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.

Triazolinedione protein modification: from an overlooked off-target effect to a tryptophan-based bioconjugation strategy

“…7 Despite the indole side chain not being the most chemically tractable target, several groups have reported methodologies for selective modification of tryptophan in peptides and proteins. [8][9][10][11] Many of these strategies employ transition metal catalysed reactions and/or conditions limiting downstream biochemical applications. These reactions are typically alkynylations and C-H arylations of the indole.…”

Peptide Late-Stage Diversifications by Rhodium-Catalyzed Tryptophan C7 Amidation

“…Furthermore, successive C-H alkynylation was realized under manganese catalysis 36 for the di-functionalization toward amino acid 7c, which should prove instrumental for subsequent diversifications by click reactions. Moreover, a manganese-catalyzed C(2)-H allylation 31 reaction took place successfully, furnishing peptides 7d and 7e with erucic acid amide on tryptophan C7 and allyl group on C2, both of which contain synthetically useful alkenyl groups.…”

“…In sharp contrast, catalyzed C-H activation has recently emerged as a complementary strategy for step-economical late-stage modifications. [12][13][14][15][16][17][18] C-H activation has, thus, been recognized as an enabling tool for late-stage peptide functionalizations, [19][20][21][22] with major contributions by Albericio and co-workers, 23 Lavilla and co-workers, 24 Shi and co-workers, 25 Wang and co-workers, 26 Yu and co-workers, 27,28 and Ackermann and co-workers [29][30][31][32][33][34][35][36][37] In this context, the functionalization of tryptophan-containing peptides has attracted considerable interest, due to tryptophan's low natural abundance as well as its unique impact on biological events. 38 However, all tryptophan C-H activations are severely limited to the activated C2 position (Figure 1B), which is in sharp contrast to the predominance of C7-substituted indoles/tryptophans in numerous bioactive agents and important structurally complex peptide-natural products (Figure 1A).…”

Pd-catalyzed site-selective C(sp2)–H chalcogenation of amino acids and peptides using a picolinamide auxiliary

“…[21][22][23][24][25][26][27][28][29][30][31][32][33][34] Directing group (DG)-assisted metal-catalyzed C(sp 3 )-H bond functionalizations of amino acids and peptides have been well investigated, [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] in contrast to the poorly investigated C(sp 2 )-H activation on aromatic rings of aromatic amino acids and their peptides. [54][55][56][57][58][59] However, the C-H functionalizations of phenylalanine and phenylglycine have shown significant progress. [60][61][62][63][64][65][66][67]…”