of asymmetric aldol reaction of isatin and cyclohexanone

catalyst amine time yield(a) (c) entry solvent dr(b) ee (mol%) (mol%) (h) (%)

Y(OiPr)3

1 (10) aniline (10) DCM 48 0 - -

BINOL (30)

Y(OTf)3 (10)

2 PyBOX 1 aniline (10) DCM 24 trace - 8 (10)

Y(OTf)3 (10) 3 aniline (10) DCM 24 trace - - BOX 1 (10)

chiral 4 - toluene 24 0 - - arylamine (10)

chiral 5 Y(OTf)3 (10) THF 3 81 3:1 0 arylamine (10)

chiral 6 Y(OTf)3 (10) toluene 12 75 4:1 46 arylamine (10)

chiral d 7 Y(OTf)3 (10) toluene 12 79 10:1 95 arylamine (20)

The reactions were performed with 0.1 mmol of isain and 0.05 ml of cyclohexanone in 1 ml solvent. (a) The yields were determined by 1H NMR analysis of crude reaction mixtures. (b) The diastereomeric ratios were determined by 1H NMR analysis of crude reaction mixtures. (c) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

2.3.1.2 Arylamine/Acid Catalyzed Asymmetric Aldol Reaction of Enone and Cyclic Ketones The direct aldol reaction of enone 1 and cyclohexanone was also conducted. The condition screening of the aldol reaction was first performed. As shown in Table 2.3, a metal Lewis acid or aniline cannot catalyze the reaction independently (entries 1 and 2).

These results are similar to the results from aldol reaction of isatin in 2.2.1.1. When catalytic amount of aniline was combined with a Cu(OTf)2, the reaction proceeded smoothly to give the desired aldol products with 53% yield (entry 3). It also supports the conclusion from 2.2.1.1. that arylamine can serve as enamine catalyst in the presence of hard metal Lewis aicd. The results from entries 4 and 5 again illustrate the much better compatibility of arylamines with harder metal Lewis acids.

Table 2.3 Condition screening for direct aldol reaction of enone and cyclohexanone

catalyst time yield(a) ee(b) entry aniline (mol%) solvent (mol%) (d) (%) (%) Cu(OTf) 1 2 - THF 6 2 0 (10) 2 - 20 THF 3 trace - Cu(OTf) 3 2 20 THF 3 53 0 (10) Cu(OTf) 4 2 hexylamine (20) THF 6 trace 0 (10) Cu(OTf) N,N-dimethylaniline 5 2 THF 6 trace 0 (10) (20) The reactions were performed with 0.1 mmol of enone and 0.05 ml of cyclic ketone in 1 ml solvent. (a) The yields were determined by 1H NMR analysis of crude reaction mixtures. (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

In order to realize the asymmetric version of this aldol reaction, chiral ligand

BOX 1 were tested to combine with Cu(OTf)2 and arylamine as shown in Table 1.2. However, only 7% ee can be obtained. Then the combinantion of chiral phosphoric acid and arylamine was tested (entries 3 to 11). As it turned out, aniline can combine with a Brønsted acid to catalyze the aldol reaction of enone 1a. The asymmetric version of the

28 aldol reaction of enone 1 was effectively achieved through using a chiral phosphoric acid TRIP (entry 11, 12.5:1 dr, 89% ee, 87% yield). These data suggest that an arylamine can also serve as an amine catalyst in conjunction with a Brønsted acid. The stereoselectivity can be introduced through a chiral acid.

Table 2.4 Condition screening of asymmetric aldol reaction of enone and cyclohexanone

catalyst aniline time yield(a) entry solvent dr(b) ee(c) (mol%) (mol%) (d) (%) Cu(OTf) (10) 1 2 20 THF 3 trace - 7 BOX 1 (20) Cu(OTf) (10) 2 2 20 THF 3 - - 4 HCPA (10) 3 HCPA (10) 20 THF 2 - - 21 (R)-TRIP 4 20 THF 2 75 11:1 70 (10) (R)-TRIP 5 0 THF 2 0 - - (10) (R)-TRIP 6 10 THF 2 71 11:1 81 (10) (R)-TRIP 7 10 DCM 4 30 15:1 75 (10) (R)-TRIP 8 10 MeOH 4 26 3:1 3 (10) (R)-TRIP 9 10 CH CN 4 18 9:1 18 (10) 3

(R)-TRIP 10 10 Neat 1.5 57 6:1 75 (10) (R)-TRIP 11 10 toluene 1.5 87 12.5:1 89 (10) The reactions were performed with 0.1 mmol of enone and 0.05 ml of cyclic ketone in 1 ml solvent. (a) The yields were determined by 1H NMR analysis of crude reaction mixtures. (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

After the solvent screening for asymmetric aldol reaction of enone 1 by combination of (R)-TRIP and aniline (entries 6-11), substrate scope was accomplished in Table 2.5.

Table 2.5 Substrate scope of asymmetric aldol reaction of enone 1 and cyclic ketone

2.3.2 Three-Component Aza-Diels-Alder Reaction (ADAR) of Enones, Cyclic Ketones, and Arylamines After achieving two aldol reactions catalyzed by combing catalysts of arylamine and metal Lewis acid, a more difficult three-component inverse-electron-demand ADAR

30 of , -unsaturated -ketoester, cyclic ketones and aromatic amines was investigated. The concept, that arylamine can serve as efficient enamine catalyst, is also further proved.

The asymmetric aza-Diels-Alder reaction (ADAR) is the most convenient and powerful tool to construct nitrogen-containing heterocycles, representing one class of the most important structural motifs in natural products, pharmaceuticals and biosystems.20 While normal electron demand ADARs based on dienamines and imine dienophiles have achieved considerable recent progress,21-23 little has been done for the inverse-electron- demand ADARs involving enamines as the dienophiles.24-28 The Chen group reported the first two-component organocatalytic asymmetric inverse-electron-demand ADAR of carbonyl compounds in 2008.24 In this reaction, an aldehyde reacted with a preformed 1- azadienes activated by a N-sulfonyl group.

Figure 2.3 Chen's inverse-electron-demand ADAR of carbonyl compounds However, enamine-based inverse-electron-demand ADAR reaction of ketones has never appeared in the literature. Very recently, we have developed a difficult inverse- electron-demand hetero-Diels-Alder reaction of ketones with unsaturated ketoesters via an enamine-metal Lewis acid bifunctional apporach.29 Encourged by this success, we developed a three-component inverse-electron-demand ADAR of , -unsaturated - ketoester, cyclic ketones and aromatic amines (Figure 2.4). A three-component reaction will avoid the preformation of the dienophiles and the much troublesome preparation of unstable 1-azadienes.30 In this section, the research details of an extremely challenging highly chemo- and enantioselective three-component aza-Diels-Alder reaction through incorporating arylamines with metal Lewis acids is presented.

Figure 2.4 Proposed inverse-electron-demand aza-Diels-Alder reaction 2.3.2.1 Racemic Three-Component ADAR of Enones, Cyclic Ketones, and Arylamines We envisioned that arylamines, such as aniline, can reversibly form enamine intermediate with cyclic ketones serving as the enamine catalyst; on the other hand, they can also reversibly form 1-azadienes (3) with , -unsaturated -ketoester (1) in the presence of a metal Lewis acid; the in situ formed 1-azadienes, which can be strongly activated by a metal Lewis acid, can react with the enamine leading to an irreversible ADAR reaction predominately under optimized conditions to give dihydropyridine 4 (Figure 2.4).

We started the investigation by screening a variety of metal salts for the three- component reaction of cyclohexanone, enone 1b and p-methoxyaniline in THF (Table 1). Most of the metal salts screened were able to give the desired ADAR product dihydropyridines 4b. Y(OTf)3, Yb(OTf)3, La(OTf)3 and Zn(OTf)2 displayed high activity for this ADAR in terms of reaction time (< 4 h) and yield (78-91%); the formation of 4a was confirmed using 1H and 13C NMRs, DEPT, COSY, HSQC and MS (HRMS and ESI) techniques.

Table 2.6 Metal screening of the three-component ADAR

entry metal yield (%)(a) time (h)

1 Y(OTf)3 91 2

2 Cu(OTf)2 trace 24

3 Yb(OTf)3 85 3 4 EuFOD 0 36

5 In(SbF6)3 21 12

6 La(OTf)3 61 12

7 Sc(OTf)3 56 12

8 Zn(OTf)2 78 4 (b) 9 YCl3 trace 24 The reactions were performed with 0.1 mmol of 1b and 0.05 ml of cyclohexanone in the presence of 0.1 mmol of p-methoxyaniline in 1 ml of THF. (a) The yields were determined by 1H NMR analysis of crude reaction mixtures. (b) The reaction was carried out in 1 ml of toluene.

2.3.2.2 Asymmetric Three-Component ADAR of Enones, Cyclic Ketones, and Arylamines Having established the possibility of a three-component ADAR reaction, we proceeded to pursue an asymmetric version of this reaction. The availability of an asymmetric ADAR will largely broaden the utility of this reaction. Since arylamines also

33 act as a reactant in the reaction, the asymmetry can only be induced through the metal. A general way is to use chiral ligands.

First, I screened a number of chiral ligands including BOX, PyBOX, naphthol and

Salen ligands, in combination with Y(OTf)3, Yb(OTf)3, La(OTf)3 and Zn(OTf)2. However, only low to modest enantioselectivity (<42% ee) was obtained with decreased activity and/or increased side reactions (see Table 2.7).

Table 2.7 Chiral ligand screening for asymmetric three-component ADAR

entry metal Ligand yield (%)(a) time (h) solvent ee (%)(b)

1 Y(OTf)3 PyBOX 1 80 24 THF 20

2 Y(OTf)3 PyBOX 1 83 12 THF 14

3 Y(OTf)3 BOX 2 - 12 THF 15

4 Y(OTf)3 PyBOX 2 - 24 THF 27

5 Y(OTf)3 BINOL 80 24 THF 0 6 BINOL - 0 120 THF -

7 Salen-Cr - trace 120 THF 28

8 Y(OTf)3 PyBOX 1 36 12 DCM 17

9 Y(OTf)3 PyBOX 1 75 12 CH3CN 7

10 Y(OTf)3 PyBOX 1 79 12 toluene 29

11 Y(OTf)3 PyBOX 1 42 12 neat 0

12 Yb(OTf)3 PyBOX 1 - 24 THF 17

13 Yb(OTf)3 BOX 1 - 12 THF 10

14 La(OTf)3 PyBOX 1 - 24 THF 13

15 La(OTf)3 BOX 1 - 12 THF 15 16 Zn(OTf)2 PyBOX 1 35 36 THF 42 17 Zn(OTf)2 BOX 1 46 12 THF 30 The reactions were performed with 0.1 mmol of 1b and 0.05 ml of cyclohexanone in the presence of 0.1 mmol of p-methoxyaniline in 1 ml of solvent. (a) The yields were determined by 1H NMR analysis of crude reaction mixtures. (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

We then investigated the possibility of using a chiral metal phosphate to introduce chirality to this three-component ADAR. By using a method modified on the procedure reported by the Toste group31, chiral silver phosphate 5 was prepared.

Figure 2.5 Preparation of chiral silver phosphate

We initiated the search by combining a M(III)Cl3 with this simple chiral silver phosphate (5) for the three-component reaction of cyclohexanone, enone 1b and p- methoxyaniline. After extensive exploration of the reaction conditions including solvent screening and metal screening (Table 2.8, 2.9, and 2.10), high enantioselectivity was obtained for 4b through incorporating YCl3 (10 mol%) and silver phosphate 5 (5 mol%) in toluene. In addition, it is found that the silver phosphate 5 must be prepared at higher temperature (50 °C) in order to obtain high enantioselectivity.

Table 2.8 Screening of metals for asymmetric three-component ADARs using chiral metal phosphate complex

entry metal yield(a) (%) time (h) ee (%)(b)

1 YCl3 80 12 86

2 YbCl3 73 12 85

3 InCl3 64 12 -10

4 LaCl3 78 12 29

5 ZnCl2 trace 12 -22

6 ScCl3 trace 12 -9 7 - trace 24 - The reactions were performed with 0.1 mmol of 1b and 0.05 ml of cyclohexanone in the presence of 0.1 mmol of p-methoxyaniline in 1 ml of solvent. (a) The yields were determined by 1H NMR analysis of crude reaction mixtures. (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

Table 2.9 Screening of solvents for asymmetric three-component ADARs using chiral metal phosphate complex

entry solvent yield (%)(a) time (h) ee (%)(b) 1 toluene 80 12 86 2 DCM 18 18 7 3 THF 28 18 26

4 CH3CN 45 18 13 5 Neat 10 18 5 6 MeOH 29 8 16 7 benzene 70 12 76 8 xylene 73 12 81 The reactions were performed with 0.1 mmol of 1b and 0.05 ml of cyclohexanone in the presence of 0.1 mmol of p-methoxyaniline in 1 ml of solvent. (a) The yields were determined by 1H NMR analysis of crude reaction mixtures. (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

Table 2.10 Further condition optimization of asymmetric three-component ADARs using chiral metal phosphate complex

YCl entry 3 5 (mol%) yield (%)(a) time (h) ee (%)(b) (mol%) 1 0 10 trace 24 - 2 10 0 trace 24 0 3 5 15 73 12 83 4 5 10 77 12 81 5 5 5 70 12 80 6 10 5 80 12 89 7 20 5 71 12 78 The reactions were performed with 0.1 mmol of 1b and 0.05 ml of cyclohexanone in the presence of 0.1 mmol of p-methoxyaniline in 1 ml of solvent. (a) The yields were determined by 1H NMR analysis of crude reaction mixtures. (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

Using the optimized conditions, we investigated the substrate scope of enone 1, the arylamine, and the ketone (Table 2.11). The ,-unsaturated-ketoesters with both electron-donating and electron-withdrawing aromatic substituents at the -position reacted smoothly with cyclohexanone and p-methoxyaniline to give the ADAR product 4 in very good to excellent enantioselectivity (entries 1-10, 4a-4j, 87-96% ee) in good yields (68-90%). These reactions were highly chemoselective under the optimized conditions, leading to the dominating formation of HDAR products. With the amines, in addition to the electron-rich p-methoxyaniline, less electron-rich aniline, p-bromoaniline and p-chloroaniline all reacted with enone 1 (when R1, R2 = Cl, H) and cyclohexanone producing the ADAR products in very high enantioselectivity and chemoselectivity (entries 11-13, 4k-4m, 93-96% ee, 68-72% yield). It is notable that the much more electron-deficient p-nitroaniline were able to give the ADAR product in quantitative yield when Y(OTf)3 was used as the catalyst, although when the chiral anion approach was applied, the resulting phosphate was not strong enough to activate the ADAR. Similar to cyclohexanone, hetero-atom containing dihydrothiopyran-4-one also underwent ADAR smoothly giving 4n in 93% ee and 73% yield (entry 14).

Table 2.11 Scope of asymmetric three-component inverse-electron-demand ADARs

entry 4 time (h) Z R1, R2 yield (%)(a) ee (%)(b)

1 4a 12 OMe Cl, H 85 96

2 4b 12 OMe H, Ph 72 89

3 4c 12 OMe CH3, Ph 70 86

4 4d 12 OMe Cl, Ph 90 93

5 4e 12 OMe H, H 80 92

6 4f 12 OMe Br, Ph 88 93

7 4g 12 OMe Br, H 85 95

8 4h 12 OMe OMe, H 78 93

9 4i 12 OMe NO2, CH3 68 92

10 4j 12 OMe H, p-nitrophenyl 80 87

11 4k 24 H Cl, H 70 94

12 4l 24 Cl Cl, H 68 96

13 4m 24 Br Cl, H 72 93

14 4n 24 OMe Cl, H 73 93

The reactions were performed with 0.1 mmol of enone and 0.05 ml of cyclic ketone in the presence of 0.1 mmol of arylamine in 1 ml of toluene. (a) Yields refer to isolated product. (c) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

The absolute configuration of 4d was established as (4R) by X-ray crystallographic analysis of compound 6. Compound was prepared by reduction of 4d. Since no reaction happened at the chiral center (C4) of 4d in the reduction, 4d has the same absolute configuration as 6 at C4. All the rest of the compounds were assumed to have similar configurations as 4d.

Figure 2.6 Reduction of compound 4d

2.3.2.3 Study of Catalytic Role of Arylamine In order to further illustrate the much better compatibility of arylamines with metal Lewis acids, we replaced the arylamine with an aliphatic amine (hexylamine) in the three-component reaction in the presence of Y(OTf)3 (Figure 2.7). The reaction became very messy. Starting enone 1b was not completely consumed even after two days. No

ADAR product was detected. On the other hand, when the metal Lewis acid (Y(OTf)3) was replaced by a Brønsted acid (benzoic acid or phosphoric acid), similar results were obtained (Figure 2.7). These data clearly suggest the necessity of using both an arylamine and a metal Lewis acid in this reaction.

Figure 2.7 Compatibility study of arylamines with metal Lewis acids

We believe that the arylamines participated in the reaction not only as reactants, but also as amine catalysts activating the ketones through enamine intermediates. To better understand the catalytic role of the amines, we carried out the two-component reaction of 1-azadiene 732 with cyclohexanone (Figure 2.8). In the absence of an arylamine, the reaction of 7 with cyclohexanone gave less than 10% of ADAR product

(4i) in the presence of Y(OTf)3 after 36 h with major recovery of starting material 7 and the corresponding enone resulting from the decomposition of 7 (eq. 1); the reaction rate increased when aniline was added (eq. 2), and the reaction was completed in 24 h giving 70% of 4i; when N,N-dimethylaniline, a tertiary amine slightly more basic than aniline,

40 was added to the reaction mixture (eq. 3), the reaction proceeded similarly to eq. 1, indicating that N,N-dimethylaniline did not play a role in this reaction; 7 did not react with cyclohexanone in the absence of a metal Lewis acid (eq. 4); when a aliphatic primary amine (hexylamine) was used in the presence (eq. 5) and in the absence of

Y(OTf)3 (eq. 6), both reactions did not give any ADAR product with recovery of starting 7. These data strongly support that the three-component ADAR is mediated by both a metal Lewis acid and an arylamine via the formation of enamine intermediates.

Figure 2.8 Two-component ADAR reaction.

2.4 Conclusion In conclusion, the combination of organo-aminocatalysis with harder metal Lewis acid catalysis is very difficult because of the aforementioned acid-base quenching reaction leading to catalyst-inactivation. We have shown that using arylamines to replace the aliphatic amines generally used in organo-amino catalysis can circumvent the problem. Very importantly, we have demonstrated that an arylamine can effectively act as an amine catalyst activating the ketones through enamine intermediates either through combining a Brønsted or a metal Lewis acid. Using these new concepts, a very challenging three-component inverse-electron-demand aza-Diels-Alder reaction of cyclic ketones with enones were developed through the combination of an arylamine with a stronger metal Lewis acid. The enantioselectivity of these reactions was achieved through

41 a simple chiral anion approach. The availability of a large variety of arylamines, their easily tunable nucleophilicity through the introduction of different electronic groups at the aromatic ring(s), and the fact that the stereoselectivity of the reactions can be induced either through a chiral amine or a chiral acid offer great flexibility to these approaches, and will thus promise their broad applications.

2.5 Experiment Section

2.5.1 Reaction Set Up Synthesis of substrates

Substrates 1a-1n were synthesized using known procedures.33-34

Chiral silver phosphate 5 was prepared from the corresponding phosphoric acid purchased from Aldrich using a method modified on the procedure reported by the Toste 31 group. One portion of Ag2CO3 (79 mg, 0.29 mmol) was added into the solution of (R)-

(−)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (200 mg, 0.57 mmol ) in CH2Cl2 (15 ml) followed by the addition of distilled H2O (3 ml) in the dark. The resulting mixture was stirred vigorously for 12 h at 45°C. The reaction mixture was evaporated under reduced pressure to afford the product as white solid.

General procedure of racemic three-component ADARs

To a one dram vial equipped with a magnetic stir bar was added enone 1 (0.2 mmol, 1.0 equiv), arylamines (0.2 mmol, 1.0 equiv), and cyclic ketone (0.1ml). The reaction was then carried out in 1 ml THF in the presence of Y(OTf)3 (10.7 mg, 0.02 mmol, 10 mol%). The resulting solution was stirred at room temperature until the reaction was completed (monitored by TLC). The reaction mixture was filtered through a silica gel plug, and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (eluent: mixture of hexane and ethyl acetate) to give the pure products.

General procedure of asymmetric three-component ADARs

A mixture of YCl3 (3.9 mg, 0.02 mmol, 10 mol%), 5 (4.6 mg, 0.01 mmol, 5 mol%), and cyclic ketone (0.1ml) was stirred at room temperature for 3 h in 1 ml of toluene. The appropriate enone 1 (0.2 mmol, 1.0 equiv) and arylamines (0.2 mmol, 1.0 equiv) were then added. The resulting suspension was stirred at room temperature until the reaction was completed (monitored by TLC). The reaction mixture was filtered through a silica gel plug, and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (eluent: mixture of hexane and ethyl acetate) to give the pure products. The ee values were determined by chiral HPLC analysis. Full experimental details and characterization data (1H, 13C, DEPT, COSY, and HSQC spectroscopy, HPLC data, and high-resolution mass spectrometry) for all new compounds are included in the following sections.

General procedure of asymmetric aldol reactions of enones and cyclohexanone

To a one dram vial was added (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′- binaphthyl-2,2′-diyl hydrogenphosphate (7.5 mg, 0.01 mmol, 10 mol%) and aniline (1 µl, 0.01 mmol, 10 mol%). The mixture was dissolved in toluene (1 ml) and stirred for 1 hour at room temperature. The appropriate enone 1 (0.1 mmol, 1.0 equiv) and cyclohexanone (0.05ml) were added. The resulting solution was stirred at room temperature until the reaction was completed (monitored by analytical TLC). The reaction mixture was directly subject to column chromatography on silica gel (eluent: mixture of Hexane and ethyl acetate) to give the pure aldol product.

The ee values were determined by chiral HPLC analysis. Racemic samples were prepared from enone 1 (1.0 equiv), and cyclohexanone (0.05ml) in 1 ml of toluene in the presence of Cu(OTf)2 (3.6 mg, 0.01 mmol, 10 mol%) and aniline (1 µl, 0.01 mmol, 10 mol%).

General procedure of asymmetric aldol reaction of isatin and cyclohexanone

To a one dram vial equipped with a magnetic stir bar was added Y(OTf)3 (5.3 mg, 0.01 mmol, 10 mol%), (R)-(+)-6,6′-dimethyl-2,2′-biphenyldiamine (4.2 mg, 0.02 mmol, 20 mol%), isatin (14.7 mg, 0.1 mmol, 1.0 equiv), cyclic ketone (0.05 ml) and 1 ml of toluene. The resulting suspension was stirred at room temperature until the reaction was

43 completed (monitored by TLC). The reaction mixture was then filtered through a silica gel plug. The filtrate was washed with methanol and concentrated. The resulting residue was purified using column chromatography on silica gel (eluent: mixture of hexane and ethyl acetate) to give the pure products.

The ee values were determined by chiral HPLC analysis. Racemic samples were prepared from isatin (14.7 mg, 0.1 mmol, 1.0 equiv) and cyclohexanone (0.05ml) in 1ml of toluene in the presence of Y(OTf)3 (5.3 mg, 0.01 mmol, 10 mol%) and aniline (1 µl, 0.01 mmol, 10 mol%).

General procedure of two-component ADARs

1-Azadiene 7 was synthesized following literature reported procedures. The catalyst(s) (eq 1: Y(OTf)3 (5.3 mg, 0.01 mmol, 10 mol%); eq 2: Y(OTf)3 (5.3 mg, 0.01 mmol, 10 mol%), p-methoxyaniline (12.3 mg, 0.1 mmol); eq 3: Y(OTf)3 (5.3 mg, 0.01 mmol, 10 mol%), N, N-dimethylaniline (12.1 mg, 0.1 mmol); eq 4: p-methoxyaniline (12.3 mg, 0.1 mmol)) was added to a dram vial equipped with a magnetic stir bar, followed by the addition of 7 (35.4mg, 0.1 mmol, 1.0 equiv) and cyclohexanone (0.1 ml). The reaction mixture was stirred in 1 ml of THF at room temperature. After a certain time (monitored by TLC), the reaction mixture was filtered through a silica gel plug, and the filtrate was concentrated. The yield of 4i was determined by crude 1H NMR spectroscopy.

Procedure for synthesis of (2S,4S,4aS,8aS)-benzyl 4-(4-chlorophenyl)-1-(4- methoxyphenyl)decahydroquinoline-2-carboxylate 6

To a solution of 4d (97.2 mg, 0.2 mmol) in CH2Cl2 (3.0 mL) and glacial acid (1 mL), a solution of NaBH(OAc)3 (0.24 g, 1.1 mmol ) in CH2Cl2 (5.0 mL) was added gradually over 10 minutes. And the reaction was stirred for 12 hours at room temperature. The reaction was monitored by TLC until 4d was completely consumed. Then saturated aqueous sodium hydrogen carbonate was added in. The mixture was extracted with

CH2Cl2, and the organic layer was dried over anhydrous sodium sulfate. After removal of solvent, the residue is purified through flash chromatography to give pure product 6 in 83% yield.

2.5.2 Characterization Data and HPLC Conditions 4a: Prepared according to the general procedure from

enone 1e (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (85% 25 yield, ee = 96%). [α]D = 142.8 (c = 0.18, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 3/97,

0.5 ml/min; 214 nm, tr (minor) = 11.05 min, tr (major) = 13.05 min.

13 C NMR (125MHz, CDCl3): δ 164.94, 158.20, 136.79, 134.78, 134.52, 132.23, 130.35, 129.29, 128.68, 114.54, 113.65, 109.06, 55.28, 51.62, 45.08, 28.21, 27.13, 22.96, 22.41.

+ + MS (ESI) (M-H) 408.1; HRMS (TOF) calculated for (C24H24O3NCl-H) 408.1366, found 408.1363.

4b: Prepared according to the general procedure from

enone 1a (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (72% 25 yield, ee = 89%). [α]D = 80.0 (c = 0.20, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95,

0.7 ml/min; 214 nm, tr (minor) = 13.67 min, tr (major) = 16.46 min.

1 H NMR (500 MHz, CDCl3): δ 7.38 (d, J = 4.0 Hz, 4H), 7.29-7.27 (m, 4H), 7.21 (dd, J = 2.0, 7.0 Hz, 2H), 7.13-7.11 (m, 2H), 6.82 (d, J = 9.0 Hz, 2H), 5.89 (d, J = 5.0 Hz, 1H),

5.02 (d, J = 12.0 Hz, 1H), 4.89 (d, J = 12.0 Hz, 1H), 4.13 (d, J = 4.5 Hz, 1H), 3.82 (s, 3H), 1.96-1.93 (m, 1H), 1.81-1.77 (m, 3H), 1.65 (t, J = 6.5 Hz, 1H), 1.53-1.44, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 164.57, 158.07, 145.20, 137.04, 135.57, 134.62, 134.20, 130.37, 128.51, 128.22, 128.05, 127.94, 126.48, 115.87, 113.58, 109.64, 66.35, 55.24, 45.70, 28.25, 27.14, 22.96, 22.41.

+ MS (ESI) (M-H) 450.1; HRMS (TOF) calculated for (C30H29O3N+Na) 474.2045, found 474.2030.

4c: Prepared according to the general procedure from

enone 1c (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil (70% 25 yield, ee = 86%). [α]D = 68.2 (c = 0.22, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 3/97,

0.5 ml/min; 214 nm, tr (minor) = 13.33 min, tr (major) = 16.35 min.

1 H NMR (500 MHz, CDCl3): δ 7.31-7.28 (m, 5H), 7.24-7.21 (m, 4H), 7.15-7.13 (m, 2H), 6.83 (d, J = 7.0 Hz, 2H), 5.91 (d, J = 5.0 Hz, 1H), 5.03 (d, J = 12.0 Hz, 1H), 4.90 (d, J = 12.0 Hz, 1H), 4.11 (d, J = 5.0 Hz, 1H), 3.84 (s, 3H), 2.40 (s, 3H), 1.94-1.92 (m, 1H), 1.88-1.78 (m, 3H), 1.68-1.65 (m, 1H), 1.55-1.45, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 164.58, 158.05, 142.30, 137.15, 136.04, 135.61, 134.51, 134.10, 130.38, 129.23, 128.30, 128.23, 127.94, 116.23, 113.58, 109.83, 66.32, 55.25, 45.24, 28.24, 27.15, 22.99, 22.44, 21.02.

+ + MS (ESI) (M-H) 464.1; HRMS (TOF) calculated for (C31H31O3N-H) 464.2226, found 464.2207.

4d: Prepared according to the general procedure from

enone 1d (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (70% 25 yield, ee = 93%). [α]D = 80.0 (c = 0.19, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes =

3/97, 0.5 ml/min; 214 nm, tr (minor) = 13.33 min, tr (major) = 16.35 min.

13 C NMR (125MHz, CDCl3): δ 164.42, 158.16, 143.83, 136.72, 135.50, 134.89, 134.44, 132.21, 130.30, 129.29, 128.64, 128.21, 127.92, 114.72, 113.63, 109.09, 66.40, 55.21, 45.11, 28.22, 27.10, 22.92, 22.37.

+ + MS (ESI) (M-H) 484.1; HRMS (TOF) calculated for (C30H28O3NCl-H) 484.1679, found 484.1662.

4e: Prepared according to the general procedure from

enone 1b (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (80% 25 yield, ee = 92%). [α]D = 95.8 (c = 0.18, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 3/97,

0.5 ml/min; 214 nm, tr (minor) = 11.28 min, tr (major) = 17.57 min.

1 H NMR (500 MHz, CDCl3): δ 7.39 (d, J = 4.0 Hz, 4H), 7.29-7.27 (m, 1H), 7.21 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 5.84 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 5.0 Hz, 1H),

3.83 (s, 3H), 3.50 (s, 3H), 1.96-1.92 (m, 1H), 1.87-1.75 (m, 3H), 1.67-1.64 (m, 1H), 1.54- 1.45, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 165.06, 158.10, 145.29, 137.10, 134.53, 134.28, 130.40, 128.53, 128.02, 126.48, 115.61, 113.59, 109.58, 55.27, 51.56, 45.64, 28.23, 27.15, 22.99, 22.44.

+ + MS (ESI) (M-H) 374.1; HRMS (TOF) calculated for (C24H25O3N-H) 374.1756, found 374.1748.

4f: Prepared according to the general procedure from

enone 1f (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as orange oil (88% 25 yield, ee = 93%). [α]D = 62.1 (c = 0.19, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 3/97,

0.5 ml/min; 214 nm, tr (minor) = 14.09 min, tr (major) = 16.99 min.

1 H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 8.5 Hz, 2H), 7.28-7.26 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 9.0 Hz, 2H), 7.09-7.11 (m, 2H), 6.80 (d, J = 8.5 Hz, 2H), 5.79 (d, J = 5.0 Hz, 1H), 4.91 (d, J = 12.0 Hz, 1H), 4.88 (d, J = 12.0 Hz, 1H), 4.08 (d, J = 5.0 Hz, 1H), 3.81 (s, 3H), 1.94-1.82 (m, 2H), 1.75-1.73 (m, 2H), 1.62-1.65 (m, 1H), 1.52-1.48, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 164.94, 158.13, 144.31, 136.68, 135.46, 134.85, 134.46, 131.59, 130.29, 129.70, 128.23, 128.22, 127.98, 120.30, 114.69, 113.61, 109.01, 66.42, 55.23, 45.17, 28.22, 27.09, 22.91, 22.35.

+ + MS (ESI) (M-H) 528.0; HRMS (TOF) calculated for (C30H28O3NBr-H) 528.1174, found 528.1181.

4g: Prepared according to the general procedure from enone

1g (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as a orange oil (85% 25 yield, ee = 95%). [α]D = 122.0 (c = 0.18, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95,

0.7 ml/min; 214 nm, tr (major) = 9.97 min, tr (minor) = 15.53 min.

1 H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.19- 7.16 (m, 2H), 6.86-6.83 (m, 2H), 5.73 (d, J = 5.0 Hz, 1H), 4.07 (d, J = 5.0 Hz, 1H), 3.80 (s, 3H), 3.47 (s, 3H), 1.91-1.79 (m, 2H), 1.74-1.69 (m, 2H), 1.64-1.60 (m, 1H), 1.51-1.45, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 164.94, 158.19, 144.42, 136.78, 134.78, 134.56, 131.65, 130.35, 129.71, 120.33, 114.49, 113.65, 109.00, 55.31, 51.66, 45.15, 28.22, 27.13, 22.96, 22.41.

+ + MS (ESI) (M-H) 452.0; HRMS (TOF) calculated for (C24H24O3NBr-H) 452.0861, found 452.0858.

4h: Prepared according to the general procedure from

enone 1h (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (78% 25 yield, ee = 93%). [α]D = 109.2 (c = 0.17, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95,

0.7 ml/min; 214 nm, tr (major) = 13.43 min, tr (minor) = 18.37 min.

1 H NMR (500 MHz, CDCl3): δ 7.30 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 5.83 (d, J = 5.0 Hz, 1H), 4.08 (d, J = 5.0 Hz,

1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.50 (s, 3H), 1.95-1.90 (m, 1H), 1.86-1.83 (m, 2H), 1.77- 1.72 (m, 1H), 1.-1.64 (m, 1H), 1.54-1.48, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 165.07, 158.31, 158.06, 137.59, 137.16, 134.32, 134.03, 130.35, 128.89, 115.91, 113.92, 113.56, 109.86, 55.25, 55.21, 51.53, 44.71, 28.17, 27.14, 23.00, 22.44.

+ + MS (ESI) (M-H) 404.1; HRMS (TOF) calculated for (C25H27O4N-H) 404.1862, found 404.1655.

4i: Prepared according to the general procedure from

enone 1i (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as orange oil (68% 25 yield, ee = 92%). [α]D = 163.8 (c = 0.18, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 3/97,

0.5 ml/min; 214 nm, tr (minor) = 20.60 min, tr (major) = 31.47 min.

1 H NMR (500 MHz, CDCl3): δ 8.22 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.5Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.65 (d, J = 5.0 Hz, 1H), 4.24 (d, J = 4.5 Hz, 1H), 3.94-3.94 (m, 2H), 3.80 (s, 3H), 1.94-1.83 (m, 2H), 1.73-1.63 (m, 3H), 1.53-1.43 (m, 3H), 1.00 (t, 7.0Hz, 3H).

13 C NMR (125MHz, CDCl3): δ 164.49, 158.36, 152.83, 146.76, 136.38, 135.68, 135.03, 130.37, 128.73, 123.95, 113.69, 112.29, 108.01, 60.82, 55.37, 45.76, 28.41, 27.13, 22.90, 22.35, 13.78.

+ + MS (ESI) (M-H) 433.1; HRMS (TOF) calculated for (C25H26O5N2-H) 433.1763, found 433.1760.

4j: Prepared according to the general procedure from enone 1j (0.2 mmol).

Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as orange oil (83% 25 yield, ee = 87%). [α]D = 61.0 (c = 0.18, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 10/90,

1.0 ml/min; 214 nm, tr (minor) = 20.73 min, tr (major) = 29.13 min.

1 H NMR (500 MHz, CDCl3): δ 8.10 (d, J = 9.0 Hz, 2H), 7.40-7.38 (m, 4H), 7.30-7.27 (m, 1H), 7.20-7.18 (m, 4H), 6.80 (d, J = 8.5 Hz, 2H), 5.91 (d, J = 5.5 Hz, 1H), 5.11 (d, J = 13.5 Hz, 1H), 4.97 (d, J = 13.5 Hz, 1H), 4.14 (d, J = 5.0 Hz, 1H), 3.81 (s, 3H), 1.97-1.93 (m, 1H), 1.88-1.83 (m, 1H), 1.80-1.74 (m, 2H), 1.67- 1.64 (m, 1H), 1.53-1.50, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 164.35, 158.19, 147.46, 144.98, 142.85, 136.99, 134.28, 134.20, 130.28, 128.59, 128.4, 128.01, 126.60, 123.41, 116.53, 113.63, 109.85, 64.77, 55.25, 28.24, 27.12, 22.93, 22.36.

+ + MS (ESI) (M-H) 404.1; HRMS (TOF) calculated for (C30H28O5N2-H) 404.1862, found 404.1655.

4k: Prepared according to the general procedure from

enone 1k (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (70% 25 yield, ee = 94%). [α]D = 105.7 (c = 0.21, CHCl3); Reaction time 24 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 2/98, 0.5

ml/min; 214 nm, tr (minor) = 9.64 min, tr (major) = 11.58 min.

13 C NMR (125MHz, CDCl3): δ 164.88, 144.23, 143.79, 134.58, 134.18, 132.29, 129.31, 129.30, 128.73, 128.56, 126.85, 115.31, 109.30, 51.64, 45.12, 28.29, 27.24, 22.96, 22.37.

+ + MS (ESI) (M-H) 378.1; HRMS (TOF) calculated for (C23H22O2NCl-H) 378.1261, found 378.1248.

4l: Prepared according to the general procedure from

enone 1l (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (70% 25 yield, ee = 94%). [α]D = 105.7 (c = 0.19, CHCl3); Reaction time 24 hrs.

HPLC analysis chiralcel OJ-H, i-PrOH/hexanes = 5/95,

0.7 ml/min; 214 nm, tr (minor) = 11.30 min, tr (major) = 20.75 min.

13 C NMR (125MHz, CDCl3): δ 164.61, 143.48, 142.93, 134.18, 134.02, 132.57, 132.43, 130.64, 129.28, 128.81, 116.24, 109.89, 51.78, 45.02, 28.23, 27.25, 22.93, 22.32.

+ + MS (ESI) (M-H) 412.0; HRMS (TOF) calculated for (C23H21O2NCl2-H) 412.0871, found 412.0859.

4m: Prepared according to the general procedure from

enone 1l (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil (72% 25 yield, ee = 93%). [α]D = 79.5 (c = 0.17, CHCl3); Reaction time 24 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95,

0.7 ml/min; 214 nm, tr (major) = 8.16 min, tr (minor) = 16.48 min.

1 H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 5.88 (d, J = 5.5 Hz, 1H), 4.11 (d, J = 4.5 Hz,

1H), 3.52 (s, 3H), 1.95-1.91 (m, 2H), 1.87-1.83 (m, 2H), 1.68-1.65 (m, 1H), 1.55-1.47, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 164.61, 143.48, 142.93, 134.18, 134.02, 132.57, 132.43, 130.64, 129.28, 128.81, 116.24, 109.89, 51.78, 45.02, 28.23, 27.25, 22.93, 22.32.

+ + MS (ESI) (M-H) 456.0; HRMS (TOF) calculated for (C23H21O2NClBr-H) 456.0366, found 456.0345.

4n: Prepared according to the general procedure from enone

1n (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (72% 25 yield, ee = 93%). [α]D = 79.5 (c = 0.16, CHCl3); Reaction time 24 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95, 0.7 ml/min; 214 nm, tr (major) = 21.86 min, tr (minor) = 31.21 min.

13 C NMR (125MHz, CDCl3): δ 164.51, 158.50, 142.93, 135.92, 135.84, 134.56, 132.67, 130.76, 129.52, 129.21, 128.95, 128.84, 114.31, 113.78, 107.33, 55.31, 51.72, 45.18, 28.59, 28.55, 25.52.

+ + MS (ESI) (M-H) 426.0; HRMS (TOF) calculated for (C23H22O3NSCl-H) 426.0931, found 426.0941.

12: Prepared according to the general procedure f from 4d. Chromatography on SiO2 (5/1, 25 hexanes/EtOAc) afforded the product as white solid (83% yield, ee = 96%). [α]D = -45.5

(c = 0.25, CHCl3).

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95,

0.7 ml/min; 214 nm, tr (major) = 16.62 min, tr (minor) = 13.44 min.

1 H NMR (500 MHz, CDCl3): δ 7.33-7.29 (m, 5H), 7.24 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 3.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 4.96 (d, J = 12.5 Hz, 1H), 4.85 (d, J = 12.5 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 1H), 3.19 (s, 1H), 3.08 (d, J = 13 Hz, 1H), 2.51 (dd, J = 12.5, 25 Hz, 2H), 2.02-1.87 (m, 3H), 1.76-1.64 (m, 2H), 1.42 (d, J = 13 Hz, 1H), 1.18- 1.12 (m, 2H), 1.08 (dd, J = 12.5, 25 Hz, 1H), 0.96 (d, J = 11 Hz, 1H).

13 C NMR (125MHz, CDCl3): δ 172.59, 157.55, 141.83, 135.66, 131.76, 128.71, 128.28, 128.25, 127.92, 113.90, 69.43, 66.02, 61.70, 55.19, 44.81, 43.51, 29.95, 28.93, 26.32, 20.19, 20.09.

+ + MS (ESI) (M+H) 490.2; HRMS (TOF) calculated for (C23H22O3NSCl-H) 490.2149, found 490.2129.

2a: Prepared according to the general procedure from corresponding enone 1 (0.2 mmol).

Chromatography on SiO2 (4/1, hexanes/EtOAc) afforded the product as yellow solid (74% 25 yield, ee = 86%, dr = 11:1). [α]D = 172.3 (c = 0.18, CHCl3); Reaction time 36 hrs.

HPLC analysis chiralpak AS-H, i-PrOH/hexanes = 5/95, 0.5 ml/min; 254 nm, tr (minor) =

29.48 min, tr (major) = 50.27 min.

1 H NMR (500 MHz, CDCl3): δ (ppm) 7.38 (d, J = 7.0 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 7.0 Hz, 1H), 6.88 (d, J = 16.0 Hz, 1H), 6.02 (d, J = 15.5 Hz, 1H), 3.77 (s, 3H), 3.66 (br, 1H), 3.14-3.10 (m, 1H), 2.44-2.32 (m, 2H), 2.16-2.04 (m, 2H), 1.95-1.92 (m, 1H), 1.73-1.63 (m, 3H). This compound has been previously reported in enantioenriched form35-36. The spectroscopic data are identical to those in reference 5 and 6.

2b: Prepared according to the general procedure from corresponding enone 1 (0.2 mmol).

Chromatography on SiO2 (4/1, hexanes/EtOAc) afforded the product as yellow solid (82% 25 yield, ee = 89%, dr = 12.5:1). [α]D = 98.4 (c = 0.20, CHCl3); Reaction time 36 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95, 0.8 ml/min; 254 nm, tr (major)

= 25.96 min, tr (minor) = 30.12 min.

1 H NMR (500 MHz, CDCl3): δ (ppm) 7.31-2.60 (m, 4H), 6.84 (d, J = 16.0 Hz, 1H), 5.99 (d, J = 16.0 Hz, 1H), 3.77 (s, 3H), 3.12-3.09 (m, 1H), 2.44-2.32 (m, 2H), 2.15-2.04 (m, 2H), 1.95-1.92 (m, 1H), 1.72-1.63 (m, 3H). This compound has been previously reported in enantioenriched form[4a]. The spectroscopic data are identical to those in reference 4a.

2c: Prepared according to the general procedure from corresponding enone 1 (0.2 mmol).

Chromatography on SiO2 (4/1, hexanes/EtOAc) afforded the product as yellow solid (75% 25 yield, ee = 80%, dr = 10:1). [α]D = 136.7 (c = 0.17, CHCl3); Reaction time 36 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95, 0.8 ml/min; 254 nm, tr (major)

= 41.81 min, tr (minor) = 52.33 min.

1 H NMR (500 MHz, CDCl3): δ (ppm) 7.32 (d, J = 9.0 Hz, 2H), 7.85 (t, J = 9.0 Hz, 2H), 6.81 (d, J = 15.5 Hz, 1H), 5.87 (d, J = 15.5 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.60 (s, 1H), 3.12-3.08 (m, 1H), 2.44-2.31 (m, 2H), 2.16-2.08 (m, 2H), 1.95-1.92 (m, 1H), 1.72- 1.58 (m, 3H).

13 C NMR (125MHz, CDCl3): δ 212.04, 175.05, 159.49, 130.97, 128.92, 127.89, 125.22, 114.00, 76.85, 57.19, 55.30, 52,98, 42.26, 27.32, 27.12, 24.87.

+ MS (ESI) (M+Na) 341.2; HRMS (TOF) calculated for (C18H22O5+Na) 341.1365, found 341.1360.

2d: Prepared according to the general procedure from corresponding enone (0.2 mmol).

Chromatography on SiO2 (4/1, hexanes/EtOAc) afforded the product as yellow solid (66% 25 yield, ee = 81%, dr = 10:1). [α]D = 96.4 (c = 0.17, CHCl3); Reaction time 36 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 5/95, 0.5 ml/min; 254 nm, tr (major) =

20.44 min, tr (minor) = 25.71 min.

1 H NMR (500 MHz, CDCl3) δ (ppm) 7.18 (d, J = 98.5 Hz, 2H), 7.51 (t, J = 8.5 Hz, 2H), 6.97 (d, J = 16.0 Hz, 1H), 6.22 (d, J = 16.0 Hz, 1H), 4.28-4.22 (m, 2H), 3.69 (s, 1H), 3.20-3.16 (m, 1H), 2.46-2.34 (m, 2H), 2.10-2.06 (m, 2H), 1.95-1.92 (m, 1H), 1.75-1.64 (m, 3H), 1.29 (t, J = 7.0 Hz, 3H). This compound has been previously reported in enantioenriched form[4b]. The spectroscopic data are identical to those in reference 4b.

Prepared according to the general procedure from isatine (0.2 mmol). Chromatography on SiO2 (3/1, hexanes/EtOAc) afforded the product as white solid (71% yield, ee = 95%, 25 dr = 10:1). [α]D = -24.5 (c = 0.19, CHCl3); Reaction time 12 hrs.

HPLC analysis chiralcel OJ-H, i-PrOH/hexanes = 15/85, 0.8 ml/min; 254 nm, tr (major) =

19.93 min, tr (minor) = 24.67 min.

1 H NMR (500 MHz, DMSO-d6) δ (ppm) 10.22 (s, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.22- 7.7.18 (m, 1H), 6.91-6.87 (m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 5.84 (s, 1H), 3.11 (dd, J = 18.0, 5.0 Hz, 1H), 2.64-2.54 (m, 1H), 2.39-2.32 (m, 1H), 2.08-1.98 (m, 2H), 1.92-1.83 (m,

1H), 1.75-1.66 (m, 1H), 1.55-1.46 (m, 1H). This compound has been previously reported in enantioenriched form[5]. The spectroscopic data are identical to those in references.

X-ray crystal structure of compound 6

Crystal of compound 6 suitable for X-ray diffraction analysis was obtained by slow evaporation from acetone. Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre (CCDC 917466). Copies of the data can be obtained free of charge on application to the CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: (+44)-1223-336-033; e-mail: [email protected].

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Chapter 3: Enantioselective Lewis-Acid-Assisted Lewis Acid Catalysts Derived from Chiral Metal Phosphates: Three- Component Asymmetric ADARs of Cyclic Ketones

Abstract

A new type of chiral Lewis acid assisted Lewis acid catalysts formed from a metal

Lewis acid and a chiral metal phosphate (MLA/M[P]3-LLA) was disclosed. Through combining metal Lewis acid catalysis with organo-enamine catalysis, asymmetric three- component inverse-electron-demand aza-Diels-Alder reactions (ADARs) of cyclohexanone, unsaturated ketoesters and arylamines was successfully achieved in the presence of YCl3/Y[P]3-LLA, affording fused bicyclic dihydropyridines in high yields

(79–90%) and enantioselectivities (ee 93–99%). By replacing YCl3 with Y(OTf)3, catalytic activity of the in situ prepared MLA/M[P]3-LLA was significantly improved.

Yb(OTf)3/Y[P]3-LLA effectively catalyzed the asymmetric ADARs of cyclopentanone and cycloheptanone with good chemo- and enantioselectivity. 1H and 31P NMR and EPR spectroscopic study, MALDI-Tof mass spectrometry and preliminary X-ray crystallographic analysis reveal a bimetallic structure of the Y(Yb)(III)/Y[P]3 complexes with bridging chiral phosphate ligands

3.1 Introduction to Lewis Acid Assisted Lewis Aicd Combined acid catalysis (CAC)1-3 aims to achieve higher reactivity, selectivity, and versatility than can be obtained with an individual acid catalyst, and it has proven to be a useful tool in organic synthesis. The extension of CAC to asymmetric catalysis has recently received much attention.4-20 Lewis-acid-assisted Lewis acid (LLA) catalysts have been explored in a variety of organic transformations, such as direct aldol reactions of aldehydes and ketones,13-14 asymmetric Diels-Alder reactions,8,15-16 and Mannich-type reactions.9,17 Despite these considerable advances, the development of LLA catalysis has been very slow. The complex structure of the catalysts makes it difficult to discern the true nature of the reaction mechanisms. Perhaps more importantly, the lack of chirality in the LLA catalysts explored thus far limits their broader application in asymmetric catalysis, a potential that is far from fully recognized.

Almost all reported LLA catalysts are based either on 1,1'-bi-2-naphthol (BINOL)4-11 or oxazaborolidine18-20 scaffolds. The development of new chiral ligands for LLA catalysts has the potential to open them to previously inaccessible reaction space. In choosing potential components, one must consider chiral phosphoric acids, which have seen some of the most rapid development over the past decade.21-24 Their corresponding Lewis acid counterparts, chiral metal phosphate salts, have also received a great deal of attention as asymmetric catalysts. In particular, chiral phosphates of alkali25-26 and alkaline earth metals27-33 have displayed remarkable catalytic activity and stereoselectivity in a range of asymmetric organic transformations. Chiral rare earth phosphates have also been employed as catalysts.34-38

Phosphate anions can form both mono- and bidentate complexes with metals, and are known to serve as bridging ligand for bimetallic complexes.39-40 Thus, a chiral phosphate would be able to bind multiple metals in one structural entity, as required for LLA catalysis. We speculated that chiral phosphate anions might serve as a new platform for the development of new types of chiral Lewis-acid-assisted Lewis acid catalysts.

In this chapter, we report the development of a new type of LLA catalytic system based on the combination of a metal salt with a chiral metal phosphate. These bimetallic

LLA catalysts (e.g., YCl3/Y[P]3 and Yb(OTf)3/Y[P]3; OTf = triflate, [P] = chiral 62 phosphate), are highly active and enantioselective in catalyzing a novel, asymmetric three-component aza-Diels-Alder reaction of cyclic ketones, unsaturated ketoesters and arylamines with wide substrate scope (Figure 3.1). The structure of these bimetallic LLA catalysts was studied using 1H and 31P NMR, EPR spectroscopy, and MALDI-Tof mass spectrometry. A preliminary X-ray crystallographic analysis of a Y(OTf)3/Y[P]3 complex is also included here.

3.2 Results and Discussion

Figure 3.1 Asymmetric three-component inverse-electron-demand ADAR of cyclic ketones through the combination of enamine and metal Lewis acid catalysis

In our continuing effort to develop enamine-metal Lewis acid bifunctional catalysis to achieve difficult organic transformations that cannot be achieved through organocatalysis or metal Lewis acid catalysis alone, asymmetric inverse-electron-demand ADAR was developed in Chapter 2, affording dihydropyridines (DHPs) (Figure 3.1),41 a class of highly important molecular skeletons abundant in natural products, pharmaceuticals, agrochemicals, and functional materials.42-45

In this asymmetric inverse-electron-demand ADAR (Figure 3.1), the arylamine serves as both a reactant and an amine catalyst. Thus, the asymmetry of the reaction must be introduced through their catalytic partner, the metal Lewis acid. Inspired by the counter anion approach developed by the Toste group,46 we developed a chiral yttrium (III) complex using a simple chiral phosphate in the previous work (Figure 3.1, note the chiral silver phosphate Ag[P] used in this procedure was prepared with Method B in Figure 3.2). However, while this catalytic system displayed high activity and enantioselectivity in ADARs of six-membered cyclic ketones, the activity and stereoselectivity of ADARs were significantly decreased when other types of ketones were employed (Figure 3.1). Re-investigation of this catalytic system is presented in this section. Research detail of the novel LLA system of a hard metal Lewis acid and a chiral metal phosphate is disclosed. For simplicity, in the remaining of this manuscript we will use the notation MLA/M[P]3-LLA, where MLA refers to the Lewis acid co-catalyst and

M[P]3 refers to the chiral metal phosphate.

3.2.1 Development of Metal Lewis Acid-Assisted Metal Lewis Acid Catalysts

(MCl3/M[P]3-LLA) In our previous work,41 the chiral metal catalyst was prepared following a modified procedure first reported by the Toste group.46 In this procedure, the aimed chiral yttrium (III) phosphate was prepared in situ from the treatment of YCl3 (10 mol%) with chiral silver phosphate (5 mol%), which was prepared using Method B in Figure 3.2. The resulting metal complex was effective in catalyzing the reaction of cyclohexanone, α- ketoesters 1 and arylamines affording DHPs in high yields and enantioselectivity (Table 3.1, entry 4).

Figure 3.2 Different methods for preparation of Y[P]3

Table 3.1 Condition optimization of asymmetric ADARs of cyclohexanone, p-methoxyaniline and 1a

catalyst preparing yield ee entry metal Lewis acid chiral metal t (h) method (%)(a) (%)(b) (mol %) complex (mol %)

1 - Ag[P] (10) B 72 trace - 2 YCl3 (10) - B 72 trace -

3 YCl3(5) Ag[P] (15) B 12 79 90

4 YCl3(10) Ag[P] (5) B 12 90 93

5 - Y[P]3 (10) A 72 trace -

6 - Y[P]3 (10) B 72 trace -

7 - Y[P]3 (10) C 72 trace -

8 - Y[P]3 (10) D 72 trace -

9 YCl3 (5) Y[P]3 (5) A 4 92 93

10 YCl3 (5) Y[P]3 (5) B 8 86 88

11 YCl3 (5) Y[P]3 (5) C 10 83 86

12 YCl3 (5) Y[P]3 (5) D 4 90 92 All reactions were conducted using 0.1 mmol 1a and 0.1 mmol p-methoxyaniline with 0.05 ml cyclohexanone in 0.5 ml toluene. Notes: (a) Yields were determined by 1H NMR spectroscopic analysis of crude reaction mixtures; (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

Theoretically, three equivalents of silver phosphate are required to react with one equivalent of YCl3 to obtain the desired Y[P]3. We noticed that the use of excess YCl3 resulted in a little higher enantioselectivity and activity of the ADA reaction (compare entry 3 and 4 in Table 3.1). We also noticed that both YCl3 and the chiral silver phosphate (Ag[P]) do not dissolve well in the working solvent (toluene). These observations suggested that a more complicated metal complex catalytic system than a simple chiral Y[P]3 might form in this process. In order to better understand the nature of this chiral yttrium (III) complex, we decided to prepare the yttrium(III) phosphate (Y[P]3) using a different method. Thus yttrium(III) tris(isopropoxide) (Y(Oi-Pr)3) was treated with chiral phosphoric acid to afford Y[P]3 (Figure 3.2, Method A). To our surprise, the

Y[P]3 prepared this way did not catalyze the ADARs of cyclohexanone (Table 3.1, entry

5). Similarly, YCl3 alone also did not give the desired ADA product (Table 3.1, entry 2).

When the isopropoxide-derived Y[P]3 was combined with YCl3 in situ, the aza-Diels- Alder reaction of cyclohexanone, α-ketoesters 1a and p-methoxyaniline started working again, giving the desired ADA product 2a in 92% yield and 93% ee (Table 3.1, entry 9).

It is notable that the reaction time was shortened from 12 hours (using YCl3/Ag[P], entry

41 4) to 4 hours using YCl3/Y[P]3, likely due to the more effective formation of the active

YCl3/Y[P]3 catalyst.

In order to further confirm that it requires the combined YCl3/Y[P]3 system to catalyze the reaction, we prepared yttrium (III) phosphate (Y[P]3) using other two different methods (Figure 3.2, Methods C and D). We also isolated the Y[P]3 in the

YCl3/Ag[P] approach (Figure 3.2, Methods B) to see it can make a difference from the

“in situ formation” version. As expected, Y[P]3 alone, which was prepared from different methods, showed no catalytic activities for the aza Diels-Alder reaction (Table 3.1, entries 5-8). On the other hand, when the Y[P]3 prepared from different methods was combined with YCl3, good catalytic activity and enantioselectivity were obtained for the ADA reaction (>83% yield, >86% ee, Table 3.1. entries 9-12). These data strongly suggest that a metal Lewis acid-assisted Lewis acid catalyst (YCl3/Y[P]3) was formed during the process, offering much stronger Lewis acidity and stereoselectivity than the individual metal complexes.

We next investigated the effect of the ratio of YCl3/Y[P]3 to establish the stoichiometry of the active YCl3/Y[P]3-LLA. Keeping Y[P]3 at 5 mol %, when 3 mol % of YCl3 was used, the reaction time prolonged to 8 hours and the yield slightly decreased to 86% (Table 3.2, entry 1, compare with Table 3.1, entry 9); increasing the loading of

YCl3 beyond the 1:1 stoichiometry ratio to 10 mol % or 15 mol % (Table 3.2, entries 2 and 3) had virtually no effect on reaction time, yield and enantioselectivity. These data indicate that the most efficient YCl3/Y[P]3-LLA was formed at a 1:1 ratio, and that excess YCl3 co-catalyst does not affect the outcome of the reaction (noting YCl3 alone does not catalyze the reaction in toluene).

Table 3.2 Further condition optimization of asymmetric ADARs of cyclohexanone, p- methoxyaniline and 1a

catalyst (a) (b) entry metal Lewis acid chiral metal complex t (h) yield (%) ee (%) (mol %) (mol %)

1 YCl3 (3) Y[P]3 (5) 8 86 93

2 YCl3 (10) Y[P]3 (5) 4 92 93

3 YCl3 (15) Y[P]3 (5) 4 93 92

4 YbCl3 (5) Y[P]3 (5) 4 90 92

5 InCl3 (5) Y[P]3 (5) 12 81 64

6 LaCl3 (5) Y[P]3 (5) 8 84 88

7 NaCl (5) Y[P]3 (5) 24 39 60 All reactions were conducted using 0.1 mmol 1a and 0.1 mmol p-methoxyaniline with 0.05 ml cyclohexanone in 0.5 ml toluene. Y[P]3 was prepared using Method A. Notes: (a) Yields were determined by 1H NMR spectroscopic analysis of crude reaction mixtures; (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

We also investigated the possibility of other metal chlorides to form active LLA catalysts with Y[P]3. The YbCl3/Y[P]3 system provided activity and enantioselectivity

(90% yield, 92% ee) similar to YCl3/Y[P]3 LLA system (Table 3.2, entry 4). Although inferior to YCl3/Y[P]3, InCl3/Y[P]3, LaCl3/Y[P]3 and NaCl/Y[P]3 displayed good to modest activity and enantioselectivity (Table 3.2, entries 5-7). CuCl2/Y[P]3 showed very poor catalytic activity for this ADAR, nevertheless it afforded the opposite enantiomer, suggesting the possible formation of a CuCl2/Y[P]3-LLA species.

Solvent screening was next conducted to obtain optimal conditions for the three- component ADARs of cyclohexanone, α-ketoesters 1 and arylamines. It turned out that more polar solvents such as THF or methanol resulted in lower enantiomeric excess values, and less polar solvent, i.e. toluene, proved to be an optimal medium. The substrate scope of the three-component ADARs of cyclohexanone is summarized in Table 3.3.

Under optimized conditions (YCl3 (5 mol %) and Y[P]3 (5 mol %) in toluene),

YCl3/Y[P]3 displayed exceptional activity in the ADARs of cyclohexanone with a range

68 of enones and arylamines, giving DHPs 2 with excellent enantioselectivity (ee 93–99%) in high yields (79–90%). It is notable that the activity and enantioselectivity of the 41 YCl3/Y[P]3-LLA are much superior to those of the YCl3/Ag[P] system, likely due to the more efficient formation of the LLA catalyst using the current approach.

Table 3.3 Substrate scope of asymmetric three-component ADAR of cyclohexanone catalyzed by YCl3/Y[P]3-LLA

entry Z X R1, R2 t (h) 2 yield (%)(a)

1 OMe CH2 Cl,CH2Ph 4 2a 92

2 OMe CH2 Cl, H 4 2b 91

3 OMe CH2 H, H 4 2c 89

4 OMe CH2 OMe, H 4 2d 86

5 H CH2 Cl, H 6 2e 82

6 Cl CH2 Cl, H 6 2f 79 7c OMe S Cl, H 6 2g 89 All reactions were conducted using 0.2 mmol 1 and 0.2 mmol arylamine with 0.1 ml cyclic ketone in 1.0 ml toluene. Notes: (a) Isolated yield; (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis; (c) 1.0 mmol dihydrothiopyran-4- one was used.

3.2.2 M(OTf)3/M[P]3-LLA: Asymmetric Three-Component ADARs of Cyclopentanone and Cycloheptanone. Having established the formation of a new type of LLA catalyst, we investigated the asymmetric three-component ADARs of cyclopentanone and cycloheptanone using

YCl3/Y[P]3-LLA. The asymmetric three-component ADARs of cyclopentanone and cycloheptanone would generate enantiomerically pure, novel DHPs containing 5/6 and 7/6 fused bicyclic rings respectively, which are very difficult to obtain using traditional

69 synthetic organic methods. However, YCl3/Y[P]3-LLA showed moderate activity in the ADAR of cyclopentanone, enone 1a and p-methoxyaniline, offering modest enantioselectivity (ee 45%) and chemoselectivity after 3 days (Table 3.4, entry 1), only slightly better than the data obtained using YCl/Ag[P] approach in the previous work41 (Scheme 1). Although disappointing, these results were not surprising. Cyclic ketones with different ring size often exhibit varying reactivity in organic transformations due to their discrete electronic and steric characteristics.

We considered replacing YCl3 with a much stronger metal Lewis acid, such as

Y(OTf)3, in the hope of enhancing the Lewis acidity of the chiral LLA catalyst. Unlike

YCl3, which does not catalyze the ADAR alone, 10 mol % Y(OTf)3 can catalyze the reaction leading to 2h in 42% yield in 16 hr in toluene (Table 3.4, entry 2). Therefore, in order to achieve high stereoselectivity, the proposed Y(OTf)3/Y[P]3-LLA must either be a much more efficient catalyst than Y(OTf)3 alone, and/or Y(OTf)3 forms a tight complex with Y[P]3, such that no free Y(OTf)3 is present in the reaction system. Initially, we combined the Y(OTf)3 and Y[P]3 in a 1:3 molar ratio in order to minimize free Y(OTf)3 present in the reaction mixture. This ratio showed both activity and enantioselectivity for the ADARof cyclopentanone, providing 71% ee and 74% yield in 6 hr (Table 3.4, entry 3). Encouraged by these results, we varied the stoichiometry further. At 1:1 molar ratio of

Y(OTf)3/Y[P]3, ADAR of cyclopentanone, p-methoxyaniline, and 1a proceeded smoothly giving similar yield (80%) and ee (70%) in toluene (Table 3.4, entry 4). Not surprisingly, when Y(OTf)3 and Y[P]3 were combined at > 1:1 molar ratio (Table 3.4, entries 5 and 6), the reaction time was reduced, as was the enantioselectivity, likely due to the presence of free Y(OTf)3 (noting Y(OTf)3 alone can catalyze the reaction). These data again support that the most effective Y(OTf)3-Y[P]3 LLA was formed at 1:1 molar ratio, and strong binding between Y(OTf)3 and Y[P]3 is possible.

Examination of a range of solvents (Table 3.4, entries 7-13) demonstrated again that polar solvents, such as methanol or nitromethane, gave lower enantiomeric excess values than less polar toluene and xylene. Considering that YbCl3/Y[P]3-LLA catalyst also offered good activity and selectivity for ADAR of cyclohexanone (Table 3.2, entry

4), we prepared Yb(OTf)3/Y[P]3-LLA catalyst. The in situ formed heterobimetallic

Yb(OTf)3/Y[P]3-LLA was effective in catalyzing the ADAR of cyclopentanone, giving higher ee than Y(OTf)3/Y[P]3-LLA in toluene (78% ee, Table 3.4, entry 14). Lowering the temperature to 4°C further improved the enantioselectivity (83% ee, Table 3.4, entry 15).

Table 3.4 Condition optimization of asymmetric ADAR of cyclopentanone, p-methoxyaniline and 1a

catalyst yield ee entry solvent t (h) (a) (b) Lewis acid Y[P]3 (%) (%) (mol %) (mol %)

1 YCl3 (5) 5 toluene 72 37 45

2 Y(OTf)3 (10) - toluene 16 42 -

3 Y(OTf)3 (5) 15 toluene 6 74 71

4 Y(OTf)3 (5) 5 toluene 6 80 70

5 Y(OTf)3 (10) 5 toluene 4 81 67

6 Y(OTf)3 (15) 5 toluene 4 84 41

7 Y(OTf)3 (5) 5 MeOH 14 67 51

8 Y(OTf)3 (5) 5 DCM 14 65 59

9 Y(OTf)3 (5) 5 CH3CN 18 48 60

10 Y(OTf)3 (5) 5 neat 24 60 67

11 Y(OTf)3 (5) 5 benzene 4 78 68

12 Y(OTf)3 (5) 5 chlorobenzene 4 80 65

13 Y(OTf)3 (5) 5 xylene 6 76 70

14 Yb(OTf)3 (5) 5 toluene 4 79 78

All reactions were conducted using 0.1 mmol 1a and 0.1 mmol p-methoxyaniline with 0.05 ml cyclopentanone in 0.5 ml solvent. Notes: (a) Yields were determined by 1H NMR spectroscopic analysis of crude reaction mixtures; (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis. (c) Reaction was carried out at 4°C for 4 hours until enone was fully consumed, then reaction temperature was raised to room temperature for another 8 hours.

Using the optimized conditions, we screened the substrate scope of the ADARs of cyclopentanone (Table 3.5, entries 1-9). β, γ-Unsaturated-α-ketoesters (1) with both electron-donating and electron-withdrawing aromatic substituents at the γ position reacted smoothly with cyclopentanone and p-methoxyaniline, providing the ADAR products in good yields (70% - 81%) and ee values (82% - 89%)(Table 3.5, entries 1-7). In addition to the electron-rich p-methoxyaniline, aniline also reacted with enone and cyclopentanone generating the desired ADAR product with good enantioselectivity (ee 83%, Table 3.5, entry 8). When more electron-deficient p-chloroaniline was used, only modest enantioselectivity (ee 63%) and yield (66%) were obtained (Table 3.5, entry 9).

With the more powerful Yb(OTf)3/Y[P]3 LLA catalyst, ADAR of cyclohexanone was reexamined, offering the desired DHP 2a in 94% yield and 91% ee (Table 3.5, entry

10), which is comparable to the outcomes from YCl3/Y[P]3 LLA (Table 3.1, entry 9).

Table 3.5 Substrate scope of asymmetric three-component ADAR of cyclopentanone catalyzed by Yb(OTf)3/Y[P]3-LLA

entry Z R1, R2 t (h) 2 yield (%)(a) ee (%)(b)

1 OMe Cl, Ph 16 2h 70 83 2 OMe Cl, H 16 2i 74 82 3 OMe Br, Ph 16 2j 77 84 4 OMe F, Ph 16 2k 79 85 5 OMe F, H 16 2l 81 82

6 OMe OMe, Ph 16 2m 75 89 7 OMe OMe, H 16 2n 78 88 8 H F, H 18 2o 69 83 9 Cl OMe, Ph 18 2p 66 63 10d OMe Cl, Ph 2 2a 94 91 All reactions were conducted using 0.2 mmol 1 and 0.2 mmol arylamine with 0.1 ml cyclic ketone in 1.0 ml toluene. Notes: (a) Isolated yield; (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis; (c) Reactions were performed at room temperature; (d) Cyclohexanone was used.

Yb(OTf)3/Y[P]3-LLA also exhibited high activity and selectivity for the asymmetric ADARs of cycloheptanone, enones, and arylamines (Table 3.6, entries 1-8). Moreover, heteroatom-containing tetrahydro-4H-pyran-4-one also underwent ADAR smoothly in the presence of Yb(OTf)3/Y[P]3-LLA, giving ADAR product 2y in 70% ee and 80% yield (Table 3.6, entry 9).

Table 3.6 Substrate scope of asymmetric three-component ADAR of cycloheptanone catalyzed by Yb(OTf)3/Y[P]3-LLA

entry Z R1, R2 t (h) 2 yield (%)(a) ee (%)(b)

1 OMe CH3, H 16 2q 78 81 2 OMe OMe, H 16 2r 74 89 3 OMe OMe, Ph 16 2s 71 87 4 OMe Cl, H 16 2t 80 80 5 OMe F, H 16 2u 79 84 6 OMe Br, H 16 2v 75 85 7(c) H F, H 18 2w 70 84

8(c) Cl OMe, Ph 18 2x 63 60 9(d) OMe Cl, H 4 2y 80 70 All reactions were conducted using 0.2 mmol 1 and 0.2 mmol arylamine with 0.1 ml cyclic ketone in 1.0 ml toluene. Notes: (a) Isolated yield; (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis; (c) Reactions were carried out at room temperature; (d) The reaction was performed with 0.2 mmol of enone and 0.05 mL of tetrahydro-4H-pyran-4-one in the presence of 0.1 mmol of arylamine in 1 mL of toluene.

3.2.3 Further Investigation of Metal Lewis Acid/Chiral Metal Phosphate LLA.

These exciting results obtained from Yb(OTf)3/Y[P]3 and Y(OTf)3/Y[P]3 LLA catalysts stimulate us to further investigate into these LLA catalytic systems. In this section, we discuss about the findings from our investigations. The structure of the 1 31 Y(OTf)3/Y[P]3 was studied using H and P NMR spectroscopy and MALDI-Tof mass spectrometry; Electronic Paramagnet Resonance (EPR) spectroscopic analysis was conducted for the Yb(III)/Y (Yb)[P]3 LLA catalysts. A set of preliminary x-ray crystal data was also collected for Y(OTf)3/Y[P]3 LLA catalyst.

3.2.3.1 The Effects of Metal Phosphate and Y2BINOL3 on Bimetallic LLA Catalytic System.

As shown in the preceding section, when the chiral Y(III) phosphate (Y[P]3) was combined with different metal salts, the resulting LLA catalysts displayed different activities and stereoselectivities in the asymmetric ADARs (Table 3.1, Table 3.2, and Table 3.3). We were interested in finding out if other metal phosphates could form chiral

LLA catalysts with Yb(OTf)3. The results are summarized in Table 3.7. Yb(OTf)3 alone catalyzed the three-component ADAR of cyclopentanone, p-methoxyaniline and 1a in toluene (Table 3.7, entry 1); all the chiral metal phosphates M[P]n (M = Yb(III), La(III), Sm(III), Sc(III), Zn(II), n = 2, 3) were inactive for this reaction (entries2, 4, 6, 8, and 10).

When combined with Yb(OTf)3, all these Yb(OTf)3/M[P]n systems showed enhanced activities relative to the individual metal salts Table 6, entries 3, 5, 7, 9, and 11) with variable stereoselectivity. These data suggest association of the M[P]n and Yb(OTf)3 present in the system.

Table 3.7 Metal phosphate effects on Yb(OTf)3/M[P]3-LLA catalysts for ADAR

catalyst (a) (b) entry metal Lewis acid t (h) yield (%) ee (%) M[P] (mol %) (mol %) n

1 Yb(OTf)3 (5) - 16 44 -

2 - Yb[P]3 (10) 24 trace -

3 Yb(OTf)3 (5) Yb[P]3 (5) 6 71 70

4 - La[P]3 (10) 24 trace -

5 Yb(OTf)3 (5) La[P]3 (5) 6 75 54

6 - Sm[P]3 (10) 24 trace -

7 Yb(OTf)3 (5) Sm[P]3 (5) 8 63 27

8 - Sc[P]3 (10) 24 trace -

9 Yb(OTf)3 (5) Sc[P]3 (5) 12 58 3

10 - Zn[P]2 (10) 24 trace -

11 Yb(OTf)3 (5) Zn[P]2 (7.5) 6 77 62 All reactions were conducted using 0.1 mmol 1a and 0.1 mmol p-methoxyaniline with 0.05 ml cyclopentanone in 0.5 ml toluene. Notes: (a) Yields were determined by 1H NMR spectroscopic analysis of crude reaction mixtures; (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

We also tested Y(III)-BINOL complex, i.e. bis-Y(III) tris(binaphthoxide)

(Y2BINOL3), to investigate the possibility to replace the above chiral Y[P]3 in the active

Y(OTf)3/Y[P]3 LLA catalyst. BINOL is the most often used chiral scaffold in known chiral LLA catalysts,47-50 sharing a similar chiral binaphthyl backbone with the chiral phosphate ligand used here. Metal-phosphates, however, are expected to display higher

Lewis acidity than the corresponding metal alkoxides, due to their lower pKa values (2-4 for phosphoric acids, 9-11 for BINOL). As shown in Table 3.8 (entries 1, and 2), neither

Y2BINOL3 nor the combined Y2BINOL3/YCl3 catalyzed the aza-Diels-Alder reaction in toluene. The combined Y2BINOL3/Y(OTf)3 was active in catalyzing the ADA reaction, providing quantitative ADA product, however, with almost no enantioselectivity (Table

3.8, entries 4), similar to the results obtained using Y(OTf)3 only (Table 3.8, entry 4).

These results suggest that strong associations between Y(OTf)3 and Y2BINOL3 do not exist, further confirming the important role of the chiral phosphate ligand in this novel LLA catalytic system.

Table 3.8 The combination of Y2BINOL3 with metal Lewis acid for ADAR

catalyst yield ee entry t (h) solvent (a) (b) metal Lewis acid M[P]n (%) (%) (mol %) (mol %)

Y BINOL 1 - 2 3 72 toluene trace - (10) Y BINOL 2 YCl 2 3 72 toluene trace - 3 (5)

3 Y(OTf)3 (5) - 16 toluene 78 - Y BINOL 4 Y(OTf) (5) 2 3 16 toluene 74 4 3 (5) All reactions were conducted using 0.1 mmol 1a and 0.1 mmol p-methoxyaniline with 0.05 ml cyclohexanone in 0.5 ml toluene. Notes: (a) Yields were determined by 1H NMR spectroscopic analysis of crude reaction mixtures; (b) The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

1 31 3.2.3.2 H and P NMR Spectroscopic Analysis of Y(OTf)3/Y[P]3-LLA Catalyst.

Having established the effectiveness of Y(OTf)3/Y[P]3-LLA catalyst in 1,4- dioxane, we conducted 1H and 31P NMR spectroscopic studies of the combined

1 31 Y(OTf)3/Y[P]3 systems in 1,4-dioxane-d8 (Figure 3.3, 3.4, and 3.5). Both the H and P

NMR spectra of Y[P]3 showed broad peaks (Figure 3.4 & 3.5), suggesting an oligomeric 29 structure. When Y(OTf)3 was added to Y[P]3 in 1,4-dioxane-d8 in increasing amount with in situ stirring for 30 minutes, new sharper peaks appeared (Figure 3.4), suggesting association of Y(OTf)3 with Y[P]3. With a 1:2 molar ratio of Y(OTf)3/Y[P]3, two sets of 1H NMR shifts were resulted: the sharp peaks represent the formation of a new species; the broad peaks are reminiscent of unreacted Y[P]3 (Figure 3.4, yellow spectra). When the ratio of Y(OTf)3/Y[P]3 reached to 1:1, the broad peaks disappeared and the sharper peaks become more defined (Figure 3.4, purple spectra), indicating that Y[P]3 was all 1 converted to LLA. When more Y(OTf)3 was added to the system, the H NMR spectra remained unchanged (Figure 3.4, green spectra), indicating that the formation of a stabilized species in 1,4-dioxane was complete.

Figure 3.3 Protons assignment for HCPA and Y(OTf)3/Y[P]3-LLA (1,4-dioxane-d8)

Y(OTf)3:Y[P]3= 2:1

Y(OTf)3:Y[P]3= 1:1

Y(OTf)3:Y[P]3= 1:2

Y[P]3

HCPA

1 Figure 3.4 H NMR spectra of HCPA, Y[P]3, and Y(OTf)3/Y[P]3-LLA in 1,4-dioxane-d8 Comparison of the 1H NMR spectra of the chiral phosphoric acid (HCPA) with

Y(OTf)3/Y[P]3-LLA catalyst suggests that all the binaphthyl phosphate ligands in the LLA catalyst are identical with only one set of proton shifts. The proton shifts of both 1 HCPA and Y(OTf)3/Y[P]3-LLA catalyst are assigned based on their H NMR and COSY spectra (Figure 3.3). All the protons of the Y(OTf)3/Y[P]3-LLA catalyst are downfield shifted relative to those of HCPA with H3 showing the largest downfield shift (ΔH3 =

0.23) (Table 3.9), in consistent with the binding of the Y(OTf)3 to the binaphthyl phosphate scaffold.

Table 3.9 1H NMR and 31P NMR data for select compounds(a)

1H (ppm) 31 Compound [ML]:[MP]3 P H3 H4 H5 H6 H7 H8

7.59 8.09 7.47 7.99 2.75 HCPA - 7.35 d 7.30 t d d t d s 7.48 7.91 6.99 - 6.99 - 7.54 7.91 -2.82 Y[P] - 3 d br 7.42 br 7.42 br br br br

7,71 7.97 7.54 8.02 -2.69 Y(OTf) /Y[P] 1:1 7.49 d 7.40 t 3 3 d d t d t (a) Assignments are based on literature values and two-dimensional spectroscopy [COSY]. Solvent: 1,4-dioxane-d8

31 P NMR spectroscopic studies were also conducted for Y(OTf)3/Y[P]3-LLA 31 catalyst, Y[P]3 and HCPA. P NMR spectra show one triplet resonance for

Y(OTf)3/Y[P]3-LLA catalyst, a singlet peak for HCPA, and two broad peaks with 31 different intensity for Y[P]3 (Figure 3.5). The more complicated P NMR spectra of 1 Y[P]3 once again reflect its oligomeric nature, as having been demonstrated in its H 29 NMR spectra. The triplet shift for Y(OTf)3/Y[P]3-LLA catalyst is originated from the nuclear spin coupling between 89Y atom(s) and the phosphorus atom(s) (2J(89Y-31P) = 10.0 Hz), suggesting that one phosphorus atom is closely associated with two identical yttrium atoms. Coupling between yttrium (89Y 100% abundance, I = 1/2) and phosphorus has been reported.51

Y(OTf)3:Y[P]3= 2:1

Y(OTf)3:Y[P]3= 1:1

Y(OTf)3:Y[P]3= 1:2

Y[P]3

HCPA

31 Figure 3.5 P NMR spectra of HCPA, Y[P]3, and Y(OTf)3/Y[P]3-LLA in 1,4-dioxane-d8.

Based on the above 1H and 31P NMR spectroscopic study, we are able to conclude that the Y(OTf)3/Y[P]3-LLA catalyst adopts a symmetric structure bearing two identical Y atoms.

3.2.3.3 Preliminary Crystal Structure and MALDI-TOF Spectrometry of

Y(OTf)3/Y[P]3-LLA. X-ray crystallography offers a reliable way to reveal the structure of a crystal. We have been engaged in growing a single crystal for the bimetallic complexes. However, it turned out that these materials are difficult to pack into crystals in most organic solvents attempted. We managed to obtain single crystals through slow vapor diffusion of hexane into the dioxane solution of the metal complex. This preliminary crystal structure provides some insightful information about the Y(OTf)3/Y[P]3-LLA catalysts in solution, showing a pseudo-C4-symmetrical distribution of four bridging phosphate ligands centered at a biyttrium core with a molecular formula of Y2[P]4(OTf)2. The chemical structure of the crystal revealed by the single crystal X-ray analysis is illustrated in Figure 3.6; this chemical structure correlates well with the data obtained from 1H and 31P NMR.

MALDI-TOF mass spectrometry displayed multiple peaks correlating to Y2[P]3,

Y2[P]4 and Y2[P]5 respectively (see Experimental section Figure 3.7), once again supporting a bimetallic structure of the Y(III)/Y[P]3 complex.

In order to gain better understanding of the relationships between the two metal centers in the Y(III)/Y[P]3 complex, we collaborated with Dr. David L. Tierney to carry out Electron Paramagnetic Resonance (EPR) spectroscopic study of these metal complexes. Based on the EPR study of AgP/YbCl3, Yb[P]3/YbCl3 and Yb[P]3/Yb(OTf)3 systems, it is suggested that the two metals must be in intimate contact with each other in the LLA system. These results are consistent with the bimetallic structure of the

Y(III)/Y[P]3 complex.

3.3 Conclusion We have demonstrated for the first time that a metal Lewis acid can be strongly associated with a chiral metal phosphate to form an efficient metal Lewis acid-assisted metal Lewis acid (MLA/M[P]3-LLA) catalyst. While YbCl3/Y[P]3-LLA exhibited very high activity and enantioselectivity for a novel asymmetric three-component ADAR of cyclohexanone, unsaturated ketoesters and arylamines, Yb(OTf)3/Y[P]3-LLA proved to be an even more active catalyst for this reaction. Yb(OTf)3/Y[P]3-LLA catalysts also showed to be an effective catalyst for the asymmetric three-component ADARs of the more inert 5-membered and 7-membered cyclic ketones, affording unusual 5/6 and 7/6 fused bicyclic DHPs in good yields with good enantioselectivity. Preliminary structural studies have revealed that these LLA catalysts have a bimetallic center with bridging phosphate ligands, representing a novel class of metal complexes for group 3 and lanthanide metals. The Lewis acidity and stereoselectivity of the MLA/M[P]3-LLA catalysts can be easily tuned by changing either the Lewis acid co-catalyst, or the chiral metal phosphate component, forming either homobimetallic or heterobimetallic catalysts. In addition, these LLA catalysts are readily accessible, and are structurally flexible given the availability of a wide variety of chiral metal phosphates. Furthermore, these catalysts are neither air- nor moisture-sensitive. The discovery of this new type of LLA catalysts furnishes a new strategy for metal Lewis acid catalyzed asymmetric organic

81 transformations. We anticipate that this new class of LLA catalysts will find broad applications in catalysis and organic synthesis.

3.4 Experiment Section

3.4.1 Reaction Set Up

Preparation of chiral metal phosphate (Y[P]3)

Method A: One portion of Y(O-i-Pr)3 (53.2 mg, 0.2 mmol) was added into the solution of (R)-(−)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (208.8 mg, 0.6 mmol ) in dry solvent (CH2Cl2/MeOH (10/10 ml)). The resulting mixture was stirred vigorously for 4 h at 50°C. The reaction mixture was evaporated under reduced pressure to afford the product as white solid which was dried 12 hours under vacuum.

Method B: One portion of Ag2CO3 (27.6 mg, 0.1 mmol) was added into the solution of (R)-(−)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (69.7 mg, 0.2 mmol ) in

CH2Cl2/MeOH (4/4 ml) in the dark. The resulting mixture was stirred vigorously for 12 h at 50°C. The reaction mixture was evaporated under reduced pressure to afford Ag[P] as white solid which was dried overnight under vacuum. The produced Ag[P] (41.0 mg, 0.09 mmol) dissolved in solution of mixed water (2 ml) and THF (5 ml). After adding

YCl3 (5.9 mg, 0.03 mmol) to the corresponding solution of Ag[P], the resulting mixture was stirred vigorously for 12 h at 50°C. Then, the reaction mixture was filtrated and washed with water. The filtrates were evaporated under reduced pressure to give a white solid which was dried 12 hours under vacuum.

Method C: One portion of Y2(CO3)3 (18.0 mg, 0.05 mmol) was added into the solution of (R)-(−)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (104.5 mg, 0.3 mmol ) in

MeOH (10 ml) followed by the addition of distilled H2O (2 ml). The resulting mixture was stirred vigorously for 12 h at 50°C. The reaction mixture was evaporated under reduced pressure to afford the product as white solid which was dried 12 hours under vacuum.

Method D: One portion of tris[N,N-bis(trimethylsilyl)amide]yttrium (28.5 mg, 0.05 mmol) was added into the solution of (R)-(−)-1,1′-binaphthyl-2,2′-diyl

82 hydrogenphosphate (52.3 mg, 0.15 mmol ) in dry solvent (CH2Cl2/MeOH (3ml/3 ml)). The resulting mixture was stirred vigorously for 4 h at 50°C. The reaction mixture was evaporated under reduced pressure to afford the product as white solid which was dried 12 hours under vacuum.

General procedure of asymmetric three-component inverse-electron-demand aza- Diels–Alder reactions catalyzed by metal Lewis acid assisted metal Lewis catalysts

(Y(OTf)3/Yb[P]3-LLA)

To a one dram vial equipped with a magnetic stir bar was added Y(OTf)3 (0.01 mmol,

5 mol%), and Yb[P]3 (0.01 mmol, 5 mol%). The Y(OTf)3/Yb[P]3-LLA was then prepared in 1 ml toluene at room temperature for 3 hours and was cooled down to 4 °C. Enone 1 (0.2 mmol, 1.0 equiv), arylamines (0.2 mmol, 1.0 equiv), and cyclic ketone (0.1ml) were added into the one dram vial. The resulting solution was stirred at 4 °C until enone was completely consumed (monitored by TLC). Then reaction temperature was raised to room temperature until the reaction was completed. The reaction mixture was filtered through a silica gel plug, and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (eluent: mixture of hexane and ethyl acetate) to give the pure products.

General procedure of racemic three-component inverse-electron-demand aza-Diels– Alder reactions

Preparation of Y2(BINOL)3

One portion of Y(O-i-Pr)3 (13.3 mg, 0.05 mmol) was added into the solution of (R)-

[1,1'-binaphthalene]-2,2'-diol (21.5 mg, 0.075 mmol ) in dry solvent (CH2Cl2/MeOH (5/5 ml)). The resulting mixture was stirred vigorously for 12 h at 50°C. The reaction mixture was evaporated under reduced pressure to afford the product as white solid which was dried 12 hours under vacuum.

Preparation of Y[P]3/Y(OTf)3 –LLA for NMR study

Y[P]3 (2.8 mg , 0.0025 mmol) and Y(OTf)3 (1.3 mg, 0.0025 mmol) were mixed in 0.5 1 13 31 ml 1,4-dioxane-d8 and stirred for 2 hours. Then H NMR, C NMR, and P NMR of

Y[P]3/Y(OTf)3 –LLA were carried out.

Crystallisation of Y[P]3/Y(OTf)3 –LLA for X-Ray Structural Analyses

Y[P]3 (11.2 mg , 0.01 mmol) and Y(OTf)3 (5.4 mg, 0.01 mmol) were mixed in 3 ml 1,4-dioxane and stirred for 2 hours. The compound was crystallized by vapor diffusion of hexane to 1,4-dioxane solution of LLA.

3.4.2 Characterization Data and HPLC Conditions

The MALDI-TOF analysis with major peak corresponding to Y2[P]4+H2O (1584.254).

Y2[P]4+H2O

Figure 3.7 MALDI-TOF spectra of Y(OTf) /Y[P] -LLA 3 3

2a: Prepared according to the general procedure at room temperature from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (92% yield, ee = 93%). Reaction time 4 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (minor) =

13.33 min, tr (major) = 16.35 min.

1 H NMR (500 MHz, CDCl3): δ 7.38-7.30 (m, 7H), 7.20 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 3.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.83 (d, J = 5.0 Hz, 1H), 5.03 (d, J = 12.5 Hz, 1H), 4.92 (d, J = 12.5 Hz, 1H), 4.13 (d, J = 4.5 Hz, 1H), 3.84 (s, 3H), 1.94-1.85 (m, 2H), 1.79- 1.78 (m, 2H), 1.68-1.66 (m, 1H), 1.54-1.52, (m, 3H). This compound has been previously reported in enantioenriched form by our group.41 The spectroscopic data are identical to those in reference 41.

2b: Prepared according to the general procedure at room temperature from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (91% yield, ee = 96%). Reaction time 4 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (minor) =

11.05 min, tr (major) = 13.05 min.

1 H NMR (500 MHz, CDCl3): δ 7.33 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 5.73 (d, J = 5.0 Hz, 1H), 4.09 (d, J = 5.0 Hz, 1H), 3.80 (s, 3H), 3.48 (s, 3H), 1.90-1.88 (m, 1H), 1.83-1.80 (m, 1H), 1.75-1.73 (m, 2H), 1.64-1.62 (m, 1H), 1.50-1.48, (m, 3H). This compound has been previously reported in enantioenriched form by our group.41 The spectroscopic data are identical to those in reference 41.

2c: Prepared according to the general procedure at room temperature from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (89% yield, ee = 93%). Reaction time 4 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (minor) =

11.28 min, tr (major) = 17.57 min.

1 H NMR (500 MHz, CDCl3): δ 7.39 (d, J = 4.0 Hz, 4H), 7.29-7.27 (m, 1H), 7.21 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 5.84 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 5.0 Hz, 1H), 3.83 (s, 3H), 3.50 (s, 3H), 1.96-1.92 (m, 1H), 1.87-1.75 (m, 3H), 1.67-1.64 (m, 1H), 1.54- 1.45, (m, 3H). This compound has been previously reported in enantioenriched form by our group.41 The spectroscopic data are identical to those in reference 41.

2d: Prepared according to the general procedure at room temperature from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (86% yield, ee = 96%). Reaction time 4 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95, 0.7 ml/min; 214 nm, tr (major)

= 13.43 min, tr (minor) = 18.37 min.

1 H NMR (500 MHz, CDCl3): δ 7.30 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 5.83 (d, J = 5.0 Hz, 1H), 4.08 (d, J = 5.0 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.50 (s, 3H), 1.95-1.90 (m, 1H), 1.86-1.83 (m, 2H), 1.77- 1.72 (m, 1H), 1.-1.64 (m, 1H), 1.54-1.48, (m, 3H). This compound has been previously reported in enantioenriched form by our group.41 The spectroscopic data are identical to those in reference 41.

2e: Prepared according to the general procedure at room temperature from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (82% yield, ee = 99%). Reaction time 6 hrs.

HPLC analysis chiralcel OD-H, i-PrOH/hexanes = 2/98, 0.5 ml/min; 214 nm, tr (minor) =

9.64 min, tr (major) = 11.58 min.

1 H NMR (500 MHz, CDCl3): δ 7.36-7.33 (m, 2H), 7.30-7.28 (m, 2H), 7.27-7.24 (m, 5H), 5.80 (d, J = 5.0 Hz, 1H), 4.10 (d, J = 5.0 Hz, 1H), 3.45 (s, 3H), 1.96-1.92 (m, 1H), 1.86- 1.82 (m, 1H), 1.76-1.74 (m, 2H), 1.66-1.62 (m, 1H), 1.52-1.43, (m, 3H). This compound has been previously reported in enantioenriched form by our group.41 The spectroscopic data are identical to those in reference 41.

2f: Prepared according to the general procedure at room temperature from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (79% yield, ee = 96%). Reaction time 6 hrs.

HPLC analysis chiralcel OJ-H, i-PrOH/hexanes = 5/95, 0.7 ml/min; 214 nm, tr (minor) =

11.30 min, tr (major) = 20.75 min.

1 H NMR (500 MHz, CDCl3): δ 7.33-7.28 (m, 4H), 7.26-7.24 (m, 2H), 7.20-7.17 (m, 2H), 5.84 (d, J = 5.5 Hz, 1H), 4.07 (d, J = 5.0 Hz, 1H), 3.48 (s, 3H), 1.92-1.87 (m, 1H), 1.83- 1.76 (m, 1H), 1.75-1.73 (m, 2H), 1.65-1.61 (m, 1H), 1.51-1.45, (m, 3H). This compound has been previously reported in enantioenriched form by our group.41 The spectroscopic data are identical to those in reference 41.

2g: Prepared according to the general procedure at room temperature from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1, hexanes/EtOAc) afforded the product as yellow oil (89% yield, ee = 93%). Reaction time 6 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95, 0.7 ml/min; 214 nm, tr (major)

= 21.86 min, tr (minor) = 31.21 min.

1 H NMR (500 MHz, CDCl3): δ 7.35 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.75 (d, J = 5.0 Hz, 1H), 4.16 (d, J = 4.5 Hz, 1H), 3.80 (s, 3H), 3.48 (s, 3H), 2.86 (dd, J = 17.0, 27.0 Hz, 2H), 2.71-2.57 (m, 2H), 2.24-2.10 (m, 2H). This compound has been previously reported in enantioenriched form by our group.41 The spectroscopic data are identical to those in reference 41.

2h: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (70% yield, ee = 83%). [α]D = 39.5 (c = 0.19, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (major)

= 18.76 min, tr (minor) = 16.17 min.

1 H NMR (500 MHz, CDCl3): δ 7.51 (d, J = 8.5 Hz, 2H), 7.29-7.25 (m, 5H), 7.12-7.07 (m, 4H), 6.81 (d, J = 8.5 Hz, 2H), 5.80 (d, J = 4.5 Hz, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.93 (d,

J = 12.0 Hz, 1H), 4.40 (s, 1H), 3.82 (s, 3H), 2.24-2.18 (m, 2H), 2.15-2.12 (m, 1H), 2.08- 2.02 (m, 1H), 1.85-1.79, (m, 1H ), 1.75-1.70, (m, 1H).

13 C NMR (125MHz, CDCl3): δ 164.51, 157.83, 143.25, 139.07, 137.42, 135.32, 135.16, 132.24, 129.36, 128.59, 128.33, 128.25, 128.05, 127.72, 115.75, 113.93, 112.21, 66.64, 55.28, 42.27, 32.31, 32.31, 20.46.

+ + MS (ESI) (M+Na) 494.1; HRMS (TOF) calculated for (C30H32O3NCl+Na) 494.1499, found 494.1515.

2i: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as orange oil 25 (74% yield, ee = 82%). [α]D = 59.8 (c = 0.41, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (major)

= 14.61 min, tr (minor) = 12.47 min.

1 H NMR (500 MHz, CDCl3): δ 7.31 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.73 (d, J = 4.5 Hz, 1H), 4.38 (s, 1H), 3.80 (s, 3H), 3.50 (s, 3H), 2.21-2.13 (m, 2H), 2.12-2.10 (m, 1H), 2.03-2.01 (m, 1H), 1.83-1.77, (m, 1H ), 1.75-1.68, (m, 1H).

13 C NMR (125MHz, CDCl3): δ 164.94, 157.87, 143.34, 139.16, 137.43, 134.91, 132.25, 129.33, 128.61, 127.85, 115.45, 113.93, 112.04, 55.32, 51.81, 42.25, 32.28, 31.87, 20.45.

+ + MS (ESI) (M+Na) 418.1; HRMS (TOF) calculated for (C23H22O3NCl+Na) 418.1186, found 418.1188.

2j: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as orange oil 25 (77% yield, ee = 84%). [α]D = 44.1 (c = 0.27, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (major)

= 19.41 min, tr (minor) = 17.04 min.

1 H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 8.5 Hz, 2H), 7.29-7.27 (m, 3H), 7.21 (d, J = 8.0 Hz, 2H), 7.10-7.07 (m, 4H), 6.81 (d, J = 8.5 Hz, 2H), 5.79 (d, J = 4.5 Hz, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.93 (d, J = 12.0 Hz, 1H), 4.39 (s, 1H), 3.82 (s, 3H), 2.24-2.22 (m, 2H), 2.17-2.11 (m, 1H), 2.06-2.01 (m, 1H), 1.83-1.78, (m, 1H ), 1.75-1.72, (m, 1H).

13 C NMR (125MHz, CDCl3): δ 164.49, 157.84, 143.76, 139.10, 137.40, 135.32, 135.08, 131.55, 129.76, 128.33, 128.25, 128.05, 127.72, 120.36, 115.65, 113.94, 112.12, 66.65, 55.29, 42.35, 32.31, 31.86, 20.46.

+ + MS (ESI) (M-H) 514.1; HRMS (TOF) calculated for (C29H26O3NBr-H) 514.1018, found 514.1000.

2k: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (79% yield, ee = 85%). [α]D = 28.6 (c = 0.23, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (major)

= 19.58 min, tr (minor) = 16.01 min.

1 H NMR (500 MHz, CDCl3): δ 7.29-7.26 (m, 5H), 7.12-7.03 (m, 6H), 6.81 (d, J = 8.5 Hz, 2H), 5.82 (d, J = 4.5 Hz, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.93 (d, J = 12.0 Hz, 1H), 4.41 (s, 1H), 3.82 (s, 3H), 2.24-2.19 (m, 2H), 2.16-2.11 (m, 1H), 2.05-1.99 (m, 1H), 1.83-1.79, (m, 1H ), 1.75-1.71, (m, 1H).

13 C NMR (125MHz, CDCl3): δ 164.59, 157.82, 138.90, 137.52, 135.36, 134.92, 129.44, 129.37, 128.34, 128.25, 128.05, 127.37, 116.23, 115.31, 115.14, 113.94, 112.55, 66.63, 55.30, 42.10, 32.35, 31.89, 20.46.

+ + MS (ESI) (M-H) 454.2; HRMS (TOF) calculated for (C29H26O3NF-H) 454.1818, found 454.1829.

2l: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (81% yield, ee = 82%). [α]D = 32.9 (c = 0.24, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (major)

= 16.69 min, tr (minor) = 13.17 min.

1 H NMR (500 MHz, CDCl3): δ 7.30-7.27 (m, 2H), 7.15 (dd, J = 2.0, 7.0 Hz, 2H), 7.06 (tr, J = 3.5 Hz, 2H), 6.88 (dd, J = 2.0, 7.0 Hz, 2H), 5.77 (d, J = 4.0 Hz, 1H), 4.41 (s, 1H), 3.82 (s, 3H), 3.53 (s, 3H), 2.23-2.21 (m, 2H), 2.16-2.11 (m, 1H), 2.07-2.02 (m, 1H), 1.85- 1.81, (m, 1H ), 1.80-1.70, (m, 1H).

13 C NMR (125MHz, CDCl3): δ 165.01, 157.85, 138.99, 137.53, 134.77, 129.41, 129.34, 127.85, 115.89, 115.32, 115.15, 113.93, 112.37, 55.32, 51.80, 42.08, 32.31, 31.89, 20.46.

+ + MS (ESI) (M-H) 378.2; HRMS (TOF) calculated for (C23H22O3NF-H) 378.1505, found 378.1502.

2m: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (75% yield, ee = 89%). [α]D = 38.9 (c = 0.18, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (major)

= 28.45. min, tr (minor) = 25.65 min.

1 H NMR (500 MHz, CDCl3): δ 7.29-7.26 (m, 3H), 7.24 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H), 7.09-7.07 (m, 2H), 6.91 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.86 (d, J = 4.0 Hz, 1H), 5.00 (d, J = 12.5 Hz, 1H), 4.92 (d, J = 12.5 Hz, 1H), 4.35 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 2.25-2.20 (m, 2H), 2.14-2.12 (m, 1H), 2.11-2.05 (m, 1H), 1.82-1.78, (m, 1H ), 1.75-1.70, (m, 1H).

13 C NMR (125MHz, CDCl3): δ 164.68, 158.32, 157.74, 138.63, 137.78, 137.13, 135.46, 134.65, 128.98, 128.33, 128.25, 128.01, 127.75, 117.15, 113.92, 113.87, 113.09, 66.56, 55.32, 55.28, 41.94, 32.40, 31.96, 20.50.

+ + MS (ESI) (M-H) 466.2; HRMS (TOF) calculated for (C30H29O4N-H) 466.2018, found 466.2005.

2n: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (78% yield, ee = 88%). [α]D = 70.0 (c = 0.23, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.7 ml/min; 214 nm, tr (major)

= 16.01 min, tr (minor) = 13.19 min.

1 H NMR (500 MHz, CDCl3): δ 7.24 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.82 (d, J = 4.0 Hz, 1H), 4.36 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.52 (s, 3H), 2.23-2.21 (m, 2H), 2.15-2.10 (m, 1H), 2.08-2.04 (m, 1H), 1.84-1.80, (m, 1H ), 1.78-1.71, (m, 1H).

13 C NMR (125MHz, CDCl3): δ 165.11, 158.32, 157.77, 138.73, 137.21, 134.49, 128.95, 127.86, 116.84, 113.91, 113.89, 112.90, 55.34, 55.28, 32.36, 31.97, 20.50.

+ + MS (ESI) (M-H) 390.2; HRMS (TOF) calculated for (C24H25O4N-H) 390.1705, found 390.1693.

2o: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (69% yield, ee = 83%). [α]D = 25.4 (c = 0.20, CHCl3); Reaction time 18 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.7 ml/min; 214 nm, tr (major)

= 8.22 min, tr (minor) = 7.11 min.

1 H NMR (500 MHz, CDCl3): δ 7.34 (tr, J = 8.0 Hz, 2H), 7.28-7.18 (m, 5H), 7.03 (tr, J = 8.5 Hz, 2H),), 5.82 (d, J = 4.5 Hz, 1H), 4.39 (s, 1H), 3.48 (s, 3H), 2.27-2.25 (m, 2H), 2.13-2.11 (m, 1H), 2.04-1.99 (m, 1H), 1.81-1.79, (m, 1H ), 1.74-1.68, (m, 1H).

13 C NMR (125MHz, CDCl3): δ 165.00, 144.66, 138.52, 134.54, 129.44, 129.38, 128.85, 126.50, 126.27, 116.79, 115.37, 115.20, 112.78, 51.82, 42.10, 32.53, 31.90, 20.53.

+ + MS (ESI) (M-H) 348.1; HRMS (TOF) calculated for (C22H20O2NF-H) 348.1400, found 348.1396.

2p: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (66% yield, ee = 63%). [α]D = 18.7 (c = 0.20, CHCl3); Reaction time 18 hrs.

HPLC analysis chiralpak OJ-H, i-PrOH/hexanes = 5/95, 0.7 ml/min; 214 nm, tr (major) =

37.44 min, tr (minor) = 28.67 min.

1 H NMR (500 MHz, CDCl3): δ 7.28-7.26 (m, 3H), 7.20-7.18 (m, 4H), 7.07 (d, J = 8.5 Hz, 2H), 7.05-7.02 (m, 2H), 6.88 (d, J = 8.5 Hz, 2H), 5.84 (d, J = 4.0 Hz, 1H), 4.98 (d, J = 12.5 Hz, 1H), 4.89 (d, J = 12.0 Hz, 1H), 4.32 (s, 1H), 3.81 (s, 3H), 2.24-2.22 (m, 2H), 2.12-2.03 (m, 2H), 1.81-1.77, (m, 1H ), 1.74-1.71, (m, 1H).

13 C NMR (125MHz, CDCl3): δ 164.35, 158.41, 143.46, 137.79, 136.64, 135.17, 133.98, 131.60, 128.33, 128.20, 127.70, 118.75, 113.98, 113.93, 66.76, 55.28, 41.84, 32.53, 31.89, 20.52.

+ + MS (ESI) (M-H) 470.2; HRMS (TOF) calculated for (C29H26O3NCl-H) 470.1523, found 470.1521.

2q: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (78% yield, ee = 81%). [α]D = 54.1 (c = 0.20, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.7 ml/min; 214 nm, tr (major)

= 9.57 min, tr (minor) = 7.23 min.

1 H NMR (500 MHz, CDCl3): δ 7.31-7.27 (m, 4H), 7.19 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 5.77 (d, J = 5.0 Hz, 1H), 4.18 (d, J = 5.0 Hz, 1H), 3.81 (s, 3H), 3.48 (s, 3H), 2.36 (s, 3H), 2.16-2.14 (m, 2H), 2.03-1.98 (m, 1H), 1.90-1.85 (m, 1H), 1.60-1.54, (m, 2H ), 1.40-1.35, (m, 1H), 1.35-1.18, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 164.17, 158.11, 142.45, 140.87, 137.63, 136.11, 134.93, 131.18, 129.22, 128.45, 117.15, 115.27, 113.57, 55.28, 51.53, 46.22, 32.27, 32.06, 30.31, 26.85, 25.69, 21.05.

+ + MS (ESI) (M+Na) 426.2; HRMS (TOF) calculated for (C26H29O3N+Na) 426.2045, found 426.2035.

2r: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (74% yield, ee = 89%). [α]D = 78.7 (c = 0.25, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.7 ml/min; 214 nm, tr (major)

= 14.11 min, tr (minor) = 9.68 min.

1 H NMR (500 MHz, CDCl3): δ 7.29 (dd, J = 5.0, 9.0 Hz, 4H), 6.91 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.76 (d, J = 5.0 Hz, 1H), 4.15 (d, J = 5.0 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.48 (s, 3H), 2.15-2.13 (m, 2H), 2.03-1.98 (m, 1H), 1.88-1.83 (m, 1H), 1.59- 1.54, (m, 2H ), 1.40-1.34, (m, 1H), 1.31-1.13, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 165.20, 158.35, 158.11, 140.72, 137.73, 137.62, 134.88, 131.15, 129.48, 117.06, 115.39, 113.89, 113.58, 55.29, 55.25, 51.55, 45.76, 32.24, 32.06, 30.30, 26.85, 25.70.

+ + MS (ESI) (M-H) 418.2; HRMS (TOF) calculated for (C26H29O4N-H) 418.2018, found 418.1993.

2s: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (71% yield, ee = 87%). [α]D = 84.0 (c = 0.15, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95, 0.7 ml/min; 214 nm, tr (major)

= 17.97 min, tr (minor) = 26.45 min.

1 H NMR (500 MHz, CDCl3): δ 7.33 (d, J = 8.5 Hz, 2H), 7.30-7.28 (m, 5H), 7.15-7.12 (m, 2H), 6.94 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 5.83 (d, J = 5.0 Hz, 1H), 5.02 (d, J = 12.5 Hz, 1H), 4.90 (d, J = 12.5 Hz, 1H), 4.18 (d, J = 5.0 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 2.19-2.16 (m, 2H), 2.06-2.00 (m, 1H), 1.91-1.86 (m, 1H), 1.61-1.57, (m, 2H ), 1.44- 1.35, (m, 1H), 1.33-1.29, (m, 1H), 1.22-1.16, (m, 2H).

13 C NMR (125MHz, CDCl3): δ 164.66, 158.33, 158.09, 140.64, 137.67, 137.52, 135.62, 134.96, 131.19, 129.52, 128.26, 128.19, 127.95, 117.12, 115.32, 113.85, 113.56, 66.29, 55.25, 55.22, 45.78, 32.22, 32.03, 30.18, 26.81, 25.64.

+ + MS (ESI) (M+Na) 518.2; HRMS (TOF) calculated for (C32H33O4N+Na) 518.2307, found 518.2400.

2t: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (80% yield, ee = 80%). [α]D = 69.4 (c = 0.18, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.7 ml/min; 214 nm, tr (major)

= 9.07 min, tr (minor) = 7.43 min.

1 H NMR (500 MHz, CDCl3): δ 7.34-7.31 (m, 4H), 7.26 (d, J = 9.0 Hz, 2H), 7.85 (d, J = 9.0 Hz, 2H), 5.69 (d, J = 5.0 Hz, 1H), 4.18 (d, J = 5.0 Hz, 1H), 3.81 (s, 3H), 3.49 (s, 3H), 2.15-2.12 (m, 2H), 2.01-1.96 (m, 1H), 1.87-1.82 (m, 1H), 1.60-1.54, (m, 2H ), 1.41-1.34, (m, 1H), 1.31-1.12, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 165.08, 158.24, 144.04, 141.18, 137.23, 135.34, 132.33, 131.12, 129.84, 128.67, 115.72, 114.56, 113.66, 55.32, 51.66, 46.13, 32.27, 31.99, 30.20, 26.81, 25.63.

+ + MS (ESI) (M+Na) 446.2; HRMS (TOF) calculated for (C25H26O3NCl+Na) 446.1499, found 446.1506.

2u: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (79% yield, ee = 84%). [α]D = 39.4 (c = 0.18, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.5 ml/min; 214 nm, tr (major)

= 12.87 min, tr (minor) = 10.12 min.

1 H NMR (500 MHz, CDCl3): δ 7.35-7.32 (m, 2H), 7.26 (d, J = 8.5 Hz, 2H), 7.05 (t, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.71 (d, J = 5.0 Hz, 1H), 4.20 (d, J = 5.0 Hz, 1H),

3.80 (s, 3H), 3.49 (s, 3H), 2.15-2.12 (m, 2H), 2.02-1.96 (m, 1H), 1.87-1.82 (m, 1H), 1.59- 1.55, (m, 2H ), 1.41-1.34, (m, 1H), 1.29-1.19, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 165.15, 158.22, 140.99, 137.34, 135.20, 131.12, 129.95, 129.88, 116.11, 115.37, 115.20, 114.89, 113.65, 55.31, 51.64, 45.94, 32.24, 32.02, 30.22, 26.81, 25.66.

+ + MS (ESI) (M+Na) 430.2; HRMS (TOF) calculated for (C25H26O3NF+Na) 430.1794, found 430.1798.

2v: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (75% yield, ee = 85%). [α]D = 71.1 (c = 0.30, CHCl3); Reaction time 16 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95, 0.7 ml/min; 214 nm, tr (major)

= 10.52 min, tr (minor) = 12.01 min.

1 H NMR (500 MHz, CDCl3): δ 7.52 (d, J = 8.0 Hz, 2H), 7.30-7.26 (m, 4H), 6.87 (d, J = 9.0 Hz, 2H), 5.71 (d, J = 5.0 Hz, 1H), 4.21 (d, J = 5.0 Hz, 1H), 3.83 (s, 3H), 3.51 (s, 3H), 2.18-2.15 (m, 2H), 2.03-1.98 (m, 1H), 1.89-1.85 (m, 1H), 1.61-1.58, (m, 2H ), 1.42-1.38, (m, 1H), 1.34-1.17, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 165.05, 158.23, 144.54, 141.22, 137.20, 135.34, 131.61, 131.11, 130.23, 120.44, 115.61, 114.46, 113.66, 55.31, 51.66, 46.20, 32.27, 31.98, 30.19, 26.81, 25.62.

+ + MS (ESI) (M+Na) 490.1; HRMS (TOF) calculated for (C25H26O3NBr+Na) 490.1435, found 430.1430.

2w: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (70% yield, ee = 84%). [α]D = 56.0 (c = 0.20, CHCl3); Reaction time 18 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.7 ml/min; 214 nm, tr (major)

= 7.42 min, tr (minor) = 6.05 min.

1 H NMR (500 MHz, CDCl3): δ 7.36-7.33 (m, 6H), 7.26 (s, 1H), 7.06 (t, J = 8.5 Hz, 2H), 5.76 (d, J = 5.0 Hz, 1H), 4.22 (d, J = 5.0 Hz, 1H), 3.47 (s, 3H), 2.17-2.14 (m, 2H), 2.00- 1.97 (m, 1H), 1.88-1.84 (m, 1H), 1.59-1.56, (m, 2H ), 1.40-1.31, (m, 1H), 1.31-1.14, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 165.06, 144.78, 140.71, 135.02, 130.12, 129.97, 129.90, 128.58, 127.03, 116.61, 115.40, 115.23, 115.14, 51.64, 45.95, 32.22, 31.99, 30.23, 26.75, 25.58.

+ + MS (ESI) (M-H) 376.2; HRMS (TOF) calculated for (C24H24O2NF-H) 376.1713, found 376.1715.

2x: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (63% yield, ee = 60%). [α]D = 21.7 (c = 0.20, CHCl3); Reaction time 18 hrs.

HPLC analysis chiralpak OD-H, i-PrOH/hexanes = 3/97, 0.7 ml/min; 214 nm, tr (major)

= 11.29 min, tr (minor) = 9.25 min.

1 H NMR (500 MHz, CDCl3): δ 7.31-7.27 (m, 7H), 7.25 (d, J = 9.0 Hz, 2H), 7.13-7.11 (m, 2H), 6.94 (d, J = 8.5 Hz, 2H), 5.92 (d, J = 4.5 Hz, 1H), 5.02 (d, J = 12.5 Hz, 1H), 4.90 (d, J = 12.0 Hz, 1H), 4.17 (d, J = 4.5 Hz, 1H), 3.84 (s, 3H), 2.17-2.14 (m, 2H), 2.05-2.00 (m, 1H), 1.92-1.87 (m, 1H), 1.61-1.58, (m, 2H ), 1.40-1.38, (m, 1H), 1.31-1.15, (m, 3H).

13 C NMR (125MHz, CDCl3): δ 164.32, 158.43, 143.63, 140.12, 137.17, 135.42, 134.41, 132.47, 131.48, 129.49, 129.70, 128.34, 128.28, 128.13, 118.57, 116.21, 113.94, 66.47, 55.24, 45.70, 32.17, 31.94, 30.22, 26.69, 25.57.

+ + MS (ESI) (M-H) 498.19; HRMS (TOF) calculated for (C31H30O3NCl-H) 498.1836, found 495.1839.

2y: Prepared according to the general procedure from the corresponding enone 1 (0.2 mmol). Chromatography on SiO2 (5/1 hexanes/EtOAc) afforded the product as yellow oil 25 (80% yield, ee = 70%). [α]D = 56.3 (c = 0.18, CHCl3); Reaction time 18 hrs.

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 2/98, 0.7 ml/min; 214 nm, tr (major)

= 20.59 min, tr (minor) = 18.51 min.

1 H NMR (500 MHz, CDCl3): δ 7.36 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 9.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 5.73 (d, J = 4.5 Hz, 1H), 4.16 (d, J = 4.5 Hz, 1H), 3.89-3.74 (m, 3H), 3.83 (s, 3H), 3.65-3.60 (m, 1H), 3.51 (s, 3H), 2.51 (d, J = 16.5 Hz, 1H), 2.96 (d, J = 16.5 Hz, 1H).

13 C NMR (125MHz, CDCl3): δ 164.60, 158.46, 143.01, 135.67, 134.52, 132.70, 132.12, 130.07, 129.12, 128.94, 113.94, 113.89, 106.98, 66.77, 64.59, 55.36, 51.83, 41.31, 26.75.

+ + MS (ESI) (M-H) 410.12; HRMS (TOF) calculated for (C23H22O4NCl-H) 410.1159, found 410.1143.

1 H NMR (500 MHz, 1,4-dioxane-d8)  ppm 7.30 (t, J = 7.3 Hz, 2 H) 7.35 (d, J = 8.3 Hz, 2 H) 7.47 (t, J = 7.5 Hz, 2 H) 7.59 (d, J = 8.7 Hz, 2 H) 7.99 (d, J = 8.3 Hz, 2 H) 8.09 (d, J = 8.9 Hz, 2 H).

31 P NMR (200 MHz, 1,4-dioxane-d8)  ppm 2.752 (s, 1 P).

Y[P]3: Prepared according to the general procedure of Method A for preparation of

Y[P]3

1 H NMR (500 MHz, 1,4-dioxane-d8)  ppm 6.99 - 7.42 (m, 6 H) 7.48 (br s, 2 H) 7.54 (br s, 2 H) 7.91 (br s, 4 H).

31 P NMR (200 MHz, 1,4-dioxane-d8)  ppm -2.82 (br s, 1 P).

Y[P]3/Y(OTf)3 -LLA: Prepared according to the procedure as reported in reaction set up.

1 H NMR (500 MHz, 1,4-dioxane-d8)  ppm 7.40 (t, J = 8.0 Hz, 2 H) 7.49 (d, J = 8.3 Hz, 2 H) 7.54 (t, J = 7.3 Hz, 2 H) 7.71 (d, J = 10.3 Hz, 2 H) 7.97 (d, J = 8.9 Hz, 2 H) 8.02 (d, J = 8.5 Hz, 2 H).

13 C NMR (125 MHz, 1,4-dioxane-d8)  ppm 122.15 (s, 1 C) 122.67 (s, 1 C) 126.65 (s, 1 C) 127.75 (s, 1 C) 127.88 (s, 1 C) 129.54 (s, 1 C) 131.89 (s, 1 C) 132.70 (s, 1 C) 133.22 (s, 1 C) 149.10 (d, 1 J = 9.3 Hz, C).

31 P NMR (200 MHz, 1,4-dioxane-d8)  ppm -2.69 (t, J = 10.0 Hz 1 P).

Calculated Mass for C80H50O17P4Y2 (Y2[P]4+H2O), 1584.01, Found MS (MALDI-TOF),

1584.254 (Y2[P]4+H2O) m/z.

NMR spectra for HCPA, YX3 and Y[P]3/Y(OTf)3 -LLA

1H NMR spectra of HCPA

Acquisition Time (sec) 2.1823 Comment YMD-6-HCPA HNMR Date 12 May 2014 19:00:16 Date Stamp 12 May 2014 19:00:16 File Name C:\Users\dengy\Desktop\lla\YMD-6-LLA\YMD-6-LLA\16\PDATA\1\1r Frequency (MHz) 500.13 Nucleus 1H Number of Transients 16 Origin spect Original Points Count 16384 Owner Wang Points Count 32768 Pulse Sequence zg30 Receiver Gain 128.00 SW(cyclical) (Hz) 7507.51 Solvent Dioxane Spectrum Offset (Hz) 3232.5708 Spectrum Type STANDARD Sweep Width (Hz) 7507.28 Temperature (degree C) 20.160

HCPA HNMR DIXOANE-D8.ESP 3.53

HCPA HNMR DIXOANE-D8.ESP

7.34

7.59

8.08

7.58

8.09

7.98

8.00

7.47

7.32

7.31

7.36

7.34

7.46

7.49

7.59

8.08

7.29

7.58

8.09

7.98

8.00

7.47

7.32 7.31

7.36 2.00 2.00 1.98 2.03 2.03 2.03 7.49

7.29 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 Chemical Shift (ppm)

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 Chemical Shift (ppm)

31P NMR spectra of HCPA

Acquisition Time (sec) 0.4063 Comment YMD-6-HCPA PNMR Date 12 May 2014 19:13:04 Date Stamp 12 May 2014 19:13:04 File Name C:\Users\dengy\Desktop\lla\YMD-6-LLA\YMD-6-LLA\18\PDATA\1\1r Frequency (MHz) 202.46 Nucleus 31P Number of Transients 32 Origin spect Original Points Count 32768 Owner Wang Points Count 32768 Pulse Sequence zg30 Receiver Gain 23170.50 SW(cyclical) (Hz) 80645.16 Solvent Dioxane Spectrum Offset (Hz) -10122.8604 Spectrum Type STANDARD Sweep Width (Hz) 80642.70 Temperature (degree C) 20.160

HCPA PNMR dixoane-d8.esp 2.75

3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 Chemical Shift (ppm)

26 24 22 20 18 16 14 12 10 8 6 4 2 0 -2 -4 -6 -8 -10 -12 -14 Chemical Shift (ppm)

COSY spectra of HCPA

1 H NMR spectra of Y[P]3

Acquisition Time (sec) 2.1823 Comment YMD-6-YX3 Date 13 May 2014 16:52:16 Date Stamp 13 May 2014 16:52:16 File Name C:\Users\dengy\Desktop\lla\YMD-6-LLA\YMD-6-LLA\36\PDATA\1\1r Frequency (MHz) 500.13 Nucleus 1H Number of Transients 16 Origin spect Original Points Count 16384 Owner Wang Points Count 32768 Pulse Sequence zg30 Receiver Gain 128.00 SW(cyclical) (Hz) 7507.51 Solvent Dioxane Spectrum Offset (Hz) 3232.5708 Spectrum Type STANDARD Sweep Width (Hz) 7507.28 Temperature (degree C) 20.160

YX3 HNMR dixoane-d8 2.esp 3.53

Y[P]3

YX3 HNMR dixoane-d8 2.esp

7.91

7.38

7.48

7.54

7.17

7.91

7.38

7.48 7.54

7.17 3.82 8.00

8.5 8.0 7.5 7.0 6.5 Chemical Shift (ppm)

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 Chemical Shift (ppm)

31 P NMR spectra of Y[P]3

Acquisition Time (sec) 0.4063 Comment YMD-6-YX3 1.0eq enone-PNMR cpd Date 16 May 2014 16:45:52 Date Stamp 16 May 2014 16:45:52 File Name C:\Users\dengy\Desktop\lla\YMD-6-LLA\YMD-6-LLA\56\PDATA\1\1r Frequency (MHz) 202.46 Nucleus 31P Number of Transients 128 Origin spect Original Points Count 32768 Owner Wang Points Count 32768 Pulse Sequence zgpg30 Receiver Gain 20642.50 SW(cyclical) (Hz) 80645.16 Solvent Dioxane Spectrum Offset (Hz) -10122.8604 Spectrum Type STANDARD Sweep Width (Hz) 80642.70 Temperature (degree C) 20.260

YX3 enone PNMR CPD dixoane-d8.esp -2.74

Y[P]3

8 6 4 2 0 -2 -4 -6 -8 -10 -12 -14 Chemical Shift (ppm)

18 16 14 12 10 8 6 4 2 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 -20 -22 Chemical Shift (ppm)

COSY spectra of Y[P]3

100

Y[P]3

1 H NMR spectra of Y(OTf)3/Y[P]3-LLA

Acquisition Time (sec) 2.1823 Comment YMD-6-YX3/Y(OTf)3=1/1-HNMR Date 12 May 2014 20:08:32 Date Stamp 12 May 2014 20:08:32 File Name C:\Users\dengy\Desktop\lla\YMD-6-LLA\YMD-6-LLA\21\PDATA\1\1r Frequency (MHz) 500.13 Nucleus 1H Number of Transients 16 Origin spect Original Points Count 16384 Owner Wang Points Count 32768 Pulse Sequence zg30 Receiver Gain 128.00 SW(cyclical) (Hz) 7507.51 Solvent Dioxane Spectrum Offset (Hz) 3233.4873 Spectrum Type STANDARD Sweep Width (Hz) 7507.28 Temperature (degree C) 20.160

YX3 Y(OTF)3=1 1 HNMR DIXOANE-D8.ESP 3.53

Y(OTf)3/Y[P]3-LLA

YX3 Y(OTF)3=1 1 HNMR DIXOANE-D8.ESP

7.72

7.48

7.96

7.70

8.01

7.98

8.02

7.54

7.41

7.43

7.53

7.72

7.56

7.48

7.96

7.70

7.40

8.01

8.02

7.54 7.41

7.56 2.14 1.95 2.00 2.12 2.01 2.06 7.40

8.0 7.5 7.0 Chemical Shift (ppm)

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 Chemical Shift (ppm)

31 P NMR spectra of Y(OTf)3/Y[P]3-LLA

101

Acquisition Time (sec) 0.4063 Comment YMD-6-YX3/Y(OTf)3=1/1-P31 CPD Date 13 May 2014 15:54:40 Date Stamp 13 May 2014 15:54:40 File Name C:\Users\dengy\Desktop\lla\YMD-6-LLA\YMD-6-LLA\35\PDATA\1\1r Frequency (MHz) 202.46 Nucleus 31P Number of Transients 32 Origin spect Original Points Count 32768 Owner Wang Points Count 32768 Pulse Sequence zgpg30 Receiver Gain 20642.50 SW(cyclical) (Hz) 80645.16 Solvent Dioxane Spectrum Offset (Hz) -10122.8604 Spectrum Type STANDARD Sweep Width (Hz) 80642.70 Temperature (degree C) 20.160

YX3 Y(OTF)3=1 1 PNMR (CPD) DIXOANE-D8.ESP -2.69

Y(OTf)3/Y[P]3-LLA

-2.65

-2.74

-2.65 -2.74

-2.1 -2.2 -2.3 -2.4 -2.5 -2.6 -2.7 -2.8 -2.9 -3.0 -3.1 Chemical Shift (ppm)

20 18 16 14 12 10 8 6 4 2 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 -20 Chemical Shift (ppm)

13 C NMR spectra of Y(OTf)3/Y[P]3-LLA

Acquisition Time (sec) 1.0813 Comment YMD-6-LLA Eric-CNMR Date 23 May 2014 11:19:28 Date Stamp 23 May 2014 11:19:28 File Name C:\Users\dengy\Desktop\lla\YMD-6-LLA\YMD-6-LLA\113\PDATA\1\1r Frequency (MHz) 125.76 Nucleus 13C Number of Transients 262 Origin spect Original Points Count 32768 Owner Wang Points Count 32768 Pulse Sequence zgpg30 Receiver Gain 9195.20 SW(cyclical) (Hz) 30303.03 Solvent Dioxane Spectrum Offset (Hz) 13945.0752 Spectrum Type STANDARD Sweep Width (Hz) 30302.11 Temperature (degree C) 20.160

YMD-6-LLA.113.001.1r.esp 66.66

Y(OTf)3/Y[P]3-LLA

132.70

133.22

129.54

127.75

127.88

122.67

131.89

126.65

122.15

149.05 149.12

155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 Chemical Shift (ppm)

COSY spectra of Y(OTf)3/Y[P]3-LLA

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Reference: (1) Yamamoto, H.; Futatsugi, K. Angew Chem Int Ed Engl 2005, 44, 1924-1942. (2) Li, P. F.; Yamamoto, H. Top Organometal Chem 2011, 37, 161-183. (3) Yamamoto, H.; Ishihara, K. Acid catalysis in modern organic synthesis; Wiley- VCH ; John Wiley, distributor: Weinheim Chichester, 2008. (4) Li, P.; Yamamoto, H. J Am Chem Soc 2009, 131, 16628-16629. (5) Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki, M. J Am Chem Soc 2005, 127, 13419-13427. (6) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J Am Chem Soc 2003, 125, 16178- 16179. (7) Wang, G.; Zhao, J.; Zhou, Y.; Wang, B.; Qu, J. J Org Chem 2010, 75, 5326-5329. (8) Ishihara, K.; Kobayashi, J.; Inanaga, K.; Yamamoto, H. Synlett 2001, 394-396. (9) Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron 1999, 55, 8857-8867. (10) Tosaki, S. Y.; Hara, K.; Gnanadesikan, V.; Morimoto, H.; Harada, S.; Sugita, M.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J Am Chem Soc 2006, 128, 11776-11777. (11) Wooten, A. J.; Carroll, P. J.; Walsh, P. J. J Am Chem Soc 2008, 130, 7407-7419. (12) Gotoh, R.; Yamanaka, M. Molecules 2012, 17, 9010-9022. (13) Mahrwald, R. Org Lett 2000, 2, 4011-4012. (14) Mahrwald, R.; Ziemer, B. Tetrahedron Lett 2002, 43, 4459-4461. (15) Reilly, M.; Oh, T. Tetrahedron Lett 1994, 35, 7209-7212. (16) Reilly, M.; Oh, T. Tetrahedron Letters 1995, 36, 221-224. (17) Trost, B. M.; Terrell, L. R. J Am Chem Soc 2003, 125, 338-339.

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(18) Futatsugi, K.; Yamamoto, H. Angew Chem Int Ed Engl 2005, 44, 1484-1487. (19) Liu, D.; Canales, E.; Corey, E. J. J Am Chem Soc 2007, 129, 1498-1499. (20) Canales, E.; Corey, E. J. J Am Chem Soc 2007, 129, 12686-12687. (21) Adair, G.; Mukherjee, S.; List, B. Aldrichim Acta 2008, 41, 31-39. (22) Doyle, A. G.; Jacobsen, E. N. Chemical Reviews 2007, 107, 5713-5743. (23) Akiyama, T. Chemical Reviews 2007, 107, 5744-5758. (24) Terada, M. Synthesis-Stuttgart 2010, 1929-1982. (25) Hatano, M.; Ikeno, T.; Matsumura, T.; Torii, S.; Ishihara, K. Adv Synth Catal 2008, 350, 1776-1780. (26) Shen, K.; Liu, X.; Cai, Y.; Lin, L.; Feng, X. Chemistry 2009, 15, 6008-6014. (27) Larson, S. E.; Li, G.; Rowland, G. B.; Junge, D.; Huang, R.; Woodcock, H. L.; Antilla, J. C. Org Lett 2011, 13, 2188-2191. (28) Ingle, G. K.; Liang, Y.; Mormino, M. G.; Li, G.; Fronczek, F. R.; Antilla, J. C. Org Lett 2011, 13, 2054-2057. (29) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew Chem Int Ed Engl 2010, 49, 3823-3826. (30) Alix, A.; Lalli, C.; Retailleau, P.; Masson, G. J Am Chem Soc 2012, 134, 10389- 10392. (31) Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J Am Chem Soc 2011, 133, 3339-3341. (32) Zhang, Z.; Zheng, W.; Antilla, J. C. Angew Chem Int Ed Engl 2011, 50, 1135- 1138. (33) Drouet, F.; Lalli, C.; Liu, H.; Masson, G.; Zhu, J. Org Lett 2011, 13, 94-97. (34) Suzuki, S.; Furuno, H.; Yokoyama, Y.; Inanaga, J. Tetrahedron-Asymmetr 2006, 17, 504-507. (35) Hayano, T.; Sakaguchi, T.; Furuno, H.; Ohba, M.; Okawa, H.; Inanaga, J. Chem Lett 2003, 32, 608-609. (36) Furuno, H.; Kambara, T.; Tanaka, Y.; Hanamoto, T.; Kagawa, T.; Inanaga, J. Tetrahedron Lett 2003, 44, 6129-6132. (37) Furuno, H.; Hayano, T.; Kambara, T.; Sugimoto, Y.; Hanamoto, T.; Tanaka, Y.; Jin, Y. Z.; Kagawa, T.; Inanaga, J. Tetrahedron 2003, 59, 10509-10523. (38) Hanamoto, T.; Furuno, H.; Sugimoto, Y.; Inanaga, J. Synlett 1997, 79-&. (39) Parra, A.; Reboredo, S.; Castro, A. M. M.; Aleman, J. Org Biomol Chem 2012, 10, 5001-5020. (40) Hrdina, R.; Guenee, L.; Moraleda, D.; Lacour, J. Organometallics 2013, 32, 473- 479. (41) Deng, Y.; Liu, L.; Sarkisian, R. G.; Wheeler, K.; Wang, H.; Xu, Z. Angew Chem Int Ed Engl 2013, 52, 3663-3667. (42) Bossert, F.; Vater, W. Med Res Rev 1989, 9, 291-324. (43) Boumendjel, A.; Baubichon-Cortay, H.; Trompier, D.; Perrotton, T.; Di Pietro, A. Med Res Rev 2005, 25, 453-472. (44) Hilgeroth, A.; Dressler, C.; Neuhoff, S.; Spahn-Langguth, H.; Langguth, P. Pharmazie 2000, 55, 784-785. (45) Safak, C.; Simsek, R. Mini-Rev Med Chem 2006, 6, 747-755. (46) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496-499.

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(47) Wang, X.; Shi, L.; Li, M.; Ding, K. Angew Chem Int Ed Engl 2005, 44, 6362- 6366. (48) Sasai, H.; Arai, T.; Shibasaki, M. J Am Chem Soc 1994, 116, 1571-1572. (49) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. J Am Chem Soc 1997, 119, 2329-2330. (50) Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J Am Chem Soc 2001, 123, 2725-2732. (51) Grim, S. O.; Sangokoya, S. A. J Chem Soc Chem Comm 1984, 1599-1600.

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Chapter 4: Trio Catalysis of Arylamine, BINOL-phosphoric Acid, and Metal Lewis Acid: Asymmetric Three-component Aza-Diels Alder Reaction of Substituted Cinnamaldehyde, Cyclic Ketone, and Arylamine

Abstract

Highly chemo- and enantioselective three-component aza-Diels Alder reaction of substituted cinnamaldehyde, cyclic ketone, and arylamine was first realized by a trio catalyst system involving arylamine, BINOL-phosphoric acid, and Y(OTf)3. 17 examples of optically active 1,4-dihydropyridine (DHP) derivatives were synthesized through three-component aza-Diels Alder reactions with 91% to 99% ee and 59% to 84% yield. DHPs bearing a chiral quaternary carbon center were also provided with good enantioselectivity and moderate yield (3 examples).

106

4.1 Introduction In recent years, significant advances have been achieved in multicatalysis1-5 and multicomponent reactions (MCRs),6-13 providing powerful tools in synthetic organic chemistry to mimick nature’s capacity,14 such as mimicking cellular reactions15-18. Multicatalyst mediated multicomponent reactions have emerged as a valuable means to constructe structural complexity and diversity with maximal yield and selectivity while minimizing time and waste.1,5 However, the development of multicatalytic MCRs is still at an early stage. One of the major challenges lies in the incompatibility of catalysts as well as reactants throughout the entire organic transformation.

As disclosed in Chapter 2, our group reported the first application of arylamines as the amine catalysts in enamine catalysis.19 We already proved that with the help of hard metal Lewis acid, arylamines can effectively activate cyclic ketones through enamine formation. Using this concept, three-component inverse electron-demand aza- Diels–Alder reactions (ADARs) were achieved with high yield and enantioselectivity. In addition, through combining with a phosphoric acid, arylamines successfully catalyzed the aldol reaction of cyclohexanone and enones. All these results proved the good compatibility of arylamines with both hard metal Lewis acid and phosphoric acids.

BINOL-derived chiral phosphoric acid is drawing more and more attention in asymmetric catalysis since 2004.20-28 Recently, an in-situ prepared metal–phosphoric acid combined catalyst from a free phosphoric acid and a metal Lewis acid has been introduced.29-37 The researchers claimed a dual ligand and acid catalyst model for the BINOL-phosphoric acid in the complex (Fig. 4.1 top right).30-37 With this binary acid strategy, various organic transformations have been studied such as the Friedel–Crafts reaction,30-31 hetero-Diels–Alder reaction,33 tert-aminocyclization,32 and Nazarov Reaction35-36. However, this methodology is still limited to one or two-component reactions. These investigations delivered a key message that a metal Lewis acid is compatible with a BINOL-phosphoric acid to act as catalyst together in chemical transformations.

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4.2 Design Plan As discussed in the introduction, an arylamine has good compatibility with both a hard metal Lewis acid and a phosphoric acid to serve as the amine catalyst in enamine catalysis. On the other hand, the binary acid system of a metal Lewis acid and a BINOL- phosphoric acid exhibited good catalytic activities for several chemical transformations. Based on this knowledge, in this chapter we designed a trio catalyst system from an arylamine, a metal Lewis acid, and a BINOL-phosphoric acid (Fig. 4.1). This trio catalyst system possesses two key features:

a). This trio catalyst system allows for combinatorial flexibility from arylamine, metal Lewis acid, and BINOL-phosphoric acid, which provides easy tunable catalytic activity.

b). Multi-catalytic cycles involving enamine catalysis, hydrogen-bonding catalysis and metal Lewis acid catalysis, could be accomplished in one-pot reaction through assembling an arylamine, a metal Lewis acid, and a BINOL-phosphoric acid.

Figure 4.1 Concept of trio catalysis with metal Lewis acid, BINOL-phosphoric acid and arylmine The three-component asymmetric ADAR of β,γ-unsaturated α-ketoesters, cyclic ketones, and aromatic amines developed by our research group provides a convenient and powerful approach to building up diverse dihydropyridines (DHPs).19 DHPs are found in many biologically active natural products, pharmaceuticals, agrochemicals, and functional materials.38-42 The development of new methodologies and substrates to access 108 unsymmetrical DHPs, especially optically pure C4-substituted DHPs, is in need.9 In order to further extend the scope of this multicomponent ADAR, substituted cinnamaldehydes, which are either commercially available or readily prepared, are considered to be ideal building blocks to construct functional DHP derivatives. However, to the best of our knowledge, only Mannich products have been reported for the three- component reaction of cinnamaldehyde, cyclic ketone, and arylamine.43 No ADAR of substituted cinnamaldehyde, cylic ketone, and arylamine has been reported. This is mainly because Mannich reactions of simple aldehydes, ketones and amines are favored through activation using Brønsted acid, such as BINOL-phosphoric acid.44-48

We hoped that, with the help of our designed trio catalyst, an ADAR of substituted cinnamaldehyde, cylic ketone, and arylamine could be favored over the Mannich reaction (Figure 4.2). In this proposed ADAR, in the presence of a metal Lewis acid, arylamines can reversibly form enamine intermediates with cyclic ketones and thus serve as the enamine catalysts. On the other hand, 1-azadienes are formed from arylamines and substituted cinnamaldehydes. Taking advantages of the binary acid catalyst of metal Lewis acid/BINOL-phosphoric acid, an irreversible ADAR would predominately occur between the in-situ formed enamine and 1-azadiene intermedate.

In this chapter, we address the application of a trio catalyst system composed of arylamine, Y(OTf)3, and BINOL-phosphoric acid to a three-component ADAR of substituted cinnamaldehyde, cyclic ketone, and arylamine affording a series of 1,4-DHPs with excellent enantioselectivities (up to 99% ee).

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Figure 4.2 Top: previous reported Mannich reactions of aldehydes, ketones, and amines. Bottom: proposed three-component ADAR of substituted cinnamaldehyde, cyclic ketone, and arylamine catalyzed by a trio catalyst.

4.3 Results and Discussion 4.3.1 Conditions Screening and Reaction Optimization We started the investigation using 2-methylcinnamaldehyde 1a, cyclohexanone, and 4-chloroaniline (Table 4.1). Initially, different Brønsted acids were examined for this three-component reaction (Table 4.1, entries 1-5). For all the Brønsted acids screened in THF, the Mannich product was produced as the major product, along with low to moderate yield of ADA product. Good enantioselectivity can be obtained by using 5b as a solo catalyst, however, only 24% yield of ADA product (AP) was obtained with dominating Mannich product (MP) (Table 4.1, entry 5, ADAP : MP = 1 : 2.6). These results agree well with the previous study that Brønsted acids mainly promote Mannich reaction of simple aldehyde, ketone, and amine.44-48 Then the catalytic activity of

Y(OTf)3 was tested (Table 4.1, entry 6). In the presence of Y(OTf)3 only, the ADA product was obtained with 61% yield as the major product.

In-situ prepared binary acid catalysts were also explored (Table 4.1, entries 7-15).

As shown in entry 8, the combination of 5b and Y(OTf)3 of 1:1 ratio led to ADA product

110 with 89% ee without any loss in enantioselectivity compared to entry 5, in which only 5b was used (88% ee). More importantly, higher chemoselectivity (ADAP : MP = 1 : 0.39) was achieved than either Y(OTf)3 (entry 5) or 5b (entry 6) used as solo catalyst. These results indicate that the binary acid catalyst was successfully formed and catalysed the

ADA reaction efficiently. Combination of other phosphoric acids and Y(OTf)3 behaved as the same but with lower selectivity (entries 7 and 9). Further metal Lewis acids screening was conducted and the results are summarized in Table 4.1 (entries 10-15). The combined catalysts from Yb(OTf)3, La(OTf)3, In(OTf)3, or Sm(OTf)3 with 5b all catalyzed the three-component reaction favoring ADA product with moderate enantioselectivities (45% to 77% ee). Zn(OTf)2 and YCl3 did not exhibit good catalytic activities for ADAR (entries 11 and 15).

Table 4.1 Catalysts screening for three-component ADAR of 1a, 2a, and 3a

MLA BA ADAP: Yield (ADAP)a eeb Time Entry (5 mol%) (5 mol%) MP (%) (%) (h)

1 - TFA 1:5.3 7 - 48 benzoic 2 - 1:2.4 11 - 48 acid 3 - (+) CSA 1:7.4 5 0 48 4 - 5a 1:3.4 19 21 48 5 - 5b 1:2.6 24 88 72

6 Y(OTf)3 - 1:0.45 61 - 48

7 Y(OTf)3 5a 1:0.77 53 18 48

8 Y(OTf)3 5b 1:0.39 62 89 48

9 Y(OTf)3 5c 1:0.95 44 35 48

111

10 Yb(OTf)3 5b 1:0.1 73 45 48

11 Zn(OTf)2 5b - trace 55 48

12 La(OTf)3 5b 1:0.20 59 77 48

13 In(OTf)3 5b 1:0.17 61 64 48

14 Sm(OTf)3 5b 1:0.51 29 74 48

15 YCl3 5b - trace - 48 MLA: metal Lewis acid; BA: Brønsted acid; ADAP: product of ADAR; MP: product of Mannich reaction. All reactions were conducted using 0.1 mmol 1a and 0.13 mmol p- chloroaniline with 0.05 ml cyclohexanone in 0.5 ml THF at room temperature. Notes: a Yields were determined by 1H NMR spectroscopic analysis of crude reaction mixtures; b The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

To further improve the chemoselectivity, solvent screening of the model three- component reaction was carried out with the binary catalyst 5b/Y(OTf)3 (Table 4.2). When the reaction was proceeded in dry DCM or DCE, both excellent chemoselectivity (ADAP : MP = 1 : 0.04) and enantioselectivity (98% ee) were realized (Table 4.2, entries 9 and 10). It is important to point out that both chemoselectivity and enantioselectivity decreased when regular DCE (ACS grade) was utilized in the reaction (entry 11).

Table 4.2 Solvent screening for three-component ADAR of 1a, 2a, and 3a

Yielda Entry Solvent ADAP : MP eeb (%) Time (h) (ADAP) (%)

1 toluene 1:0.94 38 92 48

2 CH3CN 1:0.02 70 35 48 3 Neat 1:2.6 15 80 48 4 MeOH 1:0.3 67 93 48 5 1,4-dioxane 1:0.91 44 43 48

112

6 H2O 1:0.68 50 99 48

7 CHCl3 1:0.04 87 69 24 8 acetone 1:0.06 78 88 24 9 DCM 1:0.04 81 98 24 10 DCE 1:0.04 84 98 24 11 DCEc 1:0.22 71 93 24 All reactions were conducted using 0.1 mmol 1a and 0.13 mmol p-chloroaniline with 0.05 ml cyclohexanone in 0.5 ml solvent at room temperature. Notes: a Yields were determined by 1H NMR spectroscopic analysis of crude reaction mixtures; b The values of enantiomeric excess (ee) were determined by chiral HPLC analysis. c ACS grade DCE was used as solvent without drying by distillation.

Despite broad practicability of the binary acid catalyst, the structures of free phosphoric acid-metal complexes remain elusive so far. Nevertheless, Cheng et al. reported a catalytic active complex involving a 1:1 ratio of phosphoric acid and metal based on mass, NMR, and related studies.30-32,37 In this work, ratio study of 5b to

Y(OTf)3 in the binary acid system was performed (Table 4.3). As indicated in Table 4.3, entries 1 and 2, when metal Lewis acid or chiral phosphoric acid was applied as solo catalyst in DCE for the ADAR, only low to moderate chemoselectivities and yields of

ADA product can be obtained. With 1:2 ratio of Y(OTf)3 to 5b as combined catalyst (Table 4.3, entry 3), ADAR was completed with excellent enantioselectivity (98% ee), however, with moderate chemoselectivity (ADAP : MP = 1 : 0.11, 72% yield of ADAP). It suggests that the existence of uncoordinated free 5b led to low chemoselectivity in Table 4.3, entry 3. Additionally, when the amount of metal Lewis acid was increased to more than 1 equivalent to phosphoric acid, both chemoselectivity and enantioselectivity significantly decreased (Table 4.3, entry 5) owing to free Y(OTf)3 catalyzed reactions.

These results confirmed that a 1:1 complexation between 5b and Y(OTf)3 in the transformation. An ESI-MS analysis (anionic mode) of a solution containing 1 : 1 5b and

Y(OTf)3 gave one dominant new peak at m/z 1287 corresponding to TRIP·Y(OTf)3 (See

ESI ). It also supports that complexes in 1 : 1 ratio of 5b and Y(OTf)3 were

113 predominantly formed. Although mechanistically complicated, this methodology is operationally simple and practical.

Table 4.3 Ratio study of 5b to Y(OTf)3 in binary acid catalyst for ADAR

Yielda Y(OTf) 5b ADAP : eeb Time Entry 3 (ADAP) (mol%) (mol%) MP (%) (h) (%)

1 5 - 1:1.21 21 - 48 2 - 5 1:0.45 47 99 48 3 2.5 5 1:0.11 72 98 48 4 5 5 1:0.04 84 98 24 5 10 5 1:0.21 72 70 24 All reactions were conducted on a 0.1 mmol scale with 0.1 ml 2a in 1ml DCE (mol ratio of 1a/3a/MLA/BA, 1 : 1.3 : 0.05 : 0.05). Notes: a Yields were determined by 1H NMR spectroscopic analysis of crude reaction mixtures; b The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

4.3.2 Substrate Scope of Three-Component ADAR of Substituted Cinnamaldehyde, Cyclic Ketone, and Arylamine With the optimized condition in hand, the scope of this three-component ADAR was performed in dry DCE with in-situ prepared catalyst from 5 mol% Y(OTf)3 and 5 mol% 5b at room temperature. The substrate scope of the ADAR of arylamines, 2- methylcinnamaldehydes and cyclohexanone is summarized in Figure 4.3. Both electron- rich p-methoxyaniline (4b), and more electron-deficient arylamines including aniline (4c), p-chloroaniline (4a), m-chloroaniline (4e), and p-bromoaniline (4d) reacted with 1a and cyclohexanone to produce the ADAR products in high enantioselectivities and yields (92-

114

99% ee, 66-79% yield). 2-Methylcinnamaldehydes with both electron-donating and electron-withdrawing aromatic substituents reacted smoothly with cyclohexanone and p- chloroaniline to give the ADAR product 4 in high to excellent enantioselectivities (94-99% ee) and good yields (59-84%) (4f-4k). It is notable that 2-methylcinnamaldehyde with electron-withdrawing aromatic substituent exhibited higher activity (reaction time: 16 h) in ADAR with high yield (4k, 84% yield) and high enantioselectivity (98% ee).

In addition, ADARs of cyclopentanone and heteroatom-containing cyclic ketones were also explored as shown in Figure 4.3. Regarding ADARs of cyclopentanone, high enantioselectivities were achieved (4l–4o, 91–98% ee); however, these ADARs resulted in lower yields (60–68% yield) comparing to the ADARs of cyclohexanone. Dihydrothiopyran-4-one and tetrahydro-4H-pyran-4-one also underwent ADARs smoothly, giving 4p (98% ee and 73% yield) and 4q (95% ee, 70% yield) in 30 hours, respectively. 4r from ADAR of 4-methylcyclohexanone was attained with 78% yield, 92% ee, and 10:1 dr under optimized conditions.

115

All reactions were conducted using 0.2 mmol 1 and 0.26 mmol arylamine with 0.1 ml cyclicketone in 1.0 ml DCE at room temperature. Notes: Yield of isolated product after chromatography. The values of enantiomeric excess (ee) were determined by chiral HPLC analysis.

Figure 4.3 Substrate scope of three-component ADAR of cinnamaldehyde, cyclic ketone, and arylamine Construction of DHPs bearing a chiral quaternary carbon center (Figure 4.4, 4s– 4u) was also realized from ADAR of enal 1h, cyclic ketones, arylamines under the optimized protocol. 4u was obtained with 96% enantiomeric excess and moderate yield (58%). However, only 32% yield of DHPs 4s and 4t from cyclohexanone, enal 1h, arylamine was achieved with moderate enantioselectivities (80% ee and 77% ee).

116

Figure 4.4 ADARs of enal 1h Furthermore, α-ethyl, butyl, and bromo cinnamaldehydes were also explored in this three-component reaction and the results are summarized in Table 4.4. When R =

CH2CH3 (Table 4.4, entry 2), moderate yield (64%) and ee (60%) of ADA product was obtained. However, when ADAR was carried out with α-butyl cinnamaldehyde (entry 3), almost racemic ADA product (5% ee) was resulted with 53% yield in 2 days. This suggests that the introduction of a more sterically hindered alkyl group at the α position of cinnamaldehyde significantly damages the enantioselectivity while keeping good chemoselectivity of the ADA reaction. In addition, as shown in entry 4, three-component reaction of α-bromocinnamaldehyde only led to the dominant formation of Mannich product.

Table 4.4 Three component reactions of α-ethyl, butyl, and bromo-cinnamaldehydes

Yield (ADAP) Entry R 4 ADAP : MP ee (%) Time (h) (%)

117

1 CH3 4k 1:0.05 84 98 16 2 ethyl 4u 1:0.02 64 60 48 3 t-butyl 4v 1:0.01 53 5 48 4a Br - 1:25 3 - 48 All reactions were conducted using 0.2 mmol 1 and 0.26 mmol arylamine with 0.1 ml cyclicketone in 1.0 ml DCE at room temperature. a α-bromocinnamaldehyde was used in reaction

The absolute configuration of 4k was established as (4R) by X-ray crystallography of compound 6, which was prepared from 4k through reduction with

NaBH(OAc)3.

Figure 4.5 Preparation of 6 and crystal structure of 6 4.4 Conclusion In summary, the trio catalysis system involving BINOL-phosphoric acid, metal Lewis acid, and arylamine was introduced for the first time in this work. With this trio catalyst, we developed an asymmetric three-component ADA reaction of substituted cinnamaldehydes, cyclicketone, and arylamine. In the presence of the binary acid of (R)-

TRIP 5b/Y(OTf)3, a wide range of arylamines and cyclic ketones reacted with substituted cinnamaldehydes leading to the formation of DHPs with good yields and good

118 to excellent enantioselectivities (up to 99% ee). DHPs bearing a chiral quaternary carbon center (C4) were also obtained with moderate to high enantioselectivities and moderate yields.

4.5 Experimental Section

4.5.1 Reaction Set Up (R)-3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (5b) was purchased from Sigma-Aldrich and used without further treatment. 1,2- dichloroethane (DCE) was distilled from CaH2 prior to use.

Synthesis of substrates 1

α-substituted cinnamaldehydes 1 were prepared according to literature reported procedures.49 Enal 1h was synthesized in three steps from acetophenone according to literature reported procedures.50

General procedure of racemic three-component aza-Diels–Alder reactions

To a one dram vial equipped with a magnetic stir bar was added aldehylde 1 (0.2 mmol, 1.0 equiv), arylamine (0.26 mmol, 1.3 equiv), and cyclic ketone (0.2 ml). The reaction was then carried out in 2 ml THF in the presence of Y(OTf)3 (10.7 mg, 0.02 mmol, 10 mol%). The resulting solution was stirred at room temperature until the reaction was completed (monitored by TLC). The reaction mixture was filtered through a silica gel plug, and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (eluent: mixture of hexane and ethyl acetate) to give the pure products.

General procedure of asymmetric three-component aza-Diels–Alder reactions catalyzed by binary acid of Y(OTf)3 and 5b

To an argon protected flame-dried Schlenk tube was added Y(OTf)3 (0.01 mmol, 10 mol%, 5.36 mg), 5b (0.01 mmol, 5 mol%, ). Distilled anhydrous DCE (2 mL) was added to the mixture. After stirring for 2 h at room temperature, aldehyde 1 (0.2 mmol, 1.0 equiv), arylamine (0.26 mmol, 1.3 equiv), and cyclic ketone (0.2 ml) were added under

119 argon protection. The resulting solution was stirred at room temperature until the reaction was completed (monitored by TLC). The reaction mixture was filtered through a silica gel plug, and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (eluent: mixture of hexane and ethyl acetate) to give the pure products. 4a: yellow oil; isolated yield: 78%.

Procedure for reduction of 4k to compound (3R,4R,4aS,8aR)-1-(4-chlorophenyl)-3- methyl-4-(4-nitrophenyl)decahydroquinoline 6

To a solution of 4k (76.1 mg, 0.2 mmol) in CH2Cl2 (3.0 mL) and glacial acid (1 mL), a solution of NaBH(OAc)3 (0.24 g, 1.1 mmol ) in CH2Cl2 (5.0 mL) was added gradually over 10 minutes. And the reaction was stirred for 12 hours at room temperature. The reaction was monitored by TLC until 4k was completely consumed. Then saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with CH2Cl2, and the organic layer was dried over anhydrous sodium sulfate. After removal of solvent, the residue is purified through flash chromatography to give pure product 6 in 78% yield.

4.5.2 Characterization Data and HPLC Conditons 4a: Prepared according to the general procedure at room temperature from

the corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (78% yield, ee = 98%). 25 Reaction time 24 hrs. [α]D = -48.5 (c = 0.18, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr

(major) = 13.47 min, tr (minor) = 16.25 min.

1 H NMR (500 MHz, CDCl3) δ 7.29 - 7.35 (m, 6 H), 7.19 - 7.24 (m, 1 H), 7.09 - 7.14 (m, 2 H), 6.08 (q, J = 1.15 Hz, 1 H), 3.75 (s, 1 H), 1.99 - 2.07 (m, 1 H), 1.74 - 1.87 (m, 3 H), 1.50 - 1.62 (m, 4 H), 1.47 (d, J = 0.92 Hz, 3 H)

13 C NMR (126MHz, CDCl3) δ 145.7, 143.3, 130.5, 129.6, 129.0, 128.1, 128.0, 128.0, 126.5, 126.2, 110.1, 110.0, 51.3, 28.2, 27.0, 23.2, 22.8, 18.6

+ + MS (ESI) (M-H) 334.1; HRMS (TOF) calculated for (C22H22ClN-H) 334.1363, found 334.1371.

120

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (79% yield, ee = 99%). Reaction time 18 25 hrs. [α]D = -82.1 (c = 0.15, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr (major) = 22.38 min, tr (minor) = 18.45 min.

1 H NMR (500 MHz, CDCl3) δ 7.28 - 7.37 (m, 4H), 7.18 - 7.23 (m, 1H), 7.12 (d, J = 8.71 Hz, 2H), 6.88 (d, J = 8.94 Hz, 2H), 6.00 (d, J = 1.15 Hz, 1H), 3.82 (s, 3H), 3.77 (s, 1H), 1.93 (d, J = 16.27 Hz, 1H), 1.74 - 1.83 (m, 3H), 1.46 - 1.62 (m, 4H), 1.44 (s, 3H)

13 C NMR (126 MHz, CDCl3) δ 157.5, 146.2, 137.9, 130.4, 128.7, 128.0, 128.0, 127.2, 126.0, 114.0, 108.4, 107.9, 55.5, 51.4, 28.2, 26.9, 23.2, 22.9, 18.7

+ + MS (ESI) (M-H) 330.2; HRMS (TOF) calculated for (C23H25NO-H) 330.1858, found 330.1887.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (72% yield, ee = 94%). Reaction time 24 25 hrs. [α]D = -38.6 (c = 0.21, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr

(major) = 15.51 min, tr (minor) = 17.13 min.

1 H NMR (500 MHz, CDCl3) δ 7.35 - 7.42 (m, 6H), 7.20 - 7.29 (m, 4H), 6.18 (d, J = 1.00 Hz, 1H), 3.82 (s, 1H), 2.07 - 2.15 (m, 1H), 1.83 - 1.93 (m, 3H), 1.55 - 1.68 (m, 4H), 1.52 (s, 3H)

13 C NMR (126 MHz, CDCl3) δ 146.0, 144.7, 129.9, 128.8, 128.0, 128.0, 126.9, 126.9, 126.1, 125.2, 109.3, 109.2, 51.4, 28.2, 27.0, 23.2, 22.8, 18.6

+ + MS (ESI) (M-H) 300.2; HRMS (TOF) calculated for (C22H23N-H) 300.1752, found 300.1751.

121

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (71% yield, ee = 92%). Reaction time 24 25 hrs. [α]D = -78.6 (c = 0.23, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr

(major) = 14.70 min, tr (minor) = 17.49 min.

1 H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 8.48 Hz, 2H), 7.30 (d, J = 4.35 Hz, 4H), 7.17 - 7.23 (m, 1H), 7.05 (d, J = 8.48 Hz, 2H), 6.08 (s, 1H), 3.73 (s, 1H), 1.99 - 2.08 (m, 1H), 1.74 - 1.87 (m, 3H), 1.49 - 1.63 (m, 4H), 1.46 (s, 3H)

13 C NMR (126 MHz, CDCl3) δ 145.7, 143.8, 132.0, 129.6, 128.3, 128.1, 128.0, 126.5, 126.2, 118.2, 110.3, 110.1, 51.3, 28.2, 27.0, 23.2, 22.8, 18.6

+ + MS (ESI) (M-H) 378.1; HRMS (TOF) calculated for (C22H22BrN-H) 378.0857, found 378.0872.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (66% yield, ee = 99%). Reaction time 30 25 hrs. [α]D = -37.5 (c = 0.15, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr (major) = 15.30 min.

1 H NMR (500 MHz, CDCl3) δ 7.27 - 7.32 (m, 2H), 7.24 - 7.27 (m, 1H), 7.21 (dd, J = 4.93, 8.36 Hz, 1H), 7.13 - 7.18 (m, 2H), 7.06 (d, J = 8.02 Hz, 1H), 6.11 (s, 1H), 3.72 (s, 1H), 2.00 - 2.11 (m, 1H), 1.76 - 1.86 (m, 3H), 1.54 - 1.61 (m, 4H), 1.46 (s, 3H)

13C NMR (126 MHz, CDCl3) δ 145.9, 145.6, 129.8, 129.4, 128.1, 127.9, 126.6, 126.4, 126.2, 125.0, 124.7, 123.6, 110.6, 110.3, 51.2, 28.2, 27.0, 23.2, 22.7, 18.6

+ + MS (ESI) (M-H) 334.1; HRMS (TOF) calculated for (C22H22ClN-H) 334.1363, found 334.1373.

122

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (73% yield, ee = 98%). Reaction time 24 hrs. 25 [α]D = -75.1 (c = 0.19, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr

(major) = 31.66 min, tr (minor) = 37.40 min.

1 H NMR (500 MHz, CDCl3) δ 7.28 - 7.33 (m, 0H), 7.18 - 7.24 (m, 2H), 7.07 - 7.12 (m, 2H), 6.82 - 6.88 (m, 2H), 6.05 (d, J = 1.37 Hz, 0H), 3.80 (s, 3H), 3.68 (s, 1H), 1.97 - 2.05 (m, 1H), 1.72 - 1.89 (m, 3H), 1.49 - 1.62 (m, 4H), 1.45 (d, J = 0.69 Hz, 3H)

13 C NMR (126 MHz, CDCl3) δ 158.1, 143.4, 138.0, 130.5, 129.4, 129.0, 128.8, 127.9, 126.4, 113.5, 110.3, 110.2, 55.2, 50.3, 28.2, 27.0, 23.2, 22.8, 18.6

+ + MS (ESI) (M-H) 364.2; HRMS (TOF) calculated for (C23H24ClNO-H) 364.1468, found 364.1457.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (64% yield, ee = 98%). Reaction time 24 25 hrs. [α]D = -62.3 (c = 0.18, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100, 0.3 ml/min; 214 nm, tr

(major) = 14.99 min, tr (minor) = 16.51 min.

1 H NMR (500 MHz, CDCl3) δ 7.28 - 7.32 (m, 2H), 7.17 - 7.20 (m, 2H), 7.07 - 7.13 (m, 4H), 6.05 (q, J = 1.15 Hz, 1H), 3.69 (s, 1H), 2.33 (s, 3H), 1.97 - 2.05 (m, 1H), 1.74 - 1.88 (m, 3H), 1.47 - 1.57 (m, 4H), 1.45 (d, J = 0.92 Hz, 3H)

13 C NMR (126 MHz, CDCl3) δ 143.4, 142.7, 135.7, 130.4, 129.5, 129.0, 128.8, 127.9, 127.8, 126.5, 110.3, 110.2, 50.8, 28.2, 27.0, 23.2, 22.8, 21.1, 18.6

+ + MS (ESI) (M-H) 348.2; HRMS (TOF) calculated for (C23H24ClN-H) 348.1519, found 348.1520.

123

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (71% yield, ee = 99%). Reaction time 24 25 hrs. [α]D = -42.2 (c = 0.16, CHCl3).

HPLC analysis chiralpak OD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr (major) = 15.07 min, tr (minor) = 16.18 min.

1 H NMR (500 MHz, CDCl3) δ 7.29 - 7.33 (m, 2H), 7.26 (d, J = 1.15 Hz, 2H), 7.21 - 7.24 (m, 2H), 7.07 - 7.10 (m, 2H), 6.05 (q, J = 1.37 Hz, 1H), 3.72 (s, 1H), 1.96 - 2.03 (m, 1H), 1.72 - 1.81 (m, 3H), 1.49 - 1.59 (m, 4H), 1.44 (d, J = 0.92 Hz, 3H)

13 C NMR (126 MHz, CDCl3) δ 144.3, 143.2, 131.8, 130.8, 129.9, 129.2, 129.0, 128.3, 128.1, 126.8, 109.5, 109.3, 50.7, 28.1, 27.0, 23.1, 22.8, 18.5

+ + MS (ESI) (M-H) 368.1; HRMS (TOF) calculated for (C22H21Cl2N-H) 368.0973, found 368.0988.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (67% yield, ee = 94%). Reaction time 24 25 hrs. [α]D = -43.3 (c = 0.21, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr

(major) = 15.89 min, tr (minor) = 17.63 min.

1 H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 8.02 Hz, 2H), 7.31 (d, J = 8.48 Hz, 2H), 7.18 (d, J = 8.02 Hz, 2H), 7.08 (d, J = 8.25 Hz, 2H), 6.05 (s, 1H), 3.71 (s, 1H), 1.95 - 2.03 (m, 1H), 1.71 - 1.82 (m, 3H), 1.44-1.50 (m, 3H), 1.43 (s, 3H)

13 C NMR (126 MHz, CDCl3) δ 144.8, 143.1, 131.2, 130.8, 130.0, 129.7, 129.1, 128.1, 126.8, 119.9, 109.4, 109.3, 50.8, 28.2, 27.0, 23.1, 22.8, 18.5

+ + MS (ESI) (M-H) 412.1; HRMS (TOF) calculated for (C22H21BrClN-H) 412.0468, found 412.0483.

124

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (59% yield, ee = 94%). Reaction time 40 25 hrs. [α]D = -32.6 (c = 0.14, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr

(major) = 25.37 min, tr (minor) = 29.88 min.

1 H NMR (500 MHz, CDCl3) δ 7.79 - 7.85 (m, 3H), 7.68 (s, 1H), 7.54 (dd, J = 1.60, 8.48 Hz, 1H), 7.41 - 7.49 (m, 2H), 7.32 - 7.36 (m, 2H), 7.13 - 7.18 (m, 2H), 6.13 (d, J = 1.15 Hz, 1H), 3.93 (s, 1H), 2.01 - 2.08 (m, 1H), 1.76 - 1.90 (m, 4H), 1.52 - 1.61 (m, 3H), 1.47 (s, 3H)

13 C NMR (126 MHz, CDCl3) δ 143.3, 142.9, 133.2, 132.5, 130.6, 129.8, 129.0, 128.1, 128.0, 127.7, 127.6, 126.8, 126.4, 126.1, 125.8, 125.2, 109.9, 109.7, 51.5, 28.2, 27.0, 23.2, 22.8, 18.7

+ + MS (ESI) (M-H) 384.2; HRMS (TOF) calculated for (C26H24ClN-H) 384.1519, found 384.1548.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as orange oil (84% yield, ee = 98%). Reaction time 16 hrs. 25 [α]D = -66.9 (c = 0.16, CHCl3).

HPLC analysis chiralpak OJ-H, hexanes = 2/98, 0.5 ml/min; 214 nm, tr (major)

= 31.42 min, tr (minor) = 43.07 min.

1 H NMR (500 MHz, CDCl3) δ 8.15 - 8.20 (m, 2H), 7.44 - 7.48 (m, 2H), 7.31 - 7.35 (m, 2H), 7.08 - 7.12 (m, 2H), 6.09 (q, J = 1.15 Hz, 1H), 3.89 (s, 1H), 1.96 - 2.04 (m, 1H), 1.70 - 1.85 (m, 3H), 1.49 - 1.61 (m, 4H), 1.44 (d, J = 0.92 Hz, 3H)

13 C NMR (126 MHz, CDCl3) δ 153.5, 146.7, 142.8, 131.2, 130.7, 129.2, 128.6, 128.2, 127.4, 123.6, 108.3, 108.2, 51.5, 28.3, 27.0, 23.0, 22.7, 18.5

125

+ + MS (ESI) (M-H) 379.1; HRMS (TOF) calculated for (C22H21ClN2O2-H) 379.1213, found 379.1207.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (68% yield, ee = 91%). Reaction time 24 25 hrs. [α]D = -37.1 (c = 0.20, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr

(major) = 31.87 min, tr (minor) = 37.00 min.

1 H NMR (500 MHz, CDCl3) δ 7.28 - 7.34 (m, 4H), 7.18 - 7.23 (m, 1H), 7.08 - 7.12 (m, 2H), 6.84 - 6.90 (m, 2H), 6.09 (s, 1H), 4.11 (s, 1H), 3.81 (s, 3H), 2.34 - 2.44 (m, 1H), 2.25 - 2.34 (m, 1H), 2.10 - 2.18 (m, 1H), 2.00 - 2.08 (m, 1H), 1.71 - 1.89 (m, 2H), 1.47 (s, 3H)

13 C NMR (126 MHz, CDCl3) δ 156.9, 145.1, 138.1, 135.3, 128.1, 128.0, 126.9, 126.1, 126.0, 114.0, 112.3, 109.8, 55.5, 48.2, 32.2, 31.7, 21.1, 18.8

+ + MS (ESI) (M-H) 316.2; HRMS (TOF) calculated for (C22H23NO-H) 316.1701, found 316.1725.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (60% yield, ee = 94%). Reaction time 24 25 hrs. [α]D = -24.5 (c = 0.18, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr

(major) = 21.75 min, tr (minor) = 23.81 min.

1 H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 7.33 Hz, 5H), 7.18 - 7.23 (m, 2H), 7.06 - 7.10 (m, 2H), 6.14 (s, 2H), 4.08 (s, 1H), 2.42 - 2.52 (m, 1H), 2.27 - 2.37 (m, 1H), 2.10 - 2.18 (m, 1H), 2.01 - 2.09 (m, 1H), 1.76 - 1.88 (m, 2H), 1.48 (s, 3H)

13 C NMR (126 MHz, CDCl3) δ 144.6, 143.2, 134.3, 128.9, 128.2, 128.0, 126.2, 126.0, 125.3, 114.2, 111.4, 48.1, 32.1, 31.9, 21.2, 18.8

126

+ + MS (ESI) (M-H) 320.1; HRMS (TOF) calculated for (C21H20ClN-H) 320.1206, found 320.1206.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as orange oil (63% yield, ee = 98%). Reaction time 24 25 hrs. [α]D = -27.5 (c = 0.19, CHCl3).

HPLC analysis chiralpak OJ-H, hexanes = 100%, 0.8 ml/min; 214 nm, tr

(major) = 13.07 min, tr (minor) = 20.62 min.

1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.71 Hz, 2H), 7.43 (d, J = 8.71 Hz, 2H), 7.30 (d, J = 8.71 Hz, 6H), 7.07 (d, J = 8.71 Hz, 5H), 6.18 (s, 1H), 4.23 (s, 1H), 2.41 - 2.47 (m, 1H), 2.28 - 2.37 (m, 1H), 2.13 (d, J = 7.79 Hz, 1H), 1.93 - 2.01 (m, 1H), 1.84 - 1.92 (m, 1H), 1.75 - 1.81 (m, 1H)

13 C NMR (126 MHz, CDCl3) δ 152.2, 146.6, 142.8, 135.3, 130.1, 129.1, 128.7, 126.9, 125.5, 123.6, 112.4, 109.6, 48.3, 32.0, 31.8, 21.2, 18.8

+ + MS (ESI) (M-H) 365.1; HRMS (TOF) calculated for (C21H19ClN2O2-H) 365.1057, found 365.1059.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (68% yield, ee = 98%). Reaction time 24 hrs. 25 [α]D = -34.4 (c = 0.24, CHCl3).

HPLC analysis chiralpak OD-H, hexanes = 100%, 0.3 ml/min; 214 nm, tr

(major) = 43.18 min, tr (minor) = 52.47 min.

1 H NMR (500 MHz, CDCl3) δ 7.26 - 7.31 (m, 2H), 7.18 (d, J = 8.25 Hz, 2H), 7.07 (d, J = 8.71 Hz, 2H), 6.85 (d, J = 8.48 Hz, 2H), 6.12 (s, 1H), 4.02 (s., 1H), 3.80 (s, 3H), 2.40 - 2.50 (m, 1H), 2.33 (d, J = 7.10 Hz, 1H), 2.02 - 2.17 (m, 2H), 1.73 - 1.88 (m, 2H), 1.47 (s, 3H)

127

13 C NMR (126 MHz, CDCl3) δ 158.1, 143.2, 137.0, 134.1, 129.4, 128.9, 128.8, 125.8, 125.2, 114.5, 113.5, 111.6, 55.2, 47.2, 32.1, 31.9, 21.2, 18.8

+ + MS (ESI) (M-H) 350.1; HRMS (TOF) calculated for (C22H22ClNO-H) 350.1312, found 350.1318.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as orange oil (73% yield, ee = 98%). Reaction time 30 hrs. 25 [α]D = -199.5 (c = 0.22, CHCl3).

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 2/98, 0.5 ml/min; 254 nm, tr (major) = 19.92 min, tr (minor) = 22.49 min.

1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.71 Hz, 2H), 7.50 (d, J = 8.71 Hz, 2H), 7.08 - 7.13 (m, 2H), 6.87 - 6.93 (m, 2H), 6.02 (d, J = 1.15 Hz, 1H), 3.97 (s, 1H), 3.82 (s, 3H), 2.91 (d, J = 16.5 Hz, 1H), 2.83 (d, J = 16.5 Hz, 1H), 2.55 - 2.67 (m, 2H), 2.20 - 2.28 (m, 1H), 2.05 - 2.14 (m, 1H), 1.42 (d, J = 0.69 Hz, 3H)

13 C NMR (126 MHz, CDCl3) δ 158.1, 152.9, 146.8, 136.7, 132.7, 128.9, 128.6, 127.9, 123.7, 114.4, 107.1, 104.1, 55.5, 51.7, 28.5, 28.4, 25.4, 18.4

+ + MS (ESI) (M-H) 393.1; HRMS (TOF) calculated for (C22H22N2O3S-H) 393.1273, found 393.1298.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as orange oil (70% yield, ee = 95%). Reaction time 30 hrs. 25 [α]D = -191.3 (c = 0.24, CHCl3).

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 2/98, 0.7 ml/min; 214 nm, tr

(major) = 14.32 min, tr (minor) = 25.58 min.

1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.71 Hz, 2H), 7.48 (d, J = 8.71 Hz, 2H), 7.10 (d, J = 8.94 Hz, 2H), 6.90 (d, J = 8.94 Hz, 2H), 6.07 (d, J = 0.92 Hz, 1H), 3.95 (s, 1H),

128

3.87 - 3.92 (m, 1H), 3.82 (s, 3H), 3.70 - 3.78 (m, 2H), 3.63 (ddd, J = 4.58, 6.53, 11.11 Hz, 1H), 2.00 - 2.07 (m, 1H), 1.90 - 1.97 (m, 1H), 1.43 (s, 3H)

13 C NMR (126 MHz, CDCl3) δ 158.0, 152.8, 146.8, 136.1, 129.3, 128.5, 128.5, 127.7, 123.7, 114.3, 106.9, 104.0, 66.9, 64.5, 55.5, 47.4, 26.3, 18.6

+ + MS (ESI) (M-H) 377.2; HRMS (TOF) calculated for (C22H22NO4-H) 377.1502, found 377.1529.

Prepared according to the general procedure at room temperature from the

corresponding 1 (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as orange oil (78% yield, ee = 92%, d.r. = 10:1). 25 Reaction time 16 hrs. [α]D = -69.4 (c = 0.24, CHCl3).

HPLC analysis chiralpak OJ-H, i-PrOH/hexanes = 2/98, 0.5 ml/min; 214 nm, tr (major) = 27.47 min, tr (minor) = 47.40 min.

1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.71 Hz, 5H), 7.48 (d, J = 8.71 Hz, 2H), 7.10 (d, J = 8.71 Hz, 2H), 6.88 (d, J = 8.71 Hz, 2H), 6.00 (s, 1H), 3.87 - 3.95 (m, 1H), 3.82 (s, 3H), 1.99 (dd, J = 3.09, 11.80 Hz, 1H), 1.85 - 1.94 (m, 2H), 1.78 (dd, J = 4.58, 16.27 Hz, 1H), 1.68 (br. s., 1H), 1.57 - 1.63 (m, 1H), 1.42 (s, 3H), 1.31 - 1.39 (m, 1H), 0.84 (d, J = 6.64 Hz, 3H)

13 C NMR (126 MHz, CDCl3) δ 157.9, 153.8, 146.6, 137.5, 131.2, 129.1, 128.5, 128.0, 123.5, 114.1, 106.7, 105.4, 55.4, 52.0, 37.5, 31.1, 29.0, 26.8, 21.4, 18.5

+ + MS (ESI) (M-H) 389.2; HRMS (TOF) calculated for (C24H26N2O3-H) 389.1865, found 389.1856.

Prepared according to the general procedure at room temperature from the

corresponding 1h (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (32% yield, ee = 80%). Reaction time 24 hrs. 25 [α]D = -66.5 (c = 0.14, CHCl3).

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 1/99, 0.3 ml/min; 214 nm, tr (major)

= 13.23 min, tr (minor) = 12.79 min.

129

1 H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 7.33 Hz, 2H), 7.33 (t, J = 7.68 Hz, 2H), 7.14 - 7.19 (m, 1H), 7.11 (d, J = 8.71 Hz, 2H), 6.86 (d, J = 8.94 Hz, 2H), 6.01 (d, J = 7.79 Hz, 1H), 4.32 (d, J = 7.79 Hz, 1H), 3.81 (s, 3H), 2.00 - 2.08 (m, 1H), 1.87 - 1.94 (m, 1H), 1.76 - 1.85 (m, 1H), 1.62 (s, 3H), 1.56-1.57 (m, 1H), 1.54 (s, 2H), 1.36 (dd, J = 5.61, 8.82 Hz, 1H)

13 C NMR (126 MHz, CDCl3) δ 157.6, 151.3, 137.9, 130.6, 129.3, 128.9, 127.8, 127.1, 125.2, 114.0, 111.8, 108.0, 55.4, 41.9, 27.5, 27.4, 24.7, 23.3, 23.2

+ + MS (ESI) (M+H) 332.2; HRMS (TOF) calculated for (C23H25NO+H) 332.2014, found 332.2003.

Prepared according to the general procedure at room temperature from the

corresponding 1h (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the product as yellow oil (32% yield, ee = 77%). Reaction time 24 hrs. 25 [α]D = -30.3 (c = 0.15, CHCl3).

HPLC analysis chiralpak AD-H, hexanes = 100, 0.3 ml/min; 214 nm, tr (major)

= 13.87 min, tr (minor) = 14.69 min.

1 H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 8.02 Hz, 2H), 7.28 - 7.36 (m, 4H), 7.17 (t, J = 7.22 Hz, 1H), 7.11 (d, J = 8.48 Hz, 2H), 6.06 (d, J = 7.79 Hz, 1H), 4.40 (d, J = 7.56 Hz, 1H), 2.02 (d, J = 9.39 Hz, 1H), 1.94 (d, J = 17.18 Hz, 1H), 1.80 (d, J = 16.95 Hz, 1H), 1.65 (s, 1H), 1.61 (s, 3H), 1.57 (d, J = 6.19 Hz, 3H), 1.39 (d, J = 5.50 Hz, 1H)

13 C NMR (126 MHz, CDCl3) δ 150.7, 143.2, 131.0, 129.7, 129.0, 128.7, 128.5, 127.9, 127.0, 125.4, 113.5, 109.1, 41.8, 27.5, 27.3, 24.8, 23.3, 23.1

+ + MS (ESI) (M+H) 336.2; HRMS (TOF) calculated for (C22H22ClN+H) 336.1519, found 336.1513.

Prepared according to the general procedure at room temperature from the

corresponding 1h (0.2 mmol). Chromatography on SiO2 (8/1, hexanes/EtOAc)

130

25 afforded the product as yellow oil (58% yield, ee = 96%). Reaction time 24 hrs. [α]D = -

57.8 (c = 0.15, CHCl3).

HPLC analysis chiralpak OJ-H, hexanes = 100%, 0.5 ml/min; 214 nm, tr (major) = 30.29 min, tr (minor) = 40.99 min.

1 H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 8.02 Hz, 2H), 7.34 (t, J = 7.45 Hz, 2H), 7.29 (d, J = 8.48 Hz, 2H), 7.18 (t, J = 6.99 Hz, 1H), 7.07 (d, J = 8.48 Hz, 8H), 6.19 (d, J = 7.79 Hz, 1H), 4.52 (d, J = 7.79 Hz, 1H), 2.33 - 2.44 (m, 3H), 1.98 - 2.07 (m, 1H), 1.69 - 1.86 (m, 2H), 1.62 (s, 3H)

13 C NMR (126 MHz, CDCl3) δ 149.7, 143.0, 133.7, 129.8, 128.9, 127.9, 127.9, 126.9, 125.6, 125.5, 117.7, 110.3, 40.8, 32.1, 29.7, 27.5, 20.9

+ + MS (ESI) (M-H) 320.1; HRMS (TOF) calculated for (C21H20ClN-H) 320.1206, found 320.1207.

Prepared according to the general procedure at room temperature from the corresponding 1 (0.2 mmol).

Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the 25 product as orange oil (64% yield, ee = 60%). Reaction time 48 hrs. [α]D = -32.4 (c =

0.22, CHCl3).

HPLC analysis chiralpak OJ-H, i-PrOH/hexanes = 15/85, 0.8 ml/min; 214 nm, tr (major)

= 7.27 min, tr (minor) = 10.00 min.

1 H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.25 Hz, 2H), 7.45 (d, J = 8.25 Hz, 2H), 7.34 (d, J = 8.48 Hz, 2H), 7.11 (d, J = 8.48 Hz, 2H), 6.10 (s, 1H), 3.96 (s, 1H), 2.00 (d, J = 16.95 Hz, 1H), 1.72 - 1.86 (m, 5H), 1.56 - 1.63 (m, 2H), 1.45 - 1.52 (m, 2H), 0.94 (t, J = 7.33 Hz, 3H)

13 C NMR (126 MHz, CDCl3) δ 154.0, 146.7, 143.0, 131.1, 130.7, 129.2, 128.5, 128.2, 126.4, 123.6, 114.0, 108.6, 49.8, 28.3, 27.0, 25.3, 23.0, 22.7, 11.7

+ + MS (ESI) (M-H) 320.1; HRMS (TOF) calculated for (C23H23ClN2O2-H) 320.1206, found 320.1207.

131

Prepared according to the general procedure at room temperature from the corresponding 1 (0.2 mmol).

Chromatography on SiO2 (8/1, hexanes/EtOAc) afforded the 25 product as orange oil (53% yield, ee = 5%). Reaction time 48 hrs. [α]D = -1.5 (c = 0.28,

CHCl3).

HPLC analysis chiralpak OJ-H, i-PrOH/hexanes = 1/99, 0.3 ml/min; 214 nm, tr (major) =

26.90 min, tr (minor) = 38.92 min.

1 H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.71 Hz, 2H), 7.46 (d, J = 8.48 Hz, 2H), 7.33 (d, J = 8.71 Hz, 2H), 7.10 (d, J = 8.71 Hz, 2H), 6.10 (s, 1H), 3.95 (s, 1H), 2.00 (d, J = 16.73 Hz, 1H), 1.71 - 1.80 (m, 4H), 1.47 - 1.61 (m, 4H), 1.34 - 1.40 (m, 1H), 1.19-1.30 (m, 4H), 0.83 (t, J = 6.99 Hz, 3H)

13 C NMR (126 MHz, CDCl3) δ 154.0, 146.6, 142.9, 131.1, 130.6, 129.2, 128.6, 128.2, 127.1, 123.5, 112.5, 108.7, 49.7, 32.1, 29.1, 28.3, 27.0, 23.0, 22.7, 22.4, 13.9

+ + MS (ESI) (M-H) 421.2; HRMS (TOF) calculated for (C25H27ClN2O2-H) 421.1683, found 421.1687.

Prepared according to the procedure for reduction of 4k. Chromatography on SiO2 (7/1, 25 hexanes/EtOAc) afforded the product as white solid (78% yield, ee = 88%). [α]D = 42.1

(c = 0.15, CHCl3).

HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 2/98, 0.5 ml/min; 214 nm,

tr (major) = 10.85 min, tr (minor) = 12.86 min.

1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 6.87 Hz, 2H), 7.35 (d, J = 5.27 Hz, 2H), 7.29 (d, J = 8.02 Hz, 2H), 7.11 (d, J = 7.79 Hz, 2H), 3.14 (d, J = 10.08 Hz, 1H), 2.56 (t, J = 10.65 Hz, 1H), 2.45 (t, J = 8.48 Hz, 1H), 2.09 (d, J = 9.85 Hz, 2H), 1.6-1.70 (m, 3H), 1.55 (d, J = 12.83 Hz, 1H), 1.13 - 1.23 (m, 2H), 1.02 - 1.10 (m, 2H), 0.84 - 0.92 (m, 1H), 0.60 (d, J = 5.27 Hz, 3H)

13 C NMR (126 MHz, CDCl3) δ 151.9, 150.6, 146.6, 129.0, 127.1, 123.6, 65.4, 64.6, 57.0, 47.6, 37.5, 31.5, 30.1, 25.9, 25.0, 17.4

132

+ + MS (ESI) (M+H) 385.2; HRMS (TOF) calculated for (C22H25ClN2O2+H) 385.1683, found 385.1687.

Reference (1) Zhou, J. Chemistry, an Asian journal 2010, 5, 422-434. (2) Ambrosini, L. M.; Lambert, T. H. Chemcatchem 2010, 2, 1373-1380. (3) Gasser, C. A.; Hommes, G.; Schaffer, A.; Corvini, P. F. Appl Microbiol Biotechnol 2012, 95, 1115-1134. (4) Wende, R. C.; Schreiner, P. R. Green Chem 2012, 14, 1821-1849. (5) Ramachary, D. B.; Jain, S. Org Biomol Chem 2011, 9, 1277-1300. (6) Grondal, C.; Jeanty, M.; Enders, D. Nat Chem 2010, 2, 167-178. (7) de Graaff, C.; Ruijter, E.; Orru, R. V. Chem Soc Rev 2012, 41, 3969-4009. (8) Domling, A.; Wang, W.; Wang, K. Chem Rev 2012, 112, 3083-3135. (9) Wan, J. P.; Liu, Y. Y. Rsc Adv 2012, 2, 9763-9777. (10) Brauch, S.; van Berkel, S. S.; Westermann, B. Chem Soc Rev 2013, 42, 4948- 4962. (11) Pellissier, H. Tetrahedron 2013, 69, 7171-7210. (12) Orru, R.; Ruijter, E.; van der Heijden, G. Synlett 2013, 24, 666-685. (13) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem 2014, 16, 2958. (14) Mayer, S. F.; Kroutil, W.; Kurt, F. Chem Soc Rev 2001, 30, 332-339. (15) Roessner, C. A.; Scott, A. I. Annu Rev Microbiol 1996, 50, 467-490. (16) Scott, A. I. J Nat Prod 1994, 57, 557-573. (17) Kajiwara, Y.; Santander, P. J.; Roessner, C. A.; Perez, L. M.; Scott, A. I. J Am Chem Soc 2006, 128, 9971-9978. (18) A. Roessner, C.; B. Spencer, J.; J. Stolowich, N.; Wang, J.; Parmesh Nayar, G.; J. Santander, P.; Pichon, C.; Min, C.; T. Holderman, M.; Ian Scott, A. Chemistry & Biology 1994, 1, 119-124. (19) Deng, Y.; Liu, L.; Sarkisian, R. G.; Wheeler, K.; Wang, H.; Xu, Z. Angew Chem Int Ed Engl 2013, 52, 3663-3667. (20) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew Chem Int Ed Engl 2004, 43, 1566-1568. (21) Uraguchi, D.; Terada, M. J Am Chem Soc 2004, 126, 5356-5357. (22) Connon, S. J. Angew Chem Int Ed Engl 2006, 45, 3909-3912. (23) Akiyama, T. Chem Rev 2007, 107, 5744-5758. (24) Adair, G.; Mukherjee, S.; List, B. Aldrichim Acta 2008, 41, 31-39. (25) Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org Biomol Chem 2010, 8, 5262-5276. (26) Terada, M. Curr Org Chem 2011, 15, 2227-2256. (27) Lv, F. P.; Liu, S. Y.; Hu, W. H. Asian J Org Chem 2013, 2, 824-836. (28) Yu, J.; Shi, F.; Gong, L. Z. Acc Chem Res 2011, 44, 1156-1171. (29) Alper, H.; Hamel, N. J Am Chem Soc 1990, 112, 2803-2804. (30) Lv, J.; Li, X.; Zhong, L.; Luo, S.; Cheng, J. P. Org Lett 2010, 12, 1096-1099. (31) Lv, J.; Zhang, L.; Zhou, Y.; Nie, Z.; Luo, S.; Cheng, J. P. Angew Chem Int Ed Engl 2011, 50, 6610-6614.

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(32) Chen, L. J.; Zhang, L.; Lv, J.; Cheng, J. P.; Luo, S. Z. Chem-Eur J 2012, 18, 8891-8895. (33) Lv, J.; Zhang, L.; Hu, S.; Cheng, J. P.; Luo, S. Chem-Eur J 2012, 18, 799-803. (34) Lv, J.; Zhang, L.; Luo, S.; Cheng, J. P. Angew Chem Int Ed Engl 2013, 52, 9786- 9790. (35) Xi, Z. G.; Zhu, L.; Luo, S.; Cheng, J. P. J Org Chem 2013, 78, 606-613. (36) Zhu, L.; Xi, Z. G.; Lv, J.; Luo, S. Org Lett 2013, 15, 4496-4499. (37) Lv, J.; Luo, S. Chem Commun 2012, 49, 847-858. (38) Bossert, F.; Vater, W. Med Res Rev 1989, 9, 291-324. (39) Boumendjel, A.; Baubichon-Cortay, H.; Trompier, D.; Perrotton, T.; Di Pietro, A. Med Res Rev 2005, 25, 453-472. (40) Hilgeroth, A.; Dressler, C.; Neuhoff, S.; Spahn-Langguth, H.; Langguth, P. Pharmazie 2000, 55, 784-785. (41) Safak, C.; Simsek, R. Mini-Rev Med Chem 2006, 6, 747-755. (42) Murakami, Y.; Kikuchi Ji, J.; Hisaeda, Y.; Hayashida, O. Chem Rev 1996, 96, 721-758. (43) Qiu, R.; Yin, S.; Zhang, X.; Xia, J.; Xu, X.; Luo, S. Chem Commun 2009, 4759- 4761. (44) Guo, Q. X.; Liu, H.; Guo, C.; Luo, S. W.; Gu, Y.; Gong, L. Z. J Am Chem Soc 2007, 129, 3790-3791. (45) Manabe, K.; Kobayashi, S. Org Lett 1999, 1, 1965-1967. (46) Bhadury, P. S.; Li, H. Synlett 2012, 23, 1108-1131. (47) Chen, Y. Y.; Jiang, Y. J.; Fan, Y. S.; Sha, D.; Wang, Q. F.; Zhang, G. L.; Zheng, L. Y.; Zhang, S. Q. Tetrahedron-Asymmetr 2012, 23, 904-909. (48) Chang, T.; He, L. Q.; Bian, L.; Han, H. Y.; Yuan, M. X.; Gao, X. R. Rsc Adv 2014, 4, 727-731. (49) Brenna, E.; Gatti, F. G.; Monti, D.; Parmeggiani, F.; Sacchetti, A. Chemcatchem 2012, 4, 653-659. (50) Mo, J.; Chen, X.; Chi, Y. R. J Am Chem Soc 2012, 134, 8810-8813.

134

Chapter 5: Synthesis of Unsymmetrically Functionalized Benzoporphyrins

Abstract

A series of unsymmetrical push-pull benzoporphyrins was synthesized. The design and synthesis of the unsymmetrically functionalized porphyrins take advantage of a concise and versatile method developed in our laboratory for the synthesis of benzoporphyrins and the unique set of reactivity of 2-nitro-tetraarylporphyrins.

135

5.1 Introduction -Extended porphyrins in which one or more aromatic rings are fused to the porphyrin periphery at the, ’-positions have attracted intense attention owing to their unique combination of photophysical, optoelectronic, and physicochemical properties, and their potential applications in many areas.1-6 Although known for decades, the investigation of -extended porphyrins has been restricted to symmetrical structures. Reports for unsymmetrical -extended porphyrins, in particular -extended porphyrins with unsymmetrically substituted functional groups, remain elusive in the literature due to the very limited synthetic approaches to these compounds. However, unsymmetrically substituted porphyrins are expected to display different electronic and photophysical properties than their symmetrical counterparts due to the splitting of the molecular orbitals, and are of much broader interest as they promise much broader applications such as in optics, in material science as well as in photomedicines. Herein, in this chapter synthesis of a series of unsymmetrically functionalized benzoporphyrins is presented.

5.2 Results and Discussion The design and synthesis of the unsymmetrically functionalized porphyrins (Figure 5.1, 2-5) take advantage of a concise and versatile method developed in our laboratory for the synthesis of benzoporphyrins7 and the unique set of reactivity of 2- nitro-tetraarylporphyrins.8 In this method, an alkene reacts with a ,'-dibromoporphyrin through a three-step cascade reaction involving a vicinal two-fold Heck reaction, 6- electrocyclization, and subsequent aromatization to afford benzoporphyrins.

A series of unsymmetrical push-pull benzoporphyrins was synthesized as shown in Figure 5.1. The presence of the nitro group directs the bromination of the free base porphyrin to the , ’-positions at the opposite pyrrole ring to afford dibromoporphyrin 1.9 After metal insertion of free base porphyrin 1, the resulting Zn(II) dibromoporphyrin 2 reacted with methyl acrylate through the three-step cascade reaction leading to benzoporphyrin 3. Both the attached ester groups and the nitro group can serve as a “pull” functionality; the nitro group was then reduced to an amine (A) using NaBH4 which was further converted into an amide by acylation (4 and 5).10-12 The amide group can serve as

136 a “push” functionality. For comparison, symmetrical benzoporphyrin 6 was also prepared through denitration of 3.

Figure 5.1 Preparation of unsymmetrically functionalized benzoporphyrins 5.3 Experimental Section

5.3.1 Reaction Set Up General procedure for the synthesis of substituted monobenzoporphyrins 3

137

Zinc inserted dibromoporphyrin 2 was prepared according to published procedures.9 Substituted monobenzoporphyrin 3 was synthesized based on a concise and versatile method developed in our laboratory for the synthesis of benzoporphyrins.7,13 Dibromoarylporphyrin 2 (0.045 mmol), palladium acetate (0.011 mmol), triphenylphosphine (0.030 mmol) and K2CO3 (0.10 mmol) were added to a schlenk tube and dried under vacuum. The vacuum was released under argon to allow the addition of dry DMF (10 mL) and dry Toluene (10 mL) and methyl acrylate (25-fold excess). The mixture was then degassed via four freeze-pump-thaw cycles before the vessel was purged with argon again. The schlenk flask was sealed and heated to refluxing for 60h.

After 60 h, the mixture was diluted with CHCl3 and washed with water for 3 times. The organic layer was removed under vacuum. The residue was subjected to preparative column chromatography. The bands containing the desired porphyrins were collected and recrystallized from CHCl3/MeOH (yield 55%). General procedure for the synthesis of porphyrin 4 (H1)

i. General procedure for the synthesis of 2-aminoporphyrin A

This procedure was based upon the literature protocol for similar compound.14 In a two- neck round-bottom flask porphyrin 3 (50 mg, 0.053 mmol), dry dichloromethane (12 mL), and dry methanol (12 mL) was taken. Palladium (10% on carbon, 44 mg) was added to the solution and the solution was purged with argon and stirred at room temperature for 1 h, and then placed into the ice-bath. Over a 10 min period sodium borohydride (48 mg, 1.28 mmol) was added to the solution in small portions. Progress of the reaction was monitored by UV-Visble spectroscopy, which shows shift in a Soret band at 442 nm and also by TLC using DCM/Cyclohexane (1:1) as eluent. Complete consumption of starting material was observed after 1.2 h of the reaction. Solvent was removed by using rotary evaporator, and the residue was passed through a plug of Celite using dichloromethane as

138 eluent in the dark. The crude product was concentrated in vacuum, and was directly used for the next reaction without further purification due to the unstability against photo- oxidation. ii. General procedure for acetylation of porphyrin 4 (H1) This procedure was based upon the literature protocol for similar compound.14 Pyridine (0.4 mL) and acetic anhydride (4 mL) was added to Porphyrin A (40 mg, 0.044 mmol). Solution was stirred overnight at room temperature. The reaction mixture was poured into water and stirred for another 15 minutes and was extracted with chloroform. TLC was carried out using DCM/cyclohexane (20:1) as eluent, which showed the formation of porphyrin 4, which was separated by column chromatography. General procedure for the synthesis of porphyrin 5 (H4)

Porphyrin A (40 mg, 0.044 mmol) was dissolved in chloroform (10ml) and pyridine (0.016 mL) and benzoyl chloride (0.010 mL) was added to it. The solution was stirred for 8 hours at room temperature. The reaction mixture was poured into water and stirred for another 15 minutes and was extracted with chloroform. TLC was carried out using DCM/cyclohexane (15:1), which showed a new spot. Using short plug of silica porphyrin 5 was collected. General procedure for the synthesis of porphyrin 6 (H3)

Denitration of porphyrin 3 was carried out using literature reported procedure by Smith et 9 al. Porphyrin 3 (50 mg, 0.053 mmol) and NaBH4, (4 mg, 0.106 mmol) was added to a cold solution (ice/NaCl) of dried THF (10 mL) under argon. The resulting reaction

139 mixture was stirred for 2 h but the ice bath was removed after one hour. Progress of the reaction was monitored by UV-Visble spectroscopy. When the Soret band shifted from 448 to 441 nm, dichloromethane (100 mL) was added to the reaction mixture and the solution was poured into water. The organic phase was collected and evaporated to dryness. The residue was re-dissolved in dichloromethane and passed through a short alumina plug. Solvent was evaporated and the crude product was used directly in the next step.

The crude product from the last step was dissolved in chloroform (40 mL) followed by addition of silica gel (2 g). The resulting reaction mixture was refluxed for 1 d under argon. The reaction mixture was then cooled down to room temperature and filtered to remove the silica gel and washed thoroughly with dichloromethane. Solvent was evaporated. The crude product was purified through column chromatography (silica/DCM).

5.3.2 Characterization Data 3: Yield (55%). mp > 320 °C. UV-Vis λmax

(CH2Cl2)/nm 446 (log ε = 6.59), 569 (5.81), 625 (5.74);

1H-NMR (500 MHz, CDCl3, Me4Si) δ 9.05-8.73 (5 H, m, β-H), 8.01-7.93 (8 H, m, o-Ph–H), 7.60-7.44 (8 H, m, m-Ph–H), 7.39 (2 H, s, fused-benzene-H), 3.77 (6 H, d,-

OCH3 ), 2.74-2.63 (12 H, m, methyl-H ); 13C-NMR

(500 MHz, CDCl3, Me4Si) δ 21.61, 29,71, 52.44, 118.08, 118.53, 121.28, 124.42, 125.88, 127.90, 128.75, 129.31, 129.62, 129.89, 131.58, 133.87, 134.88, 135.39, 137.69, 138.33, 138.86, 139.20, 141.26, 142.98, 143.15, 146.35, 150.58, 150.98, 152.77, 168.06; Calculated Mass, 943.235,

Found MS (MALDI-TOF), m/z 898.014 (M-NO2).

140

4: Yield (66%). UV-Vis λmax (CH2Cl2)/nm 441 (log ε = 6.89), 566 (6.04), 607 (5.82); 1H-NMR

(500 MHz, CDCl3, Me4Si) δ 9.25 (1 H, s, NH-H), 8.88-8.66 (5 H, m, β-H), 8.01-7.97 (8 H, m, o-Ph– H), 7.66-7.47 (10 H, m, benzene-H), 3.90 (6 H, s,- OCH3 ), 2.76-2.66 (12 H, m, methyl-H ), 1.73 (3 H, s, methyl-H), 13C-NMR (500 MHz, CDCl3, Me4Si) δ 21.45, 21.59, 29.68, 52.43, 114.19, 118.42, 118.53, 119.16, 119.77, 121.96, 122.36, 126.28, 127.90, 128.75, 129.31, 129.62, 129.89, 131.58, 133.87, 134.88, 135.39, 137.69, 138.33, 138.86, 139.20, 141.26, 142.98, 143.15, 146.35,149.39, 149.47, 150.06, 150.59, 151.39, 167.06, 168.06 Calculated Mass, 955.103, Found MS (MALDI-TOF), m/z 955.143. 5: Yield (33%). mp > 320 °C. UV-Vis λmax

(CH2Cl2)/nm 444 (log ε 7.30), 569 (6,22), 608 (5.77);

1H-NMR (500 MHz, C6D6) δ 10.47 (1 H, s, NH-H), 9.08 (2 H, d, J = 5.0 Hz, o-NHCOPh-H), 9.07 (2 H, dd, J = 5.0, 12.0 Hz, m-NHCOPh-H), 8.68 (1 H, d, J = 5.0 Hz, p-NHCOPh-H), 8.31 (2 H, d, J = 7.5 Hz, o- Ph–H), 8.09-8.06 (4 H, m, o-Ph–H), 8.00 (2 H, d, J = 12.5 Hz, fused-benzene-H), 7.93 (2 H, d, J = 7.5 Hz, o-Ph–H), 7.55 (2 H, d, J = 7.5 Hz, m-Ph–H), 7.47- 7.44 (4 H, m, m-Ph–H), 7.40 (2 H, d, J = 7.5 Hz, m-Ph–H), 7.15-7.11 (5 H, m, β-H), 3.65

(6H, s, OCH3-H), 2.57 (3H, s, methyl-H), 2.56 (3H, s, methyl-H), 2.42 (3H, s, methyl-H), 2.28 (3H, s, methyl-H). 6: Yield (33%). mp > 320 °C. UV-Vis λmax

(CH2Cl2)/nm 437 (log ε = 6.62), 562 (5,74), 626

(5.59); 1H-NMR (500 MHz, CDCl3, Me4Si) δ 8.93- 8.86 (6 H, m, β-H), 8.07-7.99 (8 H, m, o-Ph–H), 7.64-7.52 (10 H, m, benzene-H), 3.90 ( 6H, s, methyl H), 2.77 (12 H, d, methyl-H), 13C-NMR (500 MHz, CDCl3, Me4Si) δ 21.65, 29.72, 52.49,

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118.48, 122.81, 126.39, 127.36, 128.40, 131.37, 131.68, 132.19, 133.17, 134.24, 137.25, 138.15, 139.61, 139.88, 140.82, 144.48, 149.38, 150.20, 151.60, 168.45; Calculated Mass, 898.182, Found MS (MALDI-TOF), m/z 898.141.

Reference (1) Baluschev, S.; Yakutkin, V.; Miteva, T.; Avlasevich, Y.; Chernov, S.; Aleshchenkov, S.; Nelles, G.; Cheprakov, A.; Yasuda, A.; Mullen, K.; Wegner, G. Angew Chem Int Ed Engl 2007, 46, 7693-7696. (2) Borek, C.; Hanson, K.; Djurovich, P. I.; Thompson, M. E.; Aznavour, K.; Bau, R.; Sun, Y. R.; Forrest, S. R.; Brooks, J.; Michalski, L.; Brown, J. Angewandte Chemie- International Edition 2007, 46, 1109-1112. (3) Ongayi, O.; Gottumukkala, V.; Fronczek, F. R.; Vicente, M. G. H. Bioorg. Med. Chem. Lett. 2005, 15, 1665-1668. (4) Mack, J.; Bunya, M.; Shimizu, Y.; Uoyama, H.; Komobuchi, N.; Okujima, T.; Uno, H.; Ito, S.; Stillman, M. J.; Ono, N.; Kobayashi, N. Chem. Eur. J. 2008, 14, 5001- 5020. (5) Young, S. W.; Qing, F.; Harriman, A.; Sessler, J. L.; Dow, W. C.; Mody, T. D.; Hemmi, G. W.; Hao, Y. P.; Miller, R. A. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 6610- 6615. (6) Okujima, T.; Hashimoto, Y.; Jin, G.; Yamada, H.; Uno, H.; Ono, N. Tetrahedron 2008, 64, 2405-2411. (7) Deshpande, R.; Jiang, L.; Schmidt, G.; Rakovan, J.; Wang, X.; Wheeler, K.; Wang, H. Org Lett 2009, 11, 4251-4253. (8) Kadish, K. M.; Smith, K. M.; Guilard, R. THe Porphyrin Handbook; Academic Press: Boston, 2000; Vol. 6. (9) Jaquinod, L.; Khoury, R. G.; Shea, K. M.; Smith, K. M. Tetrahedron 1999, 55, 13151-13158. (10) Pereira, A.; Alonso, C. M. A.; Neves, M.; Tome, A. C.; Silva, A. M. S.; Paz, F. A. A.; Cavaleiro, J. A. S. J. Org. Chem 2008, 73, 7353-7356. (11) Khoury, T.; Crossley, M. J. Chem. Communs 2007, 4851-4853. (12) Feng, D. J.; Wang, G. T.; Wu, J.; Wang, R. X.; Li, Z. T. Tetrahedron Letters 2007, 48, 6181-6185. (13) Jiang, L.; Engle, J. T.; Sirk, L.; Hartley, C. S.; Ziegler, C. J.; Wang, H. Org Lett 2011, 13, 3020-3023. (14) Baldwin, J. E.; Crossley, M. J.; Debernardis, J., Tetrahedron, 1982, 38, 685-692.

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Chapter 6: Conclusions

6.1 Cooperative Catalysis with Arylamines and Acids Since the realization of the first combination of enamine catalysis with transition metal catalysis in 2006 by the Cόrdova group, 1 considerable progress has been made on cooperative enamine-transition metal catalysis. Several strategies, including soft/hard combination of a Lewis acid and a Lewis base, the utilization of a chelating ligand to construct bifunctional catalysts, as well as mixing an ammonium salt with a Lewis acid, have been developed to overcome catalyst incompatibility problems. As discussed in Chapter 1, a number of new organic transformations have been developed through cooperative/synergistic enamine-transition metal catalysis. In particular, significant advances have been achieved in asymmetric direct α-allylations and α-propargylations of aldehydes in the past several years.2-6 Even the challenging asymmetric α-arylations and α-alkenylations have been achieved with high yields and stereoselectivities.7,8

The studies in this dissertation have proved that arylamines, much softer bases than aliphatic amines, can serve as effective amine catalysts to promote enamine formation when combined with hard metal Lewis acids. Using this concept, a challenging three-component inverse-electron-demand aza-Diels–Alder reaction of cyclic ketones, enones, arylamines was developed using an arylamine and Y(OTf)3. High enantioselectivities of the reaction for 6-membered cyclic ketones were achieved (up to

96% ee) when a chiral anion approach was employed through treatment of YCl3 with a simple chiral silver phosphate.

Taking advantage from the good compatibilities between arylamines, BINOL- phosphoric acids, and metal Lewis acids, a novel trio catalysis system with arylamines,

BINOL-phosphoric acids, and Y(OTf)3 was designed in Chapter 4. Using this trio catalysis, a highly chemo- and enantioselective three-component ADA reaction of substituted cinnamaldehydes, cyclic ketones, and arylamines was successfully achieved. A series of functionlized DHPs were obtained through the ADARs with good yields and good to excellent enantioselectivities (up to 99% ee).

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Compared to the earlier years, cooperative enamine-transition metal catalysis has attracted much more attention, and has grown much more rapidly in recent years. Given the new strategies and new reaction modes developed, the judicious selection of metals and amines, the ease and the flexibility of the combination, and, very importantly, that many unknowns remain unexplored in this field, we believe that this research area is about to take off and will prosper in the near future.

6.2 Lewis-Acid-Assisted Lewis Acid Catalysts Derived from Chiral Metal Phosphates Lewis-acid-assisted Lewis acid catalysts, one of the most important classes in combined acid catalysis,9 have been explored in a variety of organic transformations.10-17 However, the lack of chirality in the LLA catalysts explored thus far limits their broader application in asymmetric catalysis, a potential that is far from fully recognized.

The studies in Chapter 3 disclosed an efficient metal Lewis acid-assisted metal

Lewis acid (MLA/M[P]3-LLA) catalyst from a chiral metal phosphate associated by a metal Lewis acid. This bimetallic LLA catalyst exhibited high activity and enantioselectivity for a novel asymmetric three-component ADAR of cyclic ketones, unsaturated ketoesters and arylamines. The asymmetric three-component ADARs of the more inert 5-membered and 7-membered cyclic ketones, were successfully achieved by

Yb(OTf)3/Y[P]3-LLA catalysts affording unusual 5/6 and 7/6 fused bicyclic DHPs in good yields with good enantioselectivity. Preliminary structural studies have revealed that these LLA catalysts have a bimetallic center with bridging phosphate ligands, representing a novel class of metal complexes for group 3 and lanthanide metals.

The easily tunable activity, stereoselectivity and readily accessibility of this LLA catalyst make it a new strategy for metal Lewis acid catalyzed asymmetric organic transformations. We anticipate that this new class of LLA catalysts will find broad applications in catalysis and organic synthesis.

Reference (1) Ibrahem, I.; Cordova, A. Angew Chem Int Ed Engl 2006, 45, 1952-1956. (2) Bihelovic, F.; Matovic, R.; Vulovic, B.; Saicic, R. N. Org Lett 2007, 9, 5063-5066. (3) Usui, I.; Schmidt, S.; Breit, B. Org Lett 2009, 11, 1453-1456. 144

(4) Jiang, G.; List, B. Angew Chem Int Ed Engl 2011, 50, 9471-9474. (5) Binder, J. T.; Crone, B.; Haug, T. T.; Menz, H.; Kirsch, S. F. Org Lett 2008, 10, 1025-1028. (6) Gómez-Bengoa, E.; García, J. M.; Jiménez, S.; Lapuerta, I.; Mielgo, A.; Odriozola, J. M.; Otazo, I.; Razkin, J.; Urruzuno, I.; Vera, S.; Oiarbide, M.; Palomo, C. Chem Sci 2013, 4, 3198. (7) Yoshida, A.; Ikeda, M.; Hattori, G.; Miyake, Y.; Nishibayashi, Y. Org Lett 2011, 13, 592-595. (8) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065-1068. (9) Yamamoto, H.; Futatsugi, K. Angew Chem Int Ed Engl 2005, 44, 1924-1942. (10) Mahrwald, R. Org Lett 2000, 2, 4011-4012. (11) Mahrwald, R.; Ziemer, B. Tetrahedron Lett 2002, 43, 4459-4461. (12) Reilly, M.; Oh, T. Tetrahedron Lett 1994, 35, 7209-7212. (13) Reilly, M.; Oh, T. Tetrahedron Letters 1995, 36, 221-224. (14) Trost, B. M.; Terrell, L. R. J Am Chem Soc 2003, 125, 338-339. (15) Futatsugi, K.; Yamamoto, H. Angew Chem Int Ed Engl 2005, 44, 1484-1487. (16) Liu, D.; Canales, E.; Corey, E. J. J Am Chem Soc 2007, 129, 1498-1499. (17) Canales, E.; Corey, E. J. J Am Chem Soc 2007, 129, 12686-12687.

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