The Functionalization of Amino Acids, Peptides, and Derivatives by Cross‐Dehydrogenative Coupling

Abstract

Modified or unnatural amino acids and peptides are required for a number of applications, which include drug development, diagnostics, to study protein function, for vaccine development, and also for synthetic building blocks and catalysts. By joining two native CH bonds directly, cross‐dehydrogenative coupling provides an efficient, atom‐economical, and environmentally friendly methodology for the α‐functionalization of these substances. Many oxidants, including air, may be utilized to facilitate the loss of hydrogen, and several types of catalysts, metal or organocatalysts and even light, are now known that activate CH bonds for a variety of applications. Site‐selective peptide functionalization is possible in some cases, compatible with the presence of many functional groups in the molecules, and also asymmetric synthesis. This article revises the literature available on this topic, covering at the same time the reaction mechanisms involved and studies performed to elucidate them, aiming to interest the reader in potential future applications.

A Mild and Sustainable Procedure for the Functionalization of Morpholin-2-Ones by Oxidative Imidation Reactions

“…Amongst the substrates explored successfully for CDC reactions have been αaminocarbonyl compounds, of which amino acids and peptides/peptidomimetics are the best representatives [10][11][12][13]. α-Alkylation or α-heterofunctionalization of these substances leads to the formation of modified amino acids and peptides which are of prime interest for the pharmaceutical industry [14][15][16][17].…”

“…In this context, morpholinones, which can subsequently be incorporated into peptides, seemed a good subject for research. CDC methodologies have been so far utilized for the α-functionalization of α-amino esters and α-amino amides or small peptides in some instances with alkynes, alkenes, indoles and other heteroarenes, ketones, β-ketoesters, nitroalkanes, ethers, diphenyl phosphine oxide and H-phosphonates, α-diazocarbonyl compounds, aziridines, as well as alcohols, thiols, naphthols, pyrroles [10,11,32] and amides and imides (Figure 1a) [33][34][35]. The αfunctionalization of 3,4-dihydro-1,4-benzoxazin-2-ones with indoles (Figure 1b) [36] and with malonates (Figure 1c) [37] have been described, but to the best of our knowledge, morpholinones have not been employed in CDC reactions so far and became the subject of our studies (Figure 1d).…”