Dynamic Kinetic Resolution of Flavonoids via Asymmetric Allylic Alkylation: Construction of Two Contiguous Stereogenic Centers on Nucleophiles

Abstract

The extension of racemization strategies of dynamic kinetic resolution in organic synthesis is a longstanding challenge, especially racemizing two or more stereogenic centers simultaneously. Through the combination of a palladium-catalyzed asymmetric allylic alkylation and a base-promoted retro-oxa-Michael addition, a dynamic kinetic resolution of 2,3-disubstituted flavonoids was achieved with up to 99% enantioselectivities, and two contiguous stereocenters (including a quaternary stereogenic center) were constructed simultaneously on the nucleophile flavonoids. The key feature of the reaction was a base-promoted retro-oxa-Michael addition for fast racemization of two stereogenic centers on the nucleophiles, which can pave the way to developing asymmetric reactions of flavonoids through dynamic kinetic resolution.

Chiral Flavonoids as Antitumor Agents

“…Enantioseparation of flavonoids by LC with chiral stationary phases (CSP) started with polysaccharide columns, including cellulose and amylose derivatives, followed by cyclodextrin columns [112,113]. Dynamic kinetic resolution has also been recently described [114].…”

Synergistic Palladium/Chiral Phosphoric Acid-Catalyzed Kinetic Resolution via Stereoselective Intramolecular Substitution of Unactivated Allylic Alcohols

“…The asymmetric reaction has been successfully applied to the kinetic resolution (KR) of racemic allylic substrates, yielding substitution products with a high enantiomeric excess (Scheme a). , By contrast, the KR of racemic nucleophiles via EAS remains relatively unexplored . For instance, Hou et al reported the KR of racemic 2,3-dihydro-2-substituted 4-quinolones via enantioselective allylic alkylation, yielding C -allylated products (Scheme b). , In addition, the KR of racemic 2-substituted indolines via enantioselective allylic amination was also investigated, yielding N -allylated products (Scheme c) . However, the resolution of racemic nucleophiles in these examples generally required a stoichiometric base and activated (derivatized) allylic alcohols (e.g., allylic phosphates or allylic carbonates).…”

Asymmetric Transfer Hydrogenation of 2,3-Disubstituted Flavanones through Dynamic Kinetic Resolution Enabled by Retro-Oxa-Michael Addition: Construction of Three Contiguous Stereogenic Centers

“…Asymmetric (transfer) hydrogenation of multiple substituted ketones has been regarded as a promising method to synthesize functional chiral alcohol derivatives using transition-metal catalysts. , Recently, our group observed that 2,3-disubstituted flavanones are easy to proceed retro-oxa-Michael addition under basic conditions, leading to racemization of two stereocenters simultaneously. Then, a palladium-catalyzed asymmetric allylic alkylation with this strategy was achieved, constructing chiral flavanone derivatives with two contiguous stereocenters (including a quaternary stereogenic center) . Encouraged by this result, we envisioned whether this strategy could be utilized in the asymmetric reduction of flavanoids with a basic catalyst system, which would enable enantioselective synthesis of flavanols with three contiguous stereogenic centers (Scheme ).…”