Rapid Synthesis of Cyclopeptide Alkaloid‐Like <i>para</i>‐Cyclophanes by Combined Use of Ugi‐4CR and Intramolecular S<sub>N</sub>Ar Reaction

Cristau, P; Vors, Jean‐Pierre; Zhu, Jieping

doi:10.1002/qsar.200540214

Cited by 25 publications

(10 citation statements)

References 33 publications

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“…Several other groups have exploited the complexity-generating character of the Ugi reaction for the assembly of natural product-like peptide architectures that are macrocyclized by non-MCR methods. In 2006, two independent reports , described the preparation of analogues of cyclopeptide alkaloid-like macrocycles utilizing an initial Ugi reaction and followed by dissimilar ring closing steps. Thus, Zhu and coworkers employed an intramolecular S N Ar for the macrocyclization of Ugi reaction-derived peptide skeleton, while Wessjohann and collaborators used a macro-etherification for the same purpose.…”

Section: Sequential Mcr/macrocyclization Approach To Cyclic Peptidesmentioning

confidence: 99%

Multicomponent Reaction Toolbox for Peptide Macrocyclization and Stapling

2019

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In the past decade, multicomponent reactions have experienced a renaissance as powerful peptide macrocyclization tools enabling the rapid creation of skeletal complexity and diversity with low synthetic cost. This review provides both a historical and modern overview of the development of the peptide multicomponent macrocyclization as a strategy capable to compete with the classic peptide cyclization methods in terms of chemical efficiency and synthetic scope. We prove that the utilization of multicomponent reactions for cyclizing peptides by either their termini or side chains provides a key advantage over those more established methods; that is, the possibility to explore the cyclic peptide chemotype space not only at the amino acid sequence but also at the ring-forming moiety. Owing to its multicomponent nature, this type of peptide cyclization process is well-suited to generate diversity at both the endo-and exo-cyclic fragments formed during the ring-closing step, which stands as a distinctive and useful characteristic for the creation and screening of cyclic peptide libraries. Examples of the novel multicomponent peptide stapling approach and heterocycle ring-forming macrocyclizations are included, along with multicomponent methods incorporating macrocyclization handles and the one-pot syntheses of macromulticyclic peptide cages. Interesting applications of this strategy in the field of drug discovery and chemical biology are provided.

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Section: Sequential Mcr/macrocyclization Approach To Cyclic Peptidesmentioning

confidence: 99%

Multicomponent Reaction Toolbox for Peptide Macrocyclization and Stapling

2019

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“…The synthesis of cyclopeptide alkaloids‐like para ‐cyclophanes by combining the Ugi reaction and the intramolecular S N Ar reaction was reported by Zhu and co‐workers in 2006 [34] (Scheme 11). In this work, different components for the Ugi reaction were examined, including the arylated or alkylated aldehydes, amines, carboxylic acids and isonitriles.…”

Section: Diverse Synthetic Approaches To the Macrocycles In Cyclopeptmentioning

confidence: 99%

Approaches to Cyclophane‐Types of Cyclopeptide Alkaloids

Wang

Joullié

2021

The Chemical Record

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The cyclopeptide alkaloids are cyclic depsipeptides incorporating cyclophanes with polyamide units 13‐, 14‐ and 15‐membered macrocyclic systems. Although various pharmacological activities have been ascribed to cyclopeptide alkaloids from plants of the Rhamnacea family, these studies have been hampered by their low availability due to the lack of reasonable amounts distributed in nature. Therefore, novel and efficient synthetic approaches should be an important aim, which inspired us to examine how to diversely construct the unique structures of this type of natural products. In this account, several typical strategies are presented in terms of efficient, stereocontrolled and regioselective synthesis of cyclopeptide alkaloids.

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“…The same authors also published a similar solution-phase sequence towards cyclophane based-macrocycles having an aryl- N -alkyl bridge ( Scheme 93 ) [ 241 ]. In this route the Ugi reaction was performed with aliphatic carboxylic acids, furnishing the dipeptides 323 in 32–92% yield.…”

Section: Reviewmentioning

confidence: 99%

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

Koopmanschap¹,

Ruijter²,

Orru³

2014

Beilstein J. Org. Chem.

233

117

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SummaryIn the recent past, the design and synthesis of peptide mimics (peptidomimetics) has received much attention. This because they have shown in many cases enhanced pharmacological properties over their natural peptide analogues. In particular, the incorporation of cyclic constructs into peptides is of high interest as they reduce the flexibility of the peptide enhancing often affinity for a certain receptor. Moreover, these cyclic mimics force the molecule into a well-defined secondary structure. Constraint structural and conformational features are often found in biological active peptides. For the synthesis of cyclic constrained peptidomimetics usually a sequence of multiple reactions has been applied, which makes it difficult to easily introduce structural diversity necessary for fine tuning the biological activity. A promising approach to tackle this problem is the use of multicomponent reactions (MCRs), because they can introduce both structural diversity and molecular complexity in only one step. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs) are most relevant for the synthesis of peptidomimetics because they provide peptide-like products. However, these IMCRs usually give linear products and in order to obtain cyclic constrained peptidomimetics, the acyclic products have to be cyclized via additional cyclization strategies. This is possible via incorporation of bifunctional substrates into the initial IMCR. Examples of such bifunctional groups are N-protected amino acids, convertible isocyanides or MCR-components that bear an additional alkene, alkyne or azide moiety and can be cyclized via either a deprotection–cyclization strategy, a ring-closing metathesis, a 1,3-dipolar cycloaddition or even via a sequence of multiple multicomponent reactions. The sequential IMCR-cyclization reactions can afford small cyclic peptide mimics (ranging from four- to seven-membered rings), medium-sized cyclic constructs or peptidic macrocycles (>12 membered rings). This review describes the developments since 2002 of IMCRs-cyclization strategies towards a wide variety of small cyclic mimics, medium sized cyclic constructs and macrocyclic peptidomimetics.

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Rapid Synthesis of Cyclopeptide Alkaloid‐Like para‐Cyclophanes by Combined Use of Ugi‐4CR and Intramolecular S_NAr Reaction

Cited by 25 publications

References 33 publications

Multicomponent Reaction Toolbox for Peptide Macrocyclization and Stapling

Multicomponent Reaction Toolbox for Peptide Macrocyclization and Stapling

Approaches to Cyclophane‐Types of Cyclopeptide Alkaloids

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

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Rapid Synthesis of Cyclopeptide Alkaloid‐Like para‐Cyclophanes by Combined Use of Ugi‐4CR and Intramolecular SNAr Reaction

Cited by 25 publications

References 33 publications

Multicomponent Reaction Toolbox for Peptide Macrocyclization and Stapling

Multicomponent Reaction Toolbox for Peptide Macrocyclization and Stapling

Approaches to Cyclophane‐Types of Cyclopeptide Alkaloids

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

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Rapid Synthesis of Cyclopeptide Alkaloid‐Like para‐Cyclophanes by Combined Use of Ugi‐4CR and Intramolecular S_NAr Reaction