Improved Methodology for the Preparation of Chiral Amines

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H 3 CO H 3 CO H 3 CO NC C 2 H 5 H2 /PtO NH 2 O O C 2 H 5 O OC 2 H 5 H 3 CO C 2 H 5 OOC HN C 2 H 5 COOC 2 H 5 H 3 CO H 3 CO N C 2 H 5 POCl 3 Adams Catalyst H 3 CO H 3 CO O N COOC 2 H 5 C 2 H 5 1. H 3 CO H 3 CO NH 2 2.POCl 3 3.H 2 /PtO COOC 2 H 5 H 3 CO H 3 CO H 3 CO N C 2 H 5 CH 2 NH H 3 CO Scheme 4.5. Synthesis of Emitine 4.1.6. Synthesis of Taltobulin: Taltobulin is an anticancer drug which interferes with tubulin function inhibiting the formation of microtubules that form the microskeleton of cells. This process has provided some valuable antitumor activity. [7] The synthetic strategy depends on the separate synthesis of two intermediates and combining them at the final step. One arm of the synthesis begins with the construction of acrylatecontaining moiety through condensation of the t-BOC protected α-aminoaldehyde derived from valine with the arbethoxymethylene phosporane resulting in the amino ester. Removal of the protecting group is carried out under acidic condition producing the free amine. The other arm of this synthetic strategy starts with condensation of that tertiary butyl-substituted 86
aminoacid producing the protected amide which can be deprotected under acidic condition. The second arm of this synthetic strategy starts with the addition of a pair of methyl groups to the benzylic position of pyruvate through addition of methyl iodide to ketoacid in the presence of hydroxide. The addition of methylamine and diborane results in the reductive amination of the carbonyl group, and thus formation of α-aminoacid as a mixture of the two isomers. Condensation of this moiety with dipeptide formed previously under peptide forming condition resulted in the formation of amide product which is separated by column chromatography affording the desired isomer of taltobulin. t-BOC N CHO N (C 6 H 5 ) 3 P CO 2 C 2 H 5 t-Boc CO 2 C 2 H 5 H + HN CO2 C 2 H 5 O CO 2 H CH 3 I NaOH O CO 2 H CO 2 H NHCH 3 t-BOC N H CO 2 H DCC O N H NHCH 3 O N CO 2 R R N H O N CO 2 C 2 H 5 Scheme 4.6. Synthesis of Taltobulin 4.1.7. Synthesis of Perzinfote: Perzinfote is a nonaddictive opiate alternative which is currently used to treat chronic pain. [7] Preparation starts with the reductive amination of the acetaldehyde derivative with monocarbobenzyloxy ethylenediamine leading to the disubstituted ethylenediamine (116). The amine is reacted with the commercially available cyclobutenedione derivative (117) resulting in the replacement of one of the ethoxy groups in (117) by the free amino group in (116) to afford the coupled product (118). Transfer hydrogenation of the (118) with 1,4- cyclohexadiene/Pd leads to the loss of the carbobenzoxy group and the formation of the transient primary amine (119) which is then cyclised to form eight-membered ring (120). 87
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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
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
Page 97 and 98: Scheme 4.2. Synthesis of Muraglitaz
Page 99: Studies showed that the active isom
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 and 142: [2] Farina, V.; Grozinger, K.; Mül
Page 143 and 144: congested which should be favored.
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
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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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