Chemodivergent Manganese-Catalyzed C–H Activation: Modular Synthesis of Fluorogenic Probes

Bioorthogonal diversification of peptides is generally dependent on impractical prefunctionalization methods. Here, the authors develop a manganese(I)-catalyzed C–H fluorescent labeling with BODIPY probes, which enables the development of activatable fluorophores to image cell function

Fluorescent amino acids as versatile building blocks for chemical biology

Fluorophores have transformed the way we study biological systems, enabling non-invasive studies in cells and intact organisms, which increase our understanding of complex processes at the molecular level. Fluorescent amino acids have become an essential chemical tool because they can be used to construct fluorescent macromolecules, such as peptides and proteins, without disrupting their native biomolecular properties. Fluorescent and fluorogenic amino acids with unique photophysical properties have been designed for tracking protein–protein interactions in situ or imaging nanoscopic events in real time with high spatial resolution. In this Review, we discuss advances in the design and synthesis of fluorescent amino acids and how they have contributed to the field of chemical biology in the past 10 years. Important areas of research that we review include novel methodologies to synthesize building blocks with tunable spectral properties, their integration into peptide and protein scaffolds using site-specific genetic encoding and bioorthogonal approaches, and their application to design novel artificial proteins, as well as to investigate biological processes in cells by means of optical imaging. [Figure not available: see fulltext.]

Late-stage peptide C–H alkylation for bioorthogonal C–H activation featuring solid phase peptide synthesis

Methods for the late-stage diversification of structurally complex peptides hold enormous potential for advances in drug discovery, agrochemistry and pharmaceutical industries. While C-H arylations emerged for peptide modifications, they are largely limited to highly reactive, expensive and/or toxic reagents, such as silver(I) salts, in superstoichiometric quantities. In sharp contrast, we herein establish the ruthenium(II)-catalyzed C-H alkylation on structurally complex peptides. The additive-free ruthenium(II)carboxylate C-H activation manifold is characterized by ample substrate scope, racemization-free conditions and the chemo-selective tolerance of otherwise reactive functional groups, such as electrophilic ketone, bromo, ester, amide and nitro substituents. Mechanistic studies by experiment and computation feature an acid-enabled C-H ruthenation, along with a notable protodemetalation step. The transformative peptide C-H activation regime sets the stage for peptide ligation in solution and proves viable in a bioorthogonal fashion for C-H alkylations on user-friendly supports by means of solid phase peptide syntheses.peerReviewe