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Amino Acids

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On-resin multicomponent 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides as an efficient tool for the synthesis of amidino depsipeptide mimics

  • Raffaella BucciEmail author
  • Federico Dapiaggi
  • Helena Macut
  • Stefano Pieraccini
  • Maurizio Sironi
  • Maria Luisa Gelmi
  • Emanuela Erba
  • Sara PellegrinoEmail author
Original Article
  • 28 Downloads

Abstract

Depsipeptides are biologically active peptide derivatives that possess a high therapeutic interest. The development of depsipeptide mimics characterized by a chemical diversity could lead to compounds with enhanced features and activity. In this work, an on-resin multicomponent procedure for the synthesis of amidino depsipeptide mimics is described. This approach exploits a metal-free 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides. In this reaction, the obtained primary cycloadduct undergoes a ring opening and molecular rearrangement giving access to a linear sulfonyl amidine functionalized with both a peptide chain and a diazoalkane. The so-obtained diazo function “one pot” reacts with the carboxylic group of N-Fmoc-protected amino acids leading to amidino depsipeptide mimics possessing a C4 aliphatic chain. An important advantage of this procedure is the possibility to easily obtain amidino-functionalized derivatives that are proteolytically stable peptide bond bioisosteres. Moreover, the conformational freedom given by the alkyl chain could promote the obtainment of cyclic depsipeptide with a stabilized secondary structure as demonstrated with both in silico calculations and experimental conformational studies. Finally, labeled depsipeptide mimics can be also synthesized using a fluorescent sulfonylazide in the multicomponent reaction.

Keywords

1,3-Dipolar cycloaddition Depsipeptide mimics Multicomponent reaction Solid-phase synthesis 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

726_2019_2805_MOESM1_ESM.docx (7.3 mb)
Supplementary material 1 (DOCX 7519 kb)

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.DISFARM-Dipartimento di Scienze Farmaceutiche, Sezione Chimica Generale e Organica “A. Marchesini”Università degli Studi di MilanoMilanItaly
  2. 2.Dipartimento di ChimicaUniversità degli Studi di MilanoMilanItaly

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