Solid-phase synthesis hydroxamic acids

Bauer U, Ho W-B, Koskinen AMP. A novel linkage for the solid-phase synthesis of hydroxamic acids. Tetrahedron Lett 1997 38 7233-7236. 

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

In 1983, Prasad et al.12 first reported the condensation of chloromethyl polystyrene with /V-hydroxyphthalimide to give the ester, hydrazinolysis of which yielded the desired resin-bound hydroxylamine. However, the sole purpose of this reagent was to react with, and hence extract ketones from, a complex steroidal mixture, and its use for the solid-phase synthesis of hydroxamic acids was not explored. Recently, the exploitation of the above solid-phase approach for the synthesis of hydroxamic acids was independently reported by three groups,7-9 all of which differ only in the method for the initial anchoring of TV-hydroxyphtha-limide to an 4-alkoxybenzyl alcohol functionalized polystyrene or trityl chloride polystyrene. Subsequent /V-deprotection was... 

In conclusion, we anticipate that A-Fmoc-aminooxy-2-chlorotrityl polystyrene will prove an indispensable reagent for the solid-phase synthesis of hydroxamic acids by multiple and combinatorial approaches. Not only is its production both efficient and cost effective, but release of the assembled hydroxamic acid derivative is readily accomplished using mild acidolytic reagents. 

The solid-phase synthesis of hydroxamic acids has been of interest in the recent chemical hterature . Typically, hydroxylamine derivatives are tethered to solid supports via the oxygen (Scheme 79), although immobilization through the nitrogen has also been observed. 

Angelo Angeli s name, along with that of Enrico Rimini (1874—1917), is often associated with the chemical reaction that bears their names. In 1896 Angeli, and independently Rimini, discovered the reaction between an aldehyde and a sulfonamide to form a hydroxamic acid they published their discoveries in the same year [115, 116]. The reaction was mainly used as a chemical test in the dairy industry for detecting the presence of aldehydes as a consequence of food storage. The Angeli-Rimini reaction has been recently applied in solid-phase synthesis [117]. 

Taddei and coworkers [49] also reported an MW-promoted solid-phase synthesis of 3,6-disubstituted perhydro-diazepin-2,5-dione 70 (Scheme 10) involving a Mitsunobu cyclization of a hydroxamic acid derivative anchored to PS-DVB 2-chlorotrityl resin (69). The prepared compound was proved to be useful as constrained peptidomimetics. 

Publications continue to appear that deal with new applications of known linkers as well as novel linkers to expand the scope of functionality which can serve as a handle for solid-phase synthesis. Prominent among recent manuscripts are linkers for a variety of nitrogen-based functional groups such as amines, sulfonamides, amidines, and hydroxamic acids (Figure 1). 

Baul997 Bauer, U., Ho, W.B. and Koskinen, A.M.P., A Novel Linkage for the Solid-Phase Synthesis of Hydroxamic Acids, Tetrahedron Lett., 38 (1997) 7233-7236. 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

Mellor, S. L. McGuire, C. Chan, W. C. M-Fmoc-Aminooxy-2-Chlorotrityl Polystyrene Resin A Facile Solid-Phase Methodology for the Synthesis of Hydroxamic Acids, Tetrahedron Lett. 1997, 38, 3311. 

The THP-based hnker can be modified in such a way as to allow fhe synthesis of hydroxamic acids 49, as outlined in Scheme 24. Linker 48 has played a role in the solid-phase synfhesis of matrix metalloproteinase inhibitors [52], Alternative linkers that yield hydroxamic acids after release have been used in connection with peptide chemistry, as well as for the preparation of combinatorial compounds [53-58]. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

In 1999, the same group applied their cyclization-carbonylation methodology in the synthesis of hydroxamic acids in both solution and solid phase. By using hydroxamates as coupling partners, the corresponding products were formed in good to excellent yields (Scheme 2.32). 

Rol996 Floyd, C.D., Lewis, C.N., Patel, S.R. and Whittaker, M., A Method for the Synthesis of Hydroxamic acids on Solid Phase, Tetrahedron Lett., 37 (1996) 8045-8048. 

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