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Chiral Separations and Stereochemical Elucidation. Fundamentals, Methods, and Applications. Edition No. 1

  • Book

  • 640 Pages
  • March 2023
  • John Wiley and Sons Ltd
  • ID: 5842380
An expert resource for chemists using stereochemical analysis methods

In Chiral Separations and Stereochemical Elucidation: Fundamentals, Methods, and Applications, a team of distinguished researchers delivers a robust and authoritative discussion of the theoretical fundamentals of chiral separation, the most commonly used chiral selectors, and stereochemical elucidation methods. The book offers expert discussions of a variety of chiral separation methods by gas chromatography (GC), supercritical fluid chromatography (SFC), capillary electrophoresis (CE), and liquid chromatography (LC).

The authors also describe several methods for stereochemical elucidation, including X-ray crystallography, nuclear magnetic resonance spectroscopy, and chiroptical methods. The explored material is ideal for practicing chemists seeking a resource to help them guide method development and optimization or to explain quality control-complements during target compound production.

Readers will also find: - A thorough introduction to the most important advances and applications in LC, GC, CE, SFC, and preparative chromatography - Comprehensive explorations of the role of 2D-LC for chiral separation methods development and applications - Practical discussions of the design, mechanisms, and applications of the most commonly used chiral selectors - Fulsome treatments of the theoretical backgrounds, advantages, limitations, and applications of stereochemical elucidation methods

Perfect for academic and industrial chemists specially in organic, analytical chemistry and pharmaceutical analysis. Chiral Separations and Stereochemical Elucidation: Fundamentals, Methods, and Applications will also benefit biochemists, environmental analysts, forensic and medicinal chemists as well as natural product chemists and those involved with stereochemistry or structural elucidation.

Table of Contents

List of Contributors xv

Preface xix

Part I Fundamentals of Chiral Separation 1

1 Chiral Separation by LC 3
Juliana Cristina Barreiro and Quezia Bezerra Cass

1.1 Introduction 3

1.2 Workflow for LC Chiral Method Development 7

1.3 New Column Technologies 9

1.4 Selected Examples of Fast Separation 12

1.5 Chiral 2D- LC 14

1.5.1 LC-LC and mLC-LC 14

1.5.2 LC × LC and sLC × LC 17

1.6 Future and Perspectives 19

References 20

2 Chiral Separation by GC 27
Oliver Trapp

2.1 Introduction 27

2.2 Chiral Recognition in Gas Chromatography 29

2.2.1 Chiral Recognition by Hydrogen Bonding 31

2.2.2 Chiral Recognition Using Chiral Metal Complexes 31

2.2.3 Chiral Recognition by Host-Guest Interactions 31

2.3 Preparation of Fused- Silica Capillaries for GC with CSPs 33

2.4 Application of CSPs in Chiral Gas Chromatography 34

2.4.1 CSPs with Diamide Selectors 34

2.4.1.1 Chirasil- Val 34

2.4.2 CSPs with CD Selectors 35

2.4.2.1 Heptakis(2,3,6- tri- O- Methyl)- β- Cyclodextrin (Permethyl- β- Cyclodextrin) 38

2.4.2.2 Heptakis(2,3,6- tri- O- Methyl)- β- Cyclodextrin Immobilized to Hydrido Dimethyl Polysiloxane (Chirasil- β- Dex) 39

2.4.2.3 Heptakis(2,6- di- O- Methyl- 3- O- Pentyl)- β- Cyclodextrin 43

2.4.2.4 Hexakis- (2,3,6-tri- O- Pentyl)- α- Cyclodextrin 47

2.4.2.5 Heptakis(2,3,6- tri- O- Pentyl)- β- Cyclodextrin 48

2.4.2.6 Hexakis- (3- O- Acetyl- 2,6- di- O- Pentyl)- α- Cyclodextrin 51

2.4.2.7 Heptakis(3- O- Acetyl- 2,6- di- O- Pentyl)- β- Cyclodextrin 51

2.4.2.8 Octakis(3- O- Butyryl- 2,6- di- O- Pentyl)- γ- Cyclodextrin 53

2.4.2.9 Hexakis/Heptakis/Octakis(2,6- di- O- Alkyl- 3- O- Trifluoroacetyl)- α/β/γ- Cyclodextrins 57

2.4.2.10 Heptakis(2,3- di- O- Acetyl- 6- O-tert- Butyldimethylsilyl)- β- Cyclodextrin (DIAC- 6- TBDMS- β- CD) 58

2.4.2.11 Heptakis(2,3- di- O- Methyl- 6- O-tert- Butyldimethylsilyl)- β- Cyclodextrin (DIME- 6- TBDMS- β- CD) 58

2.4.3 Cyclofructans 62

2.4.4 CSPs with Metal Complexes 65

2.5 Conclusion 69

References 69

3 Chiral Separation by Supercritical Fluid Chromatography 85
Emmanuelle Lipka

3.1 Introduction 85

3.2 Characteristics and Properties of Supercritical Fluids 87

3.3 Development of a Chiral SFC Method 89

3.3.1 Chiral Stationary Phases 89

3.3.2 Mobile Phases 91

3.3.2.1 Mobile Phase: Type of Co- solvent Used 93

3.3.2.2 Mobile Phase: Percentage of Co- solvent Used 94

3.3.2.3 Mobile Phase: Use of Additives 94

3.4 Operating Parameters 94

3.4.1 Effect of the Flow Rate 95

3.4.2 Effect of the Outlet Pressure (Back- pressure) 95

3.4.2.1 Effect of Pressure When the Mobile Phase is a Gas- Like Fluid 96

3.4.2.2 Effect of Pressure When the Mobile Phase is a Liquid- Like Fluid 97

3.4.3 Effect of Temperature 97

3.4.3.1 Effect of Temperature When the Mobile Phase is a Gas- Like Fluid 98

3.4.3.2 Effect of Temperature When the Mobile Phase is a Liquid- Like Fluid 98

3.5 Detection 99

3.6 Scale- Up to Preparative Separation 99

3.7 Conclusion 100

References 101

4 Chiral Separation by Capillary Electrophoresis and Capillary Electrophoresis-Mass Spectrometry: Fundamentals, Recent Developments, and Applications 103
Charles Clark, Govert W. Somsen, and Isabelle Kohler

4.1 Introduction 103

4.2 Principles of Chiral CE 105

4.2.1 Electrophoretic Mobility 105

4.2.2 CE Separation Efficiency 106

4.2.3 Chiral Resolution in CE 107

4.2.4 Chiral Micellar Electrokinetic Chromatography and Capillary Electrochromatography 109

4.3 Short History of Chiral CE Modes 111

4.3.1 Chiral CE 111

4.3.2 Chiral MEKC and Chiral CEC 111

4.4 State of the Art and Recent Developments 112

4.4.1 Common Chiral Selectors 112

4.4.2 Ionic Liquids as Chiral Selectors 117

4.4.3 Nanoparticles as Chiral Selector Carriers 117

4.4.4 Microfluidic Chiral CE 118

4.5 Applications of Chiral CE 119

4.5.1 Pharmaceutical Analysis 119

4.5.2 Food Analysis 120

4.5.3 Environmental Analysis 121

4.5.4 Bioanalysis 123

4.5.5 Forensic Analysis 126

4.6 Chiral CE- MS: Strategies and Challenges 126

4.6.1 Hyphenation Approaches 129

4.6.1.1 Sheath-Liquid and Sheathless CE- MS Interfacing 129

4.6.1.2 Partial- Filling Techniques 130

4.6.1.3 Counter- Migration Techniques 131

4.6.2 Chiral MEKC- MS 132

4.6.3 Chiral CEC- MS 133

4.7 Conclusions and Perspectives 135

References 135

5 Chiral Separations at Semi and Preparative Scale 143
Larry Miller

5.1 Introduction 143

5.2 Selection of Operating Conditions 145

5.3 Batch HPLC Purification 146

5.3.1 Analytical Method Development for Preparative Separations 146

5.3.2 Batch HPLC Examples 148

5.3.2.1 Batch HPLC Example 1 148

5.3.2.2 Batch HPLC Example 2 149

5.4 Steady- State Recycle Introduction 151

5.4.1 SSR Example 1 153

5.5 Simulated Moving Bed Chromatography - Introduction 154

5.5.1 SMB Examples for R&D and Separation of Compound 2 156

5.5.2 Development of a Manufacturing SMB Process (Compound 1) 158

5.5.3 Cost for SMB Processes 160

5.6 Introduction to Supercritical Fluid Chromatography 161

5.6.1 Analytical Method Development for Scale- up to Preparative SFC 162

5.6.2 Preparative SFC Example 1 163

5.6.3 Preparative SFC Example 2 163

5.7 Options for Increasing Purification Productivity 165

5.7.1 Closed- Loop Recycling 165

5.7.2 Stacked Injections 166

5.7.3 Choosing the Best Synthetic Intermediate for Separation 167

5.7.3.1 Choosing Synthetic Step for Separation - HPLC/SMB Example 168

5.7.3.2 Choosing Synthetic Step for Separation - SFC Example 169

5.7.4 Use of Non- Commercialized CSP 170

5.7.5 Immobilized CSP for Preparative Resolution 173

5.7.5.1 Processing of Low Solubility Racemate 173

5.7.5.2 Preparative Resolution of EMD 53986 174

5.8 Choosing a Technique for Preparative Enantioseparation 176

5.9 Conclusion 178

References 179

Part II Chiral Selectors 187

6 Polysaccharides 189
Weston Umstead, Takafumi Onishi, and Pilar Franco

6.1 Introduction 189

6.2 The Early Years 190

6.3 Polysaccharide Chiral Separation Mechanism 193

6.4 Coated Chiral Stationary Phases 197

6.5 Immobilized Chiral Stationary Phases 201

6.6 Applications of Polysaccharide- Derived CSPs 208

6.6.1 Analytical Applications 210

6.6.1.1 Pharmaceuticals 211

6.6.1.2 Agrochemicals 218

6.6.1.3 Food Analysis 219

6.6.2 Preparative Applications 220

6.7 Summation 224

References 224

7 Macrocyclic Antibiotics and Cyclofructans 247
Saba Aslani, Alain Berthod, and Daniel W. Armstrong

7.1 Introduction 247

7.2 Macrocyclic Glycopeptides Physicochemical Properties 248

7.3 Using the Chiral Macrocyclic Glycopeptides Stationary Phases 253

7.3.1 Mobile Phases and Chromatographic Modes 253

7.3.2 Chromatographic Enantioseparations 254

7.3.2.1 Amino Acids and Peptides 254

7.3.2.2 Chiral Compounds 257

7.3.2.3 Particle Structure 257

7.4 Using and Protecting Macrocyclic Glycopeptide Chiral Columns 260

7.4.1 Operating Conditions 260

7.4.2 Storage 261

7.5 Cyclofructans 261

7.5.1 Cyclofructan Structure and Properties 261

7.5.2 Chiral Separations with Cyclofructan- Based Stationary Phases 264

7.5.3 Cyclofructan Stationary Phases Used in the HILIC Mode 264

7.5.4 Cyclofructan Stationary Phases Used in Supercritical Fluid Chromatography 266

7.6 Conclusions 267

References 268

8 Cyclodextrins 273
Gerhard K. E. Scriba, Mari- Luiza Konjaria, and Sulaiman Krait

8.1 Introduction 273

8.2 Structure and Properties 274

8.3 Cyclodextrin Complexes 279

8.4 Application in Separation Science 288

8.4.1 Gas Chromatography 288

8.4.1.1 Types of Cyclodextrins 289

8.4.1.2 Types of Columns 289

8.4.1.3 Separation Mechanisms 291

8.4.1.4 Applications 293

8.4.2 Thin- Layer Chromatography 294

8.4.3 High- Performance Liquid Chromatography 294

8.4.3.1 Types of Columns 295

8.4.3.2 Types of Cyclodextrins 297

8.4.3.3 Separation Mechanisms 298

8.4.3.4 Applications 300

8.4.4 Supercritical Fluid Chromatography 300

8.4.5 Capillary Electromigration Techniques 301

8.4.5.1 Types of Cyclodextrins 301

8.4.5.2 Separation Mechanisms 302

8.4.5.3 Migration Modes and Enantiomer Migration Order Using CDs as Selectors 304

8.4.5.4 Applications 310

8.4.6 Membrane Technologies 312

8.5 Miscellaneous Applications 314

8.6 Conclusions and Outlook 315

References 315

9 Pirkle Type 325
Maria Elizabeth Tiritan, Madalena Pinto, and Carla Fernandes

9.1 Introduction 325

9.2 CSPs Developed by Pirkle’s Group: Chronological Evolution 327

9.3 Pirkle- Type CSPs Developed by Other Research Groups 334

9.4 Example of Applications in Analytical and Preparative Scales 340

9.4.1 Analytical Applications 341

9.4.2 Preparative Applications 349

9.5 Conclusions and Perspectives 349

References 350

10 Proteins 363
Jun Haginaka

10.1 Introduction 363

10.2 Preparation of Protein- and Glycoprotein- Based Chiral Stationary Phases 364

10.3 Types of Protein- and Glycoprotein- Based Chiral Stationary Phases 368

10.3.1 Proteins 368

10.3.1.1 Bovine Serum Albumin 368

10.3.1.2 Human Serum Albumin 370

10.3.1.3 Trypsin and α- Chymotrypsin 372

10.3.1.4 Lysozyme and Pepsin 372

10.3.1.5 Fatty Acid- Binding Protein 373

10.3.1.6 Penicillin G Acylase 375

10.3.1.7 Streptavidin 375

10.3.1.8 Lipase 376

10.3.2 Glycoproteins 376

10.3.2.1 Human α 1 - Acid Glycoprotein 376

10.3.2.2 Chicken Ovomucoid 377

10.3.2.3 Chicken α 1- Acid Glycoprotein 378

10.3.2.4 Avidin 380

10.3.2.5 Riboflavin- Binding Protein and Ovotransferrin 380

10.3.2.6 Cellobiohydrolase 381

10.3.2.7 Glucoamylase 383

10.3.2.8 Antibody (Immunoglobulin G) 385

10.3.2.9 Nicotinic Acetylcholine Receptor and Human Liver Organic Cation Transporter 387

10.4 Chiral Recognition Mechanisms on Proteinand Glycoprotein- Based Chiral Stationary Phases 387

10.4.1 Human Serum Albumin 387

10.4.2 Penicillin G Acylase 389

10.4.3 Human α 1- Acid Glycoprotein 390

10.4.4 Turkey Ovomucoid 392

10.4.5 Chicken α 1- Acid Glycoprotein 393

10.4.6 Cellobiohydrolase 395

10.4.7 Antibody 396

10.4.8 Nicotinic Acetylcholine Receptor and Human Liver Organic Cation Transporter 400

10.5 Conclusions 401

References 402

11 Chiral Stationary Phases Derived from Cinchona Alkaloids 415
Michael Lämmerhofer and Wolfgang Lindner

11.1 Introduction 415

11.2 Cinchona Alkaloid- Derived Chiral Stationary Phases 416

11.3 Chiral Recognition 420

11.4 Chromatographic Retention Mechanisms 424

11.4.1 Multimodal Applicability 424

11.4.2 Surface Charge of Cinchonan- Based CSPs 424

11.4.3 Retention Mechanisms and Models, and Method Development on Chiral WAX CSPs 427

11.4.4 Retention Mechanisms and Method Development on ZWIX CSPs 430

11.5 Structural Variants of Cinchona Alkaloid CSPs and Immobilization Chemistries 436

11.6 Cinchonan- Based UHPLC Column Technologies 442

11.7 Applications 446

11.7.1 Pharmaceutical and Biotechnological Applications 446

11.7.2 Biomedical Applications 453

11.8 Conclusions 460

References 460

Part III Methods for Stereochemical Elucidation 473

12 X- Ray Crystallography for Stereochemical Elucidation 475
Ademir F. Morel and Robert A. Burrow

12.1 Introduction 475

12.2 Absolute Structure and Absolute Configuration 476

12.3 Best Practices 482

12.4 Structure Validation 486

12.5 The Absolute Configuration of (+)- Lanatine A 486

12.6 The Absolute Configuration of the Diacetylated Form of Acrenol and the Acetylated Form of Humirianthol 488

12.7 The Absolute Configuration of Ester Form of Clemateol 491

12.8 Relative Configurations of Waltherione A, Waltherione B, and Vanessine 492

12.9 The Absolute Configuration of Condaline A 493

12.10 CSD Deposit Numbers 496

12.11 Conclusions and Future Directions 498

References 498

13 NMR for Stereochemical Elucidation 505
Xiaolu Li, Xiaoliang Yang, and Han Sun

13.1 Conventional NMR Methods for Stereochemical Elucidation 505

13.1.1 Determination of the Planar Structure Using 1D 1 H, 13 C NMR (DEPT), 2D HSQC, COSY, TOCSY, HMBC 506

13.1.2 Determination of Relative Configuration Using J- Couplings and NOEs/ROEs 507

13.1.2.1 Scalar Coupling 507

13.1.2.2 NOE/ROE 510

13.1.2.3 Examples of Stereochemical Elucidation Using J- Couplings and NOEs/ROEs 510

13.2 Determination of the Relative Configuration Using Anisotropic NMR- Based Methods 516

13.2.1 Basic Principles of Anisotropic NMR Parameters 517

13.2.2 Alignment Media 518

13.2.2.1 Preparation of Anisotropic Sample with PMMA Gel 520

13.2.2.2 Preparation of Anisotropic Sample with AAKLVFF 521

13.2.3 Acquisition of the Anisotropic NMR Data 522

13.2.4 Computational Approaches for Analyzing Anisotropic NMR Data 525

13.2.5 Successful Examples of Determination of Relative Configuration of Challenging Molecules Using Anisotropic NMR 528

13.3 Determination of the Relative Configuration Using DP 4 Probability and CASE- 3D 529

13.4 Determination of the Absolute Configuration Using a Combination of NMR Spectroscopy and Chiroptical Spectroscopy 533

13.5 Determination of the Absolute Configuration Using NMR Alone 534

13.5.1 Mosher Ester Analysis 535

13.5.2 Other Chiral Derivatizing Agents 536

13.6 Future Perspective 536

References 537

14 Absolute Configuration from Chiroptical Spectroscopy 551
Fernando Martins dos Santos Junior and João Marcos Batista Junior

14.1 Introduction 551

14.2 Chiroptical Methods 554

14.2.1 Optical Rotation and Optical Rotatory Dispersion 554

14.2.1.1 Instrumentation 556

14.2.1.2 Measurements 557

14.2.2 Electronic Circular Dichroism 558

14.2.2.1 Instrumentation 560

14.2.2.2 Measurements 561

14.2.3 Vibrational Circular Dichroism and Raman Optical Activity 561

14.2.3.1 Instrumentation 563

14.2.3.2 Measurements 565

14.2.4 Simulation of Chiroptical Properties 567

14.2.4.1 Common Theoretical Steps 568

14.2.4.2 OR and ORD Simulations 570

14.2.4.3 ECD Simulations 572

14.2.4.4 VCD and ROA Simulations 573

14.2.5 Examples of Application 575

14.2.5.1 OR 575

14.2.5.2 ORD 577

14.2.5.3 ECD 578

14.2.5.4 VCD 579

14.2.5.5 ROA 581

14.2.5.6 Association of Different Chiroptical Methods 582

14.3 Concluding Remarks 585

References 586

Index 593

Authors

Quezia Bezerra Cass Universidade Federal de São Carlos, Brazil. Maria Elizabeth Tiritan Universidade do Porto, Portugal. João Marcos Batista Junior Universidade Federal de São Paulo, Brazil. Juliana Cristina Barreiro Universidade de São Paulo, Brazil.