Lactam models

Kayser, M.M., Drolet, M. and Stewart, J.D. (2005) Application of newly available bio-reducing agents to the synthesis of chiral hydroxy-beta-lactams model for aldose reductase selectivity. Tetrahedron Asymmetry, 16 (24), 4004-4009. 

The carbonyl-carbonyl reductive condensation could not be reproduced on simple non-P-lactam models [82b], but worked on other iV-oxaloazetidinones, which were successfully condensed to carbapenem [82a, 162] and cephem-1,1-dioxide products [170]. 

Whereas there are numerous examples of the application of the products from diastereoselective 1,3-dipolar cycloaddition reaction in synthesis [7, 8], there are only very few examples on the application of the products from metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction in the synthesis of potential target molecules. The reason for this may be due to the fact that most metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction have been carried out on model systems that have not been optimized for further derivatization. One exception of this is the synthesis of a / -lactam by Kobayashi and Kawamura [84]. The isoxazoli-dine endo-21h, which was obtained in 96% ee from the Yb(OTf)3-BINOL-catalyzed... 

Michael reactions and, 895 Beta-keto ester, 851 alkylation of, 859-860 cyclic, 892-893 decarboxylation of, 857, 860 Michael reactions and. 895 pKd of, 852 synthesis of, 892-893 Beta-lactam antibiotics, 824-825 Beta oxidation pathway, 1133-1137 mechanism of, 1133-1136 Beta-pleated sheet (protein), 1038 molecular model of, 1039 secondary protein structure and, 1038-1039 Betaine, 720 Bextra. structure of, 544 BHA, synthesis of, 629 BHT, synthesis of. 629 Bicycloalkane. 129 Bijvoet. J. M., 299 Bimolecular, 363... 

Boyd DB, Hermann RB, Presti DE, Marsh MM. Electronic structures of cephalosporins and penicillins. 4. Modeling acylation by the beta-lactam ring. / Med Chem 1975 18 408-17. 

Hall, L. M Hall, L H Kier, L B. QSAR modeling of 3-lactam binding to human serum proteins. /. Comput.-Aided Mol. Des. 2003, 17,103-118. 

As already mentioned, Lippard and co-workers have also studied the -hydroxy dizinc unit found in metallohydrolases in a model system [Zn2L(/x-OI I)(/x-02PPh2)]2+, L = 2,7-bis [2-(2-pyridylethyl)-aminomethyl]-l,8-naphthyridine) 454 Hydrolysis of phosphodiesters and beta-lactams was studied and related to the PI nuclease and beta-lactamase enzymes. The dinuclear complex... 

With acid or basic substrates protein transfer may contribute to recognition by the model receptor, but binding to lactams involves hydrogen bonds exclusively. Recent research321 has concluded that hydrogen bonds are not so often created as they are merely exchanged in aqueous solutions, and the overall enthalpic changes are modest. 

As a simple model for the enzyme penicillinase, Tutt and Schwartz (1970, 1971) investigated the effect of cycloheptaamylose on the hydrolysis of a series of penicillins. As illustrated in Scheme III, the alkaline hydrolysis of penicillins is first-order in both substrate and hydroxide ion and proceeds with cleavage of the /3-lactam ring to produce penicilloic acid. In the presence of an excess of cycloheptaamylose, the rate of disappearance of penicillin follows saturation kinetics as the cycloheptaamylose concentration is varied. By analogy to the hydrolysis of the phenyl acetates, this saturation behavior may be explained by inclusion of the penicillin side chain (the R group) within the cycloheptaamylose cavity prior to nucleophilic attack by a cycloheptaamylose alkoxide ion at the /3-lactam carbonyl. The presence of a covalent intermediate on the reaction pathway, although not isolated, was implicated by the observation that the rate of disappearance of penicillin is always greater than the rate of appearance of free penicilloic acid. 

Cefadroxyl and cefaclor are beta-lactam antibiotics which show high affinity for the PepTl carrier system, whereas the other two beta-lactams, cephalotin and cef-metazole, are not recognized by PepTl protein and are not actively transported in the intestine. However, as the VolSurf Caco-2 model predicts that all the beta-lactams are nonpenetrating compounds, it is very probable that, as they rely only the diffusion mechanism, cefadroxyl and cefaclor will not cross the cell monolayer. 

In a related study Porter et al. showed that a-bromo-y lactams 185 containing a pyridyl moiety can react with allyltrimethylsilane enantiose-lectively in the presence of chiral Lewis acids derived from zinc and 189 (Scheme 49) [142], In contrast to the above study, the ligand of choice for substrates 185 was found to be the bisoxazoline ligand 189. Excellent ee s were obtained in the presence of two equivalents of the chiral Lewis acid. Under substoichiometric amounts of the catalyst, lower selectivities were obtained. Different substituents on the pyridyl moiety were also examined although no predictable trend was observed. A trans octahedral model simi-... 

J. R. Alvarez-Idaboy, R. Gonzalez-Jonte, A. Hernandez-Laguna, Y. G. Smeyers, Reaction Mechanism of the Acyl-Enzyme Formation in /3-Lactam Hydrolysis by Means of Quantum Chemical Modeling , J. Mol. Struct. 2000, 204, 13 - 28. 

Transition metal ions cause a dramatic increase in the rate of hydrolysis of /Madam antibiotics [75][133][134], For example, copper(II) and zinc(II) ions increase the rate of alkaline hydrolysis ca. 108-fold and 104-fold, respectively [76], It has been suggested that the metal ion coordinates with both the carboxylate group and the /3-lactam N-atom of penicillins (A, Fig. 5.20). This complex stabilizes the tetrahedral intermediate and, thus, facilitates cleavage of the C-N bond catalyzed by the HO ion [74] [75], Such a model appears applicable also to clavulanic acid, imipenem, and monobactams, but it re-... 

In cephalosporins, the lactam N-atom has a lower basicity due to ena-mine conjugation and a geometry that is less favorable for binding metal ions. Nevertheless, cephalosporins bind Cu11 ions ten times more tightly than penicillins, suggesting that the metal ion coordination site is different from that of the penicillins. Indeed, molecular models of cephalosporins seem to... 

A. Matagne, J. Lamotte-Brasseur, G. Dive, J. M. Frere, Interaction between Active Site-Serine /3-Lactamases and Compounds Bearing a Methoxy Side Chain on the a-Face of the /3-Lactam Ring Kinetic and Molecular Modelling , Biochem. J. 1993, 293, 607-611. 

Pharmacokinetic/pharmacodynamic modeling indicates that the AUC/MIC ratio is predictive of outcome for this antibacterial suggesting that telithromycin is suitable for short-duration therapy and a once-daily dosing regimen even against / -lactam and macrolide-resistant pathogens... 

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