Improved Methodology for the Preparation of Chiral Amines

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Acknowledgement All the work reported in this thesis have been carried out at the Department of Chemistry, School of Engineering and Science, Jacobs University, Bremen, Germany since joining here on August 2006 till August 2009. I would like to thank Jacobs University for the financial support and all the laboratory facilities during my stay here. In this regard I would like to thank Prof. Dr. h. c. Bernhard Kramer for approving my PhD scholarship. I would like to convey my kind regards to my supervisor Prof. Thomas C. Nugent and thank him for all his kind suggestions and deeply appreciate his skillful guidance throughout my research. It was due to his relentless efforts that I could master the various techniques and learn to solve the different scientific challenges that came by my way. Lastly, I would also acknowledge his patience and kind understanding. I would thank Prof. Nikolai Kuhnert for his kind consent to become the internal examiner of this thesis. I would also thank Dr. Pralhad Ganeshpure, Research Centre, Indian Petrochemicals Corporation Limited, 391 346 Vadodara, India (B-21, Kinnari Duplex Ellora Park, Vadodara, Gujarat 390023, India) for his kind consent to become the external examiner of this thesis. My sincere appreciation goes to all my lab mates, Dr. Rashmi R. Mohanty, Dr. Vijay N. Wakchaure, Dr. Abhijit Ghosh, Ahson J. Shaikh, Mohammad Naveed Umar, Mohammad Shoaib, A. Alvaradomendez, Abdul Sadiq, Dan Hu, Ahtaram Bibi, Satish Wakchaure, Andrei Dragan, Andrei Iosub and Daniela Negru for their constant help and encouragement in all respect. I would also thank Mrs. Müller for her continuous help. All my deepest veneration goes to my parents for everything that they have given to me. I would convey my regards to my sister and all my uncles and aunts for their constant support. I would also thank all professors and colleagues in Egypt. Especially I would like to thank iii
Prof. Mohamed El-Azizi, Prof. Abdel-Nasser Singab and Prof. Nahla Ayoub for their support and help over the past years. I would like to thank all friends at Jacobs University, Iyad Tumar, Khaled Hassan, Dr. Raed Mesleh, Mohamed Noor, Hamdy El-Sheshtawy, Salahaldin Juba, Ahmed Moussa, Ahmed El- Moasry, Hany Elgala and all other friends in Germany and Egypt for their continuous support , , iv
Page 1 and 2: Improved Methodology for the Prepar
Page 3 and 4: This dissertation is dedicated to a
Page 5: suppressing alcohol formation and p
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
Page 55 and 56: Figure 2.4 General Catalyst structu
Page 57 and 58:
2.3.2. Different Substrates Categor
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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
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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
Page 113 and 114:
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
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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
Page 167 and 168:
with etheral HCl provided the hydro
Page 169 and 170:
Research experience: Date Project S
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