Exploiting An Inherent Neighboring Group Effect Of α-amino Acids To Synthesize Extremely Hindered Dipeptides

摘要

The synthetic methodology for creating peptides is among the most highly developed synthetic methodologies in chemistry. While the creation of proteogenic peptides is largely a solved problem, the creation of highly hindered peptides that contain combinations of non-natural N-alkyl amino acids and N-alkyl-α,α-disubstituted amino acids remains a formidable challenge. Hindered, non-natural amino acids are of interest because they import resistance to proteolysis and unusual conformational properties to peptides. Toward a solution to this problem, we describe a new approach to creating extremely hindered dipeptides that is operationally simple and uses mild conditions and commercially available amino acids. The approach reduces the need for protecting groups and yields urethane-protected dipeptide acids that can be used as building blocks in the synthesis of larger peptides. This approach appears to take advantage of a previously unexploited intramolecular acyl transfer.