Research Topic

HiFSA - 1H iterative Full Spin Analysis - An Introduction

by Guido F. Pauli, UIC, Chicago (IL)

HiFSA is an NMR methodology which allows the complete interpretation of the complex resonances (aka "multiplets") typically found in 1H NMR spectra of molecules, such as organic compounds and natural products.

HiFSA can be performed using any 1D 1H NMR data set, provided that the resolution is adequate. It typically requires an iterative process, which can be performed manually with a spin simulation tool, or (semi-)automed using a computational tool such as the PERCH software.

Additional Tools for Multiplet Analysis

In preparation of HiFSA analysis, and/or to support manual analysis of complex 1H NMR signals, the following are helpful software tools:

June 2017

Rare Riolozanes Elucidated by HiFSA

The structural characterization and distinction of the stereoisomers of riolozanes, rare diterpenes from Jatropha dioica, utilized HiFSA and yielding complete J-correlation maps that were represented as quantum interaction and linkage tables (QuILTS). The absolute configuration of two epimeric riolozanes was established by means of vibrational circular dichroism and via X-ray diffraction analysis. The HiFSA profiles of the compounds provides a means of rapid dereplication with high specificity.

E Melchor-Martínez, D Silva-Mares, E Torres-López, N Waksman-Minsky, G Pauli, S-N Chen, M Niemitz, M Sánchez-Castellanos, A Toscano, G Cuevas, V Rivas-Galindo
Stereochemistry of a Second Riolozane and Other Diterpenoids from Jatropha dioica
Journal of Natural Products 80, 2252-2262 (2017)
dx.doi.org/10.1021/acs.jnatprod.7b00193

March 2017

HiFSA Enables Quantum Mechanical Quantitative NMR (QM-qNMR)

HiFSA is the basis of the next-generation of quantitative measures in qNMR analsis: representing a quantum mechanical (QM) method, QM-qHNMR that employs HiFSA to achieve quantitation that employs the entire spin system of an ananlyte, rather then discrete integrals or line fitting methods. The first systematic evaluation of QM vs. non-QM deconvolution as qHNMR quantitation measures demonstrated that QM-qHNMR can account successfully for the complexity of 1H NMR spectra of individual analytes. QM-qHNMR can also be applied to complex mixtures such as extracts and advances chemical standardization of natural health products by its inherent QM accuracy and the use of universal (non-identical) calibrants.

R. Phansalkar, C. Simmler, J. Bisson, S.-N. Chen, D. Lankin, J. McAlpine, M. Niemitz, G. Pauli
Evolution of Quantitative Measures in NMR: Quantum Mechanical qHNMR Advances Chemical Standardization of a Red Clover (Trifolium pratense) Extract
Journal of Natural Products 80, 634-647 (2017)
dx.doi.org/10.1021/acs.jnatprod.6b00923
PubMedCentral: PMC5368683 [Open Access Article]

January 2017

Absolute Stereochemistry of Oligomeric Proanthocyanidins by HiFSA

Combining 1D/2D NMR, HRESIMS, ECD and gauge-invariant atomic orbital (GIAO) chemical shift calculations with HiFSA yield data sets that empower the determination of the absolute configuration of monomeric units in higher oligomeric proanthocyanidins (n=3+4) using 13C NMR chemical shifts via diastereomeric building block (A-type dimers) analysis. When combined with with ECD reference data, HiFSA-supported NMR elevates the level of structural information achievable for these structurally demanding molecules and avoid the s need for hen degradation analysis. In the present project, HiFSA helped advancing the probing of OPAC chemical spaces for species that bind selectively to collagenous and potentially other biologically important biomacromolecules.

J.W. Nam, R. Phansalkar, D.C. Lankin, J. McAlpine, A. Leme-Kraus, C. Vidal, A. Bedran-Russo, S.-N. Chen, G. Pauli
Absolute Stereochemistry of Native Oligomeric Proanthocyanidins with Dentin Biomodification Potency
Journal of Organic Chemistry 82, 1316-1329 (2017)
dx.doi.org/10.1021/acs.joc.6b02161
[Featured in C&E News, March 2017: "Bark Extract Strengthens Bite "]

February 2016

HiFSA Facilitates Structural Correctness

Being the most accessible NMR experiment, 1D 1H spectra also encode a wealth of information about bonds and molecular geometry that may be fully mined by HiFSA. The revision of the structure of the sesquiterpene, aquatolide, from a bicyclo[2.2.0]hexane to a bicyclo[2.1.1]hexane motif via NMR, X-ray crystallography, and full synthesis exemplify that the achievement of “structural correctness” depends on the completeness of the experimental evidence. Archived FIDs and newly acquired aquatolide spectra demonstrate that archiving and rigorous interpretation of 1D 1H NMR data, particularly HiFSA, enhance the reproducibility of (bio)-chemical research and curb the growing trend of structural misassignments. Quantum interaction and linkage tables (QuILTs) are introduced for a more intuitive visualization of 1D J-coupling relationships, NOESY correlations, and heteronuclear experiments.

Pauli GF, Niemitz M, Bisson J, Lodewyk M, Soldi C, Shaw J, Tantillo D, Saya J, Vos K, Kleinnijenhuis R, Hiemstra H, Chen SN, McAlpine J, Lankin D, Friesen JB
Towards Structural Correctness: Aquatolide and the Importance of 1D Proton NMR FID Archiving
Journal of Organic Chemistry 81: 878-889 (2016)
dx.doi.org/10.1021/acs.joc.5b02456
PubMedCentral: PMC4746703 [Open Access Article]

March 2015

HiFSA Allows Assembly of Molecular Building Blocks in NMR

A fragment-based approach utilizes HiFSA to examine structurally related organic compounds by 1H NMR spectroscopy. Characteristic NMR profiles of key structural motifs were generated by HiFSA and then joined together as building blocks to recreate the 1H NMR spectra of increasingly complex molecules. To illustrate the concept, seven steviol glycosides and two structurally related isosteviol derivatives were studies. This methodology has potential impact on relevant aspects of natural product research including structural verification, chemical dereplication, and mixture analysis.

Part 26- Residual Complexity of Bioactive Natural Products
Napolitano J, Simmler C, Napolitano J, McAlpine J, Lankin D, SN Chen, Pauli GF
Digital NMR Profiles as Building Blocks: Assembling 1H Fingerprints of Steviol Glycosides
Journal of Natural Products 78: 658-665 (2015)
dx.doi.org/10.1021/np5008203
PubMedCentral: PMC4280114

June 2014

HiFSA is Essential for 1H NMR Dereplication and Adequate Reporting

Adequate precision is important when reporting the δ and J parameters of frequency domain 1H NMR (HNMR) data. Using a variety of structural classes (terpenoids, phenolics, alkaloids) from different taxa (plants, cyanobacteria) paired with HiFSA analysis, enhanced precision is shown to be essential in NMR spectroscopic analysis and rationalizes the need for reporting Δδ and ΔJ values at the 0.1–1 ppb and 10 mHz level, respectively. Spectral simulations paired with HiFSA iteration are shown to be essential tools for complete spectral interpretation, adequate precision, and unambiguous HNMR-driven dereplication and metabolomic analysis.

Part 25 - Residual Complexity of Bioactive Natural Products
Pauli GF, Chen SN, Lankin D, Bisson J, Case R, Chadwick L, Goedecke T, Inui T, Krunic A, Jaki B, McAlpine J, Mo S, Napolitano J, Orjala J, Lehtivarjo J, Korhonen SP, Niemitz M
Essential Parameters for Spectral Analysis and Structural Dereplication by 1H NMR Spectroscopy
Journal of Natural Products 77: 1473-1487 (2014)
dx.doi.org/10.1021/np5002384

September 2013

HiFSA Paints Molecular Portraits

The full quantum mechanical description achieved by HiFSA analysis is equivalent to painting a molecular portrait of any organic molecule. The following work shows that HiFSA analysis can be performed universally for molecules from 150 and 1000 amu and likely above.

Napolitano JG, Lankin D, McAlpine JB, M. Niemitz, SP Korhonen, Chen SN, Pauli GF
Proton Fingerprints Portray Molecular Structures: Enhanced Description of the 1D 1H NMR Spectra of Small Molecules
Journal of Organic Chemistry 78: 2827-2839 (2013)
dx.doi.org/10.1021/jo4011624

June 2013

Orthogonal Botanical Standardization

The present study describes the development of a 1D qHNMR-based method for simultaneous identification and quantification of green tea constituents. This approach utilizes computer-assisted 1H iterative Full Spin Analysis (HiFSA) and enables rapid profiling of seven catechins in commercial green tea extracts. The qHNMR results were cross-validated against quantitative profiles obtained with an orthogonal LC–MS/MS method.

Napolitano JG, Gödecke T, Lankin DC, Jaki BU, McAlpine JB, Chen SN, Pauli GF
Orthogonal Analytical Methods for Botanical Standardization: Determination of Green Tea Catechins by qNMR and LC-MS/MS
Journal of Pharmaceutical and Biomedical Analysis 93: 59-67 (2014)
dx.doi.org/10.1016/j.jpba.2013.06.017

May 2013

Flavonoid HiFSA Fingerprinting

This study shows the application of HiFSA methodology to the analysis of flavonoid glycosides. Flavonoids are widely distributed in nature, in particular in higher plants, and are frequently use for quality control, distinction of taxa, and the evaluation of biological activity.

Riihinen K, Velitchka M, Gödecke T, Soininen P, Laatikainen R, Veervort J, Lankin D,
Pauli GF
1H NMR Fingerprinting of Vaccinium vitis-idaea flavonoid glycosides
Phytochemical Analysis 24: 476-483 (2013)
dx.doi.org/10.1002/pca.2444

March 2013

Silybum Flavanolignans As Proof of Concept for HiFSA Methodology

The following publication reported on the general methodology which a computational approach to the full analysis os 1H NMR spin system. The historically challenging falvanolignans from Silybum marianum (Milkthistle) were used to establish the proof of concept. The cases show that even nearl identical compounds with nearly indistiguishable NMR spectra can be fully analyzed and even quantified in mixtures using the HiFSA-qHNMR approach:

Part 20 - Residual Complexity of Bioactive Natural Products
Napolitano JG, Lankin D, Graf T, Friesen JB, Chen SN, McAlpine JB, Oberlies, NH, Pauli GF
HiFSA Fingerprinting of Isomers with Near Identical NMR Spectra:
The Silybin/Isosilybin Case
Journal of Organic Chemistry 78: 2827-2839 (2013)
dx.doi.org/10.1021/jo302720h [Featured Article]

 

Related Topic: Identification of Ecdysones

The online version of The Ecdysone Handbook, 3rd edition (online), compiled by R. Lafon, J. Harmatha, F. Marion-Poll, L. Dinin, and I. Wilson, provides continuously updated information on over 450 ecdysteroids, including their UV, IR, MS, and NMR data

 

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