Ph.D. Thesis_AS_Publishing version for IRC_12 ... - Jacobs University

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Chapter 1 1.3.4 Enamine promoted asymmetric α-amination In asymmetric α-amination, a carbonyl with an acidic α-hydrogen is attacked by an amine converting a carbonyl to an enamine. The enamine in situ attacks the electrophile, making the new bond. The presented example (Scheme 1.10) is the first direct catalytic asymmetric α- amination of aldehydes. 18 H O RO 2 C N N CO 2 R (S)-proline (10 mol%) CO 2 R OH CH 3 CN N CO N HO NH 2 R H then EtOH O NaBH 4 (S)-proline R = t-Bu: 97% yield, 92% ee R = Bn: 99% yield, 86% ee Scheme 1.10. First example of catalytic asymmetric direct α-amination aldehydes via enamine. 1.3.5 Enamine promoted asymmetric α-alkylation In α-alkylation, the enamine from a carbonyl can attack the electrophilic carbon of an alkyl halide. After pioneering many other asymmetric reactions, List (2004) reported the first catalytic OHC EtO 2 C EtO 2 C I asymmetric α-alkylation of aldehydes (Scheme 1.11). 19 N H OH (S)-α-methyl proline (10 mol%) Et 3 N (1.0 equiv), CHCl 3 −30 o C, 24h OHC EtO 2 C EtO 2 C Yield = 92% ee = 95% O (S)-α-methyl proline Scheme 1.11. First example of asymmetric α-alkylation of aldehydes via enamine. 9
Chapter 1 1.4 Asymmetric Michael additions Michael additions are an important carbon-carbon and carbon-heteroatom bond forming reaction in organic synthesis. The asymmetric versions offer a powerful tool for the synthesis of a variety of useful chiral functionalized organic molecules in an atom-economical manner. Over the past few years, a variety of classes of organocatalysts have been developed for enamine catalyzed asymmetric Michael additions of aldehydes or ketones to different Michael acceptors. Herein, I will focus on two different types of organocatalytic asymmetric Michael reactions, specifically the historical literature pertaining to: • Ketone (cyclohexanone and cyclopentanone) additions to nitroolefins; • α-substituted aldehyde additions to maleimides. Before going into details for the above two sections, I will present an overview of the organocatalysts examined in the field of asymmetric Michael additions. The next section contains a generic mechanism of bifunctional catalysis (section 1.4.1), followed by an overview of the commonly used catalyst templates (section 1.4.2, Table 1.1) used for asymmetric Michael additions. Based on the published literature, examples of catalysts are provided for each template category in section 1.4.2. For more details about catalyst loadings, starting material stechiometries, reaction times, yields, drs and ees, the readers will have to wait until section 1.4.3 and 1.4.4 (Table 1.2, 1.3,1.4). 10
Page 1 and 2: Bifunctional Organocatalysts Contai
Page 3 and 4: Acknowledgements I would like to co
Page 5 and 6: EtOAc GC h HPLC HRMS Hz IR J m M Me
Page 7 and 8: Abstract The asymmetric Michael add
Page 9 and 10: 1.5 Research goals: bifunctional ba
Page 11 and 12: Chapter 6. Spectra (HPLCs and NMRs)
Page 13 and 14: Chapter 1 1.1 Organocatalysis In pa
Page 15 and 16: Chapter 1 • Easy and promising pr
Page 17 and 18: Chapter 1 Scheme 1.5 shows a possib
Page 19: Chapter 1 O O O N R (S)-proline DMS
Page 23 and 24: Chapter 1 O R Michael product R' Ar
Page 25 and 26: Chapter 1 bifunctional catalysts st
Page 27 and 28: Chapter 1 proposed that the seconda
Page 29 and 30: Chapter 1 Ph NH 2 Ph N H S N H NH N
Page 31 and 32: Chapter 1 Amino-sulfoneamides N H 2
Page 33 and 34: Chapter 1 acetone with only 16% ee.
Page 35 and 36: Chapter 1 X X NH 2 COOK NH N Cl 46
Page 37 and 38: Chapter 1 O O O O O O S O 50 51 52
Page 39 and 40: Chapter 1 Summary for the asymmetri
Page 41 and 42: Chapter 1 4 25b 13 / 5 7 120 rt 63
Page 43 and 44: Chapter 1 Table 1.4: Summary for th
Page 45 and 46: Chapter 1 20 48a O H O O N Ph 15/10
Page 47 and 48: Chapter 1 References 1. Selected re
Page 49 and 50: Chapter 1 33. B. Tan, X. Zeng, Y. L
Page 51 and 52: Chapter 2 RESULTS AND DISCUSSION: D
Page 53 and 54: Chapter 2 enamine. Meanwhile, the p
Page 55 and 56: Chapter 2 2.3 Model reaction: cyclo
Page 57 and 58: Chapter 2 2.1, entry 3). THF and a
Page 59 and 60: Chapter 2 2.4 Asymmetric Michael ad
Page 61 and 62: Chapter 2 Table 2.4: Asymmetric Mic
Page 63 and 64: Chapter 2 Ph NH N H H N Ph NH 97 98
Page 65 and 66: Chapter 2 A final convincing argume
Page 67 and 68: Chapter 2 References 1. S. H. McCoo
Page 69 and 70: Chapter 3 3.1 Introduction Asymmetr
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Chapter 3 ineraction, as shown in S
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Chapter 3 CF 3 CF 3 O S O O H 2 N N
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Chapter 3 Table 3.2: Solvent screen
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Chapter 3 4 71 99 10 O t Bu-L-threo
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Chapter 3 Table 3.4: Asymmetric Mic
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Chapter 3 20 B H O O N Ph O 134 16
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Chapter 3 16 [b], [d] 1,2-dimethoxy
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Chapter 3 To better appreciate the
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Chapter 3 Ph Me O 3.20 tBuO Ph N N
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Chapter 3 Figure 3.4. Steric based
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Chapter 3 permit fundamentally diff
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Chapter 3 These combined results de
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Chapter 3 1 H NMR (400 MHz, CDCl 3
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Chapter 3 methyl group of the minor
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Chapter 3 Figure 3.13. Expansion fr
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Chapter 3 Please refer to α-ethyl
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Chapter 3 13 C NMR (100 MHz, CDCl 3
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Chapter 3 129.19, & 131.93 ppm repr
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Chapter 3 References 1. For the reg
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Chapter 3 19. The potassium complex
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Chapter 4 4.1 General information A
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Chapter 4 4.3 Racemate formation 4.
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Chapter 4 O NO 2 (S)-2-((R)-2-nitro
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Chapter 4 MS (EI), m/z (relative in
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Chapter 4 References 1. The two ena
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Chapter 5 5.1 General information R
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Chapter 5 5.2 Racemate formation To
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Chapter 5 The ee was determined by
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Chapter 5 (S)-1-(2,5-dioxo-1-phenyl
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Chapter 5 (S)-3-(benzo[d][1,3]dioxo
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Chapter 5 (S)-2,6-dimethyl-2-((S)-2
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Chapter 6 SPECTRA (HPLCs AND NMRs)
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Chapter 6 HPLC of 2,2,2-trifluoro-N
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Chapter 6 HPLC of 2-(2-nitro-1-p-to
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Chapter 6 HPLC of 2-(1-(furan-2-yl)
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Chapter 6 HPLC of 2,2-dimethyl-4-ni
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Chapter 6 HPLC of 3-(4-methoxypheny
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Chapter 6 140
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Chapter 6 142
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Chapter 6 144
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Chapter 6 146
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Chapter 6 148
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Chapter 6 150
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Chapter 6 HPLC of 2-(1-benzyl-2,5-d
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Chapter 6 HPLC of 1-(2,5-dioxo-1-ph
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Chapter 6 HPLC of 3-(benzo[d][1,3]d
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Chapter 6 HPLC of 2-methyl-2-(2,5-d
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Chapter 6 164
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Chapter 6 166
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Chapter 6 168
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Chapter 6 170
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Chapter 6 172
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Chapter 6 174
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Chapter 6 184
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Publication # 02 Sequential Reducti
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