Improved Methodology for the Preparation of Chiral Amines

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[67] a) R. A. Sheldon, Chemtech 1994, 38; b) R. A. Sheldon, J. Chem. Technol. Biotechnol. 1997, 68, 381; c) R. A. Sheldon, J. Mol. Catal. A: Chemical 1996, 107, 75; d) R. A. Sheldon, Pure Appl. Chem. 2000, 72, 1233. [68] a) D. A. Cogan, G. Liu, J. Ellman, Tetrahedron Lett. 1999, 55, 8883; b) D. A. Cogan, J. A. Ellman, J. Am. Chem. Soc. 1999, 121, 268; c) L. C. Akullian, M. L. Snapper, A. H. Hoveyda, Angew. Chem., Int. Ed. 2003, 42, 4244; d) L. C. Akullian, J. R. Porter, J. F. Traverse, M. L. Snapper, A. H. Hoveyda, Adv. Synth. Catal. 2005, 347, 417; e) A. Côté, A. B. Charette, J. Org. Chem. 2005, 70, 10864. 80
Chapter 4 Drugs and Reductive Amination 4.1 Reductive Amination in the Synthesis of Drugs and Natural Products: Different natural products and pharmaceutical drugs contain amino group as an important part of their structure. Of course some drugs are still sold as racemic compounds but the latest trend over the past three decades is to design, develop and market new drug entities as a single isomeric form. Amino group can be introduced in the drug entity through different strategies one of these strategies is reductive amination. Older reports describing the synthesis of natural products and pharmaceutical drugs utilizing reductive amination did not involve any source of chirality resulting in the synthesis of racemic product. Recent literatures focused on utilizing the asymmetric versions of reductive amination for the synthesis of enantiopure compounds. I will try to give a brief overview on the potential applications of this powerful methodology in the synthesis of natural products and pharmaceutical drugs. We will try also to show the relevance of our developed strategy for the efficient synthesis of these entities. 4.1.1. Synthesis of Delavirdine: This compound is a member of nonnucleoside HIV-1 reverse transcriptase inhibitors. [1] This class of compounds was discovered by Upjohn scientists from a computer-directed dissimilarity analysis of the Pharmacia & Upjohn chemical library to select compounds for screening against HIV-1 reverse transcriptase. Synthesis of this compound starts with the addition of piperazine (20) to chloropyridine (21). The nitro group is reduced to the amino group and the resultant amine undergoes reductive amination with acetone to provide pyridylpiperazine (23). Coupling of (23) with 6-nitroindole-2-carboxylic acid (24) is accomplished using either 1-ethyl-3-(dimethylamino) propylcarbodiimide (EDC) or 1,10- 81
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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
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It is estimated that 3000 tonnes (a
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k R R P 1 k rac S k S P 2 Figure 1.
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(S)-(α)-Methylbenzylamine and its
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fourth chapter showing different dr
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Burk was successful in reducing ary
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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 and 82: attempts were directed for the asym
Page 83 and 84: hydrogen bonding, is chiral and its
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: [55] a) R. Kadyrov, T. H. Riermeier
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
Page 133 and 134: 4 60 86 5 50 86 6 40 84 7 20 79 8 2
Page 135 and 136: The reactions described above all u
Page 137 and 138: e.g. compare entries 1, 5, 6, and 9
Page 139 and 140: solvent in the stoichiometric and c
Page 141 and 142: [2] Farina, V.; Grozinger, K.; Mül
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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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