Formal γ−C−H Functionalization of Cyclobutyl Ketones: Synthesis of cis‐1,3‐Difunctionalized Cyclobutanes

• Published in: Angewandte Chemie International Edition 2023-06, Vol.62 (25), p.e202303948-n/a
• Main Authors: Fan, Zhoulong, Strassfeld, Daniel A., Park, Han Seul, Wu, Kevin, Yu, Jin‐Quan
• Format: Article
• Language: English
• Subjects: Amides; Aromatic compounds; Catalysis; Chemical synthesis; Cyclobutanes; C−H Functionalization; Diastereocontrol; Drug development; Esters; Functional groups; Ketones; Ligand; Palladium; Palladium - chemistry
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202303948

1,3‐Difunctionalized cyclobutanes are an emerging scaffold in medicinal chemistry that can confer beneficial pharmacological properties to small‐molecule drug candidates. However, the diastereocontrolled synthesis of these compounds typically requires complicated synthetic routes, indicating a need for novel methods. Here, we report a sequential C−H/C−C functionalization strategy for the stereospecific synthesis of cis‐γ‐functionalized cyclobutyl ketones from readily available cyclobutyl aryl ketones. Specifically, a bicyclo[1.1.1]pentan‐2‐ol intermediate is generated from the parent cyclobutyl ketone via an optimized Norrish‐Yang procedure. This intermediate then undergoes a ligand‐enabled, palladium‐catalyzed C−C cleavage/functionalization to produce valuable cis‐γ‐(hetero)arylated, alkenylated, and alkynylated cyclobutyl aryl ketones, the benzoyl moiety of which can subsequently be converted to a wide range of functional groups including amides and esters. A sequential C−H/C−C functionalization strategy was reported to effect the otherwise challenging synthesis of 1,3‐disubstituted cyclobutane building blocks. Numerous aryl, heteroaryl, alkenyl, and alkynyl groups can be installed at the 3‐position of the cyclobutane ring with exclusive cis‐selectivity.