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

The development of stereodivergent synthetic methods to access all four stereoisomers of biologically important alpha-fluoro gamma-butyrolactones containing vicinal stereocenters is of great importance and poses a formidable challenge owing to ring strain and steric hindrance. Herein, a novel asymmetric [3 + 2] annulation of alpha fluoro aazaaryl acetates with vinylethylene carbonate was successfully developed through Cu/Ir-catalyzed cascade allylic alkylation/lactonization, affording a variety of enantioenriched alpha fluoro gamma-butyrolactones bearing vicinal stereogenic centers with high reaction efficiency and excellent levels of both stereoselectivity and regioselectivity (up to 98% yield, generally > 20:1 dr and > 99% ee). Notably, all four stereoisomers of these pharmaceutically valuable molecules could be accessed individually via simple permutations of two enantiomeric catalysts. In addition, other azaaryl acetates bearing alpha-methyl, alpha-chlorine or alpha-phenyl group were tolerated well in this transformation. Reaction mechanistic investigations were conducted to explore the process of this bimetallic catalysis based on the results of reaction intermediates, isotopic labelling experiments, and kinetic studies.