Polymer-supported N-derivatized, o-linked hydroxylamine for concurrent solid-phase synthesis of diverse N-alkyl and N-H hydroxamates.

Annabella Vitalone, Janice McColl, Dean Thome, Lucio G Costa, Beatrice Tita

Index: J. Comb. Chem. 8(3) , 435-9, (2006)

Full Text: HTML

Abstract

We describe parallel/combinatorial, solid-phase, supported synthesis of diverse hydroxamates using a common intermediate, an N-derivatized, O-linked hydroxylamine. The method allows the concurrent synthesis of both N-alkyl and N-H hydroxamates and is compatible with a wide range of chemical transformations. The synthesis of NH hydroxamates includes protection of the nitrogen with a 2,4-dimethoxybenzyl group at the stage of polymer-supported benzyloxyamine. The protecting group eliminates side reactions caused by the presence of a free hydroxamate NH group and is simultaneously removed during cleavage of target compounds from the solid support. The chemical route has been thoroughly tested on model compounds with several linkers, and a high yield and purity synthesis of more than 50 hydroxamates, designed to inhibit cell proliferation of breast cancer cell lines, is described.