Site‐Selective C–H Bond Activation/Functionalization of Alpha‐Amino Acids and Peptide‐Like Derivatives

Abstract

Amino acids and peptides play an important role in nature, as well as in organic and pharmaceutical chemistry. Therefore, the easy, straightforward and versatile access of biogenic and unnatural derivatives is still highly demanding. This micro‐review intends to provide to the reader the current state of the art on site‐selective C–H bond functionalization technology applied on α‐amino acids and peptides, focusing on the different C–H positions that can successfully be addressed to date. It is structured in two main parts implying i) the α‐C–H functionalization at the peptide backbone and ii) the modification of the side‐chain. Herein, metal‐catalyzed C–H activation, oxidative C–H functionalization, as well as light mediated approaches, are discussed considering the challenges in reactivity and selectivity. The great potential of these transformations is also depicted with the derivatization and macrocyclization of complex peptides leading to products of pharmaceutical importance.

Advances in Asymmetric Amino Acid Synthesis Enabled by Radical Chemistry

“…[7,64,108,109] Given the olefinic character of ΔAla derivatives, it is not surprising that they can undergo facile addition of various radicals. [60][61][62][63][64][65][66] In this section, we will discuss the different type of ΔAla substrates featuring chiral auxiliaries (CA) attached either to the amine or the carboxyl groups that were applied in radical coupling reactions for the asymmetric synthesis of various non-proteinogenic AAs. Also, the application of achiral ΔAla derivatives as substrates for coupling with in situ generated radicals under asymmetric catalysis conditions will be covered.…”

“…[183] 6. Radicals Generated from AA Derivatives in Conjugate Additions Another promising approach for the synthesis of nonproteinogenic AAs are based on generating the αcarbon radicals from glycine equivalents [184,185] and a side-chain modification of AAs, [63,65,66] for example, Laspartic and glutamic acid derivatives via radical decarboxylation, [186] leucine and valine derivatives via radical CÀ H activation [187,188] or vinyl-and allylglycine derivatives via radical conjugate additions. [189,190] In this paragraph, we will discuss the fascinating works having a deal with these topics.…”

“…[60][61][62][63][64][65][66] Moreover, owing to the generally mild reaction conditions and often high functional group tolerance, radical chemistry represents a well-suited strategy for chemoselective modifications of peptides and proteins. [61][62][63][64][65][66] In general, radical approach [67][68][69][70][71][72] is widely applied in the field of organic synthesis for the rapid construction of complex molecular architectures [73][74][75] and the total synthesis of natural products under safe and mild conditions. [76][77][78][79][80][81] Even in nature many of oxidation processes catalyzed by heme proteins and metalloporphyrins have proceeded through a radical mechanism.…”

Site-selective modification of tryptophan and protein tryptophan residues through PdNP bionanohybrid-catalysed C–H activation in aqueous media

“…12,13 Recently, the C(sp 2 )-H arylation reactions of a-amino acids and peptide-like compounds have attracted attention, especially in the indole unit of tryptophan. [16][17][18][19][20] Over the years, several protocols with different coupling partners and oxidation systems were developed for functionalization at the indole C2-position using transition metal catalysis, in which palladium acetate has been the most used catalyst. [17][18][19][20][21][22] However, this protocol showed some limitations in the extension to protein modification.…”

“…[16][17][18][19][20] Over the years, several protocols with different coupling partners and oxidation systems were developed for functionalization at the indole C2-position using transition metal catalysis, in which palladium acetate has been the most used catalyst. [17][18][19][20][21][22] However, this protocol showed some limitations in the extension to protein modification. The conditions normally require the use of organic solvents, while protein modifications must be performed in water to preserve protein structure, and catalytic performance in enzymes.…”