Bacterial resistance development has become a very serious clinical problem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of action which involves very early inhibition of bacterial protein synthesis. We have prepared two potent, synthetic oxazolidinones, U-100592 and U-100766, which are currently in clinical development for the treatment of serious multidrug-resistant Gram-positive bacterial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100592 and U-100766 against representative strains are similar to those of vancomycin. U-100592 and U-100766 demonstrate potent in vitro activity against Mycobacterium tuberculosis. A novel and practical asymmetric synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been developed and is employed for the synthesis of U-100592 and U-100766. This involves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyrate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones.

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The synthesis and antibacterial activity of a series of 7V-acyl 3-isopropylidenyl-and 3-isopropyl 2-azetidinones having potent in vitro antibacterial activity, particularly against anaerobic organisms, is described. A distinguishing structural feature of these compounds is the lack of any ionizable moiety appendant to the lactam nitrogen. 213In our search for novel synthetic antibacterial agents, we sought to explore the potential utility of a monocyclic /Mactam doubly-activated by an exocyclic C-C double bond at position C-3, and an appropriate electron-withdrawing moiety on the lactam N-l nitrogen. The rationale behind this template design hinged on the rudimentary concept of creating additional ring strain through the juxtapositioning of two sp2-hybridized carbons within the 4-membered ring. It was envisioned that such ring strain, in concert with the electron-withdrawing effect of an appropriate N-l substituent, might serve to sufficiently activate the /Mactam carbonyl as an electrophile, thereby potentially allowing for acylation of an active site serine hydroxyl in the targeted transpeptidases involved in microbial cell wall biosynthesis.4'5) The provision of a sufficient chemical reactivity to any particular /Mactam carbonyl does not, however, in and of itself render antibacterial activity.6'7) The /Mactam must also be fitted with appropriate structural appendages that allow for, or facilitate the binding of, the electrophile at the active site.8)9) In order to address this regard, at the outset of this lead-finding program we selected for synthesis both the Z and E isomers of 3-(l-methyl-2-hydroxyethylidene)-2-azetidinone10) (the latter comprising the lactam portion of the carbapenem asparenomycins).1 1>12) Such hydroxyisopropylidenyl templates, equipped with a readily manipulable synthetic handle, could be exploited to generate a multitude of structurally-varied entities at C-3, with the objective of optimization of biological activity. Subsequently we discovered that the "parent" 7V-acyl C-3 unsubstituted isopropylidenes (a, Schemes 1 and 2) and their corresponding dihydro analogs, the 7V-acyl 3-isopropyl azetidin-2-ones (b), exhibited the highest potencies of this class. Here we report on the structure-activity relationships (SAR) of these unusual /Mactam antibacterial agents.Results and Discussion Chemistry Wehave previously described the chemistry employed in the synthesis of the requisite 3-isopropylidenylThe content of this paper has been presented in part, see references 1~3.

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