Improved Methodology for the Preparation of Chiral Amines

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It should be clear that the term chiral drug does not indicate that the drug is marketed as a single isomer it may be a racemic or unequal mixture of isomers. Through investigating the origin of chirality it was revealed that the concept was introduced long ago. Archimedes designed Archimedean water screw and studied its chiral structure. Dominique Arge (1811) discovered the rotation of plan polarized light in quartz crystal. Later the French chemist Jean Baptiste Biot was the first to introduce the modern concept of chirality when he discovered rotation of light in a sugar solution. [5] The major breakthrough in understanding the concept of chirality and its significance in chemistry was achieved by Louis Pasteur through recrystallization of sodium ammonium tartrate (optically inactive). He noticed that the crystals were of two types which he physically separated. The two types of crystals were optically active, but rotated the plane of polarized light in the opposite directions. He proposed that the molecules came in two forms, “left handed” and “right handed”. Together, the mixture of the two forms is optically inactive. This finding prompted his famous statement that the universe is chiral (l’univers est dissymme´trique). [6] Later Van’t Hoff, a Dutch young scientist proposed that the carbon atom is attached to four different substituents in space having a tetrahedral arrangement. This proposition was faced by strong opposition from scientists all over the world. Later they discovered that his proposed shape of the molecule was absolutely right and he was awarded the first noble prize in chemistry for his work. [7] Chirality is manifested by centre of dissymmetry, but it can also be represented in axes or planes of dissymmetry. [8] 1.2. Isomers and Isomerism Isomerism is the phenomenon of two or more compounds having the same number and kind of atoms. [9] Isomers can be subdivided into structural isomers, the difference between isomers is due to a different structural arrangements of the atoms that form molecules, e.g. butane and isobutene. The other division is stereoisomers, the isomers have the same structural formula, but differ in the spatial arrangement of atoms. [9] There are two types of stereoisomers: 2
1. Cis-trans or geometric isomers. 2. Optical isomers Optical isomers have the ability to rotate plane-polarized light. [8] Enantiomers are part of the optical isomers, together with diastereomers. Enantiomers are mirror image optical isomers having only one chiral centre. Enantiomers posses the same physical properties but they differ in their biochemical properties. They behave differently only in a chiral medium, such as when exposed to a polarized light or when participating in a chemical reaction catalyzed by a chiral catalyst, particularly an enzyme in the body. (+)-Glucose (“blood sugar”) is used for metabolic energy whereas (-)-glucose is not. (+)-Lactic acid is produced by reactions occurring in muscle tissue, and (-)-lactic acid is produced by the lactic acid bacteria in the souring of milk. Diastereomers are non mirror image optical isomers having more than chiral centre. Diastereomers have different physical properties allowing their separation. Enantioselectivity and diastereoselectivity are terms used to express the preferential formation of one enantiomer or diastereomer over the other and it is normally expressed as an enantiomeric excess (ee) or diastereomeric excess (de). ee (%) = R(%) - S(%) R(%) + S(%) + 100 de (%) = D 1 (%) - D 2 (%) D 1 (%) + D 2 (%) + 100 1.3. Nature is Chiral Many naturally occurring substances possess chirality, which is the property that a substance and its mirror image are not superimposable. [10] In every-day life, many examples can be found as well. Human hands are perhaps the most universally-recognized example of chirality. The left hand is a non-superimposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands to coincide. [11] In particular life depends on molecular chirality, with many biological functions/processes inherently based on the interaction of dissymmetric molecules. Many physiological phenomena arise from highly preferential molecular interactions in which a chiral host 3
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: Chapter 1 Introduction 1.1. Chiral
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 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
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Chapter 3 Reductive Amination 3.1.
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. CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 C
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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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