Iterative, Aqueous Synthesis of β³‐Oligopeptides Without Coupling Reagents.

Abstract

Iterative, Aqueous Synthesis of β 3 -Oligopeptides Without Coupling Reagents. -Isoxazolidine acetals (V) and (XX) are prepared either in optically active form (>99% e.e.) using the D-mannose derived hydroxylamine auxiliary (III) or in racemic form using the oxime (XVIII). The syntheses take advantage of Vasella's diastereoselective nitrone cycloaddition protocol that is extended to the reaction with methyl 2-methoxyacrylate (II). The isoxazolidines undergo facile peptide couplings with α-ketoacids such as (VI) in the absence of coupling reagents to give the amides (VII) or (XXI) possessing a new α-keto methyl ester functionality. Saponification offers the route to iterative peptide couplings to give a series of di-and tripeptides such as (IX). Their last terminal ketoester group of which can be directly converted into the corresponding acid (X) by oxidative decarboxylation. The amide formation is chemoselective as is shown in the reactions of (XI) or (XIV). -(CARRILLO, N.; DAVALOS, E. A.; RUSSAK, J.

Chemoselective N-Acylation via Condensations of N-(Benzoyloxy)amines and α-Ketophosphonic Acids under Aqueous Conditions

“…The present work was inspired by recent publications by the Bode group, who described a novel oxidative decarboxylation process involving hydroxylamines 1a and α-ketoacids 2b and their conversion to amides 3b (Scheme ). , Since our group had previously developed in 1997 an improved entry into N -(benzoyloxy)amines , (i.e., O -acylated hydroxylamines), e.g. 1b , and demonstrated that these could be converted to amides and incorporated into α,β-peptides in 2000, we speculated that these materials could also react with α-ketoacids ( 2a and 2b ) to yield amides ( 3a and 3b , respectively).…”

Chemical Protein Synthesis with the α-Ketoacid–Hydroxylamine Ligation

“…From our work on b-peptide synthesis with the KAHA ligation, we were aware of another class of hydroxylamines -isoxazolidines. 7 These remarkably stable and easily prepared compounds underwent KAHA ligation under aqueous conditions. Their main limitation -at least in the context of protein synthesis -was the need for higher reaction concentrations (typically 200 millimolar!…”