Total Synthesis of (−)‐2‐Oxokolavenol: A Natural Neoclerodane Diterpene with Farnesoid X Receptor Transcriptional Activity

The natural neoclerodane diterpene (−)‐2‐oxokolavenol is isolated from the twigs of Amoora stellato‐squamosa , and exhibited significant Farnesoid X receptor (FXR) transcriptional activity with an EC 50 value of 1.877 μM. However, the scarcity of its natural sources poses a considerable challenge for further biological studies. To address this limitation, herein, the first total synthesis of (−)‐2‐oxokolavenol is reported. This synthesis features stereoselective alkylation, regioselective redox transformations (including late‐stage allylic oxidation), and strategic installation of methyl groups. The overall synthesis delivers (−)‐2‐oxokolavenol in 15 steps from the cheap and readily available Wieland–Miescher ketone. In addition, this approach allows (−)‐2‐oxokolavenol with 12 synthetic intermediates for biological evaluations by using dual‐luciferase reporter assay. Preliminary investigations confirm the nuclear receptor selectivity of (−)‐2‐oxokolavenol as a FXR agonist, underscoring its potential for further bioactivity studies.