Late‐Stage Diversification through Manganese‐Catalyzed C−H Activation: Access to Acyclic, Hybrid, and Stapled Peptides

Abstract

Bioorthogonal C À Hallylation with ample scope was accomplished through av ersatile manganese(I)-catalyzed CÀHactivation for the late-stage diversification of structurally complex peptides.The unique robustness of the manganese(I) catalysis manifold was reflected by full tolerance of sensitive functional groups,such as iodides,esters,amides,and OH-free hydroxy groups,therebysetting the stage for the racemizationfree synthesis of CÀHfused peptide hybrids featuring steroids, drug molecules,n atural products,n ucleobases,a nd saccharides.

Tyrosine Conjugation Methods for Protein Labelling

“…Some transition-metal catalysts possess sufficient functional group tolerance to perform chemoselective reactions in aqueous buffers. [55][56][57][58] Francis and co-workers developed p-allylpalladium complexes for Tyr conjugation (Figure 9). [59] A particularly attractive feature of the p-allylpalladium complexes method is the possibility to switch the allylic acetate for a more hydrophilic leaving group.…”

“…Some transition‐metal catalysts possess sufficient functional group tolerance to perform chemoselective reactions in aqueous buffers [55–58] …”

Chemical modifications of tryptophan residues in peptides and proteins

“…Recently, Ackermann's group further applied a manganese catalyst to the CH allylation reaction of Trp (Figure 2D1). 36 With 30 mol % NaOAc as the additive, MnBr(CO) 5 catalyzed the reaction between N ‐pyridine‐protected Trp and Morita–Baylis–Hillman (MBH) adducts at 80°C over 16 h. In addition to applying this reaction to some short peptides and drug molecules, they successfully synthesized a 15‐membered macrocyclic stapled peptide.…”

General Access to Modified α‐Amino Acids by Bioinspired Stereoselective γ‐C−H Bond Lactonization

“…An alternative and more straightforward approach is represented by chemical modification of pre‐existing natural or synthetic α‐amino acid structures via side‐chain C−H bond functionalization [6] . Pd‐catalyzed directing group controlled reactions entailing C−H activation via organometallic intermediates stand as the most extensively pursued methods [7, 8] . In these reactions, primary C−H bonds are preferentially functionalized driven by the kinetic advantage arising from the formation of a five‐membered ring metallacycle (Figure 1 B).…”

“…[6] Pdcatalyzed directing group controlled reactions entailing CÀH activation via organometallic intermediates stand as the most extensively pursued methods. [7,8] In these reactions,p rimary C À Hb onds are preferentially functionalized driven by the kinetic advantage arising from the formation of af ivemembered ring metallacycle ( Figure 1B). [9][10][11][12][13][14][15] Procedures that can selectively target secondary CÀHb onds,a lthough less represented, have been also developed.…”