Hydroxamic acids are an important class of organic molecules playing a key role in many biologically relevant interactions. Inhibition of matrix metalloproteinases (MMPs) (see Greenwald, R. A.; Golub, L. M., Eds.; Inhibitioin of Matrix Metalloproteinases: Therapeutical Potential; New York Academy of Sciences, vol. 732 (1994), and Rockwell, A.; Melden, M.; Copeland, R. A.; Hardman, K.; Decicco, C. P.; DeGrado, W. F.; J. Am. Chem. Soc., vol. 118 (1996), p. 10337 and references therein) or a unique deacetylase of lipid A biosynthesis (see Onishi, R. H.; Pelak, B. A.; Gerckens, L. S.; Silver, L. L.; Kahan, F. M.; Chen, M-H.; Patchett, A. A.; Galloway, S. M.; Hyland, S. A.; Anderson, M. S.; Raetz C. R. H.; Science, vol. 274 (1996), p. 980) testify to the significance of this class of compounds.
Synthesis on solid support is a crucial technology for combinatorial chemistry efforts. It allows for easy automation of processes and convenient handling of polar molecules throughout the synthetic protocol. It also provides a reliable method for the preparation of mixtures of compounds (split-mix synthesis). The solid supported synthesis of hydroxamic acids, based on Wang, Sasrin, or the 2-chlorotrityl O-hydroxylamine bound resin have recently been reported. (See Richter, L. S.; Desai, M. C.; Tetrahedron Lett., vol. 38 (1997), p. 321; Gordeev, M. F.; Hui, H. C.; Gordon, E. M.; Patel, D. V.; Tetrahedron Lett., vol. 38 (1997), p. 1729; Mellor, S. L.; McGuire, C.; Chan, W. C.; Tetrahedron Lett., vol. 38 (1997), p. 3311; and Bauer, U.; Ho, W-B.; Koskinen, A. M. P.; Tetrahedron Lett., vol. 38 (1997), p. 7233.) Another alternative synthetic approach, based on resin N-linked hydroxylamine has been reported. (See Ngu, K.; Patel, D. V.; J. Org. Chem., vol. 62 (1997), p. 7088.)
We have found two major limitations of the reported methods for making hydroxamic acids using solid-support resins. First, during side chain modifications we sometimes observed undesired functionalization of the nitrogen which ultimately is part of the hydroxylamino moiety of the hydroxamic acid: Resin-ONHCOR. Second, none of the above reported methods allows application of acid labile protecting groups (e.g. Boc) during side-chain synthesis.