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Cycloaddition Reactions: Overview

Cycloaddition Reactions: Overview

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.

Cycloaddition Reactions: MO Requirements for Thermal Activation

Cycloaddition Reactions: MO Requirements for Thermal Activation

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.

Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry

Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry

Diels–Alder reactions between cyclic dienes locked in an s-cis configuration and dienophiles yield bridged bicyclic products.

Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation

Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation

Robinson annulation is a base-catalyzed reaction for the synthesis of 2-cyclohexenone derivatives from 1,3-dicarbonyl donors (such as cyclic diketones, β-ketoesters, or β-diketones) and α,β-unsaturated carbonyl acceptors. Named after Sir Robert Robinson, who discovered it, this reaction yields a six-membered ring with three new C–C bonds (two σ bonds and one π bond).

Cycloaddition Reactions: MO Requirements for Photochemical Activation

Cycloaddition Reactions: MO Requirements for Photochemical Activation

Some cycloaddition reactions are activated by heat, while others are initiated by light. For example, a [2 + 2] cycloaddition between two ethylene molecules occurs only in the presence of light. It is photochemically allowed but thermally forbidden.

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

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

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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Updated: Sep 8, 2025

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

Published on: September 28, 2022

Large Macrocyclic Libraries via Thioether Cyclization.

Alexander L Nielsen^1,2

¹Institute of Chemical Sciences and Engineering, School of Basic Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. axee@novonordisk.com.

Methods in Molecular Biology (Clifton, N.J.)

|July 15, 2025

Summary

This summary is machine-generated.

This study introduces a streamlined method for synthesizing large macrocyclic peptide libraries using automated solid-phase peptide synthesis (SPPS) and purification-free cyclization. This approach accelerates drug discovery for challenging intracellular targets.

Keywords:

Combinatorial libraries Cyclic peptides High-throughput experimentation Macrocycles

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Constructing Thioether/Vinyl Sulfide-tethered Helical Peptides Via Photo-induced Thiol-ene/yne Hydrothiolation

Published on: August 1, 2018

Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation

Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation

Published on: January 26, 2016

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Last Updated: Sep 8, 2025

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

Published on: September 28, 2022

Constructing Thioether/Vinyl Sulfide-tethered Helical Peptides Via Photo-induced Thiol-ene/yne Hydrothiolation

Constructing Thioether/Vinyl Sulfide-tethered Helical Peptides Via Photo-induced Thiol-ene/yne Hydrothiolation

Published on: August 1, 2018

Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation

Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation

Published on: January 26, 2016

Area of Science:

Medicinal Chemistry
Peptide Synthesis
Drug Discovery

Background:

Macrocyclic peptides offer high specificity and binding affinity for drug discovery.
Intracellular targets are often undruggable by small molecules.
Traditional macrocycle synthesis is labor-intensive and limits scalability.

Purpose of the Study:

To develop a streamlined protocol for synthesizing large macrocyclic peptide libraries.
To enable high-throughput generation of macrocycles for screening.
To facilitate the discovery of drug candidates for challenging targets.

Main Methods:

Utilized automated solid-phase peptide synthesis (SPPS).
Employed purification-free cyclization of linear dithiol peptides in high-throughput array formats.
Incorporated bis-electrophilic linkers for thioether cyclization and LC-MS for quality control.

Main Results:

Successfully generated diverse macrocyclic peptide libraries.
Demonstrated a robust and scalable workflow.
Enabled efficient synthesis without labor-intensive purification steps.

Conclusions:

The developed method significantly accelerates the synthesis of macrocyclic libraries.
This facilitates the discovery of novel drug candidates targeting difficult biomolecular interactions.
The protocol is suitable for large-scale screening campaigns.