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Related Concept Videos

[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction01:16

[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction

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The Diels–Alder reaction is an example of a thermal pericyclic reaction between a conjugated diene and an alkene or alkyne, commonly referred to as a dienophile. The reaction involves a concerted movement of six π electrons, four from the diene and two from the dienophile, forming an unsaturated six-membered ring. As a result, these reactions are classified as [4+2] cycloadditions.
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Cycloaddition Reactions: Overview01:16

Cycloaddition Reactions: Overview

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Cycloadditions are one of the most valuable and effective synthesis routes to form cyclic compounds. These are concerted pericyclic reactions between two unsaturated compounds resulting in a cyclic product with two new σ bonds formed at the expense of π bonds. The [4 + 2] cycloaddition, known as the Diels–Alder reaction, is the most common. The other example is a [2 + 2] cycloaddition.
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Diels–Alder Reaction Forming Cyclic Products: Stereochemistry01:28

Diels–Alder Reaction Forming Cyclic Products: Stereochemistry

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The Diels–Alder reaction is one of the robust methods for synthesizing unsaturated six-membered rings. The reaction involves a concerted cyclic movement of six π electrons: four π electrons from the diene and two π electrons from the dienophile.
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Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry01:29

Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry

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Diels–Alder reactions between cyclic dienes locked in an s-cis configuration and dienophiles yield bridged bicyclic products.
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Diels–Alder Reaction: Characteristics of Dienophiles01:24

Diels–Alder Reaction: Characteristics of Dienophiles

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In a Diels–Alder reaction, the diene is usually an electron-rich system and acts as a nucleophile, whereas the dienophile is electron-deficient and functions as an electrophile. Much like the diene, the nature of the dienophile significantly impacts the outcome of the reaction. 
Characteristics of Dienophiles
Generally, the best dienophiles are alkenes containing electron-withdrawing substituents such as carbonyl, nitrile, and nitro groups. The feasibility of a Diels–Alder reaction depends...
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Cycloaddition Reactions: MO Requirements for Thermal Activation01:16

Cycloaddition Reactions: MO Requirements for Thermal Activation

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Thermal cycloadditions are reactions where the source of activation energy needed to initiate the reaction is provided in the form of heat. A typical example of a thermally-allowed cycloaddition is the Diels–Alder reaction, which is a [4 + 2] cycloaddition. In contrast, a [2 + 2] cycloaddition is thermally forbidden.
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Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
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Diels-Alder Cycloadditions for Peptide Macrocycle Formation.

Jeffrey E Montgomery1, Raymond E Moellering2

  • 1Department of Chemistry, Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA.

Methods in Molecular Biology (Clifton, N.J.)
|October 1, 2021
PubMed
Summary
This summary is machine-generated.

Diels-Alder cycloadditions offer a versatile method for peptide macrocyclization, enhancing stability and pharmacologic properties. This approach overcomes limitations of existing chemistries, enabling diverse peptide structures in various environments.

Keywords:
Biorthogonal chemistryBiotherapeuticsCyclic peptidesDiels-Alder cycloadditionMacrocyclesPeptide ligandsPeptidomimeticsSynthetic biologics

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Area of Science:

  • Medicinal Chemistry
  • Organic Chemistry
  • Chemical Biology

Background:

  • Peptide macrocyclization enhances stability, target affinity, and membrane permeability for therapeutics and chemical probes.
  • Existing macrocyclization chemistries often lack compatibility, limiting access to desired molecular properties.
  • Diels-Alder [4+2] cycloadditions present a novel approach to peptide macrocyclization.

Purpose of the Study:

  • To present synthetic processes and characterization methods for Diels-Alder cyclized peptides.
  • To highlight the advantages of Diels-Alder chemistry for peptide macrocyclization.

Main Methods:

  • Utilized Diels-Alder [4+2] cycloadditions for peptide macrocyclization.
  • Developed and characterized synthetic routes for creating Diels-Alder cyclized peptides.
  • Evaluated the compatibility of this chemistry in organic and aqueous environments.

Main Results:

  • Diels-Alder cyclization successfully produced stable peptide scaffolds.
  • Demonstrated the ability of Diels-Alder chemistry to template diverse peptide secondary structures.
  • Showcased improved pharmacologic properties in Diels-Alder cyclized peptides.

Conclusions:

  • Diels-Alder cycloaddition is a robust and versatile method for peptide macrocyclization.
  • This chemistry overcomes limitations of traditional methods, offering broader applications in drug discovery.
  • The presented methods facilitate the synthesis and characterization of novel cyclized peptides.