Enzymatic macrocyclization of ribosomally synthesized and posttranslational modified peptides via C-S and C-C bond formation.

Covering: 2000 to 2020 Ribosomally synthesized and posttranslational modified peptides (RiPPs) are a rapidly growing class of bioactive natural products. Many members of RiPPs contain macrocyclic structural units constructed by modification enzymes through macrocyclization of linear precursor peptides. In this study, we summarize recent progress in the macrocyclization of RiPPs by C-S and C-C bond formation with a focus on the current understanding of the enzymatic mechanisms.

Late-Stage Peptide Macrocyclization by Palladium-Catalyzed Site-Selective C-H Olefination of Tryptophan.

Transition-metal-catalyzed C-H activation has shown potential in the functionalization of peptides with expanded structural diversity. Herein, the development of late-stage peptide macrocyclization methods by palladium-catalyzed site-selective C(sp2 )-H olefination of tryptophan residues at the C2 and C4 positions is reported. This strategy utilizes the peptide backbone as endogenous directing groups and provides access to peptide macrocycles with unique Trp-alkene crosslinks.

Backbone-Enabled Directional Peptide Macrocyclization through Late-Stage Palladium-Catalyzed δ-C(sp2 )-H Olefination.

C-H activation methods for peptide macrocyclization have the potential to provide peptidomimetics and cyclic peptides with expanded structural diversity. Now, a highly versatile peptide macrocyclization strategy via late-stage palladium-catalyzed δ-C(sp2 )-H olefination of phenylalanine residues has been developed. This method utilizes peptide backbone amides as internal directing groups and allows facile macrocyclization of peptides in the N-to-C direction. Combined with the previously developed ß-C(sp3 )-H arylation method for peptide macrocyclization in the C-to-N direction, a pair of palladium-catalyzed reactions were obtained that are directionally orthogonal, and the first example of one-pot synthesis of bicyclic peptides via Pd-catalyzed ß-C(sp3 )-H and δ-C(sp2 )-H activation is demonstrated.

Macrocyclization of bioactive peptides with internal thiazole motifs via palladium-catalyzed C-H olefination.

Peptides containing thiazole fragments represent a large group of bioactive compounds with potential medicinal applications. However, methods for efficient synthesis of these compounds with structural diversity are limited. Herein, we report a method for modification and macrocyclization of thiazole-containing peptides through palladium-catalyzed δ-C(sp2)-H olefination. In this protocol, the thiazole and neighboring amide bonds act as directing groups, which allows site-specific olefination of phenylalanine, tryptophan and tyrosine residues. This chemistry exhibits broad substrate scope and provides facile access to peptide-peptide conjugates and peptide macrocycles. Our results highlight the potency and applicability of thiazole motifs in promoting Pd-catalyzed functionalization of peptides.

Late-Stage Macrocyclization of Bioactive Peptides with Internal Oxazole Motifs via Palladium-Catalyzed C-H Olefination.

Oxazole is an important pharmacophore and exists in the backbone of many bioactive peptide natural products and peptidomimetics. Efficient methods for the synthesis and direct functionalization of complex oxazole-containing peptides are in high demand. Herein, we report the late-stage site-selective functionalization of oxazole-containing peptides via palladium-catalyzed δ-C(sp2)-H olefination of phenylalanine, tryptophan, and tyrosine residues. This strategy utilizes oxazole motifs as internal directing groups and provides access to oxazole-containing peptide macrocycles with bioactivities.

Macrocyclization of Biaryl-Bridged Peptides through Late-Stage Palladium-Catalyzed C(sp2)-H Arylation.

Macrocyclic peptides are promising scaffolds of bioactive compounds and clinical therapeutics. Herein, we develop a strategy for the macrocyclization of biaryl-bridged peptides through late-stage Pd-catalyzed C(sp2)-H arylation. This method displays broad substrate scope and high efficiency in the synthesis of peptide conjugates with various bioactive molecules. Furthermore, we applied this method to prepare peptide macrocycles with aryl-aryl cross-links. Our results show the effectiveness of backbone amide groups as directing groups in Pd-catalyzed C-H functionalization of peptides.

A divergent [5+2] cascade approach to bicyclo[3.2.1]octanes: facile synthesis of ent-kaurene and cedrene-type skeletons.

A solvent-dependent oxidative dearomatization-induced divergent [5+2] cascade approach to bicyclo[3.2.1]octanes was described. This novel protocol enables a facile synthesis of a series of diversely functionalized ent-kaurene and cedrene-type skeletons in good yields and excellent diastereoselectivities.