Synthesis of bioactive and stabilized cyclic peptides by macrocyclization using C(sp³)–H activation

Abstract

Synthesis of cyclic peptides with novel Cβ–Ar crosslinks has been achieved by C(sp3)–H activation, and their biological properties have been evaluated for the first time.

Peptide Cyclization at High Concentration

“…Some of the approaches include the use of bidentate directing groups, innate directing groups, or targeting aromatic amino acids with weaker C(sp 2 )-H bonds. [23][24][25][26] Albericio and Lavilla achieved this by reacting iodo-phenylalanine or iodo-tyrosine with tryptophan in the presence of palladium as a C-H activation catalyst (Figure 1, C). 27 They were able to achieve cyclization at a concentration of 3 mM with low levels of cyclodimerization.…”

Bridged bicyclic peptides: Structure and function

“…Because of the unusual crosslinks between the leucine–tryptophan–histidine side chains, the total chemical synthesis of celogentin peptides is a challenging undertaking . The total synthesis of celogentin C has been reported by several groups . The key Leu–Trp crosslink has been formed by conjugate addition .…”

“…The key Leu–Trp crosslink has been formed by conjugate addition . approaches or by Pd‐catalyzed CH activation pathways (Scheme ) . In all cases the “left‐hand” ring 70 has been formed first, with oxidative coupling of the His imidazole ring and Trp indole ring forming the CN bond between the Trp and His residues to ultimately furnish the bicyclic peptide 65 .…”

Macrocyclic peptide construction through C–H activation strategy

“…Using this protocol, 12-membered para-cyclophanes (with calculated ring strain: $12 kcal/mol) were prepared albeit in low yields ($20%); while the synthesis of 13membered para-cyclophanes or meta-cyclophanes with less conformational restriction was more successful. Finally, biological test on the cyclic peptides was also carried out; and several products were revealed with cytotoxicity towards proliferative myc-dependent cancer cells, which suggests the biological potential of these compounds in drug discovery.Instead of employing a bidentate directing auxiliary, site-selective C-C(aryl) cyclization of peptides, has also been demonstrated with a phthaloyl (Phth)-protected N-terminal amino acid (e.g., alanine) [8,9]. Palladium catalyst was previously explored to efficiently bind to Phth-protected amino acid and selectively activate C-H bonds at b-position [10].…”

“…Instead of employing a bidentate directing auxiliary, site-selective C-C(aryl) cyclization of peptides, has also been demonstrated with a phthaloyl (Phth)-protected N-terminal amino acid (e.g., alanine) [8,9]. Palladium catalyst was previously explored to efficiently bind to Phth-protected amino acid and selectively activate C-H bonds at b-position [10].…”