Improved Methodology for the Preparation of Chiral Amines

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ketone class subclass examples de acid catalyst b comment O R L = i-Pr or c-hexyl 98 Ti(O i Pr) 4 viable alternative AcOH c R L CH 3 R L = Ph 95 Ti(O i Pr) 4 other catatalysts - low yield R L O R L = Ph; R S = n-Pr 90 Ti(O i Pr) 4 other catalysts - no product R S R L = i-Pr; R S = n-Pr, n-Bu 87 Ti(O i Pr) 4 other catalysts - no product O R M = i-Bu 93 Ti(O i Pr) 4 viable alternative AcOH d R M CH 3 R M = -CH 2 CH 2 Ph 89 Yb(OAc) 3 other catalysts - low de O R S = n-hexyl 87 Yb(OAc) 3 other catalysts - low de R S CH 3 R S = n-butyl 85 Yb(OAc) 3 other catalysts - low de a Unless otherwise noted, all reactions performed at 22 o C and 120 psi H 2 . The indicated ketone classes and subclasses provide a starting point for assessing near optimal conditions for similar substrates, see reference 1c and this manuscript for specific details. b For optimal yield and de, Ti(O i Pr) 4 is always used in stoichiometric quantities while Yb(OAc) 3 can be used in 50-110 mol %. c The use of 20 mol% AcOH allows very similar results, but only at 50 o C and 290 psi (H 2 ). d The use of 20 mol% AcOH allows very similar results, but only at elevated temperature (50 o C). 7.2. Conclusion: Strategies for α-chiral amine synthesis employing preformed imines or enamines are stepwise long and can suffer from lower overall yield because of mediocre imine or enamine yield forming steps, as previously commented on. This problems can be alleviated by using a reductive amination strategy, as outlined here, and avoids the normally stepwise excessive procedures of chiral auxiliary approaches by simultaneously incorporating a nitrogen atom (from the auxiliary) and a new stereogenic center at the carbonyl carbon during step one (reductive amination). A second step, hydrogenolysis, allows the enantioenriched primary amine to be isolated in good to high overall yield. The ytterbium acetate method expounded on here unequivocally demonstrates the first example of constructive interference, by any additive, during the asymmetric 138
eductive amination of a prochiral ketone or an N-α-MBA ketimine. It also represents the first documented use of ytterbium for reductive amination. The initial mechanistic investigations elaborated on here suggest an imine isomerization pathway promoted by Yb(OAc) 3 allowing enhanced diastereoselectivity during reductive amination. A future study will be required to elaborate on these initial mechanistic proposals, would likely require computational analysis and include the investigation of chiral and other achiral Lewis acid derivatives. Investigation of heterogeneous hydrogenation catalysts prepared by different methods or supported on different materials (e.g. carbon nanostructures, alumina, etc.), could provide further beneficial insights. Finally, the general phenomenon of in situ promoted imine isomerization, with Yb(OAc) 3 , would be expected to have a beneficial impact on the study of imine/enamine chemistry in general, e.g. in conjunction with enantioselective organocatalysis. 7.3. References: [1] (a) R. W. Hoffmann, Chem Rev. 1989, 89, 1841. (b) K. W. Lee, S. Y. Hwang, C. R. Kim, D. H. Nam, J. H. Chang, S. C. Choi, B. S. Choi, H. -W. Choi, K. K. Lee, B. So, S.W. Cho, H. Shin, Org. Process Res. Dev. 2003, 7, 839. [2] (a) M. B. Eleveld, H. Hogeveen, E.P. Schudde, J. Org. Chem. 1986, 51, 3635; (b) A. L. Gutman, M. Etinger, G. Nisnevich, F. Polyak, Tetrahedron: Asymmetry 1998, 9, 4369. [3] G. Siedlaczek, M. Schwickardi, U. Kolb, B. Bogdanovic, D. G. Blackmond, Catal. Lett. 1998, 55, 67. [4] (a) A. Kraynov, A. Suchopar, L. D'Souza, R. Richards, Physical Chemistry Chemical Physics, 2006, 8, 1321. (b) T. Bürgi, A. Baiker Acc. Chem. Res. 2004, 37, 909. (c) M. Studer, H. –U. Blaser, C. Exner, Adv. Synth. Catal. 2003, 345, 45. [5] For advances in the diastereoselective reduction of (R)- or (S)-α-MBA ketimines, see: (a) D. E. Nichols,C. F. Barfknecht, D. B. Rusterholz, J. Med. Chem. 1973, 16, 480. (b) J. E.Clifton, I. Collins, P. Hallett, D. Hartley, L. H. C. Lunts, P.D. Wicks, J. Med. Chem. 1982, 25, 670. (c) M. B. Eleveld, H. Hogeveen, E. P. Schudde, J. Org. Chem. 1986, 51, 3635-3642. (d) G. Bringmann, J. –P. Geisler, Synthesis 1989, 608. (e) E. Marx, M. El Bouz,J. P. Célérier, G. Lhommet, Tetrahedron Lett. 1992, 33, 4307. (f) N. Moss, J. Gauthier, J. –M. Ferland, Synlett 1995, 142. (g) G. Lauktien, F. – 139
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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
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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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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
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Page 125 and 126: 3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
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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 and 142: [2] Farina, V.; Grozinger, K.; Mül
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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: e.g. AcOH, suppresses alcohol by-pr
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
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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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