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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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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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Cycloaddition Reactions: MO Requirements for Photochemical Activation01:12

Cycloaddition Reactions: MO Requirements for Photochemical Activation

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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.
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[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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Photochemical Electrocyclic Reactions: Stereochemistry01:26

Photochemical Electrocyclic Reactions: Stereochemistry

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The absorption of UV–visible light by conjugated systems causes the promotion of an electron from the ground state to the excited state. Consequently, photochemical electrocyclic reactions proceed via the excited-state HOMO rather than the ground-state HOMO. Since the ground- and excited-state HOMOs have different symmetries, the stereochemical outcome of electrocyclic reactions depends on the mode of activation; i.e., thermal or photochemical.
Selection Rules: Photochemical Activation
1.9K
Pericyclic Reactions: Introduction01:17

Pericyclic Reactions: Introduction

8.4K
Pericyclic reactions are organic reactions that occur via a concerted mechanism without generating any intermediates. The reactions proceed through the movement of electrons in a closed loop to form a cyclic transition state, where rearrangement of the σ and π bonds yields specific products.
Pericyclic reactions can be classified into three categories: electrocyclic reactions, cycloaddition reactions, and sigmatropic rearrangements. Electrocyclic reactions and sigmatropic...
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Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones
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A cyclase that catalyses competing 2 + 2 and 4 + 2 cycloadditions.

Hongbo Wang1, Yike Zou2, Miao Li1,3

  • 1State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China.

Nature Chemistry
|January 23, 2023
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Summary

Researchers discovered PloI4, a protein that catalyzes both 2+2 and 4+2 cycloaddition reactions. This finding reveals the first known enzyme capable of 2+2 cycloaddition and offers insights into enzyme evolution and substrate specialization.

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Area of Science:

  • Biochemistry
  • Enzymology
  • Organic Chemistry

Background:

  • Cycloaddition reactions are fundamental in chemical synthesis.
  • Nature employs enzymes like Diels-Alderases for 4+2 cycloadditions.
  • Enzymes catalyzing 2+2 cycloadditions remained undiscovered until now.

Purpose of the Study:

  • To investigate the enzymatic activity of PloI4, a protein homologous to known cyclases.
  • To explore the potential of PloI4 in catalyzing cycloaddition reactions.
  • To understand the mechanism behind PloI4's catalytic versatility.

Main Methods:

  • Biochemical characterization of PloI4.
  • Computational analysis of reaction mechanisms.
  • X-ray crystallography to determine (co)crystal structures.
  • Site-directed mutagenesis to engineer enzyme variants.

Main Results:

  • PloI4 catalyzes competitive 2+2 and 4+2 cycloaddition reactions.
  • An exo-2+2 adduct was produced alongside exo- and endo-4+2 adducts.
  • Engineered PloI4 variants selectively produced specific cycloaddition products.
  • The study rationalizes PloI4's catalytic versatility through structural and mechanistic data.

Conclusions:

  • PloI4 is the first discovered enzyme capable of catalyzing an enzymatic thermal 2+2 cycloaddition.
  • This work provides a model for enzyme evolution and substrate specialization.
  • The findings open new avenues for biocatalysis and synthetic chemistry.