Reductive amination is a step powerful methodology <strong>for</strong> <strong>the</strong> syn<strong>the</strong>sis <strong>of</strong> α-chiral amines. The correct choice <strong>of</strong> Lewis acid is critical <strong>for</strong> efficient suppression <strong>of</strong> alcohols. The diastereoselectivity obtained with or without <strong>the</strong> use <strong>of</strong> Lewis acids was <strong>the</strong> same. No precedent <strong>of</strong> increasing diastereoselectivity in reductive amination with <strong>the</strong> use <strong>of</strong> achiral Lewis acid was ever reported. The use <strong>of</strong> Yb(OAc) 3 in reductive amination resulted in a significant increase in diastereoselectivities <strong>for</strong> different 2-alaknones. Diastereoselectivity <strong>of</strong> 2-octanone increased 15% compared to <strong>the</strong> highest reported result. Aromatic and cyclic ketones were not successfully reductively aminated using Yb(OAc) 3 . Ti(O i Pr) 4 proved to be <strong>the</strong> best Lewis acid in reductive amination <strong>of</strong> <strong>the</strong>se substrates. 5.3. References: [1] a) H. Lebel, K. Huard, Org. Lett. 2007, 9, 639; b) M. Kim, J. V. Mulcahy, C. G. Espino, J. Du Bois, Org. Lett. 2005, 7, 4685; c) C. G. Espino, K. W, Fiori, M. Kim, J. Du Boisn, J. Am. Chem. Soc. 2004, 126, 15378. [2] a) J. Blacker, Innovations in Pharmaceutical Technology 2001, 1, 77; b) H. -U. Blaser, F. Spindler, A. Studer, App. Catal. Gen. 2001, 221, 119; c) H. -U. Blaser, M. Eissen, P. F. Fauquex. K. Hungerbuhler, E. Schmidt, G. Sedelmeier, M. Studer, Asymmetric Catalysis on Industrial Scale: Challenges, Approaches, and Solutions; H.-U. Blaser, E. Schmidt Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2004. [3] T. C. Nugent, <strong>Chiral</strong> Amine Syn<strong>the</strong>sis - Strategies, Examples, and Limitations. In Process Chemistry in <strong>the</strong> Pharmaceutical Industry, Second Edition: Challenges in an Ever-Changing Climate, T. F. Braish, K. Gadamasetti Eds.; CRC Press-Taylor and Francis Group: New York, 2008. [4] a) L. Storace, L. Anzalone, P. N. Confalone, W. P. Davis, J. M. Fortunak, M. Giangiordano, J. J. Haley, Jr., K. Kamholz, H.-Y. Li, P. Ma, W. A. Nugent, R. L. Parsons, Jr., P. J. Sheeran, C. E. Silverman, R. E. Waltermire, C. C. Wood, Org. Process Res. Dev. 2002, 6, 54; b) E. Juaristi, J. L. León-Romo, A. Reyes, J. Escalante, Tetrahedron: Asymmetry 1999, 10, 2441; c) G. Lauktien, F. -J. Volk, A. W. Frahm, Tetrahedron: Asymmetry 1997, 8, 3457; d) B. Speckenback, P. Bisel, A. W. Frahm, Syn<strong>the</strong>sis 1997, 1325. [5] a) T. C. Nugent, A. K. Ghosh, V. N. Wakchaure, R. R. Mohanty, Adv. Synth. Catal. 2006, 348, 1289; b) T. C. Nugent, A. K. Ghosh, V. N. Wakchaure, R. R. Mohanty, 116
WO2006030017, 2006; c) T. C. Nugent, V. N. Wakchaure, A. K. Ghosh, R. R. Mohanty, Org. lett. 2005, 7, 4967; d) T. C. Nugent, A. K. Ghosh, Eur. J. Org. Chem. 2007, 3863. [6] P. Patnaik, Handbook <strong>of</strong> Inorganic Chemicals, McGraw-Hill Companies, 2003, PP 973- 975. [7] E. Keller, B. L. Feringa, Tetrahedron Lett. 1996, 37,1882. [8] S. Sinha, B. Mandal, S. Chandrasekaran, Tetrahedron Lett. 2000, 41, 9109. [9] R. J. Lu, D. Liu, R. W. Giese, Tetrahedron Lett. 2000, 41, 2817. [10] A. Janczuk, W. Zhang, W. Xie, S. Lou, J. P. Chengb, P. G. Wang, Tetrahedron Lett. 2002, 43, 4271. [11] I. Nakamura, M. Kamada, Y. Yamamoto, Tetrahedron Lett. 2004, 45, 2903. [12] L.-M. Wang, J. Sheng, L. Zhang, J.-W. Han, Z.-Y. Fan, H. Tiana, C.-T. Qianb, Tetrahedron 2005,61,1539. [13] L.-M. Wang, Y.-H.Wang, H. Tian, Y.-F. Yao, J.-H. Shao, B. Liu, J. Fluorine Chem. 2006, 127, 1570. [14] M. Asadullah, Y.Taniguchi, T. Kitamura, Y. Fujiwara, Appl. Organometal. Chem. 1998, 12, 277. [15] T. Yokko, K. Matsumoto, K. Oshima, K. Utimoto, Chemistry Letters 1993, 571. [16] (a) G. Cainelli, D. Giacomini, A. Trerè, P. P. Boyl, J. Org. Chem. 1996, 61, 5139. (b) J. G. H. Willems, J. G. de Vries, R. J. M. Nolte, B. Zwanenburg, Tetrahedron Lett. 1995, 36, 3917. (c) V. A. Soloshonok, A. G. Kirilenko, S. V. Galushko, V. P. Kukhar, Tetrahedron Lett. 1994, 35, 5063. [17] N. Moss, J. Gauthier, J. –M. Ferland, Synlett 1995, 142. 117
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Improved Methodology for the Prepar
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This dissertation is dedicated to a
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suppressing alcohol formation and p
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Prof. Mohamed El-Azizi, Prof. Abdel
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Et EtOH EtOAc GC h HPLC HRMS Hz J K
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Table of Contents Abstract. Acknowl
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4.1.5. Synthesis of Emitine 85 4.1.
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Chapter 1 Introduction 1.1. Chiral
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1. Cis-trans or geometric isomers.
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O O O * NH Thalidomide (R)-active a
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One enantiomer may be responsible f
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1.5.1. Synthesis of Enantiomericall
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1.5.2.2. Kinetic Resolution Kinetic
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compound by the auxiliary. The auxi
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1.5.4. Stereoselective Conversion o
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It is estimated that 3000 tonnes (a
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k R R P 1 k rac S k S P 2 Figure 1.
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(S)-(α)-Methylbenzylamine and its
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fourth chapter showing different dr
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Burk was successful in reducing ary
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Table 1.1 Rhodium Catalyzed Reducti
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[8] E. L. Eliel, S. H. Wilen, Stere
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[42] a) J. Blacker, Innovations in
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[67] a) H. Qin, N. Yamagiwa, S. Mat
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of imine reduction in the past eigh
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8 years beginning from the year 200
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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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