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

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.

Synthesis of Branched Peptides via a Side-Chain Benzyl Ester

“…Based on the approach of peptide hydrazide ligation developed by Liu group [17][18][19], we have established a convenient method to synthesize branched peptides via a side-chain ligation strategy [20,21]. Specifically, we employed a building block of Fmoc-Asn (NHNHCbz)-OH bearing a benzyloxycarbamate (Cbz)-protected side-chain hydrazine in the solid-phase peptide synthesis.…”

“…Then the in situ side-chain thioester was ligated with another N-terminal cysteine peptide to give a branched peptide [20]. In an improved approach, we used Asp side-chain benzyl ester as a surrogate, which can be readily converted into various reactive functional groups including acid, amide, hydrazide, carbonyl azide, and thioester under mild conditions and therefore facilitates the synthesis of branched peptides [21].…”