Concise Enantioselective Synthesis of the Antimitotic (+)-2,3,9-Trimethoxypterocarpan via Asymmetric Transfer Hydrogenation

Abstract

(+)-2,3,9-Trimethoxypterocarpan [(+)-PTC] is a naturally occurring isoflavonoid that exhibits potent antitumor activity, putatively acting through the inhibition of kinesin-5 (Eg5), a mechanism distinct from classic tubulin-targeting agents. However, its preclinical development has been severely hampered by supply limitations, as previous synthetic routes relied on inefficient racemic strategies requiring laborious chiral resolution. Herein, we report a concise, biomimetic, and enantioselective total synthesis of (+)-PTC that overcomes these challenges. The route features a robust ligand-free Suzuki cross-coupling in PEG-400 and utilizes a ruthenium-catalyzed asymmetric transfer hydrogenation coupled with dynamic kinetic resolution (ATH-DKR) as the key stereodefining step. Optimized conditions enabled the scale-up of the key reduction with a low catalyst loading (2 mol%), delivering the pterocarpan core with high optical purity (98% ee) and excellent diastereocontrol. The synthesis was completed in just six steps with 64% overall yield, securing a sustainable supply of the bioactive enantiomer for advanced biological validation and providing divergent access to optically pure isoflavanone analogues.

Keywords:
(+)-2,3,9-trimethoxypterocarpan; asymmetric transfer hydrogenation; dynamic kinetic resolution; total synthesis; antimitotic agent; kinesin-5 (Eg5)