Conformational Analysis of Diterpene Lactone Andrographolide towards Reestablishment of Its Absolute Configuration via Theoretical and Experimental ECD and VCD Methods

Muhamad Faid A Kadir (Faculty of Applied Sciences, Universiti Teknologi MARA, 40450 Shah Alam, Selangor Darul Ehsan, Malaysia)
Agustono Wibowo (Faculty of Applied Sciences, Universiti Teknologi MARA, Pahang Branch, Jengka Campus, 26400 Bandar Tun Abdul Razak Jengka, Pahang Darul Makmur, Malaysia)
Fatimah Salim (Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Universiti Teknologi MARA, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia)
El Hassane Anouar (Department of Chemistry, College of Sciences and Humanities Studies in Al-Kharj, Prince Sattam bin Abdulaziz University, Al Kharj 11942, Saudi Arabia)
Khalijah Awang (Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia)
Moses Kiprotich Langat (Jodrell Laboratory, Natural Capital and Plant Health Department, Royal Botanic Gardens, Kew, Richmond, TW9 3DS, UK)
Rohaya Ahmad (Faculty of Applied Sciences, Universiti Teknologi MARA, 40450 Shah Alam, Selangor Darul Ehsan, Malaysia)

Indonesian Journal of Chemistry
Vol 21, No 1 (2021)

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. Its structure as determined by X-ray crystallography has been applied in molecular docking studies to explain biological activities. Nevertheless, recently there has been a number of conflicting reports concerning the stereochemistry at the C-14 and C-10 positions affecting 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 was necessary. The conformational analysis was performed by the Spartan14 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 re-establish the AC of andrographolide. Theoretical calculations were performed using TD-DFT methods by using 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.