Oxazole residues

The linkage in madumycin II (92) of the D-alanine and oxazole residues (the latter thought to arise by cyclization of an acyldehydroserine) is considered significant insofar as the cooccurrence of d- and dehydro amino acids in microbial compounds had been previously noted (61), and a possible relationship between these systems suggested. Several microbial metabolites which display antibiotic properties incorporate a,(i-dehydro amino acids and their derivatives (62). 

Scheme 7.8 A furan or an oxazole residue are synthetic equivalents of an ester function ...

In contrast to other acids, anhydrous hydrogen fluoride does not cause hydroly SIS and decarboxylation of the malonic acid residues in these reactions [5]. It is a good reagent for the cyclization of a-benzamidoacetophenones to 2,5 diphenyl-oxazoles [6] (equation 7) The same reaction with concentrated sulfuric acid gives cyclic product with only a 12% yield [6]... 

The biosynthesis 237,5381 involves enzymatic dehydration of serine and threonine residues in a manner similar to the formation of thiazoles and dihydrothiazoles vide supra) with or without subsequent oxidation to yield the 2-(l-aminoalkyl)oxazole-4-carboxylic acid and 2-(l-aminoalkyl)dihydrooxazole-4-carboxylic acid shown in Scheme 38. These cyclic peptides display interesting physiological properties such as cytotoxicity/541, 569,5831 antitumor activities, or antineoplastic effects/523,5291 but as for the sulfur-containing compounds the mechanism of action is not yet understood despite extensive SAR studies. 515,521,540,5431... 

DBU (3mL, 20 mmol) was added to methyl 2-[(benzyloxycarbonylamino)oxazolidine-4-carboxylate (2.8 g, 9.6 mmol) in CQ4/MeCN/Py (2 3 3). After 3 h at rt, the solvent was extracted with 0.5 M HC1 and the aqueous phase reextracted with EtOAc (2 x). The EtOAc phase was washed with brine, dried (MgS04), and the solvent removed. Chromatography (silica gel, EtOAc/hexane 1 1) afforded methyl 2-[(benzyloxycarbonylamino)methyl]oxazole-4-carboxylate yield 0.94 g (33%). The oxazole ester (0.29 g, lmmol) was dissolved in dioxane (15 mL) and NaOH (0.12 g, in 5mL H,0) was added. The mixture was stirred at rt for 1 hr. The soln was neutralized with 10% aq KHS04 to pH 6, and the dioxane was removed. The soln was acidified to pH 3 and taken to dryness. The residue was crystallized (EtOAc/ hexane) yield 0.24 g (90%). 

A mixture of 349 mg (1 mmol) of (3S.6S,7aS)-6-benzyl-tetrahydro-3-isopropyl-6-methyl-7a-phenylpyrro-lo[2.1 -A oxazol-5(6//)-one (9, R2 = f-Pr R4 = CH3) and 10 mL of 48% aq hydrobromic acid is heated at reflux for 24 h. After cooling to r.t., the solution is diluted with water and extracted with three portions of ethyl acetate. The combined extract is dried over anhyd Na2S04. filtered and concentrated in vacuo, and the residue is dissolved in diethyl ether. The ethereal solution is treated with excess diazomethane in diethyl ether, and the solution is filtered and concentrated. The residue is purified by preparative TLC and distilled bulb-to-bulb to give a colorless oil yield 233 mg (85%) 100% ee bp 120sC/0.07 Torr [a]D +12.8 (c = 1.2. CHC13). 

To a stirred soln of Z-(aTfm)Xaa-OH (2 mmol) in CH2C12 (10 mL) were added DIC 109 (or DCC, 115 2.2 mmol) and the N-deprotected peptide or amino acid derivative (2 mmol). The mixture was stirred at rt for 12 h [the progress of the reaction, indicated by the formation and disappearance of the oxazol-5(4H)-one, can be monitored by TLC]. 115 The precipitate was separated by filtration, the mother liquor was concentrated to dryness, and the residue was purified by flash chromatography. 

Examples of the cyclodehydration of peptide segments containing serine or threonine residues or the corresponding oxo amides to oxazoles are given in Table 2, Section 11.2.3.5. 

A solution of 5.1 grams 2-chloro-4,5-diphenyl-oxazole, 6.3 grams diethanolamine and 50 ml absolute ethanol was refluxed for 4 hours. The solvent was stripped at 1 mm and the oily residue was added at 60°C to 100 ml 50% ethanol by cooling the hydro-alcoholic solution, 4.5 grams of 2-bis((3-hydroxyethyl)amino-4,5-diphenyl-oxazole was obtained (yield, 69.5%). The product crystallized from ethyl ether + petroleum ether, with a MP of 96 to 98°C. 

Upon mixing 1.27 g of 4-methyl-5-ethoxy oxazole (0.01 mole), 0.98 g of maleic anhydride (0.01 mole) and 2.5 ml of dry benzene, a yellow color appears and heat is evolved, requiring cooling. After 3-4 min the evolution of heat ceases and the color fades. The mixture is then refluxed for about 18 h, after which the solvent is decanted and the residue treated with a small... 

The Rutaceae oxazoles are evidently derived from /V-nicotinoyl-p-(p-hydroxy)-phenylethylamide (51), with the exception of balsoxin (25) and texamine (26) in which the nicotinoyl moiety is replaced by benzoyl. The condensation of these tyramine and nicotinic acid residues does not represent any major departure from the standard routes of alkaloid biosynthesis in the Rutaceae, for it has long been recognized that the alkaloids of this family are all derived from either phenylalanine (52), tyrosine, (53), or anthranilic acid (54) (22), the latter being the acknowledged precursor to nicotinic acid in most organisms (23). The formation of the putative oxazole precursor 51 or its equivalent therefore constitutes a convergence of the two predominant modes of alkaloid biosynthesis in the family. 

It has been hypothesized that the trisoxazole moiety in kabiramide C (64) arises by cyclization of the dehydrotriserine residue 65. This conjecture is consistent with the established mode of formation of the bacterial oxazole virginia-mycin Ml 90 from an acylserine (vida infra). A more recent suggestion is that the trisoxazole 69 may arise by cyclization of the Beckmann rearrangement product 68 of the trioxime 67 derived from the polyketide 66 (27). 

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