Lactams hydroxamic acids

Apart from the syntheses of peptides, the Nps group has found useful application in the preparation of aminopenicillins,t l of O-sulfated (3-lactam hydroxamic acids,t and of the (3-lactone antibiotic (-f)-obafluorin.t l... 

P-Lactams. Hydroxamic acids obtained from aminolysis of P-lactones with O-benzylhydroxylamine undergo cyclization again with Ph,P-DIAD. 

E.M. Cordon, M.A. Ondetti, 1. Pluscec, C.M. Cimarusti, D.P. Bonner, R.B. Sykes, O-Sulfated P — lactam hydroxamic acids (monosulfactams). Novel monocyclic 3-lactam antibiotics of synthetic origin, 1 Am. Chem. Soc. 104 (1982) 6053-6060. 

Wright and Collins reduced o-nitrophenylacetic acids (37) with zinc and sulfuric acid and obtained a mixture of the hydroxamic acid (38) and lactam (39)... 

In the catalytic hydrogenation of ethyl 2-nitrophenyl acetate (43), Di Carlo observed a small amount of the cyclic hydroxamic acid (44) in addition to the expected lactam (45). Following this result, a... 

When heated at or about their melting points cyclic hydroxamic acids commonly decompose to give the corresponding lactams. Thus,... 

Reduction of cyclic hydroxamic acids generally leads to lactams or the corresponding amines. Chemical methods have frequently been preferred to catalytic hydrogenation, probably because the choice of... 

The hydroxamic acid function in most alicyclic and aromatic compounds is stable to hot dilute acid or alkali, and derivatives cannot undergo normal base-catalyzed Lessen rearrangement. Di Maio and Tardella," however, have shown that some alicyclic hydroxamic acids when treated with polyphosphoric acid (PPA) at 176°-195° undergo loss of CO, CO.2, or H2O, in a series of reactions which must involve earlj fission of the N—0 bond, presumably in a phosphoryl-ated intermediate. Thus, l-hydroxy-2- piperidone(108) gave carbon monoxide, 1-pyrroline (119), and the lactams (120 and 121). The saturated lactam is believed to be derived from disproportionation of the unsaturated lactam. 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Bromolactamization (11, 76). This reaction can be used for stereoselective preparation of 3,4-disubstituted 3-lactams.1 Thus the P,-y-unsaturated hydroxamic acid 1, prepared in several steps from tiglic acid, on reaction with bromine and K2C03 in aqueous CH,CN cyclizes mainly to a rrans-p-lactam (2). In contrast, the protected a-amino-p,y-unsaturated hydroxamic acid 3, prepared in several steps from L-methionine, cyclizes on reaction with bromine mainly to a ris-p-lactam (4). 

Photolysis of nitro-steroids 225 yields the aci-nitronate at 254 nm131. This in turn gives various products, among them are ketone 226 and hydroxamic acid 227 (equation 105) which could be formed from the intermediate anions of the Af-hydroxyoxaziridines, with a possible participation of gem-hydroxynitroso transient (or its anion see Scheme 10). For comparison, IV-butyl spiro-oxaziridine 228 in ethanol is photolysed at 254 nm (equation 106) to give 7V-butyl lactam 229 (50%) and the ketone 230 (25%). The former process is a well-known photoprocess of oxaziridine131. 

Intramolecular addition of hydroxylamines and hydroxamic acids to the non-activated double bonds is possible through oxidative cyclization. Reaction of O-Acyl fi,y-unsaturated hydroxamates (e.g. 56, equation 38) with bromine provides 3,4-substituted iV-hydroxy -lactams such as 57 with high diastereoselectivity. Analogous reaction of O-benzyl hydroxylamine 58 (equation 39) with iodine results in five-membered cyclization with 2 1 ratio of diastereomers. ... 

The literature contains several references to reductive cyclizations producing cyclic hydroxamic acids like those described above, though not in solid-phase chemistry.43-47 We showed that this reaction competes well with lactam formation. The relative extent of these two reaction pathways is highly dependent on the presence and the nature of other heteroatoms and substituents around the ring system as well as on the conditions used to effect the reduction. 

Davis, A. L. Hulme, K. L. Wilson, G. T. McCord, T. J. In Vitro Antimicrobial Activity of Some Cyclic Hydroxamic Acids and Related Lactams, Antimicrob. Agents Chemother. 1978, 13, 542. 

Aziridinones (z-lactums).3 The hydroxamic acid (1) is converted in almost quantitative yield to the a-lactam 2 when treated with triflic anhydride and triethylamine in CH2C12 at — 70°. This cyclization of a hydroxamic acid was first encountered in a thebaine derivative. 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

Moxalactam is also amenable to the popular hydroxyl amine assay for g-lactam antibiotics. In this procedure the -lactam is reacted with hydroxyl amine to cleave the e-lactam moiety and form a hydroxamic acid. The hydroxamic acid will in turn react with acidified ferric ion to form a colored complex which is measured at 480 nm. A blank correction for non-e-lactam impurities which react with hydroxyl amine is incorporated by adding hydroxylamine to an acidified sample where the acid is used to destroy all e-lactam species. 

DuPont s hybrid structure 19 [33] bears the signature of a dipeptide-based SAR on y-secretase and the reminiscent lead, which was synthesized in a matrix metalloproteinase (MMP) program. Removal of the central amide bond of the parent dipeptide, replacement of the hydroxamic acid by an amide, and introduction of a seven-membered lactam resulted in high activity and removed some of the problems associated with dipeptide lead structures. Hot labeling by photoactivation of I125-benzophenone specifically cross-linked the inhibitor to three cell-membrane proteins. 

In the reaction of O-benzoyl hydroxamic acid (56) with Bu3SnH, Bu3Sn adds to the carbonyl oxygen and subsequent p-elimination occurs to form an amidyl radical through the weak N-O bond cleavage, where finally, y-lactam (57) via 5-exo-trig manner is formed (eq. 3.18). 

These early findings, together with the ability to act as plant resistance factors towards pests, led to a cascade of some hundred papers dealing in an interdisciplinary manner with all aspects of benzoxazinoids. This name seems to be more correct than the name cyclic hydroxamic acids, which has often been used to name this class of compounds. However, it is not exact from the structural point of view, because it omits the fact that also a variety of acetal glucosides with lactam units was found in plants. They also may be split enzymatically to form lactam aglucones, but cannot undergo chemical decay into benzoxazolin-2(3H)-ones. Benzoxazinoids occur in Acanthaceae, Ranunculaceae, Scrophulariaceae,... 

Baumeler, A., Hesse, M., and Werner, C. 2000. Benzoxazinoids - cyclic hydroxamic acids, lactams and their corresponding glucosides in the genus Aphelandra (Acanthaceae). Phytochemistry 53, 213-222... 

Klein, J., Hartenstein, H. and Sicker, D. 1994. First discrimination of enantiomeric cyclic hemiacetals and methyl acetals derived from hydroxamic acids and lactams of Gramineae by means of 1H NMR using various chiral solvating agents. Magn. Reson. Chem. 32, 727-731... 

The lactim/lactam tautomerism of hydroxamic acids and their O-alkyl and O-acyl derivatives has also been studied [146], Hydroxamic acids exist in the solid state and in polar solvents as the lactam tautomer only, whereas in nonpolar solvents the hydroximic tautomer is also present. Further analogous solvent-dependent lactim/lactam equilibria have been observed for certain Schiff bases (prepared from anilines and 2(4)-hydroxybenzaldehyde [256] or 2-hydroxynaphthaldehyde [257]), for 3-hydroxypyrazole [258], and for 3-methyl-l-phenylpyrazolin-5-one [259]. 

S-Hydroxy-l-azetidinones. A biomimetic synthesis of the y3-lactam 4 from BOC-L-serine (1) has been reported. The protected serine derivative is converted into the hydroxamic acid 2 by condensation with O-benzylhydroxylamine mediated by the water-soluble l-ethyl-3(3 -dimethylaminopropyl)carbodiimide (1, 371). The product is cyclized directly in high yield to the / -lactam 3 by treatment with diethyl azodicarboxylate and triphenylphosphine. No racemization is observed. Deprotection by catalytic hydrogenation gives the N-hydroxy-jS-lactam 4. Previous biomimetic syntheses of 2-azetidinones have involved cyclization ot /3-cMoroamides with sodium hydride (e.g., 7, 335). 

N-l lydroxy-y-lactam 2 was prepared from the A -hydroxy-/ ,y-unsaturated hydroxamic acid 1 by treatment with diphenyl diselenide/ammonium thiosulfate/trifluoromethanesulfonic acid in acetonitrile. The reaction proceeded with low diastereoselectivity leading to a 66 34 diastereomeric mixture in good yield, but the structure of the diastereomers was not assigned238. 

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