Water-Based Dynamic Depsipeptide Chemistry: Building Block Recycling and Oligomer Distribution Control Using Hydration-Dehydration Cycles

C. Martin, Moran Frenkel-Pinter, Kelvin H. Smith, Victor F. Rivera-Santana, Alyssa B. Sargon, Kaitlin C. Jacobson, Aikomari Guzman-Martinez, Loren Dean Williams, Luke J. Leman, Charles L. Liotta, Martha A. Grover, Nicholas V. Hud*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The high kinetic barrier to amide bond formation has historically placed narrow constraints on its utility in reversible chemistry applications. Slow kinetics has limited the use of amides for the generation of diverse combinatorial libraries and selection of target molecules. Current strategies for peptide-based dynamic chemistries require the use of nonpolar co-solvents or catalysts or the incorporation of functional groups that facilitate dynamic chemistry between peptides. In light of these limitations, we explored the use of depsipeptides: biorelevant copolymers of amino and hydroxy acids that would circumvent the challenges associated with dynamic peptide chemistry. Here, we describe a model system of N-(α-hydroxyacyl)-amino acid building blocks that reversibly polymerize to form depsipeptides when subjected to two-step evaporation-rehydration cycling under moderate conditions. The hydroxyl groups of these units allow for dynamic ester chemistry between short peptide segments through unmodified carboxyl termini. Selective recycling of building blocks is achieved by exploiting the differential hydrolytic lifetimes of depsipeptide amide and ester bonds, which we show are controllable by adjusting the solution pH, temperature, and time as well as the building blocks' side chains. We demonstrate that the polymerization and breakdown of the depsipeptides are facilitated by cyclic morpholinedione intermediates, and further show how structural properties dictate half-lives and product oligomer distributions using multifunctional building blocks. These results establish a cyclic mode of ester-based reversible depsipeptide formation that temporally separates the polymerization and depolymerization steps for the building blocks and may have implications for prebiotic polymer chemical evolution.

Original languageAmerican English
Pages (from-to)1395-1404
Number of pages10
JournalJACS Au
Volume2
Issue number6
DOIs
StatePublished - 27 Jun 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society.

Keywords

  • abiotic chemistry
  • depsipeptide
  • dynamic covalent chemistry
  • green chemistry
  • peptidomimetic

Fingerprint

Dive into the research topics of 'Water-Based Dynamic Depsipeptide Chemistry: Building Block Recycling and Oligomer Distribution Control Using Hydration-Dehydration Cycles'. Together they form a unique fingerprint.

Cite this