Solid Phase Synthesis of Hydroxamic Acids

Abstract

The solid phase synthesis of hydroxamic acids is presented. Carboxylic acid ester linked, polymer-supported CBZ-protected amino acids were displaced from the resin with aqueous hydroxylamine to provide the corresponding hydroxamic acids.Hydroxamic acids have become an increasingly important structural class of compounds. They serve as efficient zinc ligands and are especially useful as inhibitors of matrix metalloproteinases. 1 This paper presents a useful way of preparing hydroxamic acids using solid phase techniques which allows for the rapid preparation of a large number of pure compounds for screening. Recently, there have been several published routes for the preparation of hydroxamic acids on solid phase. 2 These generally involve the preparation of a special linker to which hydroxylamine is attached to the resin or formation of a protected hydroxamic acid on solid support. Our approach obviates the need for special linkers or protecting groups, by displacing the desired hydroxamic acid from the resin directly using hydroxylamine, as illustrated below. 3

Hydroxamic Acids: Chemistry, Bioactivity, and Solutionand Solid‐Phase Synthesis

“…These polymer-bound esters can be displaced from the resin by treatment with 25 equiv. of 50% aqueous hydroxylamine in THF for 2 days to generate the corresponding hydroxamic acids [183] (the numbers of equivalents described in this section are relative to the loading of the resin). This method can also be applied to the solid-phase synthesis of a library of di-and tripeptidic hydroxamic acids, owing to its compatibility with both Fmoc and Boc chemistries [184][185][186].…”

Nucleophile Cleavable Linker Units

“…Hydroxamic acids have been obtained by displacement of supported esters using aqueous hydroxylamine in THF [76] or in methanol. [77] Although several routes have been published for the preparation of hydroxamic acids on solid phase, [78] these generally involve the preparation of a special linker to which hydroxylamine is attached.…”

“…[77] Although several routes have been published for the preparation of hydroxamic acids on solid phase, [78] these generally involve the preparation of a special linker to which hydroxylamine is attached. Dankward's approach [76] obviates the need for special linkers or protecting groups, by displacing the desired hydroxamic acid from the resin directly using hydroxylamine, as illustrated in Scheme 3.34. Polymer-supported Cbz protected amino acids esters 135 were displaced from the resin with aqueous hydroxylamine to provide the corresponding hydroxamic acids 136.…”

Solid-Phase Synthesis of Biologically Interesting Compounds Containing Hydroxamic Acid Moiety

“…The hydroxylamine can be attached to a polymer-supported linker either by oxygen The most straightforward route for the solid-phase synthesis of hydroxamic acids appears to be the direct application of the original Merrifield procedure for peptide synthesis, followed by cleavage of the polymer-supported carboxylate by hydroxylamine. Although this procedure is a traditional way to prepare hydroxamic acids in solution and has been applied to the solid phase on several occasions, it was not quantitative on hydrophobic polystyrene resin [7,8]. Substantially more successful results were obtained using PEG grafted polystyrene resins (ArgoGel or TentaGel) with yields above 70%, even for sterically hindered amino acids (50% aqueous hydroxylamine in THF, 2 days) [8].…”

“…Although this procedure is a traditional way to prepare hydroxamic acids in solution and has been applied to the solid phase on several occasions, it was not quantitative on hydrophobic polystyrene resin [7,8]. Substantially more successful results were obtained using PEG grafted polystyrene resins (ArgoGel or TentaGel) with yields above 70%, even for sterically hindered amino acids (50% aqueous hydroxylamine in THF, 2 days) [8]. This method was used to make a library of MMP inhibitors with unspecified better results compared to the trityl O-linked hydroxylamine approach [9,10].…”