Improved Methodology for the Preparation of Chiral Amines

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Enantioselective reduction of enamide is very interesting approach for the synthesis of chiral amines from the enantioselectivity prospective. On the other hand, it is a four step procedure to get the final primary amine product. Two step process N-acyl enamide synthesis and a further two steps are involved, reduction of the enamides and hydrolysis of enamide, before the primary amine is obtained. The overall yield is rarely mentioned in literature. Through calculating each step yield and estimating the overall all yield it is obvious that the yield is low (usually below 50%). Enamides generally are obtained as E and Z mixtures, but this does not seem to affect enantioselectivity. Specific substrate categories can be only utilized in enamide reduction protocol, pinacolone and aryl-alkyl ketones. [71] We will focus on enamide methods allowing alkyl-alkyl and aryl-alkyl substituted α-chiral amine synthesis. Ding immobilizes Feringa’s MonoPhos/Rh catalyst for the asymmetric hydrogenation of dehydro-α-amino acid esters and enamides. Treatment of the ditopic MonoPhos ligand with [Rh(cod)]BF 4 in DCM/toluene resulted in an immediate precipitation of an amorphous Rh-containing polymer, which were demonstrated to be effective catalysts for the asymmetric hydrogenation. Secondary amines were prepared in excellent enantioselectivity (scheme 1.11). [72] N P O O linker O O P N [Rh(cod) 2 ]BF 4 CH 2 Cl 2 /Toluene O O P N [Rh] N P O O linker linker a: b: n c: single bond R O OCH 3 NHAc R=H, CH3, Ph 12a-c, 1 mol% H 2 , 40 atm, toluene O R OCH 3 NHAc Full conversion 94-96% ee 12a-c, 1 mol% Ph NHAc H 2 , 40 atm, toluene Ph NHAc Scheme 1.11 Heterogeneous Catalysis with Self Supported Rh Catalysts. 24
Burk was successful in reducing aryl-alkyl or alkyl-alkyl enamides with high ee (>95%) utilizing Rh[Me-DUPHOS] or Rh[Me-BPE] catalysts (Figure 1.7). The substrates are acyclic and benzocyclic aryl-alkyl ketones, and only two examples for alkyl-methyl ketones with sterically encumbered groups such as t-Bu (pinacolone) or adamantly groups as alkyl substituents. As described before there is no information about the yield from the starting ketone up to the final product. Another issue regarding this work is the limited substrate breadth. [73] P P P P Figure 1.7 Examples of Chiral Ligands Used by Burk. Noyori has reported a general and straightforward method for synthesizing enantiomerically pure tetrahydroisoquinoline alkaloids through reduction of enamide. Ru-(S)-BINAP and Ru- (S)-BIPHEMP complexes. These complexes resulted in almost perfect enantioselectivities in hydrogenation for a wide array of tetrahydroquinolines. The present reaction provides access to a wide variety of alkaloids as morphinic and synthetic morphinans and benzomorphans analogues (scheme 1.12). [74] MeO MeO NCHO 1-4 bar H 2 Ru-(S)-BINAP MeOH MeO MeO NCHO R=H, R OMe ee>99% R OMe OMe Scheme 1.12. Noyori Catalyst for Enamide. 25
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 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: fourth chapter showing different dr
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
Page 63 and 64: More recently, 2008, he described t
Page 65 and 66: [22] E. Guiu, M. Aghmiz, Y. Diaz, C
Page 67 and 68: Chapter 3 Reductive Amination 3.1.
Page 69 and 70: . CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 C
Page 71 and 72: superior in terms of conversion (89
Page 73 and 74: O NHR 3 R 4 R 4 R 3 N OTi(O i Pr) 3
Page 75 and 76: Scheme 3.9. Synthesis of (S)-Metola
Page 77 and 78: groups decreased both the enantiose
Page 79 and 80: progress of the reaction was monito
Page 81 and 82: attempts were directed for the asym
Page 83 and 84: hydrogen bonding, is chiral and its
Page 85 and 86: Later he utilized this methodology
Page 87 and 88: 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
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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
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4.1.16. Synthesis of Ritonavir and
Page 111 and 112:
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
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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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Improved Methodology for the Preparation of Chiral Amines

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