Improved Methodology for the Preparation of Chiral Amines

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non-enantioselective pathways is diminished (scheme 1.9). Recently, a further decrease of catalyst loading to 10 mol % has been achieved by replacing water with isopropanol. R 1 R 2 R 3 OH tBuOOH, Ti(O i Pr) 4 L-(+)-DET, CH 2 Cl 2 ,-20 o C R 1 R 2 O OH R 3 70-90% yield 90-98% ee HO L-(+)-DET = HO COOEt COOEt Scheme 1.9. Enantioselective Epoxidation of Allylic Alcohols. The work of those great minds was rewarded with a Noble prize in 2001 by the Royal Swedish academy of sciences. 1.5.5. Asymmetric Synthesis vs Kinetic Resolution vs Chiral Pool: From the above discussions it can be concluded that each approach of the three major approaches has advantages and disadvantages. Resolution suffers from a major drawback which is the low yield of the desired product; the maximum obtainable yield is only 50% from the racemates. In case of Kinetic dynamic resolution utilizing enzymes or chiral catalysts the yield can be improved. The yield in the kinetic resolutions can be improved by fast conversion of the (S)-enantiomer into the racemic mixture and the (R)-enantiomer reacts preferably to form the desired product in high yield and ee. The ideal dynamic kinetic resolution reaction which approaches 100% conversion of 100% enantiomerically enriched product is the one in which krac>>kR>>kS (figure 1.4). If krac was in fact closer to or even slower than kR, the ee of the product would be lowered because the amount of (R) in solution would not be produced fast enough to make kS negligible. 18
k R R P 1 k rac S k S P 2 Figure 1.4. Reaction Constants for Dynamic Kinetic Resolution. 1.6. α-Chiral Amines Defining Terms: Amino compounds with a stereogenic centre at the position α-to the amino group are known as α-chiral amines. Ph NH 2 Ph Et NH 2 tBu NH 2 NH 2 COOtBu NH 2 NH2 NH 2 Figure 1.5 Examples of α-Chiral Amines. They can be addressed as chiral amine for simplicity and we will try to stick to this nomenclature throughout the whole thesis. Chiral amines are useful intermediates for alkaloid natural product synthesis, eg: morphine, codeine and tropane alkaloids. They are also incorporated in different block buster drugs as the billion dollar drugs, e.g. several ACE inhibitors and Flomax. [42] To understand the importance of this moiety in the asymmetric synthesis it is estimated that at least 40% of all optically active pharmaceutical drugs contain this moiety. Unfortunately, 19
Page 1 and 2: Improved Methodology for the Prepar
Page 3 and 4: This dissertation is dedicated to a
Page 5 and 6: suppressing alcohol formation and p
Page 7 and 8: Prof. Mohamed El-Azizi, Prof. Abdel
Page 9 and 10: Et EtOH EtOAc GC h HPLC HRMS Hz J K
Page 11 and 12: Table of Contents Abstract. Acknowl
Page 13 and 14: 4.1.5. Synthesis of Emitine 85 4.1.
Page 15 and 16: Chapter 1 Introduction 1.1. Chiral
Page 17 and 18: 1. Cis-trans or geometric isomers.
Page 19 and 20: O O O * NH Thalidomide (R)-active a
Page 21 and 22: One enantiomer may be responsible f
Page 23 and 24: 1.5.1. Synthesis of Enantiomericall
Page 25 and 26: 1.5.2.2. Kinetic Resolution Kinetic
Page 27 and 28: compound by the auxiliary. The auxi
Page 29 and 30: 1.5.4. Stereoselective Conversion o
Page 31: It is estimated that 3000 tonnes (a
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 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
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OMe OMe O HN HN HN O 2 N 71 % yield
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compared to the oil refinery indust
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[14] V. I. Tararov, R. Kadyrov, T.H
Page 93 and 94:
[55] a) R. Kadyrov, T. H. Riermeier
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Chapter 4 Drugs and Reductive Amina
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Scheme 4.2. Synthesis of Muraglitaz
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Studies showed that the active isom
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aminoacid producing the protected a
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O NH 2 1. p-TsOH/toluene 2. BH 3 -T
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O O 125 NH 2 a 93% O O 126 H Bu N T
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ethyl carbamate by acylation with e
Page 109 and 110:
4.1.16. Synthesis of Ritonavir and
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4.2. Conclusion Different important
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Chapter 5 Stoichiometric Use of Ytt
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The unique feature of this methodol
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Ytterbium triflate is the most comm
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Ruthenium(III) chloride 31.7 4 4.2
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t-Butyl methyl ether 15 - - 82 Hexa
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2-octanone starting material. When
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3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
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If a [1,3]-proton shift of the init
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enhanced stereoselectivity. For exa
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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
Page 169 and 170:
Research experience: Date Project S
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Improved Methodology for the Preparation of Chiral Amines

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