Bailey peptide synthesis

The Bailey peptide synthesis is a name reaction in organic chemistry developed 1949 by J. L. Bailey.^[1][2] It is a method for the synthesis of a peptide from α-amino acid-N-carboxylic acid anhydrides (NCAs) and amino acids or peptide esters.^[2][3] The reaction is characterized by short reaction times and a high yield of the target peptide.^[2]

The reaction can be carried out at low temperatures in organic solvents.^[2] The residues R¹ and R² can be organic groups or hydrogen atoms, R³ is the used amino acid or peptide ester:^[2]

Übersichtsreaktion der Bailey-Peptid-Synthese

Reaction mechanism

The reaction mechanism is not known in detail. Supposedly, the reaction begins with a nucleophilic attack of the amino group on the carbonyl carbon of the anhydride group of the N-carboxylic acid anhydride (1). After an intramolecular proton migration, a 1,4-proton shift and the cleavage of carbon dioxide follows, resulting in the peptide bond in the final product (2):^[2]

Übersichtsreaktion der Bailey-Peptid-Synthese

Atom economy

The advantage in atom economy of using NCAs for peptide formation is that there is no need for a protecting group on the functional group reacted with the amino acid.^[4] For example, the Merrifield synthesis depends on the use of Boc and Bzl protecting groups, which need be removed after the reaction.^[5] In the case of Bailey peptide synthesis, the free peptide is directly obtained after the reaction.^[4] However, unwanted and difficult to remove by-products may be formed.^[4] An N-substitution of the NCA (for example, by an o-nitrophenylsulfenyl group) can simplify the subsequent purification process, but on the other hand deteriorates the atom economy of the reaction. ^[4] The synthesis of NCAs can be carried out by the Leuchs reaction^[6] or by the reaction of N-(benzyloxycarbonyl)-amino acids with oxalyl chloride.^[7] In the latter case, again the procedure is less efficient in the sense of atom economy.

Synthesized peptides

The following peptides were synthesized using this method by 1949:^[3]

• DL-Ala-Gly
• L-Tyr-Gly
• DL-Tyr-Tyr
• DL-Ala-DL-Ala-Gly
• DL-di-Ala-L-cystinyl-di-Gly
• DL-Ala-L-Tyr-Gly
• DL-Ala-L-Tyr-Gly-Gly
• DL-Ala-DL-Ala-L-Tyr-Gly-Gly
• L-Tyr-L-Tyr-L-Tyr
• L-Cystinyl-di-Gly

Literature

• P. Katsoyannis: The Chemistry of Polypeptides. Springer Science & Business Media, 2012, ISBN 978-1-461-34571-8, S. 129.