First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

• Maxime Pypec,
• Laurent Jouffret,
• Claude Taillefumier and
• Olivier Roy

Beilstein J. Org. Chem. 2022, 18, 845–854, doi:10.3762/bjoc.18.85

• Maxime Pypec Laurent Jouffret Claude Taillefumier Olivier Roy Université Clermont Auvergne, Clermont Auvergne INP, CNRS, ICCF, F-63000 Clermont–Ferrand, France 10.3762/bjoc.18.85 Abstract The synthesis and conformational analysis of the first series of peptoid oligomers composed of consecutive N

• -(alkylamino)glycine units is investigated. We demonstrate that N-(methylamino)glycine homooligomers can be readily synthesized in solution using N-Boc-N-methylhydrazine as a peptoid submonomer and stepwise or segment coupling methodologies. Their structures were analyzed in solution by 1D and 2D NMR, in the

• antiparallel arrangement of mirror image molecules held together via two hydrogen bonds in the crystal lattice of dimer 2. Keywords: cis/trans isomerism; peptoid; structure; trans-inducing side chain; Introduction The term “peptoids” refers to the family of artificial oligo(poly)mers consisting of N

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• diastereomers. After converting 68 into aldehyde 69, this was reacted with cyclopropyl isocyanide 57 and acetic acid (Passerini reaction) furnishing compound 70, which was converted to telaprevir (64) in three additional steps. Macrocyclic peptoid synthesis Dömling et al. performed the combination of two

• reaction under pseudo-high dilution conditions (to avoid oligomerization) to furnish cyclopeptoids 85 and 90, respectively (Scheme 16 and Scheme 17). Ester hydrolysis and N-deprotection reactions were carried out in between. In this approach, by varying the amine component, the side chains of the peptoid

• backbone could be easily exchanged. Later on, our group introduced the use of microwave heating to this same synthetic strategy for the synthesis of a cyclic peptoid (Scheme 18) [33]. The combination of these two tools (microwave heating and consecutive IMCRs) has proved to be a particularly attractive

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• polypeptides is still not fully understood and it may appear controversial in the literature. For example, a donor–acceptor type enhancement of the face-to-face stacking of phenyl- and pentafluorophenyl groups has been suggested [36]; though, subsequent studies of α-helical [37], peptoid [38], and collagen

Synthesis of acylhydrazino-peptomers, a new class of peptidomimetics, by consecutive Ugi and hydrazino-Ugi reactions

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2016, 12, 2865–2872, doi:10.3762/bjoc.12.285

• peptidomimetics with potential biological activity. Keywords: acylhydrazino-peptomers; consecutive Ugi reactions; peptide-peptoid hybrid; peptomer; Introduction In the last decades, increasing efforts have been extensively carried out to improve the pharmacological properties of natural peptides by structural

• some of the most important classes of peptidomimetics so far obtained and highlights the differences among them. Of these, peptoids (oligomers of N-substituted glycine residues) [9][10][11][12] are the most common and may have interesting biological activities. For instance, peptoid 1 is a target for

• cancer therapeutics for being an antagonist of the vascular endothelial growth factor receptor 2 [13]; peptoid 2 is a ligand of the protooncogene Crk [14]; and peptoids 3 and 4 showed a high affinity for the α1-adrenergic and μ-specific opiate receptors [15], respectively (Figure 2). Unlike peptides, in

Synthesis of antibacterial 1,3-diyne-linked peptoids from an Ugi-4CR/Glaser coupling approach

• Martin C. N. Brauer,
• Ricardo A. W. Neves Filho,
• Bernhard Westermann,
• Ramona Heinke and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2015, 11, 25–30, doi:10.3762/bjoc.11.4

• , this reaction has been used in the synthesis of bioactive peptides and pseudopeptides, e.g., tubulysin mimetics [13], julocrotine derivatives [14], architecturally complex peptoid macrocycles [15][16], building blocks for diversity-oriented synthesis [17], and heterocyclic compounds [18]. Complex

• -diynes because it does not require expensive catalysts, ligands, or additives (Table 1) [34]. The coupling reaction was clean without notable side product formation as confirmed by TLC analysis, and the desired peptoid dimers 8a–j could be obtained in high to quantitative yields. Aromatic as well as

• to note that different protecting groups can be used: Boc-, PhAc- and Cbz-protected peptoid derivatives (Table 1, entries 8–10) reacted to the corresponding dimers 7h–j without complications. The structure of the compounds 7a–j, as well as 8a–j, have been confirmed by 1H, 13C NMR spectra, and HRMS

Synthesis of the first examples of iminosugar clusters based on cyclopeptoid cores

• Mathieu L. Lepage,
• Alessandra Meli,
• Anne Bodlenner,
• Céline Tarnus,
• Francesco De Riccardis,
• Irene Izzo and
• Philippe Compain

Beilstein J. Org. Chem. 2014, 10, 1406–1412, doi:10.3762/bjoc.10.144

• , size, charge and branching of these cyclic scaffolds influence the pharmacological profile of the products [35][36][37][38][39]. Moreover, macrocyclization enforces the rigidity of the more flexible linear peptoid skeleton and generally produces enhancement in biological activities [21][37]. In this

• by compound 9a (Figure 2i). This phenomenon, already observed for N-substituted cyclic α-peptoid derivatives [35][36][37][38][39], indicated the presence of more than one conformer in slow exchange on the NMR time scale. It is well known that the conformational heterogeneity is due to tertiary amide

Consecutive isocyanide-based multicomponent reactions: synthesis of cyclic pentadepsipeptoids

• Angélica de Fátima S. Barreto,
• Otilie E. Vercillo,
• Ludger A. Wessjohann and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2014, 10, 1017–1022, doi:10.3762/bjoc.10.101

• ]. This family of oligomers comprising poly-N-substituted glycines mimics the primary natural structure of peptides and exhibits greater proteolytic stability and increased cellular permeabilities in comparison to peptides [5][6][7]. A powerful synthetic tool for the preparation of a peptoid backbone is

• in combinatorial synthesis [40][41][42][43] and can be used strategically for the synthesis of depsipeptoids. By analogy to peptides and peptoids, a depsipeptoid would be a peptoid bearing an ester group instead of an amide group. Differences between peptide, peptoid, depsipeptide and depsipeptoid

• compounds can be achieved using a strategy based on: (a) formation of a peptoid via Ugi reaction; (b) ester hydrolysis; (c) formation of an acyclic depsipeptoid scaffold through a Passerini reaction; (d) deprotection of the amine/acid groups and (e) a macrocyclization step via an intramolecular Ugi reaction

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• functionalities. For peptoids, CuAAC has already been used successfully to introduce diverse side-chain functionalities directly during solid-phase synthesis of peptoids starting from both, azido- and alkyne-functionalized side chains [41][42]. In addition CuAAC has also been used in order to constrain peptoid

• secondary structures [43]. CuAAC reactions for the attachment of sugar residues to peptoid backbones have been reported for some cases [44][45]; however, a fully glycosylated structure is unknown (for glycodendrons see [46]). In this study, we describe the first solid-phase synthesis of glycosylated

• copper ions. In some cases, changing the base from DIPEA to DBU was beneficial (Scheme 2). After these encouraging results, we turned our attention to peptoids. For the glycosylation of peptoids, we envisaged the generation of a fully glycosylated peptoid in order to investigate the compatibility of

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

• Ricardo A. W. Neves Filho,
• Sebastian Stark,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2012, 8, 2085–2090, doi:10.3762/bjoc.8.234

• readily available to provide first SAR insight. The biological activities of the natural product and its derivatives against the Gram-negative bacterium Aliivibrio fischeri were evaluated. Keywords: antibiotic; anticancer; Gram negative bacteria; natural product; peptide coupling; peptides; peptoid

• isonitrile 4 as the key transformation was envisioned to yield racemic viridic acid (±)-1 (Scheme 1b) [12]. Besides furnishing the desired natural product in only four steps, the MCR approach allows a ready access to analogues endowed with a proteolysis-resistant peptoid moiety [13]. Recently, we

• demonstrated that chemically more stable peptoid analogues of tubulysins, named tubugis, present cytotoxicity against cancer cell lines comparable to the native natural product [14]. Thus, it was hoped that some viridic acid analogues readily accessible by MCR may also display enhanced biological activity or

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• ] reported the internalization by polylysine of methothrexate and horse radish peroxidase; Leonetti et al. [21] the internalization of oligonucleotides; and Mulders et al. [22] the internalization of adenovirus into cells. A polylysine peptoid derivative was used by Murphy et al. [23] for “gene delivery

Antifreeze glycopeptide diastereomers

• Lilly Nagel,
• Carsten Budke,
• Axel Dreyer,
• Thomas Koop and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1657–1667, doi:10.3762/bjoc.8.190

• proline replacements [5]. These peptides exhibit less antifreeze activity than monosaccharide-substituted AFGP analogues without proline residues. Peptoid glycoconjugates with carbohydrate moieties attached by CuI catalyzed azide-alkyne cycloaddition (CuAAC) were devoid of antifreeze activity [17

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

• Ricardo A. W. Neves Filho,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

• analogues possess a protease-resistant peptoid scaffold and this might lead to an enhanced activity [19][20]. In this endeavor, all Ugi reactions were initiated by pre-imine formation of 5 and reaction with formaldehyde as the oxo-component, after which the multicomponent reaction was completed by the