The Suzuki–Miyaura Cross-Coupling as a Versatile Tool for Peptide Diversification and Cyclization

Abstract

Abstract:The (site-selective) derivatization of amino acids and peptides represents an attractive field with potential applications in the establishment of structure-activity relationships and labeling of bioactive compounds. In this respect, bioorthogonal cross-coupling reactions provide valuable means for ready access to peptide analogues with diversified structure and function. Due to the complex and chiral nature of peptides, mild reaction conditions are preferred; hence, a suitable cross-coupling reaction is required for the chemical modification of these challenging substrates. The Suzuki reaction, involving organoboron species, is appropriate given the stability and environmentally benign nature of these reactants and their amenability to be applied in (partial) aqueous reaction conditions, an expected requirement upon the derivatization of peptides. Concerning the halogenated reaction partner, residues bearing halogen moieties can either be introduced directly as halogenated amino acids during solid-phase peptide synthesis (SPPS) or genetically encoded into larger proteins. A reversed approach building in boron in the peptidic backbone is also possible. Furthermore, based on this complementarity, cyclic peptides can be prepared by halogenation, and borylation of two amino acid side chains present within the same peptidic substrate. Here, the Suzuki-Miyaura reaction is a tool to induce the desired cyclization. In this review, we discuss diverse amino acid and peptide-based applications explored by means of this extremely versatile cross-coupling reaction. With the advent of peptide-based drugs, versatile bioorthogonal conversions on these substrates have become highly valuable.

Chemical space screening around Phe3 in opioid peptides: Modulating µ versus δ agonism by Suzuki-Miyaura cross-couplings

“…19–23 Previously, this bioorthogonal methodology has been applied for the derivatization of peptides, 24–28 leading to altered biological profile and therapeutic effect 27, 29 implementing both solution-phase 21 and solid-phase 30–33 Suzuki-Miyaura reactions. The functional group compatibility of Suzuki-Miyaura reactions with peptidic substrates has recently been reviewed elsewhere.…”

“…The functional group compatibility of Suzuki-Miyaura reactions with peptidic substrates has recently been reviewed elsewhere. 22, 27 …”

Solid-phase synthesis of biaryl cyclic peptides containing a histidine-tyrosine linkage

“…The formation of the biaryl bond has been achieved via a Suzuki-Miyaura cross-coupling reaction, a Pd-catalyzed C-H activation or a Cu-mediated oxidative coupling. The former reaction has allowed the synthesis of peptides containing a Trp-Tyr [4,15], a Phe-Phe [15][16][17][18], a Phe-Tyr [15,17,19] or a Tyr-Tyr [15,[19][20][21] linkage. The C-H activation reaction has been used to form the biaryl bonds Trp-Phe and Trp-Tyr [22,23], while the Cumediated oxidative phenol coupling has provided access to peptides bearing a Tyr-hydroxyphenylglycine motif [24].…”

Current Applications of Suzuki–Miyaura Coupling Reaction in The Total Synthesis of Natural Products: An update

“…This reaction has found several applications in organic synthesis due to its versatility, high stability and low toxicity of the required starting materials which mostly commercially available or readily accessible. In addition, the introduction of various substrates of organoborane reagents is practically simple and the resultants often remain unaffected throughout subsequent transformations in the presence of immensely functionalized biomolecules, molecular oxygen, water and can frequently be performed under ambient reaction conditions …”