Effectiveness of the Suzuki-Miyaura cross-coupling reaction for solid-phase peptide modification

The Suzuki-Miyaura (SM) cross-coupling reaction has recently become one of the most efficient methods for C-C bond construction opening a wide range of opportunities in organic synthesis. This study focused on the evaluation of the use of the SM reaction to modify peptides using a solid-phase synthesis approach, an avenue that was still not investigated intensively. We used as a peptide model [Ala(1,2,3), Leu(8)]Enk linked to a polystyrene support on which it was previously assembled. The aromatic residues Tyr(4) and Phe(7) of [Ala(1,2,3), Leu(8)]Enk were respectively substituted with p-iodo-Phe, and an SM-related strategy was developed. Results indicated that the reaction conditions involving K3PO4 or Na2CO3 (base), DMF (solvent), Pd(PPh3)(4) (catalyst), and temperatures ranging from 50 to 80 degrees C during 20 h were found as optimal. Finally applying those optimal conditions, a series of [Ala(1,2.3), Leu(8)]Enk analogs modified at Tyr(4) or Phe(7) positions was synthesized using diverse boronic acid derivatives.