Late‐Stage Installation of Dehydroamino Acid Motifs into Peptides Enabled by an N‐Chloropeptide Strategy

Abstract

Conventional methods for the construction of dehydroamino acids (ΔAAs), which are a unique class of nonproteinogenic amino acids, require the pre-installation of special amino acids. Herein, we report and demonstrate the practical utility of an N-chloropeptide strategy for the rapid construction of ΔAA-containing peptides. The electrophilic Nchlorination of peptide bonds is drastically accelerated by a catalytic amount of quinuclidine (ABCO), and the subsequent β-elimination of N-chloroamide efficiently provides ΔAAcontaining peptides in high yield. The strategy enables, for the first time, the construction of a wide variety of ΔAA residues in peptides without any pre-functionalized side chains and facilitates the late-stage installation of ΔAA motifs into already-constructed oligopeptides, including a medicinally important macrocyclic peptide.

Synthesis of Chlorinated Oligopeptides via γ- and δ-Selective Hydrogen Atom Transfer Enabled by the N-Chloropeptide Strategy

“…A comparison of the 1 H and 13 C NMR chemical shifts of the Cl Ile residues of 46a and 46b revealed significant differences. In particular, the chemical shifts at the δ-position adjacent to the chlorine-substituted carbon were significantly different; specifically, the 13 C NMR peak was shifted by 5 ppm. When we compared the chemical shifts at the δ-position of the Cl Ile residue of 46a and 46b and aquimarin A, we discovered that those of 46a and aquimarin A are almost identical and that other Cl Ile peaks were also similar (for details, see the Supporting Information).…”

“…In addition, 45a and 45b were successfully converted to 46a and 46b, which are N-terminus dipeptide fragments of aquimarin A. A comparison of the 1 H and 13 C NMR chemical shifts of the Cl Ile residues of 46a and 46b revealed significant differences. In particular, the chemical shifts at the δ-position adjacent to the chlorine-substituted carbon were significantly different; specifically, the 13 C NMR peak was shifted by 5 ppm.…”

“…12b,g To establish a practical approach for the rapid construction of a wide variety of γand δ-chlorinated peptides, we focused on an N-chloropeptide strategy that has recently been established in our group for the late-stage installation of a dehydroamino acid residue into peptides. 13 In this approach, the N-chlorination of peptides, which is usually hindered by the low reactivity of the substrates, was successfully achieved under 1-azabicyclo[2,2,2]octane (ABCO)-catalyzed conditions. These results revealed that the as-synthesized Nchloropeptides exhibit a good trade-off between stability and reactivity that allows for further transformations.…”

α,β-Dehydroamino Acid Synthesis through Proline-Catalyzed Aldol Condensation with a Glycine Schiff Base

“…Straightforward synthetic methods to elongate peptides in the same way as ordinary α-amino acids are highly desired. − Although synthetic approaches to peptides bearing α,β-dehydroamino acids have been intensively investigated, the results are quite limited due to the instability of α,β-dehydroamino acids. α,β-Dehydroamino acid-derived peptide synthesis is classically based on the elimination reaction of hydroxyl groups, such as serine and threonine, or olefination of prefunctionalized glycine derivatives. − These methods, however, are mainly limited to synthetic elongation at the C-terminal of α,β-dehydroamino acids, and synthetic elongation methods, especially at the N-terminal, − are largely unexplored (Scheme B) …”

Electrosynthesis of Protected Dehydroamino Acids

“…Limitations include the use of reactive t BuOCl and challenging N -protection of the sensitive enamines. Nanjo and Takemoto applied a similar N -chlorination protocol to the selective late-stage desaturation of aliphatic peptides (Scheme C) . However, carbamate protected residues were not desaturated under these conditions.…”