Ernesto G. Mata

The Polymer-Supported and Combinatorial Synthesis of β-Lactam Compounds: An Update

Solid-phase organic synthesis (SPOS) has become an effective synthetic tool for the preparation of combinatorial libraries of non-oligomeric small molecules. Owing to their high efficacy and extremely safe toxicological profile, beta-lactam antibiotics are the first choice for bacterial infectious diseases. Moreover, beta-lactam compounds have also showed other biological activities that include inhibition of prostate specific antigen, thrombin, human cytomegalovirus protein, human leukocyte elastase and cholesterol absorption. Thus, the application of combinatorial and related methodologies to the chemistry of the beta-lactam ring has been recognized as a very attractive challenge by different research groups around the world. This review covers the solid-phase and combinatorial chemistry related to mono-and multicyclic beta-lactam compounds that has been reported in the literature from 1999 to 2004.

Trapping and Characterization of a Reaction Intermediate in Carbapenem Hydrolysis by B. cereus Metallo-β-lactamase

Metallo-beta-lactamases hydrolyze most beta-lactam antibiotics. The lack of a successful inhibitor for them is related to the previous failure to characterize a reaction intermediate with a clinically useful substrate. Stopped-flow experiments together with rapid freeze-quench EPR and Raman spectroscopies were used to characterize the reaction of Co(II)-BcII with imipenem. These studies show that Co(II)-BcII is able to hydrolyze imipenem in both the mono- and dinuclear forms. In contrast to the situation met for penicillin, the species that accumulates during turnover is an enzyme-intermediate adduct in which the beta-lactam bond has already been cleaved. This intermediate is a metal-bound anionic species with a novel resonant structure that is stabilized by the metal ion at the DCH or Zn2 site. This species has been characterized based on its spectroscopic features. This represents a novel, previously unforeseen intermediate that is related to the chemical nature of carbapenems, as confirmed by the finding of a similar intermediate for meropenem. Since carbapenems are the only substrates cleaved by B1, B2, and B3 lactamases, identification of this intermediate could be exploited as a first step toward the design of transition-state-based inhibitors for all three classes of metallo-beta-lactamases.

Cleavage of carboxylic esters effected by organotin oxides and hydroxides under classical heating and microwave irradiation. A comparative study

Abstract We describe some recent findings on similarities and differences in the cleavage of selected carboxylic esters from the viewpoint of reactivity effected by organotin oxides and hydroxides, under different modes of heating (oil bath or microwave irradiation). These studies complement earlier use of bis(tributyltin) oxide and provide a simple and efficient procedure of cleavage of carboxylic esters in apolar aprotic or without solvent, under mild conditions with readily available organotin reagents.

Bis (tributyltin) oxide. A mild, neutral and selective reagent for cleavage of esters. Scope and limitation of the reaction

Abstract Bis(tributyltin)oxide acts as a mild, neutral and chemoselective ester cleavage reagent for a variety of carboxylic esters with good to excellent yields. The acyl-oxygen cleavage mechanism of (−)-(1R) menthyl acetate is discussed.

Butylstannonic acid catalyzed transesterification of carboxylic esters

Abstract Butylstannonic acid is used as catalyst for transesterification of various carboxylic esters. This method is also applicable to acetylation/deacetylation of alcohols.

Solid-Supported Cross Metathesis and the Role of the Homodimerization of the Non-immobilized Olefin

We have prepared immobilized olefins as models for the cross metathesis using different olefin partners in the presence of second generation Grubbs and Hoveyda-Grubbs precatalysts. We have demonstrated that solid-phase cross metathesis is strongly dependent on the degree of homodimerization of the non-immobilized olefin and the reactivity of such a homodimer. As in the homogeneous phase, the Hoveyda-Grubbs precatalyst was better for immobilized alpha,beta-unsaturated carbonyl compounds.

Stereoselective solid-phase synthesis of 3,4-substituted azetidinones as key intermediates for mono- and multicyclic β-lactam antibiotics and enzyme inhibitors

The polymer-supported Staudinger reaction proceeded smoothly under mild conditions to give the corresponding β-lactams in good to high overall yields with excellent cis-selectivity. Upon applying this reaction system, an efficient asymmetric synthesis of β-lactams was accomplished, when chiral acid chlorides or chiral aldehydes were used. These optically active β-lactams would be useful precursors for the generation of combinatorial libraries of potential antibiotics and enzyme inhibitors.

Mild and effective cleavage of esters with bis(tributyltin) oxide: A useful application in the deprotection of Pom penicillanate esters

Abstract (Pivaloyloxy)methyl 6,6-dihalo-, 6α-monosubstituted- and 6α-halo 1,1-dioxide penicillanates, N-benzoylglycine methyl ester and several selected esters are efficiently hydrolyzed with bis(tributyltin) oxide (nBu 3 Sn) 2 O with yields from 43 to 100%.

β-Lactams on Solid Support: Mild and Efficient Removal of Penicillin Derivatives from Merrifield Resin using Aluminum Chloride

Abstract Penicillin derivatives linked to Merrifield resin are efficiently released from this support under mild conditions using aluminum chloride in dichloromethane/nitromethane. Extension to Wang resin-linked analogues and studies on the solid-phase oxidation of penicillin is also reported.

Selective detachment of Boc-protected amino acids and peptides from Merrifield, PAM and Wang resins by trimethyltin hydroxide

Abstract We describe the development of a new non-acidolytic and non-nucleophilic method for the selective cleavage by trimethyltin hydroxide of amino acids and dipeptides at benzyl ester links attached to resins commonly used in peptide synthesis.