Solid-supported synthesis of cryptand-like macrobicyclic peptides

Area of Science:

• Organic Chemistry
• Peptide Chemistry
• Synthetic Chemistry

Background:

• Bicyclic peptides, including cryptand-like structures, are of interest for various applications.
• Solid-phase peptide synthesis (SPPS) is a cornerstone of peptide chemistry.
• Developing efficient and versatile methods for synthesizing complex peptide architectures remains a key challenge.

Purpose of the Study:

• To describe a straightforward solid-supported method for synthesizing cryptand-like bicyclic peptides.
• To introduce and utilize two novel building blocks for controlled branching in peptide synthesis.
• To establish a robust synthetic route amenable to Fmoc-based SPPS.

Main Methods:

• Solid-phase synthesis utilizing a backbone amide linker.
• Employing two novel building blocks: N-(4-methoxytrityl)-N-(2-nitrobenzenesulfonyl)-protected N,N-bis(2-aminoethyl)-beta-alanine and N-(9-fluorenylmethoxycarbonyl) protected iminodiacetic acid monoallyl ester.
• Sequential deprotection and coupling steps using Fmoc (9-fluorenylmethoxycarbonyl) and Boc (tert-butoxycarbonyl) chemistries, followed by cyclization and cleavage.

Main Results:

• Successful solid-supported synthesis of cryptand-like bicyclic peptides (compounds 1-5).
• Demonstrated utility of the novel building blocks for creating branched peptide structures.
• Established a multi-step synthetic sequence involving protection/deprotection and cyclization strategies.

Conclusions:

• The developed method provides a facile route to cryptand-like bicyclic peptides.
• The novel building blocks facilitate the construction of complex peptide scaffolds.
• This approach offers a valuable tool for the synthesis of intricate peptide architectures.