Unified Total Synthesis of PolyoxinsJ, L, and Fluorinated Analogues on the Basis of Decarbonylative Radical Coupling Reactions

• Published in: Angewandte Chemie 2017-09, Vol.129 (39), p.12027
• Main Authors: Fujino, Haruka, Nagatomo, Masanori, Paudel, Atmika, Panthee, Suresh, Hamamoto, Hiroshi, Sekimizu, Kazuhisa, Inoue, Masayuki
• Format: Article
• Language: ger
• Subjects: 5-Fluorouracil; Amino acid sequence; Antibiotics; Bacteria; Bases (nucleic acids); Chemical reactions; Chemistry; Coupling; Fluorination; Fragments; Fungi; Gram-positive bacteria; Intermetallic compounds; Structural damage; Synthesis; Tellurides; Thymine; Uracil
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201706671

PolyoxinsJ (1a) and L (1b) are important nucleoside antibiotics. The complex and densely functionalized dipeptide structures of 1a and 1b contain thymine and uracil nucleobases, respectively. Herein we report the unified total synthesis of 1a, 1b, and their artificial analogues 1c and 1d with trifluorothymine and fluorouracil structures. Decarbonylative radical coupling between [alpha]-alkoxyacyl tellurides and a chiral glyoxylic oxime ether led to chemo- and stereoselective construction of the ribonucleoside [alpha]-amino acid structures of 1a-d without damaging the preinstalled nucleobases. The high applicability of the radical-based methodology was further demonstrated by preparation of the trihydroxynorvaline moiety of 1a-d. The two amino acid fragments were connected and elaborated into 1a-d (longest linear sequence: 11steps). Compounds 1a and 1b assembled in this way exhibited potent activity against true fungi, while only 1d was active against Gram-positive bacteria.