Absolute configuration of sesquiterpene lactones with potent immunosuppressive activity

In a screening of Artemisia argyi (Asteraceae) and subsequent HPLC-based activity profiling canin (1) and the seco-tanapartholides 2 and 3 (stereoisomers) were identified as compounds with potent immunosuppressive activity in vitro. These isoprenoids were first discovered in 1969 and 1982, respectively, and have been extensively studied in the past for various biological activities[1]. Although many studies have been published examining their molecular structure and relative configuration by means of NMR and X-ray[2], the absolute configuration remained unresolved. We here established the absolute configuration of compounds 1-3 by a combination of electronic circular dichroism spectroscopy (ECD) and vibrational circular dichroism spectroscopy (VCD).

ECD spectra of 1 – 3 were measured and compared to spectra calculated ab initio for different possible stereoisomers. Thereby, the commonly described relative stereoisomer of canin (1) was established as (1R,2S,3R,4S,5S,6S,7S,10R)-canin. For compounds 2 and 3 the ECD data lowered the number of possible configurational isomers to four stereoisomers. The absolute configuration was finally established by VCD. Compound 2 was identified as (4R,5R,6S,7S)-seco-tanapartholide, and 3 as (4S,5S,6S,7S)-seco-tanapartholide. The combination of ECD and VCD can thus be considered as a powerful approach in resolving the absolute configuration of conformationally flexible molecules.

Fig. 1

[1] Knight DW. Nat Prod Rep 1995; 12: 271 – 276

[2] Hewlett MJ, Begley tlMJ, Groenewegen WA, Heptinstall S, Knight DW, May J, Salan DWU, Toplis D. J Chem Soc, Perkin Trans 1 1996: 1979 – 1986