Enantioselective Cu-catalyzed borylative cyclization via Dieckmann-Thorpe addition

The efficient and stereocontrolled synthesis of complex cyclic chiral molecules constitutes a cornerstone of modern organic chemistry, driven by the continuous demand for structurally diverse scaffolds in drug discovery and natural product synthesis. In this field, organoboranes are highly versatile intermediates due to the wide range of transformations, often stereospecific, allowed by the unique carbon–boron (C–B) bond. Transition-metal-catalyzed borofunctionalization reactions have therefore emerged as powerful tools to prepare highly functionalized molecules under mild conditions. Building on recent work by the Orlandi group on a cascade hydrocupration/Dieckmann–Thorpe cyclization, this thesis shifts the focus toward a novel enantioselective copper-catalyzed borocupration/Dieckmann–Thorpe cascade reaction. Crucially, this method provides efficient access to highly functionalized 5- and 6-membered carbo- and heterocycles, which represent privileged motifs and fundamental structural cores in a vast array of bioactive pharmaceuticals and complex chiral natural products. This newly developed methodology demonstrated high synthetic utility, providing access to diverse chiral borylated architectures with high yields and excellent enantiomeric ratios (up to 92% yield and 99:1 er). Furthermore, the origins of the ligand-controlled enantioselectivity were briefly rationalized through a stereochemical model. Finally, preliminary downstream functionalizations targeting the boron functional group and the β-amino enoate moiety were investigated to explore the application of these complex chiral scaffolds as building blocks for pharmaceutical chemistry and natural product synthesis.