Chiroptical Methods for Structural Elucidation of Natural Products

The determination of stereochemical configuration in natural products is crucial for understanding their biological activity, pharmacological potential and ecological roles. Chiroptical methods exploit the interaction of chiral molecules with polarised light, providing direct insight into absolute configuration and conformational preferences. Techniques such as optical rotation, electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) complement conventional spectroscopic and crystallographic approaches, often requiring only microgram quantities of material. Advances in computational chemistry, notably time‐dependent density functional theory (TDDFT), have greatly enhanced the predictive power of ECD and VCD, allowing calculated spectra to be matched against experiment with increasing reliability. Together, these methods form an integrated toolkit for rapid, non‐destructive stereochemical analysis of complex natural products, with applications ranging from drug discovery to quality control in nutraceuticals and agrochemicals.

Research from Nature Portfolio

Investigations into unprecedented hybrids of γ-amino acids and sugars illustrated the power of calculated ECD for absolute‐configuration assignment. The study isolated novel tail-to-tail ether-connected sugar–amino‐acid conjugates from plant roots. Extensive spectroscopic analysis was combined with TDDFT-ECD computations to determine stereochemistry unambiguously, demonstrating that even highly functionalised and flexible scaffolds can be resolved without crystalline material. This foundational work underscored chiroptical methods as a viable alternative when X-ray diffraction is impracticable.

Chiroptical Methods for Structural Elucidation of Natural Products publication trend

The graph below shows the total number of articles in chiroptical methods for structural elucidation of natural products across all publications each year (not limited to Nature Index journals).

Technical terms

Chiroptical methods: Techniques that measure differences in the absorption or rotation of polarised light by chiral molecules to determine stereochemistry.

Electronic circular dichroism (ECD): Measurement of differential absorption of left- versus right-circularly polarised UV–visible light, sensitive to electronic transitions in chiral chromophores.

Vibrational circular dichroism (VCD): Infrared counterpart of ECD, detecting differences in absorption of polarised IR light associated with vibrational transitions.

Optical rotation (OR): The rotation of plane-polarised light as it passes through a chiral medium, quantified by a specific rotation value.

Exciton chirality method: Analysis of split Cotton effects arising from coupled electronic transitions between two chromophores to infer absolute configuration.

Time‐dependent density functional theory (TDDFT): A quantum-chemical computational approach for predicting electronic excitation energies and chiroptical spectra of molecules.

References

1. Naturally occurring hybrids derived from γ-amino acids and sugars with potential tail to tail ether-bonds. Scientific Reports (2016).
2. Testing the Simplified Molecular Dynamics Approach to Improve the Reproduction of ECD Spectra and Monitor Aggregation †. International Journal of Molecular Sciences (2024).
3. Colletodiol derivatives of the endophytic fungus Trichocladium sp.. Fitoterapia (2024).
4. Hermansones A and B: Bioactive naphthazarin congeners from the European crust fungus Hermanssonia centrifuga. Fitoterapia (2024).