Related Experiment Video
Updated: Jun 3, 2026
08:55
Facile Protocol for the Synthesis of Self-assembling Polyamine-based Peptide Amphiphiles (PPAs) and Related Biomaterials
Published on: June 25, 2018
Synthesis of Dipeptides with Ψ[CH(2)0] Amide Bond Mimetics
1Department of Medicinal Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park, NC.
Methods in Molecular Medicine
|March 8, 2011
Summary
Researchers developed new synthetic methods for ether dipeptide isosteres, crucial for creating peptide-based drugs. These methods yield Phe-ψ[CH(2)O]-spiro-C(x) and Phe-ψ[CH(2)O]-Allylglycine analogs, advancing pharmaceutical development.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Peptide Chemistry
Background:
- Amide bond mimetics are essential for converting peptide leads into viable pharmaceuticals.
- Developing stable isosteres of peptide bonds is a key challenge in drug discovery.
Purpose of the Study:
- To describe synthetic procedures for novel ether dipeptide isosteres.
- To create Phe-ψ[CH(2)O]-spiro-C(x) and Phe-ψ[CH(2)O]-Allylglycine analogs.
Main Methods:
- Alkylation of template 1 with haloalkanes (C3-C6) to yield derivatives 6b-6e.
- Finklestein conversion of iodides 7b-7e.
- Cyclization to form spirocyclic derivatives 5b-5e and morpholinones.
Main Results:
- Successful synthesis of Phe-ψ[CH(2)O]-spiro-C(x) isosteres (9a-9e).
- Synthesis of Phe-ψ[CH(2)O]-Allylglycine analog (13).
- Formation of spirocyclic derivatives (5b-5e) and morpholinones.
Conclusions:
- The described synthetic strategies provide access to valuable ether dipeptide isosteres.
- These isosteres hold potential for the development of new peptide-based therapeutics.
- The methods facilitate the creation of stable amide bond mimetics.
Related Concept Videos
01:29Preparation of Amides
Amides are synthesized by treating carboxylic acids with amines in the presence of dehydrating agents like dicyclohexylcarbodiimide (DCC).
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
02:43Peptide Bonds
A peptide bond covalently attaches amino acids through a dehydration reaction. One amino acid's carboxyl group and another amino acid's amino group combine, releasing a water molecule. The resulting bond is the peptide bond. The products that such linkages form are peptides. As more amino acids join this growing chain, the resulting chain is a polypeptide. Each polypeptide has a free amino group at one end. This end has the N-terminal, or the amino-terminal, and the other end has a free...
01:19Amines to Amides: Acylation of Amines
Various carboxylic acid derivatives (such as acid chlorides, esters, and anhydrides) can be used for the acylation of amines to yield amides. The reaction requires two equivalents of amines. The first amine molecule functions as a nucleophile and attacks the carbonyl carbon to produce a tetrahedral intermediate. This is followed by the loss of the leaving group and restoration of the C=O bond.
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary amide...
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary amide...
01:28Preparation of 1° Amines: Gabriel Synthesis
Direct alkylation is not a suitable method for synthesizing amines because it produces polyalkylated products. Gabriel synthesis is the most preferred method to exclusively make primary amines. The method uses phthalimide, which contains a protected form of nitrogen that participates in alkylation only once to predominantly give primary amines.
Strong bases like NaOH or KOH deprotonate the phthalimide to form the corresponding anion, which acts as a nucleophile. Further, the anion attacks an...
Strong bases like NaOH or KOH deprotonate the phthalimide to form the corresponding anion, which acts as a nucleophile. Further, the anion attacks an...
01:07Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview
In the presence of an aqueous base and a halogen, primary amides can lose the carbonyl (as carbon dioxide) and undergo rearrangement to form primary amines. This reaction, called the Hofmann rearrangement, can produce primary amines (aryl and alkyl) in high yields without contamination by secondary and tertiary amines.
01:22Preparation of 1° Amines: Azide Synthesis
Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide synthesis method can be used.
Azide ions act as good nucleophiles and react with unhindered alkyl halides to form alkyl azides. Alkyl azides do not participate in further nucleophilic substitution reactions, thereby eliminating the chances of polyalkylated products. Alkyl azides are reduced by hydride-based reducing agents, like lithium aluminum...
Azide ions act as good nucleophiles and react with unhindered alkyl halides to form alkyl azides. Alkyl azides do not participate in further nucleophilic substitution reactions, thereby eliminating the chances of polyalkylated products. Alkyl azides are reduced by hydride-based reducing agents, like lithium aluminum...