Substitution hydroxamic acid synthesis

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. 

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. 

The A-hydroxycarboxamide group is a key fragment of many siderophores so that a convenient synthesis of this group is crucial for further progress. A variety of methods have been attempted for the preparation of hydroxamic acids starting from carboxylic acids. Although some of these methods are quite efficient for the preparation of substituted hydroxamic acids, the preparation of the parent compound is still a problem and yields are often moderately unacceptable, in part due to the low solubility of the parent hydroxylamine hydrochloride in organic solvents. 

A formal synthesis of ( )-Eseroline (69) via a 3-aza-4-oxa-Cope rearrangement was reported. An iV-aryl A-hydroxycarbamate was reacted with 2-phenylsulfanylpropanoic acid to yield the O-acylhydroxamic acid derivative 65, R = H that rearranged in the presence of potassium bis(trimethylsilyl)amide. The [3,3] and [3,5] rearrangement products, respectively 66 and 67, were formed (equation 22). If the para-substituted hydroxamic acid 65, R = OCOBu-t is used, no [3,5] rearrangement product is observed and the [3,3] rearrangement product 68 is the only product formed (equation 23). The authors proposed two parallel mechanisms, a concerted pathway and an ionic mechanism by an ion-pair recombination. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

Hydroxamic acids are an important class of compounds targeted as potential therapeutic agents. A-Fmoc-aminooxy-2-chlorotrityl polystyrene resin 61 allowed the synthesis and subsequent cleavage under mild conditions of both peptidyl and small molecule hydroxamic acids (Fig. 14) [70]. An alternative hydroxylamine linkage 62 was prepared from trityl chloride resin and tV-hydroxyphthalimide followed by treatment with hydrazine at room temperature (Scheme 30) [71]. A series of hydroxamic acids were prepared by the addition of substituted succinic anhydrides to the resin followed by coupling with a variety of amines, and cleavage with HCOOH-THF(l 3). 

Although the synthesis of 3-isoxazolols from P-keto esters and hydroxylamine suffers from the formation of 5-isoxazolones as major products, treatment of acyl chlorides with Meldrum s acid 4 followed by aminolysis gave rise to p-keto hydroxamic acids 6 that cyclised to the corresponding 5-substituted 3-isoxazolols 7 without formation of any byproduct <00JOC1003>. Cyclisation of N-substituted salicylhydroxamic acids 9 under... 

Homolytic substitution of heteroaromatic compounds, 16, 123 Hydantoins, chemistry of, 38, 177 Hydrogen cyanide derivatives, synthesis of heterocycles from, 41, 1 Hydrogen exchange base-catalyzed, 16, 1 one-step (labeling) methods, 15, 137 Hydrogenated porphyrin derivatives hydroporphyrins, 43, 73 Hydroxamic acids, cyclic, 10, 199 1 -Hydroxyindoles, 1 -hydroxytryptophans, and 1-hydroxytryptamines,... 

A type 2 intramolecular /V-acylnitroso Diels-Alder reaction of hydroxamic acid 177 followed by catalytic hydrogenation of the double bond was employed for the synthesis of substituted bridged bicyclic derivative 178, as a single diastereomer (Scheme 75 <2002OL2637>). Cleavage of the N-O bond was performed by reduction with Na(Hg) amalgam and provided m-3,7-disubstituted azocane 9, as a single isomer in 80% yield. 

The first synthesis (left pathway) affording DIBOA started from a protected 2-nitrophenoI [109], The need to handle a free donor-substituted arylhydroxylamine reduces the yield distinctly and is a serious disadvantage. The second synthesis (middle left pathway), subject of a patent issued in 1975 to Hoffman-La Roche, is also starting from an appropriate ortho-suhstituted nitrobenzene [110]. In both syntheses the hydroxamic acid is generated by reductive cyclisation and the hemiacetal by hydrolysis of a chloride precursor. However, only the second procedure is applicable to the synthesis of the 7-methoxy compound DIMBOA. Therefore, this principle has later been developed further. The strategy of the third synthesis (middle right pathway) is different [111]. After alkaline cyclisation of the dichloroacetamide precursor to the hemiacetal unit the hydroxamic acid is obtained by oxidation of the... 

Fig. 4a. Pathways of hydroxamic acid syntheses of siderophores containing Ns-hydroxyornithine building blocks, a) Starts with e-nitro-L-norvaline. Schemes b) and c) start with ornithine derivatives protected at N5 with CBZ (benzyloxycarbonyl) and Tos (toluenesulfonate), BZL (benzyl), respectively Fig. 4b. Scheme of the synthesis of aerobactin. Protected g-hydroxynorleucine 1 (P = BOC,P = CH3) is transformed into the protected hydroxamic acid 2. Deprotection of the a-NH2 grqup enables alkylation of the o-substituted hydroxamate to give compound 3...

DiJoseph, J. F., Sung, A., Sharr, M. A., Killar, L. M., Walter, T., Jin, G., Cowling, R., Tillett, J., Zhao, W., McDevitt, J., Xu, Z. B. Synthesis and structure-activity relationship of A-substituted 4-aryl-sulfonylpiperidine-4-hydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. J. Med. Chem. 2003, 46(12), 2376-2396. 

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