Improved Methodology for the Preparation of Chiral Amines

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illion) in 1996, 29% (1997), 30% (1998), 32% (1999), 34% (2000), 38% (2001) to an estimate of 39% (US $151.9 billion) in 2002. [24] 1.4. Chirality and Drug-Receptor Interaction As mentioned before biological systems are based on chirality. For example, enzymes are considered as chiral biological polymers consisting of solely L-amino acids. They are highly structured compounds: their secondary and tertiary structure is determined by the amino acid constituents. Enzymes function as molecular receptors by binding selectively to specific molecules. Due to their chirality, they commonly interact much stronger with one enantiomer of the ‘target’ molecule; or what is known as chiral recognition. ‘lock-and-key’ concept was introduced in 1894 by Fischer to explain enzyme selectivity. This simple concept sates that one enantiomer ‘fits’ in the enzyme cavity, the other enantiomer does not. This concept was reformulated later to more complicated model (three point model). [25] To get a high degree of enantioselection, a substrate must be held firmly in three dimensional space. There must be at least three different points of attachment of the substrate onto the active site. Variations and refinements to this rule have been reported. The most important one is that the interactions may be attractive or repulsive. Steric hindrance often plays an important role in chiral recognition.Chirality has also an important role in the field of fine chemical industry. Large applications are found in agrochemicals, food and fragrance industry. There are handful examples of enantiomers showing different fragrances because one is (R) and one is (S). For a chiral herbicide from the class of α-aryloxypropionic acids, the activity is present almost solely in the (R) enantiomer. Although currently most herbicides are applied as racemates, attempts towards the development of convenient large scale methodologies for the synthesis of herbicides were awarded by development of metalochlor. This trend will result in 50% reduction of dosage, which means 50% less environmental pollution. 1.5. Sources of Enantiopure Substances 8
1.5.1. Synthesis of Enantiomerically Pure Compounds The importance of chiral compounds and the strong need for enantiomerically pure substances has led to develop versatile methodologies to meet this objective. There are three main approaches for the preparation of chiral compounds as shown in figure 1.2: 1.Resolution of racemates; 2.Chiral pool approach; 3. Stereoselective conversion of prochiral substrates to enantiopure compounds (asymmetric synthesis via catalytic or stoichiometric process). Racemates Chiral Pool Prochiral Substrates Preferential Crystalization Kinetic Resolution Diastereomer Crystallization Synthesis Asymmetric Synthesis Chemical Enzymatic Figure 1.2. Sources of Enantiopure Substances. 1.5.2. Resolution Resolution technique is the most classical route to enantiopurity. Although it has many drawbacks and recently it has been overtaken by asymmetric synthesis, this method is still persisted with numerous examples on the industrial scale till present days. Resolution can be subdivided into three main techniques. 1.5.2.1. Preferential Crystallization Preferential crystallization is possible for racemates which form conglomerates. The conglomerates are mechanical mixtures of enantiomerically pure crystals of one enantiomer 9
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: One enantiomer may be responsible f
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 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
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O NHR 3 R 4 R 4 R 3 N OTi(O i Pr) 3
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Scheme 3.9. Synthesis of (S)-Metola
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groups decreased both the enantiose
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progress of the reaction was monito
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attempts were directed for the asym
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hydrogen bonding, is chiral and its
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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
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[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
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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
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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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