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

• Published in: Angewandte Chemie 2017-09, Vol.129 (39), p.12027-12031
• Main Authors: Fujino, Haruka, Nagatomo, Masanori, Paudel, Atmika, Panthee, Suresh, Hamamoto, Hiroshi, Sekimizu, Kazuhisa, Inoue, Masayuki
• Format: Article
• Language: English
• Subjects: Antibiotika; Naturstoffe; Radikalreaktionen; Tellur; Totalsynthesen
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201706671

Polyoxins J (1 a) and L (1 b) are important nucleoside antibiotics. The complex and densely functionalized dipeptide structures of 1 a and 1 b contain thymine and uracil nucleobases, respectively. Herein we report the unified total synthesis of 1 a, 1 b, and their artificial analogues 1 c and 1 d with trifluorothymine and fluorouracil structures. Decarbonylative radical coupling between α‐alkoxyacyl tellurides and a chiral glyoxylic oxime ether led to chemo‐ and stereoselective construction of the ribonucleoside α‐amino acid structures of 1 a–d without damaging the preinstalled nucleobases. The high applicability of the radical‐based methodology was further demonstrated by preparation of the trihydroxynorvaline moiety of 1 a–d. The two amino acid fragments were connected and elaborated into 1 a–d (longest linear sequence: 11 steps). Compounds 1 a and 1 b assembled in this way exhibited potent activity against true fungi, while only 1 d was active against Gram‐positive bacteria. Alles anders mit Fluor: Die Nukleosid‐Antibiotika Polyoxin J und L sowie zwei fluorierte Analoga wurden mithilfe einer radikalischen Strategie synthetisiert. Eine erste biologische Evaluierung belegt die charakteristischen antimikrobiellen Wirkspektren der synthetisierten Polyoxine.