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

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.