Epimeric Mixture Analysis and Absolute Configuration Determination Using an Integrated Spectroscopic and...

Area of Science:

• Natural Product Chemistry
• Computational Chemistry
• Spectroscopy

Background:

• Structural elucidation of natural products is complex, with misassignments being a persistent challenge.
• The discovery of novel, intricate natural structures is increasing, alongside concerns about structural misassignments.
• Integrating spectroscopic methods with molecular modeling is a growing trend for structure determination.

Purpose of the Study:

• To demonstrate the efficacy of combined computational and spectroscopic methods for full 2D and 3D structural elucidation.
• To resolve an epimeric mixture of 6-hydroxyhippeastidine, including planar structure assignment and configuration determination.
• To validate the utility of specific computational techniques, such as DFT and CASE, for natural product structure elucidation.

Main Methods:

• Density Functional Theory (DFT) calculations for chemical shift prediction to aid planar structure assignment.
• Computer-Assisted Structure Elucidation (CASE) combined with Optical Rotatory Dispersion (ORD), Electronic Circular Dichroism (ECD), and Vibrational Circular Dichroism (VCD) spectroscopies.
• Optical Rotation (OR) and ORD computations for relative and absolute configuration determination.

Main Results:

• Successfully elucidated the 2D and 3D structures of two epimers in a 6-hydroxyhippeastidine mixture.
• DFT calculations effectively assisted in assigning the planar structures.
• Relative and absolute configurations were determined using multiple CASE approaches and spectroscopic data.
• OR/ORD computations proved valuable for configuration determination, with cross-validation by ECD and VCD.
• Distinguished between enantiomeric scaffolds (crinine and haemanthamine) using OR/ORD calculations.

Conclusions:

• The integrated approach of computational chemistry and spectroscopy provides a robust solution for challenging natural product structural elucidation.
• This methodology accurately determines both relative and absolute configurations, even in complex epimeric mixtures.
• The study highlights the significant contribution of OR/ORD computations in differentiating enantiomeric structures, validated by other spectroscopic techniques.