Amide bonds are key motifs in pharmaceuticals, peptides, polymers and bioconjugates. In general amides are synthesized by reaction of an amine with a reactive acyl derivative, which is prepared in advance or in situ. A plethora of reagents are available for the activation of a carboxylic acid and amide bond formation. Which method to choose largely depends on the substrates, the compatibility with functional groups present in the molecule, and whether it is desired to form the amide bond simultaneously with the activation. The activated carboxylic acid can either get formed in situ, and thereby the amide is formed in a one-pot reaction or the active specie can be isolated for later use. Especially within bioconjugation most methods are based on the activation of the carboxylic acid derivate, however as these acyl donors are designed to be highly reactive they are also highly unstable and moisture sensitive. The development, scope, and application of a new activatable acyl donor will be presented. It is stable towards nucleophilic attack in its “off-state”, whereas in the “on-state” it reacts with nucleophiles such as amines, alcohols, and thiols. Amides are generally known to be stable towards nucleophilic attack, but acyl-pyridinium derivatives such as 4-dimethylaminopyridine (DMAP) are known to be highly reactive acyl donors. The acyl donor is activated by oxidation to form such an acyl-pyridinium derivative under mild conditions and the activation is orthogonal to most other known methods for amide bond formation. This allows in situ activation of carboxylic acid derivatives in the present of free carboxylic acids.

Oxidative activation of dihydropyridine amides to reactive acyl donors

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.