Lactam structure

The course of alkylations of 6-azauracil is in good agreement with the results of determination of the dissociation constants of 6-azauracil and of its two monomethyl derivatives. On the assumption that a methyl group does not much affect the dissociation constant, and on the basis of the lactam structure, it may be concluded from the values of the dissociation constants iKa of 6-azauracil = 7.00, of l-methyl-6-azauracil = 6.99, and of 3-methyl-6-azauracil = 9.52) that dissociation takes first place at the NH group in position 3. The same results are obtained independently by comparing the pH dependence of the XJV spectra of these compounds. These results represent an exact confirmation of the older observation by Cattelain that the monoalkyl derivatives of 6-substituted dioxotriazines possess different acidity. 

A somewhat unusual sequence to generate azepanones 80 involved the intramolecular addition of hydroxylamines to alkynes 76 to form cyclic nitrones 77. A vinyl magnesium bromide addition at low temperatures and a reduction with TiCls followed by N-Boc protection led to the azepane 78. Double bond bromination and subsequent RUO4 oxidation gave the lactam 79. Several further steps allowed the generation of the lactam structure 80 proposed for d,/-aca-cialactam, but the spectral data of the synthetic material differed from that of the natural product (Scheme 16)] [23 a, b]. 

The C=N double bond is easily reduced, e.g., by refluxing with tetraline (71TL1621). As expected, the imine double bond is also very reactive toward cycloadditions. /3-Lactam structure 55 is formed by 1,2-cycloaddition of f-butylcyanoketene to 38 (71TL1621). As with azabenzoquinones, the 1,4-addition of 1,3-dienes to 38 provides the Diels-Alder products, e.g., 56 and 57, in good yields (Scheme 15) (70JHC615 75JA1681). 

The (5-lactam antibiotics are now so extensively described that we cannot attempt to summarize the literature. Since our emphasis is on sulfur, we note that the sulfur atoms of the thiazolidine or dihydrothiazine rings derive from a common tripeptide, 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine 1, ACV or Arnstein tripeptide . ACV is converted to a (5-lactam structure, isopenicillin N 2 and thereafter, the two pathways diverge, i.e. to benzylpenicillin 3 or to cephalosporin C 4 (Scheme 1). There have been extensive studies of the genes and enzymes involved in (5-lactam biosynthesis.18,19... 

A further modification is a single (3-lactam ring as found in the mon-obactams. Characteristically, there is a sulfonate residue (derived from sulfate) on the nitrogen atom. An example is sulfazecin 8 from Pseudomonas acidophila and P. mesoacidophila. This material also contains a dipeptide unit of D-glutamate and D-alanine (Scheme 2). Pharmaceutical chemists have synthesized many variations on the (3-lactam structure and have devised semisynthetic processes. The resulting materials are not natural products and are beyond the scope of this article. 

Studies using PM3 calculations of the alkaline hydrolysis of bicyclic P-lactam structures 82 (X = NNHCHO, 0, S) have shown that cleavage of the X-CO bond is the energetically favoured pathway both in the gas and solution phase <99MI287>. 

The /3-lactam structure can also react with active-serine hydrolases other than PBPs and /3-lactamases. It has been shown that appropriately substituted cephalosporins (e.g., 5.18) are potent mechanism-based inactivators of human leukocyte elastase (HLE, EC 3.4.21.37), a serine endopeptidase involved in the pathogenesis of pulmonary emphysema and other connective tissue diseases [57-60]. Subsequent work has demonstrated that substituted /3-lactams such as 5.19 or 5.20 are more stable HLE inhibitors and have improved potencies [61-63]. 

The mechanism of acid hydrolysis is also different in acyclic amides and /1-lactams acid catalysis of acyclic amides proceeds via O-protonation (see Chapt. 4), whereas that of /1-lactams appears to be a unimolecular A1 type process, involving V-protonation (Fig. 5.6,b) [76], A-Protonation is not the result of reduced amide resonance but an intrinsic property of the /1-lactam structure, since bicyclic /1-lactams and monocyclic /1-lactams exhibit similar reactivity and behavior [76],... 

An unusual synthesis of 7-deazaguaninyl-/3-amino acid occurs via an intermediate /3-lactam structure <2006EJOC2410>. 

Sum of all residues retaining the -lactam structure expressed as desfuroylceftiofur... 

Most possibilities and most examples in the syntheses of 1,4-dihydro-3(2//)-isoquinolinone (2) and its derivatives involve the cyclization of the corresponding arylacetic acid derivatives. The opportunity arises from the lactam structure of compound 2. With suitable reagents, different o-aminomethyl-, o-hydroxymethyl-, or o-chloromethyl-phenylacetic acid derivatives (25LA225 66JPR12 69CJC864 84JHC297) and o-hydroxymethyl phenylacetonitriles (85S114) can be cyclized. 

Several derivatives of the unsaturated and saturated lactams mentioned in this review have been submitted to pharmacological investigations, and various biological activities were found. In this section, an attempt is made to enumerate some derivatives together with their biological properties. Such compounds are shown in the lactam structure. 

ANTIBIOTICS 0-LACTAMS. In the period up to 1970 most 0 lactam research was concerned with the penicillin and cephalosporin group of antibiotics. Since that time, however, a wide variety of new mono- and bicyclic 0-lactam structures have been described. The carbapenems, characterized by the presence of the bicyclic ring system (I. X =( H0 originated from natural sources the penem ring (1. X =S) and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are 7-oxo-(R)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. C7H7NO3, and 7-oxo-(7J)-4-t Ilia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 0,H5NO ,S. respectively. 

The synthesis of oxaspiro-p-lactam structures containing five- and six-membered rings was explored through RCM reaction. Unfortunately, dienes 26-29 having a... 

Among the various strategies available for p-tum mimics, the Freidinger y-lactam structure (1), or a spiro system [144] (2),has been found suitable for the design of a variety of medicinally relevant targets. In addition, it has been recently reported that use of a,a-disubstituted [S-lactam (3) could also be a good approach to promote a p-tum folding in a peptide chain [145] (Fig. 12). 

Treatment of isonicotinamide with LDA at 40°C and addition of an acylating or alkylating agent were reported in 2005 to form in good yield, a dearomatized product with spirocyclic p-lactam structure (Scheme 88), [195]... 

Lactam structures have been reported to be constructed by treatment of substituted (3-amino acids with dicyclohexylcarbodiimide (DCC) in refluxing acetonitrile (Scheme 98), [218]. The substrates were prepared by a multistep synthetic protocol previously reported [219]. 

Demain AL, Solomon NA (1983) (eds) Antibiotics containing the P-lactam structure, parts 1 2. Springer, Berlin... 

Coll M, Frau J, Vilanova B, Donoso J, Munoz F, Garcia Blanco F. Theoretical study of the alkaline hydrolysis of an oxo-P-lactam structure. J Phys Chem A 1999 103 8879-8884. 

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