Title Page

Abstract

Contents

Chapter 1. Introduction 20

Chapter 2. Synthesis of Palladium Racemization Catalysts for Dynamic Kinetic Resolution of Primary Amines 33

2.1. Synthesis of Palladium Nanoparticles on Single Walled Carbon Nanotubes for Amine Racemization Catalyst 35

2.1.1. Dispersion of Purified SWNTs in Aqueous Solution 35

2.1.2. Synthesis of Pd on SWNTs 42

2.1.3. Catalytic activity of Pd on SWNTs 47

2.1.4. Summary 50

2.2. Synthesis of Magnetically Recoverable Palladium Nanocatalyst for Amine Racemization Catalyst 52

2.2.1. Synthesis of Pd/IL, Pd/IL/Fe₃O₄, and IL Removed Pd/Fe₃O₄ Using Room Temperature Solid Ionic Liquid 52

2.2.2. Direct Synthesis of Pd/Fe₃O₄ without IL 60

2.2.3. Racemization of Amine Using Magnetically Recoverable Palladium Nanocatalyst 68

2.2.4. Summery 69

2.3. Synthesis of Palladium Nanoparticles on Aluminum Oxyhydroxide for Amine Racemization Catalyst 71

2.3.1. Synthesis and Characterization of Pd on AlO(OH) 71

2.3.2. Fast Racemization of (R)-1-Phenylethylamine Using Pd on AlO(OH) 77

2.3.3. Summary 80

Chapter 3. Dynamic Kinetic Resolution of Benzylic Amines Using Fast Racemization Catalyst 81

3.1. Kinetic Resolution of 1-Phenylethylamine Using Novozym 435 82

3.2. Optimization of DKR conditions 83

3.3. DKR of Various Benzylic Amines 85

3.4. Optimization of DKR conditions with Sodium Carbonate 90

3.5. Fast DKR of Various Benzylic Amines with Sodium Carbonate 92

3.6. Summary 95

Chapter 4. Dynamic Kinetic Resolution of Amino Acid Amides Using Fast Racemization Catalyst 96

4.1. DKR of α-Amino Acid Amide by Pd on AlO(OH) 97

4.2. DKR of β-Amino Acid Amide by Pd on AlO(OH) 101

4.3. Summary 104

Chapter 5. Asymmetric Transformation of Benzyl Ketoxime to Optically Active Amides for Synthesis of Calcimimetics (+)-NPS R-568 106

5.1. Synthesis of Calcimimetics (+)-NPS R-568 Intermediate 108

5.2. Summary 113

Chapter 6. Chemoselective Olefin Hydrogenation Using Magnetically Recoverable Palladium Nanocatalyst 114

6.1. Chemoselective Olefin Hydrogenaton Using IL Removed Pd/Fe₃O₄ 116

6.2. Chemoselective Olefin Hydrogenaton Using Direct Synthesized Pd/Fe₃O₄ without IL 118

6.3. Summary 120

Chapter 7. Experimental Section 121

7.1. Synthesis of Fast Racemization Catalyst for Dynamic Kinetic Resolution of Primary Amines 122

7.1.1. Material and Methods 122

7.1.2. Experimental Procedures 123

7.1.3. Characteristic Data of Product 133

7.2. Dynamic Kinetic Resolution of Benzylic Amines Using Fast Racemization Catalyst 133

7.2.1. Material and Methods 133

7.2.2. Experimental Procedures 134

7.2.3. Characteristic Data of Product 136

7.3. Dynamic Kinetic Resolution of Amino Acid Amides Using Fast Racemization Catalyst 141

7.3.1. Material and Methods 141

7.3.2. Experimental Procedures 142

7.3.3. Characteristic Data of Product 144

7.4. Asymmetric Transformation of Benzyl Ketoxime to Optically Active Amides for Synthesis of Calcimimetics (+)-NPS R-568 146

7.4.1. Material and Methods 146

7.4.2. Experimental Procedures 147

7.4.3. Characteristic Data of Product 148

7.5. Magnetically Recoverable Palladium Nanocatalyst for Chemoselective Olefin Hydrogenation 148

7.5.1. Material and Methods 148

7.5.2. Experimental Procedures 149

7.5.3. Characteristic Data of Product 152

Chapter 8. References 153

Curriculum Vitae 163

Table 2-1. The Catalytic Hydrogenation of Styrene 47

Table 2-2. The Heck Reaction of Bromobenzene with Styrene 48

Table 2-3. The Catalytic Oxidation of Benzyl alcohol 48

Table 2-4. The Racemization of (S)-1-Phenylethylalcohol 49

Table 2-5. Racemization of (R)-1-Phenylethylamine with 2 50

Table 2-6. Catalytic Hydrogenation of Olefin by Using Pd/IL 56

Table 2-7. Recycle Experiment of Styrene Hydrogenation Using Pd/IL/Fe₃O₄ 58

Table 2-8. Catalytic Hydrogenation of Olefin by IL Removed Pd/Fe₃O₄ 59

Table 2-9. Recycling of 3 for Hydrogenation of trans-Stilbene 60

Table 2-10. Reproducibility Test of Catalyst Preparation 62

Table 2-11. Optimization of Condition for Catalyst Preparation 63

Table 2-12. Olefin Hydrogenation Using Pd/Fe₃O₄ 67

Table 2-13. Racemization of 1-Phenylethylamine Using Magenetically Separable palladium Nanocatalyst 69

Table 2-14. Racemization of (R)-1-Phenylethylamine (6a) 78

Table 2-15. Racemization of (R)-1-Phenylethylamine (6a) with Various Conditions 79

Table 3-1. KR of 1-Phenylethylamine (6a) Using Novozym 435 82

Table 3-2. Optimization of the Reaction Condition for DKR of 6a 84

Table 3-3. DKR of 6a Using Isopropyl Methoxyacetate as an Acyl Donor 85

Table 3-4. Optimization of the Reaction Conditions for DKR of 6b 86

Table 3-5. Optimization of the Reaction Conditions for DKR of 6c 87

Table 3-6. Optimization of the Reaction Conditions for DKR of 6e 88

Table 3-7. DKR of Various Amines 89

Table 3-8. Optimization for DKR of 6a with sodium carbonate 90

Table 3-9. DKR of Various Amines with Sodium Carbonate 94

Table 4-1. KR of Phenylglycine Amide (6i) with Novozym 435 98

Table 4-2. DKR of Phenylglycine Amide (6i) 99

Table 4-3. DKR of Phenylglycine Amide (6i) without Sodium Carbonate 101

Table 4-4. The Complementary Selectivity of PSL Compared with CalA 103

Table 4-5. The DKR of β-Amino Acid Amides with PSL-5 Combination 104

Table 5-1. Asymmetric Reductive Acylation of 14k Using 1 108

Table 5-2. Dynamic Kinetic Resolution of 6k Using 5 110

Table 5-3. Asymmetric Reductive Acylation of 14k Using 5 111

Table 5-4. Asymmetric Reductive Acylation of 14a Using 5 113

Table 6-1. Catalytic Hydrogenation of Olefin by IL Removed Pd/Fe₃O₄ 117

Table 6-2. Chemoselective Olefin Hydrogenation Using Pd/Fe₃O₄ 119

Figure 1-1. Examples of Single-enantiomer Small Molecule Drug 21

Figure 1-2. The Concept of Enzymometallic DKR 22

Figure 1-3. TEM image of Pd/AlO(OH) 29

Figure 2-1. The Main Feature of Metal Nanoparticles 34

Figure 2-2. Single Walled Carbon Nanotubes 35

Figure 2-3. The Origin of Poor Solubility of SWNTs 36

Figure 2-4. Raman Spectra (solid, average value of three different areas per sample, 514.5 ㎚) of (a) Pristine SWNTs and (b) Purified SWNTs 38

Figure 2-5. Representative Photographs of Purified SWNTs Solution using (a) benzylamine (b) 10 mM NaOH 39

Figure 2-6. (a) UV-Vis spectra of purified SWNTs at a concentration of 25 ㎎/L, 20 ㎎/L, 15 ㎎/L, 10㎎/L, and 5 ㎎/L in ODCB. (b) The linear plot of concentration (㎎/L) versus the absorbance at 500 ㎚. 40

Figure 2-7. Soluble Concentrations of SWNTs in Variation of Alkyl Amine 41

Figure 2-8. TEM Images of Aqueous Solution of Purified SWNTs by Alkyl Amine Mediated Dispersion 42

Figure 2-9. (a) Schematic illustration of procedure for Pd on SWNT, (b) TEM image of Pd on SWNT, (c) the size distribution of palladium nanoparticles in Pd on SWNT, (d) control experiment: add sodium borohydride as a reductant, (e) control experiment:... 44

Figure 2-10. The TEM image of Cu on SWNT 45

Figure 2-11. The TEM image of Ru on SWNT 45

Figure 2-12. The TEM image of Rh on SWNT 46

Figure 2-13. The TEM image of Au on SWNT 46

Figure 2-14. TEM Images of Pd/IL and Size Distribution of Pd NPs 54

Figure 2-15. X-ray Diffraction Pattern of Pd/IL 55

Figure 2-16. The TEM Images of Pd/IL/Fe₃O₄ before (top) and after Recycle (bottom) 57

Figure 2-17. Photograph of Pd/IL/Fe₃O₄ in Toluene 58

Figure 2-18. Photo of Catalyst Preparation (a) before Sonication, (b) after Sonication, (c) after Sonication without Iron oxide MNPs 61

Figure 2-19. TEM Images of (a) 10 wt % Catalyst (Pd NPs: 5~10 ㎚) and (b) 1 wt % Catalyst (Pd NPs: 2~5 ㎚) 62

Figure 2-20. TEM Images of (a) Iron Oxide NPs and (b) Spherical Shaped Pd NPs (2-3 ㎚) Directly Attached on Iron Oxide NPs 64

Figure 2-21. XPS Spectrum of Pd/Fe₃O₄ 65

Figure 2-22. XRD Spectrum of Pd/Fe₃O₄ 66

Figure 2-23. (a) Recycling of Pd Nanocatalysts. (b) Pd Nanocatalysts Dispersed in Methanol Solution. (c) Pd Nanocatalysts Recovered with an External Magnet 68

Figure 2-24. High Angle Annular Dark field (HAADF) images of Pd on AlO(OH) (a, c, and e) and corresponding EDS data (b, d, and f). These results are clearly indicating that white spots are Pd nanoparticles. 73

Figure 2-25. Low magnification (a) BF and (b) HAADF images of Pd on AlO(OH). High magnification (c) BF and (d) HAADF images of Pd on AlO(OH). 74

Figure 2-26. The Size Distribution of Pd on AlO(OH) by HR STEM 75

Figure 2-27. HR STEM Images of 3.84 wt % of Pd on AlO(OH) 76

Figure 2-28. The Size Distribution of 3.84 wt % of Pd on AlO(OH) by HR STEM 77

Figure 3-1. Schematic Illustration of Isopropanol Mediated Reduction of Imine 85

Figure 3-2. Presumable Mechanism for Competition of Isopropanol with 6b 87

Figure 3-3. Schematic Illustration of Racemization of 6c 88

Figure 3-4. Comparison of Productivity and Relative Productivity 91

Figure 5-1. Structure of calcimimetics cinacalcet and (+)-NPS R-568 hydrochloride (13) 107

Scheme 1-1. (R)- and (S)-Selective DKR of Secondary Alcohols 23

Scheme 1-2. DKR of α-methylbenzylamine by Reetz Group 24

Scheme 1-3. Asymmetric Transformation of Ketoximes to Chiral Amides by Our Group 25

Scheme 1-4. DKR of Amines by Jacobs Group 25

Scheme 1-5. DKR of Amines by Backvall Group(이미지참조) 26

Scheme 1-6. DKR of Amines by Meijer Group 27

Scheme 1-7. Proposed Mechanism for Amine Racemization by Palladium and Possible Side Products 28

Scheme 1-8. Hydrogenation of Alkenes and Aerobic Oxidation of Alcohols by Pd/AlO(OH) 29

Scheme 1-9. DKR of Amines Using Pd/AlO(OH) for Racemization 30

Scheme 1-10. DKR of Amines Using Pd/AlO(OH) with Activated Acyl Donor 30

Scheme 1-11. Asymmetric Transformation of Benzylic Ketoximes Using Pd/AlO(OH) with Activated Acyl Donor 31

Scheme 1-12. DKR of α-amino acid amide Using Pd/AlO(OH) for Racemization 32

Scheme 2-1. Purification of SWNTs 37

Scheme 2-2. The Dispersion of Purified SWNTs in Aqueous Solution 38

Scheme 2-3. The Control Experiment for Physisorption of amine on SWNTs 50

Scheme 2-4. Preparation of Pd/IL 53

Scheme 2-5. Preparation of Pd/IL/Fe₃O₄ 57

Scheme 2-6. Preparation of IL Removed Pd/Fe₃O₄ 59

Scheme 2-7. Preparation of Pd/Fe₃O₄ without IL 61

Scheme 2-8. Preparation of Pd/Fe₃O₄ without IL (0.5 wt % of Pd, using 2-butanol) 61

Scheme 2-9. Optimized Condition for Preparation of Pd/Fe₃O₄ 64

Scheme 2-10. Preparation of Pd/AlO(OH) (1) 72

Scheme 2-11. Preparation of Pd on AlO(OH) (5) 72

Scheme 4-1. Two Approaches for DKR of Amino Acid Amides 97

Scheme 4-2. DKR of α-Amino Acid Amide with 5 98

Scheme 4-3. Possible Mechanism for Base Catalyzed Racemization of 7i 100

Scheme 4-4. Control Experiment for Base Catalyzed Racemization of 7i 100

Scheme 4-5. The Reason of Slow Racemization of 6i by 5 101

Scheme 4-6. The DKR of β-Amino Acid Amides by Backvall Group(이미지참조) 102

Scheme 5-1. Synthesis of (+)-NPS R-568 Hydrochloride (13) via ARA Using 1 109

Scheme 5-2. Synthesis of (+)-NPS R-568 Hydrochloride (13) via ARA Using 5 112

Since the regulation about chiral molecules by FDA, the interest in asymmetric syntheses is becoming more and more increasing due to its importance in the agricultural, food, and pharmaceutical industries. Dynamic kinetic resolution (DKR), combinations of a kinetic resolution and an in situ racemization, is one of practical methodology in preparation of optically active compounds. Moreover, DKR provides useful route for the complete transformation of racemic substrates into single enantiomeric products in contrary to conventional methods. In the last decade, the DKR by enzyme-metal combination, enzyme as a resolution catalyst together with a metal or metal complex as the racemization catalyst, have been developed by Kim-Park group and others. As a result, numerous enzyme-metal combinations are now available for the efficient DKR of secondary alcohols. However, the DKR of primary amines is rather difficult to achieve mainly due to the low activity of racemization catalyst, so few practical procedures have been developed to date. Accordingly, the amine DKRs should be performed at elevated temperature for long times (24 h or longer) to obtain satisfactory conversions. Thus, the objective of this research was to develop the highly active racemization catalyst and the practical procedure for the fast DKR of amines employing enzyme-metal combinations.

I have investigated the palladium nanoparticles adsorbed on the surface of single walled carbon nanotubes (pd on SWNTs) as a potential catalyst for racemization in the DKR of amines. Palladium nanoparticles were generated via auto-reduction by SWNTs in aqueous solution. Pd on SWNTs showed moderate activities in various palladium catalyzed reactions. However, the catalyst is poorly active in the racemization of amine. Moreover, it was proved that SWNTs are unsuitable support for amine racemization catalyst, because SWNTs are able to adsorb amines on its surface and thus leading to decrease isolated yield.

I developed magnetically separable palladium nanocatalyst (Pd on Fe₃O₄) also for practical applications. In most of the previous studies, nanocatalysts were immobilized on the modified surface of magnetic nanoparticles (MNPs). However, the surface modifications of MNPs are time-consuming and often require non-green reagents. I thus prepared palladium nanocatalysts directly adsorbed on the unmodified surface of iron oxide MNPs via simple and straightforward synthetic procedure. The catalysts are active in the chemoselective olefin hydrogenation at room temperature. However, the catalysts are poorly active in the racemization of amine.

Recently, our group employed aluminum Oxyhydroxide, AlO(OH), as a support for palladium nanocatalyst utilized in amine racemization. Although the palladium nanocatalyst still needs further improvement in activity, the AlO(OH) matrix shows good compatibility in amine DKRs. After numerous efforts, I have developed the new palladium nanocatalyst, Pd on AlO(OH), showing remarkable activity toward amine racemization. As a result, I established an efficient procedure for the fast DKR of benzylic primary amines. The fast DKR employed with Pd on AlO(OH) as racemization catalyst, Novozym 435 as a resolution catalyst, isopropyl-and ethyl methoxyacetate as an acyl donor, sodium carbonate as a base for capturing acidic impurities. Under the optimized condition for fast DKR, eight benzylic amines were tested, and all of them were resolved with good yields and high optical purities within 6 hours. To the best of our knowledge, it is the fastest DKR of primary amines.

I have explored the DKR of amino acid amides with enzyme-metal combination. However, it was proved that Pd on AlO(OH) is inappropriate in racemization of α-amino acid amide due to its electron deficient nature. I also envisaged the DKR of β-amino acid amide by PSL-Pd on AlO(OH) combination. Although the PSL shows a perfect enantioselectivity toward the resolution of β-amino acid amides, its poor thermal stability is a drawback in application. Therefore, I performed the one pot sequential reaction by adding fresh enzyme and controlling reaction temperature with good yield (90%) and excellence enantiomeric excesses (>99.5% ee).

Finally, I have studied an application of Pd on AlO(OH) in the asymmetric synthesis of chiral drug. The key intermediate of calcimimetics (+)-NPS R-568 efficiently synthesized via asymmetric reductive acylation. The use of reactive palladium nanocatalyst, a dual catalyst for reduction of ketoxime and racemization of amine, reduced the reaction time more effectively, compared to the previous procedure.