Improved Methodology for the Preparation of Chiral Amines

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q Raney-Ni Ref. Rh-C s t t-Bu tert temp TFA THF TLC TMS Ts TsOH tBuLi Ti(O i Pr) 4 Quartet ( 1 H-NMR) Raney-Nickel Reference Rhodium on carbon Singlet ( 1 H-NMR) Triplet ( 1 H-NMR) tert-Butyl Tertiary Temperature Trifluoroacetic acid Tetrahydrofuran Thin layer chromatography Trimethylsilane Tosyl p-Toluenesulfonic acid tert-Butyllithium Titanium(IV) isopropoxide vii
Table of Contents Abstract. Acknowledgment. List of Abbreviations. i ii v 1. Introduction to Chirality 1.1. Chiral Drugs 1 1.2. Isomers and Isomerism 2 1.3. Nature is Chiral 3 1.4. Chirality and Drug-Receptor Interaction 8 1.5. Sources of Enantiopure Substances 8 1.5.1. Synthesis of Enantiomerically Pure Compounds 9 1.5.2. Resolution 9 1.5.2.1. Preferential Crystallization 9 1.5.2.1. Diastereomer Crystallization 10 1.5.2.2. Kinetic Resolution 11 1.5.3. Chiral Pool Approach 12 1.5.4. Stereoselective Conversion of Prochiral Substrates to Enantiopure Compounds (Asymmetric Synthesis) 15 1.5.5. Asymmetric Synthesis vs Kinetic Resolution vs Chiral Pool 18 1.6. α-Chiral Amines Defining Terms 19 1.7. α-Chiral Amines Importance 20 1.8. α-Chiral Amine Synthesis Different Methodologies 22 1.8.1. Imine and Enamide Synthesis 23 1.8.2. Enantioselective Reduction of Enamides 23 1.9. Conclusion 28 1.10. References 28 2. Imine Reduction 2.1. Historical View 34 2.2. Asymmetric Reduction of N-Phosphinoyl Imines 35 2.2.1. Synthesis of N-Phosphinoyl Imines 35 viii
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: Et EtOH EtOAc GC h HPLC HRMS Hz J K
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
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
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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
Page 89 and 90:
compared to the oil refinery indust
Page 91 and 92:
[14] V. I. Tararov, R. Kadyrov, T.H
Page 93 and 94:
[55] a) R. Kadyrov, T. H. Riermeier
Page 95 and 96:
Chapter 4 Drugs and Reductive Amina
Page 97 and 98:
Scheme 4.2. Synthesis of Muraglitaz
Page 99 and 100:
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
Page 133 and 134:
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
Page 147 and 148:
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
Page 167 and 168:
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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