BOOK
Modern NMR Approaches to the Structure Elucidation of Natural Products
Antony Williams | Gary Martin | David Rovnyak
(2016)
Additional Information
Book Details
Abstract
The Ghanian plant Cryptolepis sanguinolenta is the source of a series of fascinating indoloquinoline alkaloids. The most unusual member of this alkaloid series was initially proposed to be a spiro nonacyclic structure, named cryptospirolepine, and was elucidated in 1993 based on the technologies available at that time. There were, however, several annoying attributes to the structure that bothered analysts for the ensuing 22 years. During the two decades that followed the initial work there have been enormous developments in NMR technology. Using new experimental approaches, specifically homodecoupled 1,1- and 1,n-HD-ADEQUATE NMR experiments developed in 2014, the structure of only a 700 µg sample of cryptospirolepine has been revised and is shown on the cover of this volume. The confluence of the NMR technological and methodological advances that allowed the revision of the structure of cryptospirolepine using a submilligram sample seems a fitting example for this book, which is dedicated to the NMR characterization of various classes of natural products.
Volume 2 considers data processing and algorithmic based analyses tailored to natural product structure elucidation and reviews the application of NMR to the analysis of a series of different natural product families including marine natural products, terpenes, steroids, alkaloids and carbohydrates. Volume 1 discusses contemporary NMR approaches including optimized and future hardware and experimental approaches to obtain both the highest quality and most appropriate spectral data for analysis. These books, bringing together acknowledged experts, uniquely focus on the combination of experimental approaches and modern hardware and software applied to the structure elucidation of natural products. The volumes will be an essential resource for NMR spectroscopists, natural product chemists and industrial researchers working on natural product analysis or the characterization of impurities and degradation products of pharmaceuticals that can be as scarce as natural product samples.
Antony J. Williams graduated with a BSc and PhD in chemistry from the University of Liverpool and University of London respectively. He subsequently became a Post-doctoral Fellow at the National Research Council in Ottawa and then an NMR Facility Director at the University of Ottawa. He has also worked as an NMR Technology Leader at Eastman-Kodak Company in Rochester and held a number of positions, including Chief Science Officer, at ACD/Labs. In 2007, he established ChemZoo, Inc and became host of ChemSpider, one of the primary internet portals for chemistry. ChemSpider was acquired by the Royal Society of Chemistry (RSC) in 2009 and Dr Williams is currently Vice-President of Strategic Development at the RSC. He presently holds an adjunct position at UNC-Chapel Hill and has been a member of the ACS since 1996.
Gary E. Martin graduated with a BS in Pharmacy in 1972 from the University of Pittsburgh and a PhD in Pharmaceutical Sciences from the University of Kentucky in 1975, specializing in NMR spectroscopy. He was a Professor at the University of Houston from 1975 to 1989, assuming the position of Section Head responsible for US NMR spectroscopy at Burroughs Wellcome, Co. in Research Triangle Park, NC, eventually being promoted to the level of Principal Scientist. In 1996 he assumed a position at what was initially the Upjohn Company in Kalamazoo, MI and held several positions there through 2006 by which time he was a Senior Fellow at what was then Pfizer, Inc. In 2006 he assumed a position as a Distinguished Fellow at Schering-Plough responsible for the creation of the Rapid Structure Characterization Laboratory. He is presently a Distinguished Fellow at Merck Research Laboratories.
David Rovnyak earned his BS from the University of Richmond, and his PhD studying high resolution NMR of quadrupolar nuclei at MIT. He transitioned to solution phase biomolecular NMR in postdoctoral work at the Harvard Medical School before joining the Chemistry Department at Bucknell University, where he has been recognized with Bucknell's Excellence in Teaching Award. He currently serves as Assistant Editor of Concepts in Magnetic Resonance. His lab pursues interdisciplinary topics in biophysical research including bile acid aggregation, methods in protein NMR, nonuniform sampling and small molecule profiling.
Table of Contents
Section Title | Page | Action | Price |
---|---|---|---|
Cover | Cover | ||
Contents | ix | ||
Foreword | v | ||
Dedication | viii | ||
Part 1 | 1 | ||
Chapter 1 Application of the Nuclear Overhauser Effect to the Structural Elucidation of Natural Products | 3 | ||
1.1 The Historical Origin of the Term ‘‘Nuclear Overhauser Effect | 3 | ||
1.2 The Theory Behind the NOE | 6 | ||
1.3 Multispin Systems | 15 | ||
1.4 The Kinetic NOE | 16 | ||
1.5 Transient NOE | 17 | ||
1.6 ROE and ROESY | 18 | ||
1.7 Scalar Couplings–Zero-quantum Filters | 21 | ||
1.8 NOE Experiments for the Structural Elucidation of Dimeric Compounds | 24 | ||
1.9 Fully Quantitative NOE in Small Molecules | 26 | ||
1.10 NOE Deconvolution–NAMFIS | 30 | ||
1.11 Conclusions | 35 | ||
References | 36 | ||
Chapter 2 Assigning Molecular Configuration by Nuclear Magnetic Resonance | 39 | ||
2.1 Assigning Relative Configuration | 39 | ||
2.1.1 Coupling Constants and NOEs | 40 | ||
2.1.2 Acetonides | 43 | ||
2.1.3 J-Based Analysis–The Murata Method | 44 | ||
2.1.4 Universal Database | 51 | ||
2.1.5 Computational Methods | 55 | ||
2.1.6 Residual Chemical Shift Anisotropy | 56 | ||
2.2 Assigning Absolute Configuration | 60 | ||
2.2.1 Chiral Anisotropic Reagents | 60 | ||
2.3 Conclusions | 66 | ||
References | 68 | ||
Chapter 3 Nuclear Magnetic Resonance Experiments Applicable to the Elucidation and Characterization of Nitrogenous Natural Products: 1H-15N Heteronuclear Shift Correlation Methods | 71 | ||
3.1 1H-15N Direct and Long-range Heteronuclear Shift Correlation | 71 | ||
3.2 15N Chemical Shift Referencing | 72 | ||
3.3 The Range of 15N Chemical Shifts | 73 | ||
3.4 15N Pulse Widths | 74 | ||
3.5 15N Chemical Shift Prediction | 76 | ||
3.5.1 Validating 15N Chemical Shift Prediction | 80 | ||
3.5.2 Setting F1 Spectral Windows | 82 | ||
3.5.3 Structure Verification using a 15N Content Database | 83 | ||
3.5.4 Enhancing 15N Chemical Shift Prediction with a ‘‘User-trained\" Database | 83 | ||
3.6 Computer-assisted Structure Elucidation–The Impact of 15N Data | 84 | ||
3.7 1JNH and nJNH Coupling Constants | 86 | ||
3.8 1H-15N Results Obtained Using Various Experiments | 86 | ||
3.8.1 1H-15N Experiments Employing an Initial 1JNH Magnetization Transfer | 87 | ||
3.8.2 1H-15N Experiments Employing an Initial nJNH Magnetization Transfer | 91 | ||
3.8.3 1H-15N HSQMBC | 95 | ||
3.8.4 1H-15N HSQMBC-TOCSY: A Hyphenated Long-range 1H-15N Experiment | 98 | ||
3.8.5 Triple-resonance 1H-15N Experiments | 107 | ||
3.9 Conclusions | 113 | ||
References | 113 | ||
Chapter 4 Application of Residual Dipolar Couplings to the Structural Analysis of Natural Products | 117 | ||
4.1 Introduction | 117 | ||
4.2 Alignment Media | 130 | ||
4.3 The Nature of the Alignment Process | 142 | ||
4.4 How RDCs are Measured | 143 | ||
4.5 Data Analysis–How the RDCs are used in the Structural Analysis of Small Molecules | 148 | ||
4.5.1 Possible Scenarios | 148 | ||
4.5.2 How to Manage Experimental Uncertainties in RDC Analysis | 153 | ||
4.5.3 The Conformational Problem | 156 | ||
4.5.4 How to Handle Symmetrical Rotors | 158 | ||
4.5.5 Software | 159 | ||
4.6 RDCs in the Structural Elucidation of Natural Products | 159 | ||
4.6.1 Dimeric Products | 166 | ||
4.7 Conclusions | 172 | ||
References | 172 | ||
Chapter 5 Applications of High-resolving Power, High-accuracy Mass Spectrometry for the Structural Elucidation of Natural Products | 177 | ||
5.1 Introduction | 177 | ||
5.1.1 Mass Spectrometry for the Structural Elucidation of Unknowns | 177 | ||
5.1.2 Brief Description of FT-ICR | 185 | ||
5.2 Examples from Literature | 190 | ||
5.2.1 Ultra-high Resolving Power to Separate the Isotopic Fine Structures | 190 | ||
5.2.2 Study of Biosynthesis Processes by Measuring Stable Isotopic-labeled Precursors using FT-ICR MS | 194 | ||
5.2.3 Metabolite Profiling of Triterpene Saponins by Combined Accurate Mass Measurement and MSn Experiments using LC FT-ICR MS | 195 | ||
5.3 Conclusions | 197 | ||
References | 197 | ||
Chapter 6 Current Pulse Sequence Developments in Small-molecule Nuclear Magnetic Resonance Spectroscopy | 199 | ||
6.1 Introduction | 199 | ||
6.2 Fast NMR | 202 | ||
6.3 Pure Shift NMR | 206 | ||
6.3.1 The ZS Experiment | 209 | ||
6.3.2 Sensitivity, Strong Coupling Effects, and Spectral Quality | 210 | ||
6.3.3 ZS Applications | 216 | ||
6.3.4 Implementing Homodecoupling in 1D and 2D NMR Experiments | 218 | ||
6.4 Perfect NMR | 227 | ||
6.4.1 Perfect Spin-echo | 228 | ||
6.4.2 Using ZQFs | 233 | ||
6.5 Ultra-long-range Correlation NMR | 234 | ||
6.5.1 Long-range HSQMBC | 236 | ||
6.5.2 HSQMBC-TOCSY | 237 | ||
6.5.3 ADEQUATE | 240 | ||
6.6 Future Perspectives | 243 | ||
Acknowledgments | 244 | ||
References | 244 | ||
Part 2 | 251 | ||
Chapter 7 Terpenes: Mono-, Sesqui-, and Higher Terpenes | 253 | ||
7.1 Introduction | 253 | ||
7.2 Types of Terpenes and Related Compounds | 254 | ||
7.3 Basic Approach to Terpene Structure Elucidation by NMR Spectroscopy | 257 | ||
7.4 Avoiding Determining the Wrong Structure | 261 | ||
7.5 Specialized Techniques that are Useful for Different Types of Terpenes | 267 | ||
7.6 Conclusions | 272 | ||
Acknowledgments | 272 | ||
References | 273 | ||
Chapter 8 Nuclear Magnetic Resonance of Steroids | 275 | ||
8.1 Prologue | 275 | ||
8.2 An Introduction to Steroids | 275 | ||
8.3 Modern and ‘‘Rare\" NMR Methods in the Steroid Field | 284 | ||
8.3.1 Recent General NMR Developments | 284 | ||
8.3.2 Covariance NMR and Steroids | 284 | ||
8.3.3 The HSQC-TOCSY Experiment | 287 | ||
8.3.4 13C-Detected Experiments | 287 | ||
8.3.5 1D and High-resolution 1D 1H Methods | 288 | ||
8.3.6 19F NMR | 290 | ||
8.3.7 Residual Dipolar Couplings | 294 | ||
8.4 Considerations | 298 | ||
8.5 Conclusions | 307 | ||
Acknowledgments | 308 | ||
References | 308 | ||
Chapter 9 Nuclear Magnetic Resonance Experiments Applicable to the Elucidation and Characterization of Alkaloid Structures Part I: Direct 1H-13C Heteronuclear Shift Correlation and Establishing Contiguous Protonated Carbon Spin Systems | 315 | ||
9.1 Introduction | 315 | ||
9.2 ‘‘First-tier\" NMR Methods for Alkaloid Structure Characterization | 316 | ||
9.2.1 Sample Preparation | 317 | ||
9.2.2 Probe Selection | 317 | ||
9.2.3 Parameter Choices | 318 | ||
9.3 Acquiring NMR Spectra | 319 | ||
9.4 1D Reference Spectra | 319 | ||
9.5 Fundamental or ‘‘First-tier\" 2D NMR Spectra | 322 | ||
9.5.1 Conventional HSQC | 322 | ||
9.5.2 Multiplicity-edited HSQC | 324 | ||
9.5.3 Incorporating BIRD-based Homonuclear Decoupling in the HSQC Experiment: PS-HSQC | 324 | ||
9.5.4 Summary of One-bond Heteronuclear Correlation Methods | 327 | ||
9.6 Intentionally Folding HSQC Spectra in Limited-sample Situations | 329 | ||
9.7 Non-uniform Sampling | 332 | ||
9.8 Long-range Heteronuclear Shift Correlation | 335 | ||
9.8.1 HMBC | 335 | ||
9.8.2 LR-HSQMBC | 338 | ||
9.9 Defining the Proton-Proton Connectivity Network | 342 | ||
9.9.1 COSY and TOCSY Spectra | 342 | ||
9.9.2 HSQC-TOCSY Spectra | 346 | ||
9.9.3 HSQMBC-COSY and HSQMBC-TOCSY Spectra | 349 | ||
9.9.4 Strategy for Employing Hyphenated 2D Experiments | 354 | ||
References | 354 | ||
Chapter 10 Nuclear Magnetic Resonance Experiments Applicable to the Elucidation and Characterization of Alkaloid Structures Part II: Advanced Techniques for the Identification of Adjacent Carbons Using H2BC, 1,1-ADEQUATE, and Variants | 358 | ||
10.1 Identification of Adjacent Carbons Using H2BC and 1,1-ADEQUATE Data | 358 | ||
10.1.1 Identification of Adjacent Protonated Carbons Using the H2BC Experiment | 359 | ||
10.1.2 Identifying Adjacent Carbons Using 1,1- and 1,1-HD-ADEQUATE | 361 | ||
10.2 1,n-ADEQUATE and Advanced Variants | 371 | ||
10.2.1 1,n-ADEQUATE | 373 | ||
10.2.2 1,n-HD-ADEQUATE | 374 | ||
10.2.3 Edited 1,n-HD-ADEQUATE | 378 | ||
10.3 Examples of the Application of Advanced NMR Methods in Structure Elucidation Studies | 380 | ||
10.3.1 Staurosporine–Is the Crew's Rule Obsolete? | 383 | ||
10.3.2 Cryptospirolepine–Resolution of a Long-standing Structural Ambiguity Using 1,1- and 1,n-HD-ADEQUATE Spectra | 386 | ||
10.3.3 Eudistidine-C | 397 | ||
10.4 Conclusions | 399 | ||
References | 400 | ||
Chapter 11 Nuclear Magnetic Resonance Case Studies in Marine Natural Products | 403 | ||
11.1 Introduction | 403 | ||
11.1.1 Case Studies | 404 | ||
11.1.2 Snapshots | 405 | ||
11.2 Marine Natural Product Case Studies | 405 | ||
11.2.1 Trachycladindoles | 405 | ||
11.2.2 Franklinolides | 406 | ||
11.2.3 Bistellettazines | 409 | ||
11.2.4 Phorbasins | 412 | ||
11.2.5 Ircinialactams | 417 | ||
11.2.6 Fascioquinols | 420 | ||
11.3 Marine Natural Product Snapshots | 426 | ||
References | 438 | ||
Chapter 12 Nuclear Magnetic Resonance Case Studies in Microbial Natural Products | 440 | ||
12.1 Introduction | 440 | ||
12.1.1 Case Studies | 441 | ||
12.1.2 Snapshots | 441 | ||
12.2 Microbial Natural Product Case Studies | 442 | ||
12.2.1 Aspergillazines | 442 | ||
12.2.2 Nocardioazines | 444 | ||
12.2.3 Heronamides | 447 | ||
12.2.4 Kibdelones | 452 | ||
12.2.5 Reveromycins | 457 | ||
12.3 Microbial Natural Product Snapshots | 463 | ||
12.3.1 Macrocyclic Lactones | 463 | ||
12.3.2 Cyclic Peptides | 463 | ||
12.3.3 Caged Structures | 463 | ||
12.3.4 Miscellaneous | 475 | ||
12.4 Conclusion | 483 | ||
References | 483 | ||
Chapter 13 Nuclear Magnetic Resonance in Saponin Structure Elucidation | 486 | ||
13.1 Introduction | 486 | ||
13.2 General Considerations | 487 | ||
13.3 Structure and Relative Stereochemistry of the Aglycone | 489 | ||
13.4 Identity of Component Monosaccharides | 493 | ||
13.5 Linkage Position and Sequence of the Oligosaccharide Chain | 497 | ||
13.6 Concluding Remarks | 499 | ||
13.6.1 Experimental | 500 | ||
References | 500 | ||
Chapter 14 Increasing the Adoption of Advanced Techniques for the Structure Elucidation of Natural Products | 502 | ||
References | 506 | ||
Subject Index | 508 |