Regioselective Annulation of 6-Carboxy-Substituted Pyrones as a Two-Carbon Unit in Formal [4 + 2] Cycloaddition
Zachary A Kohanov1,2, Suzzudul Islam Shuvo1,2, Andrew N Lowell1,2,3
1Department of Chemistry, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.
The Journal of Organic Chemistry
|June 13, 2024
Summary
This study introduces a novel annulation method to incorporate intact pyrone rings into complex molecular structures. This new synthetic strategy expands the toolkit for constructing heterocyclic compounds, crucial in pharmaceutical development.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
- Medicinal Chemistry
Background:
- Heterocyclic compounds are vital in pharmaceuticals, yet efficient construction methods are limited.
- Pyrone motifs are prevalent but challenging to integrate into larger ring systems.
Purpose of the Study:
- To develop a new synthetic methodology for incorporating intact pyrone rings into complex structures.
- To enable the construction of novel heterocyclic scaffolds for drug discovery.
Main Methods:
- A formal [4 + 2] cycloaddition reaction involving pyrones and benzylic anions.
- Utilized NMR spectroscopy for reaction optimization, addressing solubility and separation issues.
- Applied the method to various substituted pyrones and electrophiles.
Main Results:
- Successfully incorporated intact pyrone rings into larger ring systems via annulation.
- Demonstrated regioselective conjugate addition of benzylic anions to pyrones.
- Achieved aromaticity in the newly formed ring through base-driven enolate formation and elimination.
- Validated the method in the total synthesis of the natural product thermorubin.
Conclusions:
- Developed a versatile annulation strategy for pyrone incorporation.
- This method provides access to complex heterocyclic systems previously difficult to synthesize.
- The approach holds potential for pharmaceutical synthesis and natural product total synthesis.
![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
Related Concept Videos
01:27Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation
2.2K
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).
2.2K
01:16Cycloaddition Reactions: Overview
2.6K
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.
2.6K
01:16Cycloaddition Reactions: MO Requirements for Thermal Activation
3.5K
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.
3.5K
02:35Regioselectivity of Electrophilic Additions-Peroxide Effect
8.5K
In the presence of organic peroxides, the addition of hydrogen bromide to an alkene yields the isomer that is not predicted by Markovnikov’s rule. For example, the addition of hydrogen bromide to 2-methylpropene in the presence of peroxides gives 1-bromo-2-methylpropane. This addition reaction proceeds via a free radical mechanism, which reverses the regioselectivity. The free radical reaction mechanism involves three stages: initiation, propagation, and termination.
8.5K
02:36Regioselectivity and Stereochemistry of Hydroboration
8.1K
A significant aspect of hydroboration–oxidation is the regio- and stereochemical outcome of the reaction.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn...
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn...
8.1K
02:34Regioselectivity and Stereochemistry of Acid-Catalyzed Hydration
8.4K
The rate of acid-catalyzed hydration of alkenes depends on the alkene's structure, as the presence of alkyl substituents at the double bond can significantly influence the rate.
8.4K