Chiral γ-butyrolactones as the crucial scaffolds have been widely distributed in plenty of pharmaceuticals and natural products, which displayed a broad range of biological activities. Herein, a novel asymmetric [3+2] annulation of a-fluoro a-azaaryl acetates with vinylethylene carbonate was successfully developed through Cu/Ir-catalyzed cascade allylic alkylation/lactonization, affording a variety of enantioenriched a-fluoro γ-butyrolactones bearing vicinal stereogenic centers with high reaction efficiency and excellent levels of both stereoselectivity and regioselectivity (up to 98% yield, generally &gt;20:1 dr and &gt;99% ee) (Scheme 1). The chiral Cu(I) catalyst and Ir catalyst could respectively control the configurations of two adjacent stereocenters related to the nucleophilic coupling partner and the electrophilic oxy π-allyl iridium species, and thus all four possible stereoisomers of these [3+2] annulation products could be readily accessible by simple permutations of enantiomers of these two catalysts. The practical utility of this facile methodology has been readily demonstrated by a series of synthetic diversification to deliver other important γ-butyrolactones. The proposed bimetallic synergistic catalytic mechanism was rationalized through the combination of the reaction intermediate separation, isotopic labeling experiments, and kinetic studies. The deprotonation of the α-proton of α-fluoro pyridinyl acetate binding to the copper catalyst with the aid of Et3N and H-bonding interaction between Et3NH+ species and the ester group to assist the intramolecular transesterification should be related to the rate-determining step.

Stereodivergent synthesis of a-fluoro a-azaaryl γ-butyrolactones via cooperative copper and iridium catalysis

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.