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HATU is commonly encountered in amine acylation reactions (i.e., amide formation). Such reactions are typically performed in two distinct reaction steps: (1) reaction of a carboxylic acid with HATU to form the OAt-active ester; then (2) addition of the nucleophile (amine) to the active ester solution to afford the acylated product.
The scheme above shows the general mechanistic steps for EDC-mediated coupling of carboxylic acids and amines under acidic conditions. The tetrahedral intermediate and the aminolysis steps are not shown explicitly. EDC couples primary amines, and other nucleophiles, [5] to carboxylic acids by creating an activated ester leaving group. First ...
It is commonly used as the hindered base in amide coupling reactions between a carboxylic acid (typically activated, for example, as an acid chloride, as illustrated below) and a nucleophilic amine. [5] As DIPEA is hindered and poorly nucleophilic, it does not compete with the nucleophilic amine in the coupling reaction.
TCFH itself is a common reagent used in the preparation of uronium and guanidinium salts used for amide bond formation and peptide synthesis, such as HATU. [3] [4] [5]Amide bond formation with TCFH can be performed in a wide range of organic solvents, most commonly acetonitrile, but also water [6] and in the solid state. [7]
To illustrate the impact of suboptimal coupling yields for a given synthesis, consider the case where each coupling step were to have at least 99% yield: this would result in a 77% overall crude yield for a 26-amino acid peptide (assuming 100% yield in each deprotection); if each coupling were 95% efficient, the overall yield would be 25%.
A common way to synthesize an NHS-activated acid is to mix NHS with the desired carboxylic acid and a small amount of an organic base in an anhydrous solvent. A coupling reagent such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) is then added to form a highly reactive activated acid intermediate.
Another common example is the reaction of a primary amine or secondary amine with a carboxylic acid or with a carboxylic acid derivative to form an amide. This reaction is widely used, especially in the synthesis of peptides. On the simple addition of an amine to a carboxylic acid, a salt of the organic acid and base is obtained.
PyAOP ((7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate) is a reagent used to prepare amides from carboxylic acids and amines in the context of peptide synthesis. [1] It can be prepared from 1-hydroxy-7-azabenzotriazole (HOAt) and a chlorophosphonium reagent under basic conditions. [ 2 ]