Oxazoline hydroxamates

An alternative procedure for the synthesis of aliphatic 2-substituted oxazoline hydroxamates was described by Pirrung and colleagues in the context of preparing inhibitors of E. coli LpxC zinc amidase [378], As shown in Scheme 6.210 a, the protocol involved the cyclization of suitable amides, formed in situ by acylation of a serine-derived 0-2,4-dimethoxybenzyl (DMB)-protected hydroxamate. The cyclization... 

Oxazoline Hydroxamates as Potential LpxC Inhibitors and Antibacterial Agents... 

The discovery of oxazoline hydroxamates as potential inhibitors of LpxC was the result of high-throughput screening of large libraries of compounds at the Merck Research Laboratories in collaboration with the Department of Biochemistry, Duke University Medical Center [95]. The lead compound, L-573,655, was a racemic mixture of 4-carbohydroxamido-2-phenyl-2-oxazoline, which had been previously made by Stammer et al. [96] as a precursor in the chemical synthesis of cyclosporine. Namely, (R,S)-serine methyl ester hydrochloride (149) is converted into (R,S)-4-carbomethoxy-2-phenyl-2-oxazoline (150) via treatment with ethyl benzimidate using the Elliot procedure [97]. Treatment of this ester with one equivalent each of hydroxylamine and sodium methoxide in methanol at room temperature affords the desired (R,S)-4-carbohydroxamido-2-phenyl-2-oxazoline (151), as depicted in Scheme 30. 

A number of A-acyloxy-A-alkoxybenzamides 100 have been shown to decompose in mesitylene at temperatures above 100°C giving a complex mixture of products including the A-alkyl adduct 106, the corresponding alkyl ester 108, anhydride 101 and a product (up to 60% yield in cases), which was characterised as 1,4,2-di-oxazoline 104 (Scheme 21). Minor products included hydroxamic ester 105 and mesitylene adduct 109. 

A2-Oxazolines. The intramolecular cyclization of /1-hydroxy hydroxamates to /1-lactams by P(C6H5)3-CC14 (10,447-448) can be used for cyclization of a carboxylic acid and a /1-amino alcohol to form a d2-oxazoline (equation I).1... 

Fifty-six years ago the very first siderophore, mycobactin, was isolated by the crystallization of the aluminum complex. Mycobactins from Gram-positive Mycobacteria and the closely related nocobactins from Nocardia embody a series of lipid-soluble siderophores located in the lipid-rich boundary layers of these bacteria (Figure 2(c)). The X-ray structure revealed that iron binding in mycobactins is accomplished by two hydroxamates, a phenolate group, and oxazoline nitrogen. 

Growth factors (in concentrations of ca. 30 ng/mL) for Mycobacterium paratuberculosis (M. johnei), the microorganism responsible for Johne s disease in livestock. M. are iron chelators ( siderophores). 9 M. (M. A, F, H, M, N, P, R, S, and T) have been isolated from various non-pathogenic mycobacteria. They are used as taxonomic markers for mycobacteria. All M. form extremely stable hexacoordinate complexes in which the iron(III) is bound to two hydroxamic acid and one 2-(2-hydroxyphenyl)-2-oxazoline units. M. are stable towards heat and acids but unstable towards bases. On saponification the M. are cleaved to mycobactic acid and cobactin. M. show an apple green fluorescence under UV light. They are very soluble in chloroform... 

A unique example of direct olefination of a cyclopropane was also disclosed by the Yu lab [21]. An electron-deficient arylamide was employed as directing group, as the previously employed oxazoline or hydroxamic acid was unreactive in the alkenylation. The proposed mechanism for the reaction involves an amide-directed C-H insertion of the Pd(II) catalyst into the cyclopropane methylene C-H bond of 9, followed by olefin carbopalladation and p-hydride elimination to provide intermediate 10 (Scheme 3a). Pd(0) is re-oxidized back to Pd(II) by Ag(I)/Cu(II), and a tandem 1,4-addition between the amide moiety of 10 and the acrylate provides the corresponding y-lactam 11 as the sole isolated product, fii the presence of an... 

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