Facile Synthesis of N α -Protected Amino/Peptide Hydroxamic Acids Mediated by COMU

Abstract

One-pot preparation of N a -protected amino/ peptide hydroxamic acids from corresponding carboxylic acids is described using uronium-type coupling reagent COMU. The present protocol is simple and mild conditions are used. Thus the resulting hydroxamic acids are obtained in good yields without racemization.

Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors

“…Finally, we hydrolyzed the esters with sodium hydroxide in aqueous dioxane to give the corresponding carboxylic acids 5a–q . The hydroxamic acids 1a and 7b–q were obtained using (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)­dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) as an activating agent and either hydroxylamine base ( 7e–q ) or O -(tetrahydro-2 H -pyran-2-yl)­hydroxylamine ( 1a , 7b–d ), followed by acidic cleavage of the tetrahydropyranyl (THP) protecting group. On the basis of our experience, COMU was the most suitable coupling reagent because only water soluble co-products arise from this reagent which are conveniently removed during aqueous work up .…”

OxymaPure Coupling Reagents: Beyond Solid-Phase Peptide Synthesis

“…In 2014, Panguluri et al 42 reported a simple, one-pot protocol under mild conditions for the synthesis of N  -protected amino/peptide hydroxamic acids from the corresponding carboxylic acids. In this protocol, COMU was used as an acid activator in the presence of a base such as DIEA to afford the target products in good yields and without any racemization.…”

“…Furthermore, our group developed the Oxyma-B-based novel uronium-type coupling reagents TOMBU (42) and COMBU (43) (Figure 7) for use in peptide bond formation. 95 These reagents showed higher hydrolytic stability in the solvent DMF than COMU.…”

The synthesis of Nα-protected amino hydroxamic acids from Nα-protected amino acids employing versatile chlorinating agent CPI-Cl

“…11 Hydroxamic acids have been prepared by coupling mixed anhydride, obtained by the addition of carboxylic acid and ethyl chloroformate, with hydroxylamine. 7,12 Other coupling reagents like cyanuric chloride, 13 N, N'-carbonyldiimidazole (CDI), 14 1-[(1-(cyano-2ethoxy-2-oxoethylidenaminooxy)-dimethylamino-morpholinomethylene)] methaneaminium hexafluorophosphate (COMU), 15 propanephosphonic acid anhydride (T3P), 16,17 and ethyl-2-cyano-2-(4nitrophenylsulfonyloxyimino)acetate (NBsOXY), 18 were also employed to obtain hydroxamic acids from their corresponding carboxylic acids.…”