**4. Conclusions**

In this study, fifteen novel C-9 derivatives of arctigenin with C-9 substitution were successfully synthesised, and analysed for their anti-proliferative activities, for the first time. This study demonstrated the use of acyl-Claisen rearrangement as an effective method to access a dibenzylbutyrolactone framework as a single *trans* diastereomer between C-8 and C-8' and to provide C-9 analogues with a *trans*,*trans* C-8, C-8', C-9 configuration. The benefits of this divergent strategy are evident through the preparation of these derivatives. Anti-proliferative testing of the synthesised compounds showed IC50 values as low as 3.27 μM in HCT-116 (compound **32**) and 5.79 μM (compound **29**) in MDA-MB-231 cancer cell lines, which were improved over the natural product, arcitgenin, itself. These results highlight that C-9 substitution of dibenzylbutyrolactone lignans can improve the biological activity compared to the unsubstituted natural products. Furthermore, as the C-9 is rarely substituted in other lignan natural products, this work suggests the potential that other classes of lignans could be similarly modified to increase their biological activity.

**Supplementary Materials:** The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/ijms24021167/s1. Synthetic procedures for all novel compounds, 1H and 13C NMR spectra for all precursor and final compounds (Figures S1–S45). References [17,40–49] are cited in supplementary materials.

**Author Contributions:** Conceptualization, D.B.; methodology, E.K.P., E.L., L.I.P. and D.B.; validation, E.K.P. and E.L.; investigation, E.K.P. and E.L.; resources, E.L., L.I.P. and D.B.; writing—original draft preparation, E.K.P.; writing—review and editing, E.K.P., L.I.P. and D.B.; supervision, D.B. and L.I.P.; project administration, L.I.P. and D.B.; funding acquisition, D.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** Data are contained within the article.

**Acknowledgments:** The authors would like to acknowledge financial support for this work from the University of Auckland (doctoral scholarship for E.K.P.).

**Conflicts of Interest:** The authors declare no conflict of interest.

**Sample Availability:** Samples of the compounds are available from the authors.
