A One-Pot Saponification–Coupling Sequence Suitable for C-Terminus Peptide Elongation Using Lithium Carboxylates

Abstract

An efficient procedure has been developed for the saponification of common peptide esters, followed by straightforward coupling of the lithium carboxylate. Adding some water to the reaction medium gave faster saponification and did not interfere with the coupling reagent. As peptide chemistry constitutes a major application of the amidation reaction, amino acid substrates were chosen for this study, monitoring both yields and epimerization of the peptides obtained.

Key words

lithium carboxylate - peptide coupling - amide - amino acid - epimerization

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• 11 General Procedure for the Formation of Carboxylates and Subsequent Coupling Reaction: To a solution of Cbz-Ala-Phe-OMe (0.3 g, 0.81 mmol) in dioxane (2 mL) at r.t. were added LiOH (25 mg, 1 mmol) and H₂O (0.35 mL, 19.44 mmol, 24 molar equiv). Stirring at r.t. and monitoring by HPLC showed complete saponification and a clear, homogeneous solution generally after 3 h. Amino acid H-AA-OMe, HCl (0.9 mmol) and HATU (0.463 g, 1.22 mmol) were added and the mixture was stirred at r.t. until completion, generally 4 h. The diastereomeric purity was measured at this stage, before isolation and purification. After concentration in vacuo, the residue was purified by silica gel chromatography with a mixture of CH₂Cl₂–EtOAc as eluent to afford the pure tripeptide as a white solid