Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

• Published in: Nature communications Vol. 8; no. 1; pp. 14904 - 8
• Main Authors: Zhu, Yan, Chen, Xiaolan, Yuan, Chunchen, Li, Guobao, Zhang, Jingyu, Zhao, Yingsheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.04.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 639/638/403/933; 639/638/549/933; 639/638/77/888; Alanine - analogs & derivatives; Alanine - metabolism; Amino acids; Amino Acids - metabolism; Carbon - metabolism; Carboxylic Acids - metabolism; Catalysis; Fatty Acids - metabolism; Glycine - analogs & derivatives; Glycine - metabolism; Humanities and Social Sciences; Hydrogen - metabolism; Ligands; multidisciplinary; Natural products; Palladium; Peptides; Peptides - chemical synthesis; Science
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14904

α-amino acids bearing aromatic side chains are important synthetic units in the synthesis of peptides and natural products. Although various β-C-H arylation methodologies for amino acid derivatives involving the assistance of directing groups have been extensively developed, syntheses that directly employ N -protected amino acids as starting materials remain rare. Herein, we report an N -acetylglycine-enabled Pd-catalysed carboxylate-directed β-C( sp 3 )-H arylation of aliphatic acids. In this way, various non-natural amino acids can be directly prepared from phthaloylalanine in one step in good to excellent yields. Furthermore, a series of aliphatic acids have been shown to be amenable to this transformation, affording β-arylated propionic acid derivatives in moderate to good yields. More importantly, this ligand-enabled direct β-C( sp 3 )-H arylation could be easily scaled-up to 10 g under reflux conditions, highlighting the potential utility of this synthetic method. Palladium catalysed C-H functionalization of sp 3 carbons typically requires the installation and subsequent removal of a temporary directing group. Here the authors report a method allowing C-H functionalization in carboxylic acids in which the carboxylate acts as a directing group.