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

Abstract

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Direct amidation of unprotected amino acids using B(OCH2CF3)3

“…4 The only reasonably effective method involves reaction of the amino acid with the highly toxic gas hexafluoroacetone, followed by subsequent reaction with an amine. 5 Although great progress has been made in recent years on the development of new amidation methods 6 which make use of low-cost reagents 7-8 or catalysts 9 that are easy to separate from the amide products, few of these methods are applicable to highly functionalized compounds and none have been applied to the direct amidation of free amino acids. An important advantage of this method is the ease with which the amide products can be purified using a simple filtration work-up involving commercially available resins, which scavenge unreacted acid and amine as well as any boroncontaining byproducts.…”

Peptide Synthesis

“…Alternatively, in the bis(trifluoromethyl)-1,3-oxazolidin-5-one approach [344] hexafluoroacetone is used as a reagent that simultaneously protects the N a -group and activates the carboxy group of an amino acid. For such a purpose the well-known N-carboxy anhydrides (NCA) may be employed.…”

Heterocycles from Amino Acids

“…The hexafluoroacetone protection occurs site selectively even in the presence of unprotected side-chain functionalities like the b-carboxy group of aspartic acid. The carboxy-derivatization of these oxazolidinones by nucleophiles is accompanied by N-deprotection and, as a result, these bidentate reagents find extensive applications in the synthesis of peptides (Scheme 2.13) [51]. …”