spectral interpretation general process for structure elucidation of an unknown nat. prod. rep.,...
DESCRIPTION
NMR Spectroscopy Nat. Prod. Rep., 1999, 16, Possible Strategy using only C-C correlations heteroatoms can be inferred from 13 C chemical shifts -Requires high concentrations because of low sensitivity of 2D INADEQUATE -Because of 1 J CC variability may need to collect multiple 2D INADEQUATE experiments -Requires longer time than other methods, still need HMBC or NOE to bridge heteroatomsTRANSCRIPT
Spectral InterpretationSpectral Interpretation
General Process for Structure Elucidation of an Unknown
Nat. Prod. Rep.Nat. Prod. Rep., 1999, 16, 241-248, 1999, 16, 241-248
• Normally the molecular formula is derived from a combination of 13C NMR, DEPT and MS data.
• Using IR, UV and 13C NMR the functional groups can be proposed• 1H NMR coupling data or 2D NMR correlations are used to assemble substructures• The substructures are then combined into ‘working structures’ using all possible
combinations of the substructures• Check structures for consistency with the 2D-NMR data and MS fragmentations etc.• 13C chemical shifts of the surviving structure(s) are then compared with literature,
database or predicted values to confirm the 2D structure of the molecule.• To determine the relative stereochemistry of the molecule, 1H coupling constant (J)
and Nuclear Overhauser (NOE) data is used
Spectral InterpretationSpectral Interpretation
General Process for Structure Elucidation of an Unknown
Need to Verify as early as possible if the structure has already been identified
• Don’t want to waste time and effort re-discovering a compound• Done by using a combination of molecular formula, substructure and chemical
structure databases
Nat. Prod. Rep.Nat. Prod. Rep., 1999, 16, 241-248, 1999, 16, 241-248
NMR SpectroscopyNMR Spectroscopy
Nat. Prod. Rep.Nat. Prod. Rep., 1999, 16, 241-248, 1999, 16, 241-248
Possible Strategy using only C-C correlations
heteroatoms can be inferred from heteroatoms can be inferred from 1313C chemical shiftsC chemical shifts
-Requires high concentrations because of low sensitivity of 2D INADEQUATE
-Because of 1JCC variability may need to collect multiple 2D INADEQUATE experiments
-Requires longer time than other methods, still need HMBC or NOE to bridge heteroatoms
NMR SpectroscopyNMR Spectroscopy
Possible Strategy using H-H and H-C correlations
Nat. Prod. Rep.Nat. Prod. Rep., 1999, 16, 241-248, 1999, 16, 241-248
- COSY sees 2,3 & 4 bond correlation which leads to confusion
- Impossible to distinguish between 3 and 3-bond correlations in HMBC
- Angular dependence of 3JHH and 3JCH means that some expected cross peaks will not appear in the COSY and HMBC spectra
- Lower resolution in indirect 13C dimension
NMR SpectroscopyNMR Spectroscopy
Typical Experiments and Connectivity Information used in Structure Elucidation
J. Nat. Prod. 2002, 65, 693-703
NMR SpectroscopyNMR Spectroscopy
Summarizing the available NMR results is an important first step.
- Also a source of problems if data is missing from the summary.
- Don’t ignore the spectral data or rely completely on your peak lists or summary data
Magn. Reson. Chem. 2003; 41: 359–372
NMR SpectroscopyNMR Spectroscopy
Need to Generate Molecular Connectivity Diagrams of the compound- effectively summarizes all the experimental NMR data- numerous possible connectivities, increases with the complexity of the compound
NMR SpectroscopyNMR SpectroscopyProposed Structure Needs to Be Consistent with ALL the observed data- a single unaccounted for peak, or a missing peak predicted by the structure may
indicate a wrong structure.- especially if some components of the structure rely on a single observation or correlation
Magn. Reson. Chem. 2001; 39: 762–764
NMR SpectroscopyNMR SpectroscopyProposed Structure Needs to Be Consistent with ALL the observed data- missing peak predicted by the structure may indicate a wrong structure.
Corrected StructureOriginal Structure
Org. Lett., Vol. 6, No. 23, 2004
Assignment change resolved Assignment change resolved missing NOE problemmissing NOE problem
NMR SpectroscopyNMR SpectroscopyValidate or Verify Accuracy of Structure by Consistency with Databases- is the structure and experimental chemical shift assignments consistent with predicted
chemicals shifts based on the experimental structures
J. Chem. Inf. Comput. Sci. J. Chem. Inf. Comput. Sci. 2002, 2002, 42, 42, 241-248241-248
Correct Structure
NMR SpectroscopyNMR SpectroscopyValidate or Verify Accuracy of Structure by Consistency with Databases- is the structure and experimental chemical shift assignments consistent with predicted
chemicals shifts based on the experimental structures
Correct Structure
NMR SpectroscopyNMR SpectroscopyNumerous Examples of Incorrect Structures in the Literature
Example:Example:
Incorrect Correct
Verified by total synthesis
Angew. Chem. Int. Ed. 2005, 44, 1012 – 1044
key HMBC correlationskey HMBC correlations
key NOE correlationskey NOE correlations
NMR SpectroscopyNMR SpectroscopyNumerous Examples of Incorrect Structures in the Literature
J. Nat. Prod. J. Nat. Prod. 2004, 2004, 67, 67, 1996-20011996-2001
- coupling correlation not always sufficient to properly determine a structure- NOEs can provide critical correlations that are not evident simply from coupling