Library oxazolidinones

Oxazolidinone familes, synthesis of, 7 7 741 Oxazolidinone libraries, preparation of, 77 742... 

A microwave-assisted solid-phase synthesis of the antimicrobial oxazo-lidinone pharmacophore is described herein as a demonstration of the utility of this emerging technology toward drug discovery.4 The optimization process and full experimental details for the synthesis of a small library of oxazolidinones are exemplified. 

The Suzuki coupling of arylboronic acids to the solid-supported arylha-lide 4 was initially performed by conventional heating methods, DMF at 85° in an oil bath for 16 h, to provide the desired products 6 after TFA cleavage. Due to the extended heating times necessary for the Suzuki reaction, full optimization of the reaction conditions were not investigated prior to compound library synthesis. Reaction conditions sufficient for the library synthesis were determined within a couple of weeks affording moderate yields of the desired oxazolidinones. Libraries of hundreds of... 

A small library of oxazolidinones was then synthesized using the robotics of the Smith synthesizer to run sequentially each new boronic acid in the Suzuki reaction. Cleavage of the products and filtration through a small plug of silica provided excellent yields and purities of the desired oxazolidinones, including compound 12, the previous clinical candidate E3656, in 96% yield and 96% purity (Table II). 

This MA-SPOS of the oxazolidinone class of antimicrobial/antibiotics allows for the rapid synthesis of libraries of compounds that simultaneously... 

Antimicrobial oxazolidinones were successfully synthesized with the help of single-mode microwave heating on a polystyrene resin. In this case, the use of commercial multimode ovens was associated with inconsistent yields and purities, presumably due to the nonhomogeneity of the heating and a lack of sufficient temperature and pressure controls. A representative reaction is presented in Scheme 61. These solid-supported reactions proceeded smoothly in 5-10 minutes, with the boronic acid added in six equivalents and a small library with variations in both the N-acyl and the biaryl functionalities was created [145]. 

A well known reaction for the synthesis of oxazolidinones, cycloaddition of isocyanates to epoxides, was applied to resin linked substrates for the synthesis of libraries of isoxazolidinones 198 <03JCC789>. 

Recently, Delpiccolo and Mata have also explored the asymmetric synthesis of monocyclic 3,4-substituted (3-lactams (Scheme 3.15). They employed the same Staudinger-type cycloaddition reaction with the chiral glycine derivative, 4(5)-phenyloxazolidylacetyl chloride (72). The oxazolidinone moiety functioned effectively as a chiral auxiliary, and a small library of optically active p-lactams 75 were obtained following cleavage with 10% TFA/DCM and subsequent conversion to the methyl esters (diastereoselec-tivity ranged from 8/1 to >25/1). 

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