Hexafluoroacetone as Protecting and Activating Reagent: New Routes to Amino, Hydroxy, and Mercapto Acids and Their Application for Peptide and Glyco- and Depsipeptide Modification

Jan Spengler, Christoph Böttcher, Fernando Albericio, and Klaus Burger

Chem. Rev.2006; 106:4728-4746

Abstract: A considerable number of biologically active naturally occurring products are peptides, depsipeptides, and peptide conjugates. Peptide modification can be performed by backbone modification and modification of the substituent pattern of the side-chain of the monomers. Direct therapeutic applications of native peptides are limited. However, major drawbacks of peptide drugs, like low selectivity, rapid degradation by proteases, low lipophilicity, and lack of transport systems to direct peptides into cells, can be overcome by incorporation of new types of monomers into strategic positions. This concept is based on an efficient access to monomers with tailor-made side-chains of readily available R-amino and R-hydroxy acids with HFA (hydroxyfluoroacetone) as bidentate protecting reagent. If multifunctional amino acids are involved, several protection and deprotection steps are usually required. A bidentate protecting/activating concept meets this synthetic challenge by reducing the number of steps if protection of the R-functionality and activation of the adjacent 1-carboxy group as well as subsequent coupling and deprotection of the R-functionality occur simultaneously. Hexachloroacetone and 1,1,1-trichloro-3,3,3-trifluoroacetone react with the R-amino group of amino acids with chloroform elimination to give the corresponding N-trichloroacetyl and N-trifluoroacetyl amino acids, respectively. In contrast, hexafluoroacetone (HFA) forms 2,2-bis(trifluoromethyl)-1,3-oxazolidin-5-ones. Remarkably, no additional R-amino protection is required. Furthermore, HFA was also found to react readily with R-hydroxy and R-mercapto acids to give five-membered heterocycles. In a single step the R-placed functionality and R-carboxy group are protected. The lactone ring represents an activated ester and can be cleaved by various O- and N-nucleophiles in solution and on solid phase to give the corresponding unprotected derivatives in one step. HFA protection occurs site selectively in the presence of unprotected side-chain functionalities, like the α-carboxy group of Asp.