Synthesis of the Isodityrosine Moiety of Seongsanamide A-D and Its Derivatives

• Published in: Marine drugs Vol. 21; no. 7; p. 373
• Main Authors: Xie, Yang, Xu, Zhou, Hu, Pei, Tian, Xiao-Ting, Lu, Yi-Hong, Jiang, Hao-Dong, Huang, Cheng-Gang, Shang, Zhi-Cai
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.06.2023; MDPI
• Subjects: Alanine; Amino acids; Aromatic compounds; arylation; C(sp3)–H functionalization; Chemical properties; Chemical reactions; Chemical synthesis; diaryl ether; Diaryl ethers; Dihydroxyphenylalanine; Dimethylglycine; Functional groups; Health aspects; Iodides; isodityrosine; Ligands; Methods; Natural products; Palladium; Peptides; Pharmaceuticals; Phenols; Solvents; Tyrosine; China; C(sp3)–H functionalization; diaryl ether; palladium; isodityrosine; arylation
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md21070373

The concise and highly convergent synthesis of the isodityrosine unit of seongsanamide A-D and its derivatives bearing a diaryl ether moiety is described. In this work, the synthetic strategy features palladium-catalyzed C(sp )-H functionalization and a Cu/ligand-catalyzed coupling reaction. We report a practical protocol for the palladium-catalyzed mono-arylation of β-methyl C(sp )-H of an alanine derivative bearing a 2-thiomethylaniline auxiliary. The reaction is compatible with a variety of functional groups, providing practical access to numerous β-aryl-α-amino acids; these acids can be converted into various tyrosine and dihydroxyphenylalanine (DOPA) derivatives. Then, a CuI/ -dimethylglycine-catalyzed arylation of the already synthesized DOPA derivatives with aryl iodides is described for the synthesis of isodityrosine derivatives.