Dutch Resolution: Separation of Enantiomers

[Rhodium]

Feature Article:
Dutch Resolution: Separation of Enantiomers with Families of Resolving Agents. A Status Report.
Richard M. Kellogg et. al.

Synthesis (10), 1626-1638 (2003)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/dutch.resolution.pdf)
DOI:

10.1055/s-2003-40508

Abstract

Dutch Resolution is the term given to the use of mixtures (families) of resolving agents in classical resolutions. In this status report an overview is given of the latest results and new (possible) families of resolving agents are introduced. The concept of families is discussed as well as the factors that come into play on use of families. Practical aspects of Dutch Resolution in particular and resolutions in general are discussed.

[Lego]

Resolutions with Families of Resolving Agents:
Principles and Practice


Ph.D. Thesis by José Nieuwenhuijzen

http://www.ub.rug.nl/eldoc/dis/science/j.w.nieuwenhuijzen/

CHAPTER 1
Introduction

http://www.ub.rug.nl/eldoc/dis/science/j.w.nieuwenhuijzen/c1.pdf

1.1 Introduction to chirality 2
1.2 Principles in chirality 4
1.3 Chirality in industry 6
1.4 Routes to enantiomerically pure compounds 8
1.4.1 Chiral pool 8
1.4.2 Prochiral substrates 10
1.4.2.1 Use of chiral auxiliaries 10
1.4.2.2 Use of chiral reagents 11
1.4.2.3 Use of chiral catalysts 12
1.4.2.4 Biocatalysis 14
1.4.3 Starting from the racemate 15
1.4.3.1 Diastereomeric salt resolution 15
1.4.3.2 Kinetic resolution 16
1.5 Pros and cons 17
1.6 Aim and contents of this thesis 18
1.7 References 18



CHAPTER 2
Resolutions via diastereomeric salt formation

http://www.ub.rug.nl/eldoc/dis/science/j.w.nieuwenhuijzen/c2.pdf

2.1 Principles and definitions 24
2.1.1 Racemate types 24
2.1.2 Resolvability and eutectic point 27
2.1.3 Supersaturation and meta-stable zone width 28
2.1.4 Marckwald principle versus reciprocal resolutions 29
2.2 Practice 29
2.2.1 Carrying out an experiment 30
2.2.2 Commonly used resolving agents 31
2.2.3 Stoichiometry; Peachy-Pope resolutions 32
2.2.4 Recovery of enantiomers from diastereomers 33
2.2.5 Other resolution methods 33
2.3 Factors that influence the resolution efficiency 34
2.3.1 Solubility difference; eutectic point 34
2.3.2 Concentration; supersaturation 34
2.3.3 Stirring; seeding 35
2.3.4 Temperature 36
2.4 Basics of crystal growth 36
2.4.1 Nucleation 36
2.4.2 Crystal growth 39
2.4.3 Crystal habit 40
2.5 Dutch Resolution 41
2.6 Concluding remarks 42
2.7 References 42



CHAPTER 3
Benzylidene camphor sulphonates and 1-phenylethane sulphonic acids:
possible new families of resolving agents

http://www.ub.rug.nl/eldoc/dis/science/j.w.nieuwenhuijzen/c3.pdf

3.1 Introduction 48
3.2 Synthesis of benzylidene camphor sulphonates 49
3.3 Attempted resolutions with the benzylidene camphor sulphonates 53
3.4 Synthesis of benzyl camphor sulphonates 54
3.5 Attempted resolutions with the benzyl camphor sulphonates 55
3.6 A new synthetic route for the preparation of 1-PES 3.3 55
3.7 Resolution of (substituted) 1-phenylethane sulphonic acids 3.3 59
3.8 Large scale synthesis 60
3.9 Conclusions 61
3.10 Experimental section 61
General information 61
3.11 References 66



CHAPTER 4
Sodium 1,3-diphenyl-3-oxo-propanesulphonates and derivatives thereof:
synthesis and resolutions

http://www.ub.rug.nl/eldoc/dis/science/j.w.nieuwenhuijzen/c4.pdf

4.1 Introduction 70
4.2 Synthesis of sodium 1,3-diphenyl-3-oxo-propanesulphonates and derivatives thereof
70
4.3 Resolutions with sodium 1,3-diphenyl-3-oxo-propanesulphonates and derivatives
thereof 72
4.3.1 Sulphonates substituted at the X-position 72
4.3.2 Sulphonates with substituents at the Y-position 75
4.4 Large-scale synthesis 78
4.5 Use of enantiomerically pure sulphonates as resolving agents 79
4.6 Derivatives lacking one phenyl ring 81
4.6.1 Synthesis of the derivatives 81
4.6.2 Resolutions with the derivatives 4.19-4.24 83
4.7 Derivatives with an extra methyl group on the á- or â-position 84
4.7.1 Synthesis of the derivatives 84
4.7.2 Resolutions with 4.28 and 4.30 85
4.8 Attempted syntheses of sulphonates without carbonyl functionality 86
4.9 Conclusions and future prospects 87
4.10 Experimental section 87
4.11 References 104



CHAPTER 5
Sodium 1,3-diphenyl-3-oxo-propanesulphonates and derivatives thereof:
structural aspects

http://www.ub.rug.nl/eldoc/dis/science/j.w.nieuwenhuijzen/c5.pdf

5.1 Introduction 108
5.2 Crystal structure of 4.4a and 4.4b with 4.5 108
5.3 Crystal structure of 4.4e and 4.4g with 4.8 116
5.4 Gradual dissolution experiments 121
5.5 Experimental section 126
5.6 References 126



CHAPTER 6
Understanding Dutch Resolution: the role of nucleation inhibition

http://www.ub.rug.nl/eldoc/dis/science/j.w.nieuwenhuijzen/c6.pdf

6.1 Introduction 128
6.2 The dog that didn’t bark 129
6.3 Turbidity measurements 131
6.3.1 o-Nitrophenylethylamine 6.3 as additive 132
6.3.2 Substituted mandelic acids as additives 134
6.4 Ternary phase diagram 136
6.5 Second generation Dutch Resolution 138
6.6 Crystal habit 142
6.7 ‘Classic’ Dutch Resolution versus second generation Dutch Resolution 148
6.8 Synthesis of the nucleation inhibitors 149
6.8.1 Nitro-substituted phenylethylamines 149
6.8.2 Phenyl-substituted mandelic acid 150
6.9 Experimental section 150
6.10 References 154



CHAPTER 7
Conclusions and future prospects

http://www.ub.rug.nl/eldoc/dis/science/j.w.nieuwenhuijzen/c7.pdf

7.1 In retrospect 158
7.2 Follow-up on nucleation inhibition 158
7.3 Future of resolutions via diastereomeric salt formation 164
7.4 References 166

[java]

Thank you Lego for making the thesis available to the Hive.   I was initially intrigued by Rhodium's initial posting on the subject. Having the whole text to gain a better understanding, is a supplemantary plus, to the article.......java