Methods of Preparation and Evaluation of the Biological Activity of α-Ketoamides

The Passerini reaction is a three component chemical reaction involving an isocyanide, an aldehyde (or ketone), and a carboxylic acid to form a α-acyloxy amide. 28 The reaction was discovered by Mario Passerini in 1921. It is the first isocyanide based multi-component reaction developed and it is very useful in combinatorial chemistry.
Multicomponent reactions have several advantages; high convergence, extreme versatility, economy of the atom and high exploratory power.

The intermediate obtained, acyloxy amide, may be modified with a cleavage on the O-acyl group forming β-amino-α-hydroxy amides and its subsequent oxidation can form β-amino-α ketoamides. Considering the Passerini products, it is known that they are not subject to many modifications due to the formation of the ester bond which makes the whole final molecule unsuitable for further processing.
In order to make these products more interesting from a pharmacological point of view, Semple E. J. and Guanti G. have developed a strategy that involves the condensation between N-protected amino aldehydes, carboxylic acid and isocyanide, followed by amino deprotection and acyl migration.
This strategy lead to an α-hydroxy amide which can be oxidized in α-ketoamide.

In order to exploit furthermore the PADAM (Passerini reaction – Amine Deprotection – Acyl Migration)30 procedure it can be successfully transferred onto polymer resins using the solid-phase synthesis to prepare libraries of β-acylamine-α-hydroxy amides in good yields and purities.
Solid-phase chemistry presents advantages compared to traditional solution-phase synthesis and is mostly used for the preparation of libraries of compounds both with parallel and mix strategies.