Improved Methodology for the Preparation of Chiral Amines

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Chapter 2 Imine Reduction 2.1. Historical View Reduction of imines with chiral catalysts and hydride source to prepare α-chiral amines with high yield and enantioselectivity represents an important achievement in organic and pharmaceutical chemistry over the last two decades. Different catalytic systems have been developed, heterogeneous and homogenous systems and recently organocatalysis were investigated. Few of these systems were applicable on industrial scale. [1] Historically heterogeneous systems were developed first. Many attempts to attach chiral auxiliary to heterogeneous catalysts (Pt/C, Pd/C and R-Ni) were not successful to attain high enantioselectivity. Homogenous systems proved to be the systems of choice to reduce imines on the laboratory and on the industrial scales. In general all of these systems require the use of activated imines as substrates in which nitrogen atom is attached to a bulk group (phenyl, phosphinoyl, chiral auxiliary). [2,3] These groups have to be removed in the final step which adds to the total number of steps from the prochiral ketone to the α-chiral amine. Removal of these groups requires harsh conditions which is not compatible with many sensitive groups. In general cyclic imines are easier in reduction with higher enantioselectivity as they do not have anit/syn conformation. [4] They are considered important intermediates for many pharmaceutical drugs. Acyclic aryl imines were successfully hydrogenated with high enantioselectivities and yields. Metals as Rh, Ru, Ir and Ti were useful in this process. Ir was the best metal for imine reduction with different chiral auxiliaries. Ru catalysts which were developed by Noyori and proved to be highly effective in the reduction of ketones showed limited success. Titanium system which was developed by Buchwald in the nineties gave superior results in terms of yield and enantioselectivity but their industrial application was not that successful. [1] In this section of the thesis, I will focus on the achievments in the field 34
of imine reduction in the past eight years. Of course in the nineties great achievements were accomplished for complete picture please refer to the following review. [2] 2.2. Asymmetric Reduction of N-Phosphinoyl Imines Of the useful imine substrates examined to date, N-phosphinoyl imines hold the advantage of being reduced with high yields and ees. The steric bulk of the diphenylphosphine group affects the geometric form of imine (only anti isomer is obtained). [5] To access N-phosphinoyl imines researchers universally begin with a ketone and convert it to an oxime (high yield). Oximes are readily prepared from ketones and HCl.H 2 NOH, pyridine in ethanol by mixing 1.0 equiv of ketone and 1.1 hydroxyl amine hydrochloride and 1.1 equiv of pyridine. [6] Treatment of the oxime with chlorodiphenylphosphine [Ph 2 P(O)Cl] at –45-78 °C provides the N-phosphinoyl imine in mediocre to good yields. For example aryl alkyl N-phosphinoyl imines provide yield in the range of 40-70%, while alkyl alkyl N-phosphinoyl imines provide yields in the range of 50-70%. The product is purified with column chromatography (scheme 2.1). [7] 2.2.1. Synthesis of N-Phosphinoyl Imines. high yield N OH R 1 R 2 Ph 2 P(O)Cl Et 3 N, -45 °C O R 1 R 2 + H 2 N O P Ph Ph N R 1 R 2 CH 2 Cl 2 P(O)Ph 2 P(O)Ph2 reduction high yield HN R 1 * R 2 high NH 2 yield R 1 * R 2 R 1 = aryl, alkyl, heterocylic R2 = alkyl 1- Ph 2 P(O)Cl, CH 2 Cl 2 ,-78°C 2- hydrolytic work-up NOH H 2 NOH HCl O Scheme 2.1. General Strategies for Synthesis of N-Phosphinoyl Imines. 35
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 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: [67] a) H. Qin, N. Yamagiwa, S. Mat
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
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
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
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with etheral HCl provided the hydro
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Research experience: Date Project S
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Improved Methodology for the Preparation of Chiral Amines

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