A versatile entry to unnatural, disulfide-linked amino acids and peptides through the disulfuration of azlactones

23 October 2024, Version 3
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Despite the evident demand and promising potential of disulfide-functionalized amino acids and peptides in linker chemistry and peptide drug discovery, those disulfurated specifically at the α-position constitute a unique yet rather highly underexplored chemical space. In this study, we have developed a method for preparing SS-linked amino acid/peptide derivatives through a base-catalyzed disulfuration reaction of azlactones, followed by the ring-opening functionalization. The disulfuration reaction proceeds under mild conditions, yielding disulfurated azlactones in excellent yields across a variety of N-dithiophthalimides and diverse azlactones derived from various amino acids and peptides. Leveraging the ready availability of N-dithiophthalimides from several bilateral disulfurating reagents, this method allows for the modular integration of functional molecules and azlactones into SS-linkage in two-step operations. Furthermore, due to the transformability of the azlactone moiety through ring-opening with various nucleophiles, our method provides a wide variety of functional molecule-tagged amino acids and oligopeptides bearing SS-linkages in a modular and time-efficient manner, serving as a valuable tool for linker chemistry and peptide chemistry.

Keywords

Disulfide
Azlactone
Amino Acid
Peptide
Linker

Supplementary materials

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Description
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Supporting Information
Description
Experimental procedures, characterization for new compounds including NMR spectra.
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