Modern NMR Approaches to the Structure Elucidation of Natural Products, Volume 2: Data Acquisition and Applications to Compound Classes

532 Pages·2016·26.55 MB·English

by  Antony Williams (ed.)

Modern NMR Approaches to the Structure Elucidation of
Natural Products
Volume 2: Data Acquisition and Applications to Compound Classes
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Modern NMR Approaches to
the Structure Elucidation of
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0 Natural Products
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g | d Edited by
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s.rs Antony J. Williams
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6 Gary E. Martin
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2 Merck & Co., Inc., USA
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d David Rovnyak
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blis Bucknell University, USA
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pu PrintISBN:978-1-84973-393-9
p:// Two-volumesetprintISBN:978-1-84973-459-2
htt PDFeISBN:978-1-84973-468-4
on EPUBeISBN:978-1-78801-072-6
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ed Apartfromfairdealingforthepurposesofresearchfornon-commercialpurposesorfor
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68 Foreword
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oi: The complex process of the structure elucidation of natural products
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g | continues to be one of the most intensely practiced areas of scientific
or activity.Whetherthechemicalentityoriginatesasaresultofchemical(total)
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s.rs synthesis or represents a purified or semi-purified isolate from natural
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u sources, a correct structural verification, including precise stereochemical
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p:// analysis, remains of critical scientific concern. The effective use of con-
htt temporary and evolving nuclear magnetic resonance (NMR) methodologies
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6 o represents the central tool for the complete establishment of chemical
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0 structure. Volume 2 of the series Modern NMR Approaches to the Structure
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er Elucidation of Natural Products continues in the same spirit as the treatise
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e that was begun in Volume 1 on contemporary NMR techniques applied to
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De the natural product structural elucidation process.
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n 1 Volume 2 is composed of 14 chapters and, like Volume 1, is divided
d o into two parts. Following a brief introductory section, which includes a
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bli Volume 2 consists of six chapters. These include a detailed account of the
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respectiveNMRtopicssuperimposedontheoverallthemeofthesechapters,
whichemphasizesthesuccessfulexperimentalimplementationoftheNMR
experimentsbeingdiscussed.Chapter1isaconciselywrittencontemporary
overviewofthenuclearOverhausereffect(nOe)from bothatheoreticaland
anexperimentalperspective, including descriptionsofthe two-dimensional
NOESY and ROESY experiments. These are traditionally employed for
establishingspatialrelationshipswithintheprotonspinsystemsviathrough-
space dipolar interactions. In addition, there is an introduction to the
implementationofanewtechnique—NMRanalysisofmolecularflexibilityin
solutionorNAMFIS—anditsrollinnaturalproductstructureelucidation.The
experiments discussed in Chapter 1 and their role in elucidating the correct
structure and stereochemistry of natural products cannot be overstated.
ModernNMRApproachestotheStructureElucidationofNaturalProducts:
Volume2:DataAcquisitionandApplicationstoCompoundClasses
EditedbyAntonyJ.Williams,GaryE.MartinandDavidRovnyak
rTheRoyalSocietyofChemistry2017
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
v
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vi Foreword
Chapter 2 consists of a discussion of the determination of both the relative
(J-based) and absolute stereochemistry of natural products and the NMR
experiments used for obtaining this important structural information,
includingtheuseoftheMosherestermethodology.Chapter2alsoincludesa
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0 brief treatment of a cutting-edge advance afforded by a newly developed
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F technique for applying residual chemical shift anisotropy (RCSA) for stereo-
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8 chemical assignment. Going forward, it is quite likely that RCSA measure-
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3 ments will be regularly combined with nOe/rOe (Chapter 1) and residual
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4 dipolar coupling (RDC) measurements (Chapter 4). Chapter 3 describes the
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81 applications of 15N-NMR spectroscopy in natural product structure eluci-
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9/ dation,includesadiscussionofthebasicexperimentalparametersassociated
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10 with15N-NMRdataacquisitionanddetailstheexperimentalimplementation
10. of 15N-NMR in the determination of natural product structures. The import-
doi: ance of being able to incorporate results derived from 15N-NMR into the
g | structural elucidation process greatly increases the prospects of arriving at a
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c. correct structure. Chapter 4 introduces the theory and applications of RDC,
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16 pretation and a section on the caveats associated with RDC. This will be an
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er 2 importantNMRtechniqueinapplicationforsmallmoleculenaturalproducts.
mb TheuseofRDCisalsodiscussedinChapters2and8.Chapter5isanoverview
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c of contemporary high-resolution mass spectrometry and its role in natural
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2 product structural elucidation. This chapter highlights the fact that, while
n 1 NMR techniques tend to dominate much of the natural product structure
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ed elucidation process, when taken together with the requisite structural infor-
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blis mationderivedfrommassspectrometry,thecombinationprovidesapowerful
Pu one–two punch for producing correct structure determination. It is for this
reasonthatsuchachapterisincludedhere.ThecontentsofChapter6focus
on recent and future developments in NMR methodologies, with numerous
examplesillustratingexperimentalresultsintermsofstructure.Furthermore,
this chapter describes completely new NMR experiments, which may ultim-
ately have a significant impact on the structural elucidation process. This
chapter is well written and serves to illustrate cutting-edge NMR techniques
that will evolve into the mainstream of the structural elucidation process.
Part 2 of Volume 2 consists of eight chapters. The recurring theme here
that is superimposed on the material in Part 2 is the application of com-
binedNMRtechniques,whichisillustratedwithappropriateexamples.This
constitutes a powerful way of introducing useful strategies for achieving
success inthe structure elucidation process tothe spectroscopistornatural
product chemist. The chapters contain useful examples and specific case
studiesforsomeofthemoreimportantnaturalproductclasses.Chapter7is
a well-written chapter and discusses the practical applications of NMR
experimentswithexamplesofstructureelucidationdrawnfromtheterpene
class of natural products (monoterpenes, sesquiterpenes and higher
View Online
Foreword vii
terpenes). Whilethese structures may notappeartobe verycomplex onthe
surface, they nevertheless pose their own set of problems and challenges.
Chapter 8 describes NMR experiments that are applied to the structure de-
terminationofsteroids,oneofthemoststudied(byNMR)classesofnatural
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0 products.Somespecificexperimentswithexamplesarediscussed,including
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FP structural details involving 19F-NMR. Chapters 9 and 10 detail NMR experi-
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8 mentsthatpertaintothestructuredeterminationofalkaloids.Thestrategies
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3 employed for structure elucidation are approached in a systematic manner
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49 and are illustrated with good examples. 15N-NMR is of considerable utility
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8 for providing unambiguous structures of nitrogen-containing natural
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9/ products. Chapters 11 and 12 provide additional case studies of selected
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10 molecules derived from marine natural products and antimicrobial areas,
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1 respectively. Because of the structural complexity of many of these mol-
doi: ecules, different experimental strategies may be required for full structure
g | elucidation.Eachstructuremayrequireauniquesetofexperimentsand,in
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16 thesaponin.Eachofthesetwostructuralcomponentsmayrequiredifferent
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er 2 and unique strategies in order to assess their respective structures and,
mb correspondingly, different NMR experiments for the determination of each
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c structural component within the same molecule may be necessary. This is
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n 1 polysaccharide, typically containing more than one sugar moiety with
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ed differing branch points for the sugar residues. Chapter 14 is a summary
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blis perspective on both volumes and discusses the future directions of natural
Pu product structure elucidation activity.
The collective contents of the two-volume series Modern NMR Approaches
to the Structure Elucidation of Natural Products present very useful and
practical information for the practicing NMR spectroscopist and natural
product chemisttoimplementintheirownlaboratories.Allofthechapters
arewellwrittenbyrespectedexpertsinthefield.Theconsiderablevolumeof
experimental detail contained in the chapters, together with structure elu-
cidationstrategies,whenimplemented,iscertaintocontributetoanoverall
improvementinthespeedandaccuracyofnaturalproductstructuresbeing
elucidated.
David C. Lankin
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oi: For the most important women in my life—Eirlys, Rae and AnnMarie.
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g | Thank you for your love and support—Antony J. Williams
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er With gratitude to my parents, James and Virginia—David Rovnyak
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68 Contents
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g | Chapter 1 Application of the Nuclear Overhauser Effect to the
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http:// 1.1 The Historical Origin of the Term ‘‘Nuclear
on Overhauser Effect’’ 3
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1 1.2 The Theory Behind the NOE 6
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d o 1.7 Scalar Couplings—Zero-quantum Filters 21
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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
Kirk R. Gustafson, Susanna T. S. Chan and Yizhou Liu
2.1 Assigning Relative Configuration 39
2.1.1 Coupling Constants and NOEs 40
ModernNMRApproachestotheStructureElucidationofNaturalProducts:
Volume2:DataAcquisitionandApplicationstoCompoundClasses
EditedbyAntonyJ.Williams,GaryE.MartinandDavidRovnyak
rTheRoyalSocietyofChemistry2017
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
ix
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x Contents
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
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03 Chapter 3 Nuclear Magnetic Resonance Experiments Applicable to
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10. the Elucidation and Characterization of Nitrogenous
doi: Natural Products: 1H–15N Heteronuclear Shift Correlation
g | Methods 71
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htt Correlation 71
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d o 3.5.3 Structure Verification using a 15N Content
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with a ‘‘User-trained’’ Database 83
3.6 Computer-assisted Structure Elucidation—The
Impact of 15N Data 84
3.7 1J and nJ Coupling Constants 86
NH NH
3.8 1H–15N Results Obtained Using Various
Experiments 86
3.8.1 1H–15N Experiments Employing an Initial
1J Magnetization Transfer 87
NH
3.8.2 1H–15N Experiments Employing an Initial
nJ Magnetization Transfer 91
NH
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