Synthesis of unnatural amino acids through palladium-catalyzed C(sp3)H functionalization

Postassembly Modifications of Peptides via Metal-Catalyzed C–H Functionalization

“…Pd-catalyst has proven to be the most versatile among the catalytic CHF of small molecules. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Pioneering 22 The high acidity of the C 2 -H bond plays a crucial role in controlling the regioselectivity. Lane and Sames 64 reported the first C 2 -H arylation of indole with aryl iodide via a Pd 0/II catalytic cycle using a strong base and high reaction temperature.…”

“…12,[14][15][16] In this context, methods based on functionalization of C-H bonds of hydrophobic residues could offer a new set of tools to enable unprecedented peptide modification, thus, dramatically expanding the arsenal for peptide engineering. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] As shown in Scheme 1a and 1b, nature has shown that C-H functionalization (CHF) could provide a powerful means to modify and transform peptides and proteins. 33 As exemplified by C 2 -mannosylation of tryptophan (Trp) in specific membrane proteins, C 5 -alkylation of histidine (His) in elongation factor 2 protein (EF2), and C 3 -hydroxylation of proline (Pro) in collagen enzyme-catalyzed CHF reactions enable unique post-translational modification (PTM) of proteins.…”

“…Over the past three decades, metal-catalyzed CHF chemistry has been advanced markedly, offering increasingly powerful methods for synthesis and latestage modification of small molecules. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Various metal-mediated C-H cleavage pathways such as concerted oxidative addition (OA), concerted metalationdeprotonation (CMD), carbene and nitrene C-H insertion, electrophilic addition to a π system, and HAT, have been identified (Scheme 2b). Many of these reactions have been used in the synthesis and modification of single protected AA units.…”

Reprogramming natural proteins using unnatural amino acids

“…The reactivity of unactivated C(sp 3 )-H bonds, especially secondary C(sp 3 )-H bonds, is still low, which can be overcome by strategically developing new ligands and directing groups. 132 ncAA-mediated methods broaden the range of things identied and generated, such as conjugates, vaccinations, and cell-based treatments. It is also becoming clear how important it is to apply medicinal chemistry ideas to bigger proteins, i.e., protein medicinal chemistry.…”

Chiral Phosphoric Acid‐Catalyzed Enantioselective Synthesis of Pyrazole‐Based Unnatural α‐Amino Acid Derivatives

“…As a result, considerable effort has been made to construct other highly valuable unnatural α‐amino acid scaffolds, and a number of elegant methods have been reported [12] . For example, palladium‐catalyzed C( sp 3 )−H functionalization, [4a,13] visible light‐mediated decarboxylative conjugate addition to dehydroalanine, [14] photoinduced decatungstate‐catalyzed Giese reaction of aldehydes, [15a] iron catalyzed reactions of 2‐phthaloyl acrylamide with alkenes [7b] and olefin‐olefin coupling via generated radicals, [15b] and copper‐catalyzed reactions of amino acid‐derived Schiff bases [15c] were established. In addition, the synthesis of asymmetric versions of unnatural amino acids using a simple chiral amido‐thiourea catalyst, [16] the hydrogenation of N ‐acetylamino‐phenylacrylic acids using a chiral ruthenium catalyst, [3] and via visible‐light‐promoted photoredox catalysis have been developed [16b] …”