One-Pot Gram-Scale Synthesis of Cynandione A and Detailed Mechanistic Insights into its Regioselectivity

Cynandione A, a natural biaryl product with a bis-acetophenone structure isolated from Cynanchi wilfordii Radix, has garnered considerable attention because of its diverse biological activities, including anti-inflammatory, neuroprotective, antioxidant, and adipogenic effects. However, the limited natural and commercial availability of cynandione A impedes large-scale evaluations, particularly in vivo studies. Herein, we report a one-pot gram-scale synthesis of cynandione A. The key step of this synthesis is a regioselective conjugate addition of acetyl bisphenol to a benzoquinone substrate, which has been mechanistically explored using density functional theory (DFT) calculations. The significant energetic differences at the transition states among the possible pathways indicate the C3 position of the acetyl bisphenol nucleophile as the exclusive site of addition. Through careful optimization, the one-pot synthesis affords cynandione A in a gram scale with a high yield. This method presents a practical, and scalable approach for synthesizing cynandione A with excellent pot economy.