Enhancing computer-assisted structure elucidation with DFT analysis of J-couplings

Area of Science:

• Computational Chemistry
• Organic Chemistry
• Spectroscopy

Background:

• Computer-assisted structure elucidation (CASE) systems primarily use 1D and 2D NMR data.
• Standard CASE systems interpret HMBC and COSY spectra as 2- or 3-bond correlations.
• Nonstandard correlations (NSCs), involving 4+ bonds, are often present but computationally expensive to include.

Purpose of the Study:

• To develop and validate a method for verifying the reliability of nonstandard correlations (NSCs) in CASE.
• To improve the efficiency and accuracy of the fuzzy structure generation (FSG) algorithm within CASE systems.
• To leverage high-accuracy density functional theory (DFT) computed J-couplings for NSC validation.

Main Methods:

• Verification of NSCs by comparing them with DFT-computed J-couplings (^4-6J_CH).
• Analysis of strychnine to identify and quantify NSCs in HMBC spectra.
• Application of the NSC verification method to 11 natural products and a CASE study of cleospinol A isomers.

Main Results:

• 41% of observed 8-Hz HMBC cross-peaks in strychnine were identified as NSCs consistent with DFT-computed J-couplings (>0.3 Hz).
• The 0.3 Hz cutoff for J-couplings was validated across 11 real-world natural product structures.
• DFT-computed J-couplings of NSCs effectively differentiated the correct structure among six proposed isomers for cleospinol A.

Conclusions:

• The proposed method reliably verifies NSCs by correlating them with DFT-computed J-couplings.
• This approach enhances the robustness of CASE analysis and improves the accuracy of molecular structure elucidation.
• The method can aid in identifying potential discrepancies in experimental NMR data.