Pd-Catalyzed Asymmetric Tandem Allylic Alkylation/Etherification: Enantioselective Access to Medium-Sized Oxa-spirocycles

Abstract

Pd-catalyzed asymmetric tandem allylic substitution has proven to be a powerful strategy for constructing chiral rings; however, its application to chiral medium-sized spirocyclic systems remains undeveloped. Herein, we report a Pd-catalyzed asymmetric tandem allylic alkylation/etherification that enables efficient access to chiral medium-sized oxa-spirocycles in good yields (up to 98%) and high enantioselectivities (up to 95% ee). The synthetic utility is demonstrated by a gram-scale reaction and diverse derivatizations. Mechanistic control experiments revealed that the first allylic alkylation determines the absolute configuration and that a free phenolic hydroxyl group is essential for stereoselective induction. Preliminary biological evaluation indicates that the products exhibit moderate to excellent in vitro cytotoxicity against a panel of human tumor cell lines, including HepG2, MCF7, and HCT116.