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Related Concept Videos

Radical Reactivity: Overview01:11

Radical Reactivity: Overview

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Radicals, the highly reactive species, gain stability by undergoing three different reactions. The first reaction involves a radical-radical coupling, in which a radical combines with another radical, forming a spin‐paired molecule. The second reaction is between a radical and a spin‐paired molecule, generating a new radical and a new spin‐paired molecule. The third reaction is radical decomposition in a unimolecular reaction, forming a new radical and a spin‐paired...
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Radical Reactivity: Nucleophilic Radicals01:16

Radical Reactivity: Nucleophilic Radicals

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Radicals adjacent to electron-donating groups are called nucleophilic radicals. These radicals readily react with electrophilic alkenes. The SOMO–LUMO interactions are the driving force for the reaction, where the high-energy SOMO of the electron-rich, nucleophilic radicals interacts with the low-energy LUMO of the electron-deficient, electrophilic alkenes. Such SOMO–LUMO interactions are the basis of reactive radical traps, affecting the selectivity in radical reactions. For...
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Radical Formation: Addition00:47

Radical Formation: Addition

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Radicals can be formed by adding a radical to a spin-paired molecule. This is typically observed with unsaturated species, where the addition of a radical across the π bond leads to the production of a new radical by dissolving the π bond. For example, the addition of a Br radical to an alkene yields a carbon-centered radical.
Similar to charge conservation in chemical reactions, spin conservation is implicit for radical reactions. Accordingly, the product formed must possess an...
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Radical Reactivity: Steric Effects01:10

Radical Reactivity: Steric Effects

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The presence of electron-donating, electron-withdrawing, or conjugating groups adjacent to a radical center, imparts electronic stabilization to the radicals. Examples of such electronically-stabilized radicals are triphenylmethyl, tetramethylpiperidine‐N‐oxide, and 2,2‐diphenyl‐1‐picrylhydrazyl. These radicals are remarkably stable and are known as persistent radicals. Some of the persistent radicals can even be isolated and purified.
Along with electronic...
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Radical Formation: Overview01:03

Radical Formation: Overview

1.9K
A bond can be broken either by heterolytic bond cleavage to form ions or homolytic bond cleavage to yield radicals. A fishhook arrow is used to represent the motion of a single electron in homolytic bond cleavage. There are two main sources from which radicals can be formed:
Radicals from spin-paired molecules:
Radicals can be obtained from spin-paired molecules either by homolysis or electron transfer. While two radicals are formed in the former, an electron is added in the...
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Redox Reactions01:24

Redox Reactions

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Oxidation-reduction or redox reactions involve the transfer of electrons from one molecule or atom to another. When an atom gains an electron, another atom must lose an electron, meaning oxidation and reduction must occur together. Since the redox occurs in pairs, the atom that gets oxidized is also called the reducing agent or reductant, and the atom that is reduced is also called the oxidizing agent or oxidant. A straightforward way to remember the definitions of oxidation and reduction is...
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Enabling Access to sp3-Enriched Targeted Protein Degraders via Redox-Neutral Radical Cross-Coupling.

Philipp Neigenfind1, Clara Gathmann1, Emily C Cherney2

  • 1Department of Chemistry, Scripps Research, San Diego, California, USA.

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PubMed
Summary

Researchers developed a new modular synthesis for 3D glutarimide scaffolds, expanding chemical space for targeted protein degradation (TPD) drugs like CELMoDs and LDDs. This approach enables novel TPD designs with potential for new therapeutics.

Keywords:
glutarimidenickel catalysisradical cross‐couplingredox‐neutraltargeted protein degradation

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Area of Science:

  • Medicinal Chemistry
  • Organic Synthesis
  • Drug Discovery

Background:

  • Targeted protein degradation (TPD) using CRL4CRBN E3 ligases is a promising drug discovery modality.
  • Current cereblon (CRBN) binders are limited to flat, rigid glutarimide scaffolds, restricting chemical diversity.
  • Novel 3D scaffolds are needed to expand the chemical space for CRBN-binding degraders.

Purpose of the Study:

  • To develop a modular synthetic route to novel C3(sp3)-C(sp3) linked glutarimides.
  • To create sp3-rich, three-dimensional scaffolds for CELMoD and LDD design.
  • To demonstrate the utility of these scaffolds in TPD applications.

Main Methods:

  • A two-step protocol involving redox-neutral cross-coupling and palladium-catalyzed hydrogenation.
  • Synthesis of diverse C3(sp3)-C(sp3) linked glutarimide building blocks.
  • Incorporation of these building blocks into ligand-directed degraders (LDDs).

Main Results:

  • A modular, operationally simple, and chemoselective synthesis yielding functionalized glutarimides.
  • Access to sp3-rich, three-dimensional scaffolds previously unavailable.
  • Demonstration of BRD4 degradation using LDDs derived from the new scaffolds, confirming CRBN dependence.

Conclusions:

  • The developed method provides versatile, 3D building blocks for next-generation TPD design.
  • This approach overcomes limitations of flat glutarimide scaffolds in CELMoD and LDD development.
  • The new scaffolds show translational potential for developing novel therapeutics targeting protein degradation.