On-resin multicomponent 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides as an efficient tool for the synthesis of amidino depsipeptide mimics
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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.
Keywords1,3-Dipolar cycloaddition Depsipeptide mimics Multicomponent reaction Solid-phase synthesis
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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.
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- Bienaymé H, Hulme C, Oddon G, Schmitt P (2000) Maximizing synthetic efficiency: multi-component transformations lead the way. Chem A Eur J 6:3321–3329. https://doi.org/10.1002/1521-3765(20000915)6:18%3c3321:aid-chem3321%3e3.0.co;2-a CrossRefGoogle Scholar
- Inokuchi E, Yamada A, Hozumi K et al (2011) Design and synthesis of amidine-type peptide bond isosteres: application of nitrile oxide derivatives as active ester equivalents in peptide and peptidomimetics synthesis. Org Biomol Chem 9:3421–3427. https://doi.org/10.1039/c0ob01193b CrossRefPubMedGoogle Scholar
- Lee YG, Koyama Y, Yonekawa M, Takata T (2009) New click chemistry: polymerization based on 1,3-dipolar cycloaddition of a homo ditopic nitrile jv-oxide and transformation of the resulting polymers into reactive polymers. Macromolecules 42:7709–7717. https://doi.org/10.1021/ma9014577 CrossRefGoogle Scholar