Hexafluoroacetone, a valuable reagent for protection and activation of α-functionalized carboxylic acids?

Abstract

Hexafluoroacetone reacts with α-functionalized carboxylic acids (e.g. α-amino. N-alkylamino, α-hydroxy, and α-mercapto acids) to give five-membered ring systems. The net result of this heterocyclization process is the simultaneous protection of the α-functional group and the activation of the carboxylic group. The bis(trifluoromethyl)-substituted heterocyclic compounds are promising intermediates for the syntheses of various types of natural and non- natural α-amino, N-alkylamino, α-hydroxy and α-mercapto acids. Furthermore, the carboxylic group activation is high enough to give satisfactory results on aminolytic ring opening reactions with amino acid and oligopeptide esters. The peptide bond formation as well as the deblocking of the α-functionality occurs simultaneously without racemization. The synthetic potential of hexafluoroacetone will be demonstrated. The role of hexafluoroactone as a protection group is illustrated in various situations: • syntheses of various heterocyclic α-amino, α-hydroxy, and α-mercapto acids [1, 2]; • syntheses of different types of multifunctional α-amino, N-methylamino, α-hydroxy, and α-mercapto acids [3]; • stereoselective syntheses of 4-hydroxyproline and some of its derivatives; • syntheses of new types of siderophores. Its role as an activating reagent for carboxylic groups is demonstrated by economic syntheses of various open-chain dipeptides (e.g. aspartamine [4]), oligopeptides, cyclopeptides (e.g. functionalized 2,5-dioxopiperazines) and peptide analogues (e.g. depsipeptides, azapeptides).