Ugi Reaction
TLDRThe script explores the Ugi reaction, a four-component process that extends the Passerini reaction, utilizing carbonyl compounds, carboxylic acids, isonitriles, and primary amines to form alpha-acylamino amides. It delves into the reaction's mechanism, highlighting the initial imine formation and subsequent steps, and underscores its utility in chemical library synthesis for random screening. The script also discusses the reaction's potential for enantioselective synthesis and its application in synthesizing complex targets, exemplified by the creation of the Hepatitis C drug Telaprevir, showcasing the Ugi reaction's efficiency and versatility in organic synthesis.
Takeaways
- 🧪 The Passerini reaction, involving isonitriles as nucleophiles, is a three-component reaction where the CN group in isonitriles is bound via nitrogen, contrasting nitriles where it is bound via carbon.
- 🔍 Isonitriles are represented as carbenes in resonance with a zwitterion, with a positive charge on nitrogen and a negative charge on carbon, which is the preferred representation for reactions discussed.
- 🌟 The Ugi reaction, invented by Ivar Karl Ugi in 1959, is a four-component reaction extending the Passerini reaction with the addition of a primary amine.
- 🔗 The Ugi reaction forms an alpha-acylamino amide by mixing carbonyl compound, carboxylic acid, isonitrile, and primary amine in stoichiometric amounts at room temperature.
- 📚 The mechanism of the Ugi reaction begins with imine formation from aldehyde/ketone and amine, followed by protonation and nucleophilic attack by the isonitrile, leading to the formation of an electrophilic nitrilium ion.
- 🔄 The intermediate in the Ugi reaction undergoes a 1,3 intramolecular shift involving the acyl group, resulting in the formation of a more stable alpha-acylamino amide.
- 💊 The Ugi reaction is highly favored in the synthesis of chemical libraries for random screening, allowing for the creation of a vast number of compounds by varying the components.
- 📉 The reaction can lead to chiral compounds, and if R1 does not equal R2, the product will have a stereogenic center, with potential for enantioselective synthesis using chiral acids.
- 🔬 Despite the potential for enantioselective synthesis, the results are not yet satisfactory, and the field is evolving with a few examples of enantioselective Ugi reactions using chiral Brønsted acids.
- 🌐 The Ugi reaction's utility extends beyond library building for biological screening, demonstrating its importance in organic synthesis and application to complex targets.
- 🛠️ An example of the Ugi reaction's application is the synthesis of the Hepatitis C drug Telaprevir, which combines a Passerini and Ugi reaction in a clever multi-step process.
Q & A
What is the Passerini reaction?
-The Passerini reaction is a three-component reaction that involves the use of isonitriles as mild nucleophiles, along with a carbonyl compound and a carboxylic acid, resulting in the formation of an alpha-acyloxy amide.
What structural difference exists between nitriles and isonitriles?
-In nitriles, the CN group is bound to an R group via the carbon atom, whereas in isonitriles, the CN group is bound via the nitrogen atom.
How are isonitriles often represented in the context of the Passerini reaction?
-Isonitriles are often represented as carbenes in resonance with a zwitterion, with a positive charge on nitrogen and a negative charge on carbon.
Who invented the Ugi reaction and when?
-The Ugi reaction was invented by Estonian-born German chemist Ivar Karl Ugi in 1959.
What are the four components of the Ugi reaction?
-The four components of the Ugi reaction are a carbonyl compound, a carboxylic acid, an isonitrile, and a primary amine.
What is the primary product of the Ugi reaction?
-The primary product of the Ugi reaction is an alpha-acylamino amide.
How does the Ugi reaction mechanism differ from the Passerini reaction in the first step?
-The first step of the Ugi reaction involves the formation of an imine from the aldehyde or ketone and the amine, with the loss of water, which is different from the Passerini reaction.
Why is the Ugi reaction popular in the synthesis of chemical libraries for random screening?
-The Ugi reaction is popular in library synthesis because it allows for the rapid creation of a vast number of different compounds by combining various readily available ketones, carboxylic acids, primary amines, and isonitriles.
What is the significance of the Ugi reaction in the synthesis of complex targets like Telaprevir?
-The Ugi reaction, combined with a Passerini reaction, provides a highly effective and high-yielding approach to the synthesis of complex targets like Telaprevir, a Hepatitis C drug.
How does the Ugi reaction contribute to the diversity of a chemical library?
-Even if every compound in a Ugi reaction-based library is racemic, it contributes to diversity by effectively doubling the number of different compounds, as each racemic compound can be considered as two different enantiomers.
What is the role of chiral Brønsted acids in enantioselective Ugi reactions?
-Chiral Brønsted acids can be used to promote enantioselective Ugi reactions, although the results are not yet satisfactory and the field is still evolving.
What is the stereochemical outcome of the Ugi reaction in the synthesis of Telaprevir?
-In the synthesis of Telaprevir, the Ugi reaction fortuitously favors the desired S stereochemistry over the undesired R by a factor of 7:1.
Outlines
🧪 Ugi Reaction: Multi-Component Synthesis in Organic Chemistry
The script begins with a review of the Passerini reaction, a three-component reaction utilizing isonitriles as nucleophiles. Isonitriles are highlighted as less stable nitriles with a unique binding structure. The script then introduces the Ugi reaction, a four-component extension invented by Ivar Karl Ugi. It involves the same three components as the Passerini reaction plus a primary amine, resulting in the formation of an alpha-acylamino amide. The mechanism is similar to the Passerini reaction but starts with the formation of an imine. The script also discusses the Ugi reaction's popularity in chemical library synthesis for random screening, its potential for enantioselective synthesis, and its utility in organic synthesis, exemplified by the synthesis of the Hepatitis C drug Telaprevir, which cleverly combines both Passerini and Ugi reactions.
🛠️ Synthesis of Telaprevir: A Case Study in Multi-Component Reactions
This paragraph delves into the synthesis of the Hepatitis C drug Telaprevir as an example of the Ugi reaction's application in complex target synthesis. The process starts with a Passerini reaction to form an alpha-acyloxy amide, followed by dehydration to create an isonitrile. A three-component Ugi reaction is then performed using a preformed cyclic imine, yielding the product in a high yield. Subsequent hydrolysis and oxidation steps lead to the final drug. The paragraph emphasizes the drug's four stereocenters, the influence of existing stereocenters on the newly formed one, and the unpredictability of stereochemical outcomes in such reactions. The successful stereoselectivity in this case, favoring the desired S configuration, is highlighted, showcasing the Ugi reaction's importance and versatility in organic synthesis beyond library preparation for biological screening.
Mindmap
Keywords
💡Passerini Reaction
💡Isonitriles
💡Ugi Reaction
💡Imine
💡Nitrilium Ion
💡1,3 Intramolecular Shift
💡Chemical Libraries
💡Stereogenic Center
💡Enantioselective Synthesis
💡Telaprevir
💡Stereochemistry
Highlights
The Passerini reaction is a three-component reaction using isonitriles as mild nucleophiles.
Isonitriles are less stable structural isomers of nitriles, bound via the nitrogen atom.
Isonitriles are often represented as carbenes in resonance with a zwitterion.
The Ugi reaction is a four-component reaction invented by Ivar Karl Ugi in 1959.
The Ugi reaction extends the Passerini reaction by adding a primary amine.
The Ugi reaction forms an alpha-acylamino amide at room temperature.
The Ugi reaction mechanism involves imine formation, protonation, and nucleophilic attack by the isonitrile.
The reaction leads to an electrophilic nitrilium ion and subsequent carboxylate anion attack.
A 1,3 intramolecular shift of the acyl group forms the alpha-acylamino amide.
The Ugi reaction is popular in library synthesis for random screening.
Combining ten ketones, carboxylic acids, primary amines, and isonitriles yields 10,000 different compounds.
The reaction can lead to chiral compounds with a stereogenic center.
Chiral acids can promote enantioselective synthesis in the Ugi reaction.
Racemates in library building provide more diversity, with 20,000 different compounds possible.
The Ugi reaction has practical applications in organic synthesis, such as the synthesis of Telaprevir.
Telaprevir synthesis combines a Passerini and Ugi reaction in a clever way.
The Ugi reaction in Telaprevir synthesis involves a preformed cyclic imine.
The Ugi reaction is an important tool in synthesis, not limited to biological screening.
The multi-component character of the Ugi reaction is a rarity in organic synthesis.
Transcripts
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