Harnessing Multiple Roles of CO for Asymmetric Carbonylative Synthesis of Long-Range Axially Chiral Cycloalkylidenes and Amino Acids

Long-range axially chiral carbonyl-containing cycloalkylidenes, particularly amino acids, represent an important class of chiral structures, yet their direct construction via catalytic asymmetric carbonylation remains challenging. Here, we report a Pd-catalyzed asymmetric allylic carbonylation that enables the efficient synthesis of long-range axially chiral cycloalkylidene-based carbonyl compounds. This protocol accommodates a broad range of nucleophiles, including alcohols, amines, water, and complex bioactive molecules, delivering diverse esters, amides, carboxylic acids, and di- or tripeptides in high yields with excellent enantioselectivities. Mechanistic studies indicate that CO plays multiple roles, serving not only as the carbonyl source but also as a key regulator of stereochemical integrity by suppressing π-allyl–Pd isomerization through the formation of a configurationally stable acyl–Pd intermediate. The synthetic utility of this method is demonstrated through the concise and stereodivergent synthesis of the rare natural amino acid 2-amino-3-(4-amino-2-cyclohexylidene) propionic acid (Aacp) as well as applications in proteolysis-targeting chimera (PROTAC) linker design and nucleoside analogue synthesis.