Improved Methodology for the Preparation of Chiral Amines

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and its opposite enantiomer. Molecules in the crystal structure have a greater affinity for the same enantiomer than for the opposite enantiomer. The melting point of the racemic conglomerate is always lower than that of the pure enantiomer. Addition of a small amount of one enantiomer to the conglomerate increases the melting point. Success in this method depends on the fact that for a conglomerate the racemic mixture is more soluble than either of the enantiomers. Generally only 5-10% of racemates form conglomerates. [26] 1.5.2.1. Diastereomer Crystallization L. Pasteur was the one who first to fully develop this methodology in 1854. [26] In this approach, a racemate interacts with an enantiopure compound to form diastereomeric salt which can then be separated by crystallization due to unequal solubility in a given solvent. These enantiopure compounds are called resolving agents and are obtained from the chiral pool, e.g. L-tartaric acid, D-camphor sulfonic acid or some alkaloid bases. In general this approach is extremely limited to few examples. One example of such process is the crystallization of the salt of one enantiomer of 1,2 diamino cyclohexane obtained from the interaction of the racemic mixture with enantiopure tartaric acid. [27] O SO 3 H O HO 3 S H X OH N Quinine (X=OMe) Chinchonidine (X=H) HO OH H 2 O/AcOH H 3 N K 2 CO 3 H 2 N H 2 N NH 2 HOOC COOH 90 o C-5 o C HO COO COO NH 3 H 2 O/EtOH H 2 N >98% ee HO Scheme 1.1. Preparation of 1,2 Diamino Cyclohexane 10
1.5.2.2. Kinetic Resolution Kinetic resolution is based on the difference in reactivity rate of the two enantiomers with a chiral entity which is used in catalytic amount. [28] The chiral entity can be either a biological catalyst (e.g. enzyme) or a chemical catalyst (e.g. chiral metal complex or organocatalyst). Rule of thumb for kinetic resolution to be successful is that one enantiomer must react faster than the other. In such situation theoretically, 50% of the product from one enantiomer and 50% of the unreacted enantiomer should be obtained. Scheme 1.2 showing one example describing this condition in which racemic β-aryl-β-hydroxy esters with different substitution patterns on the aryl moiety provides preferably the (R)-enantiomer with 93-98% ee and 32- 41% isolated yield. [29] Ph Ph N H Ph N HO BrZnCH 2 CO 2 tBu(8equiv.) CO 2 tBu Prolinol ligand (5.0 mol%) CO 2 tBu CO 2 tBu Ar OH THF, reflux Ar OH Ar Scheme 1.2. Kinetic Resolution in Asymmetric Synthesis. . If the unwanted enantiomer is racemized in situ during resolution, a 100% theoretical yield of the enantiopure product can be theoretically reached, this is known as a kinetic dynamic resolution. This approach was successfully applied utilizing enzymes as resolving agents. [30] 11
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: 1.5.1. Synthesis of Enantiomericall
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 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
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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
Page 93 and 94:
[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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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
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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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