Improved Methodology for the Preparation of Chiral Amines

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Abstract The importance of α-chiral amines as building blocks in pharmaceutical drugs, natural products, fine chemicals and agrochemicals have encouraged scientists to develop different methodologies for their preparation. Their main goal was to develop a step wise efficient and low waste production methodology which utilizes inexpensive starting material for the synthesis of α-chiral amines in high yields and enantioselectivity. Different methodologies have been developed aiming to meet these criteria. These strategies are discussed and their importance and limitations are critically analyzed. Reductive amination is a powerful methodology for the synthesis of chiral amines in high yields and enantioselectivity. It is a two step strategy beginning from the prochiral carbonyl compound to the primary chiral amine. The historical development and the latest milestones in this field are discussed in chapter three. Different drugs and natural products which are prepared utilizing reductive amination as a key step in their synthesis are summarized in chapter four. Reductive amination utilizing chiral auxiliary/Lewis acid/ heterogeneous catalyst/ molecular hydrogen has been investigated in our group over the last five years. This combination allowed the preparation of alkyl-alkyl’ α-chiral amines in mediocre to good yields and enantioselectivities. This group of amines is known historically to be difficult synthetic task. We developed a new asymmetric reductive amination procedure using Yb(OAc) 3 (50-110 mol %) that allows increased diastereoselectivity (6-15% units) for alkyl-alkyl’ α-chiral amines that previously only provided mediocre to good diastereoselectivity. Different Lewis acids were tested under different reaction conditions of temperature, pressure and solvents and the results of these experiments are discussed in chapter five. 1d O + H 2 N Ph (S)-α-MBA Yb(OAc)3 ,MeOH-THF Raney-Ni, H 2 (120 psi) (S,S)-2d HN Ph Pd-C (S)-3d NH 2 H 2 (60 psi) 86% de 85% ee The use of catalytic Lewis acids in reductive amination has never been reported in literatures. We demonstrated the beneficial use of 10-15 mol % of Yb(OAc) 3 or Ce(OAc) 3 or Y(OAc) 3 in i
suppressing alcohol formation and promoting reductive amination in good yield but without enhanced stereoselectivity. Despite the fact that the use of Brønsted acids in reductive amination is well established no literature reports are available. We have performed and extensive study on the use of commercially available Brønsted and mineral acids in reductive amination. The scope of the reaction and the substrate categories are summarized in chapter six. A mechanism for the reaction has been proposed and the basic mechanistic experiments have been performed. An in situ cis- to trans-ketimine isomerization mechanism, promoted by Yb(OAc) 3 , has been proposed to account for the observed increase in diastereoselectivity. The experiments and the proposed mechanism are summarized in chapter seven ii
Page 1 and 2: Improved Methodology for the Prepar
Page 3: This dissertation is dedicated to a
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 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
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Figure 2.4 General Catalyst structu
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2.3.2. Different Substrates Categor
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H 2 , toluene, 25 °C, 4 h an ee of
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1). They described the role of each
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More recently, 2008, he described t
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[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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