Solid supported synthesis of hydroxamic acids

Details Solid supported synthesis of hydroxamic acids Solid supported synthesis of hydroxamic acids

2000-07-07

2001-09-18

Geist, Gary (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Hydroxamic acids, chalcogen analogs or salts thereof

C562S622000

Reexamination Certificate

active

06291709

ABSTRACT:

TECHNICAL FIELD
The subject invention relates to methods for synthesizing hydroxamic acid compounds using a solid-support resin to facilitate purification of intermediates.
BACKGROUND OF THE INVENTION
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.
SUMMARY OF THE INVENTION
The subject invention involves processes for making hydroxamic acid compounds: RC(O)NHOH, using a solid-support resin having an oxime moiety: Resin:C═N—OH, as the linking moiety of the resin, comprising the following steps:
(a) treating the resin with a carboxylic acid compound: R′C(O)OH, having a carboxyl moiety: C(O)OH, and a side chain moiety: R′, whereby the carboxylic acid compound becomes attached to the resin due to a condensation reaction between the oxime and carboxyl moieties;
(b) optionally modifying the side chain R′ to produce side chain R of the target hydroxamic acid compound or an intermediate side chain R″, through one or more reaction and purification procedures, whereby a resin, linking, and attached moiety has the structure:
Resin:C═NOC(O)R′ or Resin:C═NOC(O)R or Resin:C═NOC(O))R″;
(c) cleaving a product from the resin by treating with O-tert-butyldimethylsilylhydroxylamine: TBSONH
2
, to produce a TBS-protected hydroxamic acid compound: R′C(O)NHOTBS or RC(O)NHOTBS or R″C(O)NHOTBS;
(d) optionally modifying the side chain R′ or R″ to produce the side chain R of the target hydroxamic acid compound, whereby RC(O)NHOTBS is produced; and
(e) optionally treating the RC(O)NHOTBS with acid to produce an unprotected hydroxamic acid compound: RC(O)NHOH.


REFERENCES:
patent: WO9626223 (1996-08-01), None
patent: WO98/18754 (1998-05-01), None
Golebiowski et al, Solid Supported Synthseis of Hydroxamic Acids, accepted: Mar. 4, 1998, Tetrahedron Letters 39 (1998), pp. 3397-3400.

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