Chemoselective Amide Ligations by Decarboxylative Condensations of N‐Alkylhydroxylamines and α‐Ketoacids

Abstract

Additive‐free: The chemoselective amide‐bond‐forming ligation between N‐alkylhydroxylamines and α‐ketoacids requires no reagents and the only by‐products are water and carbon dioxide. This process proceeds on unprotected peptide substrates without epimerization, and as such, this process has the potential to serve as a novel chemoselective ligation for the synthesis of peptides and complex materials.

Oxidation of Peptides by Methyl(trifluoromethyl)dioxirane: The Protecting Group Matters

“…The typical procedures for the preparation of terminal N-hydroxy peptides are coupling of an activated protected N-hydroxy amino acid with a peptide, 11a coupling of an activated α-oximino acid with a peptide followed by reduction and separation of the diastereomers, 11a and synthesis of the oxime from a suitable α-keto amide followed by reduction and separation of the diastereomers. 11c The easy access to the terminal N-hydroxy peptides is likely to have a positive synthetic impact because these compounds are valuable synthons in a novel chemoselective amide ligation for the polypeptide synthesis by coupling with a peptide ketoacid, 17 and in the formation of hydroxamates by reaction with an acyl chloride. 11c N-hydroxy peptides are biologically interesting compounds on their own because they are involved in metabolic transformations, as demonstrated by their occurrence in animal and human tumors.…”

“…17 Thus the results reported herein yield synthons that can be utilized in this novel chemoselective amide ligation for polypeptide synthesis. 17 In order to test whether the interesting N-terminal hydroxylation of peptides by TFD is unique for the Boc protection or it is a rather general phenomenon with N-protected peptides, we decided to explore the reactivity of some N-acetyl protected amino acid and dipeptide esters, bearing alkyl side chains. Hence, we observe high regioselective side chain hydroxylation in the reaction with N-acetyl protected amino acids and dipeptides.…”

“…This is a synthetically useful transformation since N-hydroxy peptides are important synthons in the preparation of biologically active molecules. 11,17 N-Acetyl protected amino acid and dipeptide methyl esters bearing alkyl side chains undergo exclusively high regioselective side chain hydroxylation when they react with TFD. The tertiary γ-CH bond of the leucine residue displays higher reactivity in comparison to the tertiary β-CH bond of the valine residue.…”

Staudinger Ligation of Peptides at Non-Glycyl Residues

“…13 This reaction suffers, however, from the accumulation of numerous intermediates, leading to low overall rates. Modifications to the reactants or reaction conditions that overcome this intrinsic deficiency are not apparent.…”

Inspiration comes naturally

“…It is this aspect of natural-product biosynthesis that captured the attention of Yi-Lin Huang and Jeffrey Bode, and inspired their development of what they dub 'synthetic fermentation' (page 877). The process uses the groups' previously developed ketoacid-hydroxylamine (KAHA) ligation 4 to stitch together 23 building blocks into a library of 6,000 unnatural peptides. Screening of the library and deconvolution of the results led to identification of a hepatitis C virus protease inhibitor.…”