Improved Methodology for the Preparation of Chiral Amines

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1.8. α-Chiral Amine Synthesis Different Methodologies As mentioned previously chiral amines are key components of different pharmaceutical and agrochemical compounds. Over the last fifty years different methodologies have been developed for their synthesis. Some of the methodologies are industrially viable and others are better suited for pilot studies. Of course for a methodology to be applicable on industrial; scale it must fulfil certain features e.g. should be cost effective and waste generation should be low. Some processes are highly efficient in preparing chiral amines in high yield and stereoselectivity. Despite their efficiency they suffer mainly from major drawbacks as lengthy multistep procedures which hinder their applications on industrial scale. Among the versatile strategies employed is the hydrogenation of enamine esters (diastereo and enantioselective), [61] hydrogenation of α- or β-N-acetylenamide esters, [62] 1,4-addition of amines to enones, [63] Chemical, [64] and enzymatic [65] reductive amination of α- ketoacids, remote amination via C-H insertion [66] and hydroamination of olefins. [67] Reduction of unfunctionalized ketones and aldehydes is one of the major strategies for the synthesis of chiral amines. This strategy can be subdivided into various subdivisions which includes the following. 1) N-acetylenamide reduction. 2).Transfer hydrogenation or hydrogenation of imines 3). Reductive amination of ketones 4) Carbanion addition to aldimine and ketimine derivatives. 5) Sequential aminationalkylation of aldehydes. The first three methodologies are closely related as they use hydrogen from different hydride sources for the reduction of prochiral carbonyl compounds. The asymmetric version of these methodologies has been developed extensively over the past few years. N-acetylenamide reduction and transfer hydrogenation or hydrogenation of imines will be discussed in details trying to shed light on their advantages and disadvantages and their applications. Reductive amination as the core of my work will be discussed showing its historical development over the last century and the major breakthroughs in the field during the last two decades. The application of reductive amination in pharmaceutical industry will be summarized in the 22
fourth chapter showing different drug and natural product categories prepared utilizing reductive amination. 1.8.1. Imine and Enamide Synthesis A discussion about the preparation of imine and enamide are necessary as most of the examples in scientific journals focus mainly on the manipulation of imines (Nphosphinoylimines) or N-acyl enamines as starting materials without a clear picture about their preparations. The overall yield of the chiral amine products is very rarely discussed and therefore a perspective in this regard needs to be established. R O R' NH 2 OH HCl MeOH R NOH R' Fe powder NHAc Ac 2 O AcOH. Toluene, 75 o C R R' Scheme 1.10 Synthesis of N-Acyl Enamide from Ketone The commonly used method of enamide [68] synthesis is the one in which the desired compound is synthesized from different substituted ketones in two steps as carried out by Burk (scheme 1.10). [69] In the first step of this synthesis the ketone is converted to an oxime with hydroxylamine hydrochloride in MeOH, the yield of the ketoxime is generally >90%. The next step is the interaction of the resultant ketoxime with Iron powder and acetic anhydride with AcOH in toluene at a temperature of 75 °C. The yield of the enamide is generally between 30-60% in this step. [70] In general the enamide synthesis methodology is low yielding process. Besides the possibility of diacetyl formation which is considered another drawback. The E/Z mixtures which are obtained with R’ -as non-hydrogen atom- are difficult to separate. 1.8.2. Enantioselective Reduction of Enamides 23
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 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: (S)-(α)-Methylbenzylamine and its
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
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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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