Aspartic Acid Side-Chain Benzyl Ester as a Multifunctionalization Precursor for Synthesis of Branched and Cyclic Arginylglycylaspartic Acid Peptides

^◊ These authors contributed equally to this work.

Published as part of the Cluster Recent Advances in Protein and Peptide Synthesis

Abstract

Here, we report a peptide aspartic acid side-chain benzyl ester as a useful precursor that can be efficiently converted into various functional groups, including acid, amide, carbonyl hydrazide, carbonyl azide, or thio ester groups, without other protection for the peptide. With this strategy, we synthesized a series of novel branched and cyclic arginylglycylaspartic acid peptides through successive peptide C-terminal ligation and side-chain ligation based on a side-chain carbonyl azide or thio ester.

Key words

peptide side-chain ligation - side-chain benzyl ester - peptide hydrazide - arginylglycylaspartic acid peptides - branched cyclic peptides

• Notes and References

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• 22 Side-Chain Peptide Hydrazide Synthesis and Successive Side-Chain Ligation; General Procedure The side-chain benzyl ester peptide (2 mM) was treated with 5% N₂H₄ in DMF at r.t. for 15–30 mins until conversion was complete (HPLC). The product was purified by preparative HPLC, and the resulting side-chain peptide hydrazide was then treated with NaNO₂ (10 equiv) in a pH 2 buffer of 6.0 M guanidine hydrochloride and 0.2 M aq NaH₂PO₄ at –10 °C for 15 min to give the corresponding carbonyl azide. MPAA (50 equiv) was then added, the pH of the residue was adjusted to pH 5.5 with 1.0 M aq NaOH, and the mixture was kept at –10 °C for 15 min to give the side-chain thio ester. A Cys-peptide (2 equiv) or an amino-RGD peptide (5 equiv) was added then for side-chain ligation at r.t. for 4–8 h. The ligation product of the branched peptide was purified by preparative HPLC. For details and HPLC and MS data, see the Supplementary Information.
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