Conformational Analysis Of Diterpene Lactone Andrographolide Towards Reestablishment Of Its Absolute Configuration Via Theoretical And Experimental Ecd And Vcd Methods

Andrographolide, the major constituent from the terrestrial plant Andrographis paniculata is a much-studied bioactive ent-labdane diterpene lactone and has become an important medicinal intermediate. As determined by X-ray crystallography, its structure has been applied in molecular docking studies to explain biological activities. Nevertheless, recently, several conflicting reports concerning the stereochemistry at the C-14 and C-10 positions affect the absolute configuration (AC) of the compound. Since a lack of information on the molecular flexibility of the molecule can lead to misleading conclusions on biological activity, a conformational analysis of the molecule in the solution state is necessary. The conformational analysis was performed by the Spartanl4 package using the Merck Molecular Force Field (MMFF). The exciton chirality method in electronic circular dichroism spectroscopy (ECM-ECD) and vibrational circular dichroism (VCD) techniques were then jointly employed to reestablish the AC of andrographolide. Theoretical calculations were performed using TD-DFT methods employing the hybrid functionals B3LYP and CAM-B3LYP combined with 6-31G(d,p) basis set. Long-range exciton coupling of 2-naphthoyl chromophores at C-14 and C-19 led to the establishment of the AC to be 3R, 4R, 5S, 9R, 10R, and 14S. Comparison between the theoretical VCD data of 14-S and 14-R stereoisomer confirmed a configuration of S at C-14 position instead of R.