Synthesis of orthogonally protected biarylamino acid derivatives

Abstract

The efficient and direct synthesis of protected biaryl amino acids, including dityrosine (50% overall yield over 3 steps), by Negishi cross-coupling of the serine-derived organozinc reagent 4 with iodo- and di-iodobiaryls, is reported. An improved, although still not perfect, diiodination of 2,2′-biphenol has been achieved using NMe₃BnICl₂–ZnCl₂. Protection of phenolic hydroxyl groups as acetates, rather than benzyl ethers, is required for efficient cross-coupling, and evidence for acetyl migration has been observed during debenzylation of a substituted 2-acetoxy-2′-benzyloxybiaryl. Aromatic C–I to C–Cl conversion has been detected as a minor reaction pathway in the palladium-catalyzed coupling of aryl iodide 3b with organozinc reagent 4.