A clever new method of peptide synthesis involves formation...

A clever new method of peptide synthesis involves formation of an amide bond by reaction of an $\alpha$ -keto acid with an $N$ -alkylhydroxylamine: CAN'T COPY THE FIGURE The reaction is thought to occur by nucleophilic addition of the N-alkylhydroxylamine to the keto acid as if forming an oxime (Section 19.8 ), followed by decarboxylation and elimination of water. Show the mechanism.

A clever new method of peptide synthesis involves formation of an amide bond by reaction of an $\alpha$ -keto acid with an $N$ -alkylhydroxylamine:
CAN'T COPY THE FIGURE
The reaction is thought to occur by nucleophilic addition of the N-alkylhydroxylamine to the keto acid as if forming an oxime (Section 19.8 ), followed by decarboxylation and elimination of water. Show the mechanism.

Key Concepts

Elimination Reaction

Elimination reactions involve the removal of a small molecule, often water, from a substrate, leading to the formation of a double bond or a new functional group. In the given mechanism, after decarboxylation, the elimination of water completes the transformation, resulting in the formation of the stable amide linkage.

Decarboxylation

Decarboxylation is the process by which a carboxyl group is removed from a molecule as carbon dioxide. In the mechanism described, following the nucleophilic addition and formation of an oxime-like intermediate, decarboxylation occurs to release CO2, driving the reaction towards the formation of the amide bond.

Peptide Bond Formation

Peptide bond formation is the process that creates the linkage between amino acids to form peptides and proteins. This involves the creation of an amide bond through the coupling of a carboxylic acid group and an amine group, and alternative synthetic strategies (such as the one described) seek to achieve this bond under mild conditions and with high specificity.

Nucleophilic Addition

Nucleophilic addition is a fundamental reaction mechanism in organic chemistry where a nucleophile, an electron-rich species, attacks an electrophilic carbon atom, typically found in a carbonyl group. In this context, the N-alkylhydroxylamine acts as the nucleophile attacking the electrophilic keto group of the ?-keto acid, initiating the bond formation process.

Oxime Formation

Oxime formation involves the reaction of a hydroxylamine with a carbonyl compound to form an oxime, characterized by a C=N–OH group. This reaction is a key step in the mechanism, providing an intermediate that resembles the traditional oxime, which then undergoes further transformations.

Transcript

00:01 All right, so we're proposing a method of synthesis using these two molecules.

00:05 So i have this first one and then this second one.

00:17 So the book tells us that the first step is going to be nucleophilic attack by this nhydroxial amine, as if we're trying to form an oxymine.

00:28 So what that means is that the nitrogen is going to be the site of nucleophilic attack.

00:36 So i do have two electrons right there and right there that can attack this electrophilic center pushing electron density up onto that oxygen.

00:46 So when i do that, i form a product that has something that looks sort of like this.

01:05 Okay, so now if i move electron density from this oxygen, which has a six valence electrons right now, i push it back down there.

01:14 I need to determine which one's a better leaving group.

01:16 And it's worth pointing out that co2 is one of the leaving groups, right? seeing right here.

01:22 And that when co2 leaves, it produces gas, right? so when gas is released, obviously that's a very strong entropic effect, making co2 a really, really good leaving group.

01:31 So that's going to leave.

01:34 Right, leaving us with something that looks roughly like this.

01:40 Right, i've got my, got my carboxyl back, i've got my n.

01:45 I'm going to leave my r prime right...

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