Improved Methodology for the Preparation of Chiral Amines

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library of organocatalysts which were used efficiently for different organic transformations. Several research groups focused their efforts on the synthesis of novel organocatalysts for asymmetric imine reduction and reductive amination. Among these transformations are imine reduction and reductive amination. At this time, development in the application of organocatalysis for reductive amination is still in its infantile stage compared to other transformations. [56] X +2 [H] H X ∗ chiral catalyst R 1 X=CR 2 ,O,NR R 1 R 2 R 2 Scheme 3.17. Asymmetric Reduction of prochiral Compounds. Inspired by nature and how living organisms reduce imino group through the employment of organic dihydropyridine cofactors such as nicotinamide adenine dinucleotide (NADH) in combination with enzyme catalysts (figure 3.2). [57] H H O NH 2 . - O O O P O O P O - O N H H O H H OH OH O H HAdenine O H H OH OH reduced nicotinamide adenine dinucleotide (NADH) Figure 3.2. Reduced Nicotinamide Adenine Dinucleotide Scientists started to think of NADH analogues and they found that the best analogues would be Hantzsch esters. These hydrogen sources in the presence of achiral Lewis or Brønsted acid catalysts proved to be efficient in imine reduction. [58] List investigated the catalytic cycle of reductive amination utilizing Hantzsch esters. He proposed that reductive amination of ketones is initiated by protonation of the in situ generated ketimine from a chiral Brønsted acid catalyst (Scheme 3.18). The resulting iminium ion pair, which may be stabilized by 68
hydrogen bonding, is chiral and its reaction with the Hantzsch dihydropyridine could give an enantiomerically enriched amine and pyridine. After screening different phosphoric acid catalysts, catalyst 9 was found to be the best catalyst for this reaction and 1.0 mol% of the catalyst resulted in 93% ee for the product with an excellent yield of 96% (scheme 3.19). [59] OMe OMe O +PMPNH 2 -H 2 O N HN X* EtOOC N H COOEt HN PMP H HX* H 2 N H X* OMe EtOOC N COOEt Scheme 3.18. Mechanism of Chiral Brønsted Acid Catalysed Reductive Amination. O 9(1mol%),toluene,35 o C,71h, 98% HN PMP EtOOC COOEt N H (1.4 equiv) 93% ee i-Pr i-Pr O O i-Pr P O i-Pr OH i-Pr i-Pr 9 Scheme 3.19. Organocatalytic Reductive Amination Developed by List. List also investigated the reductive amination of aldehydes. He proposed that under the conditions of reductive amination an α-branched aldehyde substrate would undergo a fast racemization in the presence of the amine and acid catalyst via an imine/enamine tautomerization. The reductive amination of one of the two imine enantiomers would then 69
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Improved Methodology for the Prepar
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This dissertation is dedicated to a
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suppressing alcohol formation and p
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Prof. Mohamed El-Azizi, Prof. Abdel
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Et EtOH EtOAc GC h HPLC HRMS Hz J K
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Table of Contents Abstract. Acknowl
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4.1.5. Synthesis of Emitine 85 4.1.
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Chapter 1 Introduction 1.1. Chiral
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1. Cis-trans or geometric isomers.
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O O O * NH Thalidomide (R)-active a
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One enantiomer may be responsible f
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1.5.1. Synthesis of Enantiomericall
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1.5.2.2. Kinetic Resolution Kinetic
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compound by the auxiliary. The auxi
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1.5.4. Stereoselective Conversion o
Page 31 and 32: It is estimated that 3000 tonnes (a
Page 33 and 34: k R R P 1 k rac S k S P 2 Figure 1.
Page 35 and 36: (S)-(α)-Methylbenzylamine and its
Page 37 and 38: fourth chapter showing different dr
Page 39 and 40: Burk was successful in reducing ary
Page 41 and 42: Table 1.1 Rhodium Catalyzed Reducti
Page 43 and 44: [8] E. L. Eliel, S. H. Wilen, Stere
Page 45 and 46: [42] a) J. Blacker, Innovations in
Page 47 and 48: [67] a) H. Qin, N. Yamagiwa, S. Mat
Page 49 and 50: of imine reduction in the past eigh
Page 51 and 52: 8 years beginning from the year 200
Page 53 and 54: 2.2.3. Nguyen Special Substrates. A
Page 55 and 56: Figure 2.4 General Catalyst structu
Page 57 and 58: 2.3.2. Different Substrates Categor
Page 59 and 60: H 2 , toluene, 25 °C, 4 h an ee of
Page 61 and 62: 1). They described the role of each
Page 63 and 64: More recently, 2008, he described t
Page 65 and 66: [22] E. Guiu, M. Aghmiz, Y. Diaz, C
Page 67 and 68: Chapter 3 Reductive Amination 3.1.
Page 69 and 70: . CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 C
Page 71 and 72: superior in terms of conversion (89
Page 73 and 74: O NHR 3 R 4 R 4 R 3 N OTi(O i Pr) 3
Page 75 and 76: Scheme 3.9. Synthesis of (S)-Metola
Page 77 and 78: groups decreased both the enantiose
Page 79 and 80: progress of the reaction was monito
Page 81: attempts were directed for the asym
Page 85 and 86: Later he utilized this methodology
Page 87 and 88: OMe OMe O HN HN HN O 2 N 71 % yield
Page 89 and 90: compared to the oil refinery indust
Page 91 and 92: [14] V. I. Tararov, R. Kadyrov, T.H
Page 93 and 94: [55] a) R. Kadyrov, T. H. Riermeier
Page 95 and 96: Chapter 4 Drugs and Reductive Amina
Page 97 and 98: Scheme 4.2. Synthesis of Muraglitaz
Page 99 and 100: Studies showed that the active isom
Page 101 and 102: aminoacid producing the protected a
Page 103 and 104: O NH 2 1. p-TsOH/toluene 2. BH 3 -T
Page 105 and 106: O O 125 NH 2 a 93% O O 126 H Bu N T
Page 107 and 108: ethyl carbamate by acylation with e
Page 109 and 110: 4.1.16. Synthesis of Ritonavir and
Page 111 and 112: 4.2. Conclusion Different important
Page 113 and 114: Chapter 5 Stoichiometric Use of Ytt
Page 115 and 116: The unique feature of this methodol
Page 117 and 118: Ytterbium triflate is the most comm
Page 119 and 120: Ruthenium(III) chloride 31.7 4 4.2
Page 121 and 122: t-Butyl methyl ether 15 - - 82 Hexa
Page 123 and 124: 2-octanone starting material. When
Page 125 and 126: 3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
Page 127 and 128: If a [1,3]-proton shift of the init
Page 129 and 130: enhanced stereoselectivity. For exa
Page 131 and 132: WO2006030017, 2006; c) T. C. Nugent
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4 60 86 5 50 86 6 40 84 7 20 79 8 2
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The reactions described above all u
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e.g. compare entries 1, 5, 6, and 9
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solvent in the stoichiometric and c
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[2] Farina, V.; Grozinger, K.; Mül
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congested which should be favored.
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imine area % (GC analysis) time (mi
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Inversion at the nitrogen atom of t
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anti-6) would be expected to have m
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e.g. AcOH, suppresses alcohol by-pr
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eductive amination of a prochiral k
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Appendix Experimental Section Gener
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and the mixture was stirred for 30
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Reaction details: Yb(OAc) 3 (1.1 eq
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etention time [min]: major (S,S)-2b
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time [min]: major (S,S)-2c isomer,
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obtain the hydrochloride salt (0.41
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with etheral HCl provided the hydro
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Research experience: Date Project S
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Improved Methodology for the Preparation of Chiral Amines

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