Solid-Phase Synthesis of Biaryl Cyclic Peptides Containing a 3-Aryltyrosine

A concise and efficient solid-phase synthesis of biaryl cyclic peptides containing a PheTyr or a TyrTyr linkage has been accomplished. The key steps include a Miyaura borylation of a resin-bound 3-iodotyrosine and a microwave-assisted SuzukiMiyaura reaction for the formation of the macrocycle. First, the feasibility of the solid-phase Miyaura borylation of a 3-iodotyrosyltripeptide was established. Then, the SuzukiMiyaura reaction was applied to the cross-coupling of linear 3-boronotyrosine-containing peptidyl resins with iodobenzene and with halogenated aromatic amino acids. Finally, this methodology was extended to the synthesis of biaryl cyclic peptides through the preparation of a linear peptidyl resin containing both the required boronate and halogenated derivatives, followed by a microwave-assisted SuzukiMiyaura macrocyclization.