Suzuki–Miyaura Diversification of Amino Acids and Dipeptides in Aqueous Media

Abstract

The Suzuki-Miyaura derivatisation of free amino acids, peptides and proteins is an attractive area with much potential utility for medicinal chemistry and chemical biology. Here we report the modification of unprotected and Boc-protected aromatic amino acids and dipeptides in aqueous media, enabling heteroarylation and vinylation. We systematically investigate the impact of the peptide backbone and adjacent amino acid residues upon the reaction. Our studies reveal that whilst asparagine and histidine hinder the reaction, by utilising dppf, a ferrocene-based bidentate phosphine ligand, cross-coupling of halophenylalanine or halotryptophan adjacent to such a residue could be enabled. Our studies reveal dppf to have good compatibility with all unprotected, proteinogenic amino acid side chains.

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

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

“…Catalyst screening showed that the PdCl 2 (dppf) catalyst, which was shown to be compatible to peptide diversification in solution phase, 22 allowed to prepare the cross-coupled products with excellent conversions on support. Hence, the cross-couplings on solid-phase were realized with PdCl 2 (dppf) (10 mol%) as the precatalyst system in combination with K 2 CO 3 (5 eq) and (hetero)aromatic boronic acids (3 eq).…”

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

“…Alteration of the ligand to sulfonated 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl (SSPhos) was necessary to maintain the applicability of the Suzuki-Miyaura reaction on 7-Cl-tryptophans, as beautifully illustrated by derivatization of the natural product chloropacidamycin in mixed aqueous conditions (water/acetonitrile (AcN) 5:1) [96]. The synthesis of 7-vinyltryptophan 29 with potassium vinyltrifluoroborate and PdCl 2 (dppf), starting from 7-iodotryptophan 28 in mixed aqueous conditions ( Figure 6B), broadened the scope of halotryptophan derivatization, along with the derivatization of unprotected bromotryptophan and bromotryptophan-containing dipeptides [97]. Recently, Frese et al combined a biocatalytic and regioselective tryptophan halogenation and Suzuki-Miyaura cross-coupling in a multi-step one-pot reaction [98].…”

“…As the Suzuki-Miyaura reaction is performed in basic conditions, the base labile 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group is often not considered as part of a substrate. Nevertheless, Willemse reported Fmoc-iodophenylalanine as a substrate, and in their hands demonstrated that at 80 °C Fmoc-deprotection occurs when using PdCl2(dppf) in mixed aqueous conditions (iPrOH/H2O 1:1) with K2CO3 (not shown) [97]. However, by lowering the reaction temperature to 40°C, no deprotection occurred, but the reaction only reached a maximum conversion of 80% after 24 h. Similarly, Maity et al investigated the fluorescent properties of an amino acid containing a 4'-acetamido[1,1'-biphenyl] moiety [99].…”

“…For example, conversions in the presence of a histidine residue were greatly reduced. This can easily be rationalized by a potential complexation of unprotected side chains -but also the main chain termini-with the palladium In order to unravel side/main chain functionality that hampers the application of Suzuki-Miyaura conversions on peptides, Willemse et al performed a systematic screening of unprotected peptide main and side chain functionalities with various aqueous soluble ligands on dipeptide substrates of type 87 ( Figure 13C) [97]. It was shown that, in purely aqueous conditions, a precatalyst solution of ADHP and Pd(OAc) 2 led to efficient derivatizations of dipeptides containing 4-bromophenylalanine.…”