Abstract
Chemoselective ligation methods that preserve or introduce side chain diversity are critical for chemical synthesis of peptides and proteins. Starting from ketone substrates instead of aldehydes in oxime ligation reactions would allow substitution at the site of ligation; however, synthetic challenges to readily access ketone derivatives from common amino acid building blocks have precluded the widespread use of ketoxime peptide ligation reactions thus far. Moreover, ketones are typically much slower to react in condensation reactions compared to aldehydes. Here, one-pot catalyst-free oxidative couplings of α-substituted N-aryl peptides with alkoxyamines provide access to oxime linkages with diverse side chains. Electron-rich N-(p-Me2N-phenyl)-amino acids possessing substituents at the α-carbon were found to be uniquely capable of undergoing site-selective α-C-H oxidations in situ under an O2 atmosphere at neutral pH. Comparative studies with N-arylglycinyl peptides revealed that substitution at the α-carbon caused notable changes in reactivity, with greater sensitivity to solvent and buffer salt composition.
Highlights
Oxime ligation reactions,[1] traditionally obtained from anilinecatalyzed couplings of carbonyl compounds with alkoxyamines,[2] have been widely used in chemoselective functionalization of biomolecules
We further demonstrate that this oxidative coupling is uniquely dependent on solvent composition, with high yielding reactions conveniently occurring under aqueous conditions at neutral pH with a variety of N-aryl amino acids
Much like what we observed for the buffer salt studies, we found that Ca-substitution in N-aryl amino acids led to greater sensitivity to organic solvent composition compared to N-aryl glycinyl peptide 2a, which remained virtually unaffected by addition of up to 50% ethanol
Summary
Oxime ligation reactions,[1] traditionally obtained from anilinecatalyzed couplings of carbonyl compounds with alkoxyamines,[2] have been widely used in chemoselective functionalization of biomolecules. One-pot catalyst-free oxidative couplings of asubstituted N-aryl peptides with alkoxyamines provide access to oxime linkages with diverse side chains.
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