Synthesis of the bis-diaryl ether fragment of vancomycin via enzymatic oxidative phenolic coupling

The bis-diaryl ether cross-linked amino acid fragment, which constitutes the upper part of a vancomycin aglycone framework, was synthesized for the first time using an enzymatic oxidative phenolic coupling methodology. This was achieved via two peroxidase-catalyzed reactions of three amino acid derivatives, 2, 3a, and 4. Other C–O and C–C hetero and homo coupling products were also obtained.