Cover Feature: Late‐Stage Installation of Dehydroamino Acid Motifs into Peptides Enabled by an N‐Chloropeptide Strategy (Chem. Eur. J. 36/2022)

Abstract

A N‐chloropeptide strategy enables the rapid construction of ΔAA‐containing peptides. The quinuclidine (ABCO)‐catalyzed N‐chlorination of peptide bonds and the subsequent β‐elimination of N‐chloroamide efficiently provides ΔAA‐containing peptides in high yield. The strategy enables the late‐stage installation of ΔAA motifs into oligopeptides that have already been constructed, including into a macrocyclic peptide. More information can be found in the Research Article by T. Nanjo, Y. Takemoto, and co‐workers (DOI: 10.1002/chem.202201120).

Efficient synthetic methods for α,β-dehydroamino acids as useful and environmentally benign building blocks in biological and materials science

“…In 2022, Nanjo, Takemoto, and co-workers reported conventional methods for the construction of α,β-dehydroamino acid derivatives (Scheme 14). 32 A wide variety of amino acid derivatives were dehydrogenated through N-chlorination of the amide nitrogen. The N-chlorination of amino acid derivatives was promoted by catalytic amounts of an organic base, such as quinuclidine.…”

“…The powerful synthetic utility of N-chloropeptide strategy was demonstrated in the late-stage modification of a cyclosporin A analogue (Scheme 15). 32 Chemoselective dehydrogenation proceeded at a less crowded alanine unit on the cyclic peptide substrate. The corresponding cyclic peptide, containing a single dehydroalanine unit, was obtained in 33% yield.…”

Precision Synthesis of Chimeric Peptides through Site-Specific Azomethine Ylide–Dehydroalanine Cycloaddition

“…[11] Despite possible interference from other nucleophilic sites like prevalent lysine ɛ-amines, several techniques have been successfully developed to achieve the Nterminal-selective functionalization through imine formation (Figure 1B). [12][13] Concurrently, Dha has gained recognition as a promising handle for the site-selective late-stage modification of peptides, [14] owing to its occurrence in bacterial, fungal, and plant natural products [15] and its straightforward generation from Cys, [16] SeCys, [17] Ser (Thr), [18] and Ala [19] residues under appropriate conditions (Figure 1C). As a mildly electrophilic olefin, Dha has been exploited as Michael acceptor, radical acceptor, [14,20] and dipolarophile [21] of modest reactivity.…”