Copper-catalyzed enantioselective allylation of cyclic anhydrides for generation of multiple chiral centers

Chirality wildly exists in natural products and pharmaceuticals. The efficient construction of multiple chiral centers in a single catalytic step is challenging due to the issues of both enantioselectivity and diastereoselectivity. Herein, a catalytic protocol for simultaneous generation of multiple chiral centers is developed: a stereodivergent reaction of non-symmetric cyclic anhydrides with 1,1-disubstituted allenes affords the products with either 1,3- or 1,4-two chiral centers, which is governed by the absolute configurations of the chiral centers in the enantiomeric ligands of (R,R)-Ph-BPE or (S,S)-Ph-BPE, respectively; the Cu-catalyzed enantioselective allylative desymmetrization of meso bicyclic anhydrides with 1,1-disubstituted allenes generates chiral γ-keto carboxylic acids bearing three stereocenters. Such a protocol is successfully demonstrated for its application to prepare compounds containing four to five stereocenters. Density functional theory studies reveal that the allylation proceeds through a six-membered transition state, where the ligand-substrate steric interactions govern the observed regio-, enantio-, and diastereoselectivity. The efficient construction of multiple chiral centers in a single catalytic step is challenging due to the issues of both enantioselectivity and diastereoselectivity. Here, the authors report a copper-catalyzed reaction between non-symmetric monocyclic or meso bicyclic anhydrides and 1,1-disubstituted allenes for simultaneous generation of multiple chiral centers.