Improved Methodology for the Preparation of Chiral Amines

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Chapter 7 Stereochemical Considerations of Proposed Mechanistic Models 7.1. Introduction. The outstanding diastereoselectivities reported for different amines using stoichiometric quantities of Yb(OAc) 3 and the application of catalytic quantities of Lewis acids for first time in reductive amination of prochiral ketones were the driving force for investigating the mechanistic aspects behind this effect. It is known historically that the imine conformation plays the major role in determining the stereochemical outcome of reductive amination. Analyzing transition state structures for trans-and cis imines which controls the facial selectivity during addition of hydrogen to the imine allows the prediction of which diastereomer will be formed in excess (figure 7.1). Diastereomeric excess of the amine product depends on which enantiomer of α-MBA is used, the well known concept of allylic 1,3-strain [1] and on the earlier proposed models. [2] Although predictions obtained from this model agree with the reaction outcome, other models were also introduced aiming to describe the reason behind the improved diastereoselectivity. It was suggested previously that the reductive amination of an α-ketoester with α-MBA may involve a rotamer (about the nitrogen-benzylic carbon bond) with the phenyl ring of α-MBA coplanar to the imine double bond. [3] This proposed idea agrees with the known fact of π bonds affinity for heterogeneous hydrogenation catalyst surfaces. [4] Despite this fact, close examination of other two possible trans-ketimine rotamers, having phenyl group in a coplanar conformation with the imine double bond reveals that one rotamer suffers from high allylic 1,3-strain resulting from steric crowding of phenyl group with methyl group connected to imine carbonyl carbon the other rotamor is less sterically 128
congested which should be favored. Unfortunately this rotamer leads to the formation of the wrong diastereomer. It can be stated that phenyl group is not adsorbed on the heterogeneous surface of the catalyst during hydrogen addition step. Ph Ph Ph R H N CH 3 H N H NH Re-face addition of hydrogen to the cis-(R)-ketimine H 2 CH 3 R cis-(R)-ketimine R (S,R)-2 Si-face addition of hydrogen to the trans-(R)-ketimine H 2 CH 3 Ph Ph CH 3 R N H Ph N H R trans-(R)-ketimine HN H R (R,R)-2 Figure 7.1. Nitrogen-Benzylic Carbon Bond Rotamers Responsible for Hydrogen Addition to cis- and trans-N-α-MBA Ketimines. 7.1.1. Mechanism Behind Enhanced Stereoselectivity with Yb(OAc) 3 : Through consulting literatures regarding reductive amination, it can be stated clearly that there is no precedent for Lewis acid enhanced diastereoselectivity during reductive amination has been reported. Also with respect to the recent literatures reporting the addition of Lewis acid to an N-α-MBA ketimine no enhanced diastereoselectivity was noted. To be able to understand the origin of Yb(OAc) 3 effect on diastereoselectivity, different experiments have been conducted. In these experiments I tried to focus on detecting or isolating the ketimine intermediates. As stated previously the ketimine intermediate conformation is the key factor in determining the stereochemical outcome of the reaction. Also I tried to test the reaction before completion after certain time intervals and compare the results with results obtained from Ti(O i Pr) 4 reaction. Reductive amination of 2-octanone with Ti(O i Pr) 4 or Yb(OAc) 3 requires 12 h for complete consumption of the ketone to occur, examination of the reaction at 1 h and 3 h showed the diastereoselectivity of the product to be 129
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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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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
Page 101 and 102: aminoacid producing the protected a
Page 103 and 104: O NH 2 1. p-TsOH/toluene 2. BH 3 -T
Page 105 and 106: O O 125 NH 2 a 93% O O 126 H Bu N T
Page 107 and 108: ethyl carbamate by acylation with e
Page 109 and 110: 4.1.16. Synthesis of Ritonavir and
Page 111 and 112: 4.2. Conclusion Different important
Page 113 and 114: Chapter 5 Stoichiometric Use of Ytt
Page 115 and 116: The unique feature of this methodol
Page 117 and 118: Ytterbium triflate is the most comm
Page 119 and 120: Ruthenium(III) chloride 31.7 4 4.2
Page 121 and 122: t-Butyl methyl ether 15 - - 82 Hexa
Page 123 and 124: 2-octanone starting material. When
Page 125 and 126: 3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
Page 127 and 128: If a [1,3]-proton shift of the init
Page 129 and 130: enhanced stereoselectivity. For exa
Page 131 and 132: WO2006030017, 2006; c) T. C. Nugent
Page 133 and 134: 4 60 86 5 50 86 6 40 84 7 20 79 8 2
Page 135 and 136: The reactions described above all u
Page 137 and 138: e.g. compare entries 1, 5, 6, and 9
Page 139 and 140: solvent in the stoichiometric and c
Page 141: [2] Farina, V.; Grozinger, K.; Mül
Page 145 and 146: imine area % (GC analysis) time (mi
Page 147 and 148: Inversion at the nitrogen atom of t
Page 149 and 150: anti-6) would be expected to have m
Page 151 and 152: e.g. AcOH, suppresses alcohol by-pr
Page 153 and 154: eductive amination of a prochiral k
Page 155 and 156: Appendix Experimental Section Gener
Page 157 and 158: and the mixture was stirred for 30
Page 159 and 160: Reaction details: Yb(OAc) 3 (1.1 eq
Page 161 and 162: etention time [min]: major (S,S)-2b
Page 163 and 164: time [min]: major (S,S)-2c isomer,
Page 165 and 166: 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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