Upon reaction with IPy2BF4, 4-substituted anilines give regioselectively the corresponding o-iodoanilines in nearly quantitative yield, in a process that can be carried out on a multigram scale. Palladium-catalyzed coupling of the resulting 2-iodoanilines with (trimethylsilyl)acetylene (TMSA), followed by efficient CuI-mediated nitrogen cyclization onto alkynes with concurrent elimination of the TMS substituent, allows a straightforward elaboration of 5-mono- and 5,7-disubstituted indoles from aromatic amines. This new approach to the aforementioned indoles does not requires protective groups on nitrogen at any step and can be adapted for preparing related 7-monosubstituted indoles. Moreover, examples iterating the process are given, allowing bisannulation and sequential double annulation and resulting in synthesis of benzodipyrroles. Additionally, suitable conditions for iodination of some of the target indoles with IPy2BF4 are discussed.

The first potent inhibitors of glutamate racemase (MurI) enzyme that show whole cell antibacterial activity are described. Optically pure 4-substituted D-glutamic acid analogues with (2R,4S) stereochemistry and bearing aryl-, heteroaryl-, cinnamyl-, or biaryl-methyl substituents represent a novel class of glutamate racemase inhibitors. Exploration of the D-Glu core led to the identification of lead compounds (-)-8 and 10. 2-Naphthylmethyl derivative 10 was found to be a potent competitive inhibitor of glutamate racemase activity (K(i) = 16 nM, circular dichroism assay; IC(50) = 0.1 microg/mL high-performance liquid chromatography (HPLC) assay). Thorough structure-activity relationship (SAR) studies led to benzothienyl derivatives such as 69 and 74 with increased potency (IC(50) = 0.036 and 0.01 microg/mL, respectively, HPLC assay). These compounds showed potent whole cell antibacterial activity against S. pneumoniae PN-R6, and good correlation with the enzyme assay. Compounds 69, 74 and biaryl derivative 52 showed efficacy in an in vivo murine thigh infection model against Streptococcus pneumoniae. Data described herein suggest that glutamate racemase may be a viable target for developing new antibacterial agents.

DNA-encoded library technology (ELT) has emerged in the pharmaceutical industry as a powerful tool for hit and lead generation. Over the last 10 years, a number of DNA-compatible chemical reactions have been published and used to synthesize libraries. Among the most commonly used reactions in medicinal chemistry is the C−N bond formation, and its application to DNA-encoded library technology affords an alternative approach to identify high-affinity binders for biologically relevant protein targets. Herein we report a newly developed Pd-promoted C−N cross coupling reaction between DNA-conjugated aryl bromides and a wide scope of arylamines in good to excellent yields. The mild reaction conditions should facilitate the synthesis of novel DNA-encoded combinatorial libraries.

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The reaction of lithium enolates of achiral N-protected glycine esters with chiral alkoxyalkenylcarbene complexes of chromium provided the corresponding Michael adducts with either high anti or syn selectivity depending on the nature of the nitrogen protecting group, and high diastereofacial selectivity when carbene complexes containing the (-)-8-phenylmenthyloxy group were employed. Subsequent oxidation of the metal-carbene moiety followed by deprotection of the amine group and hydrolysis of both carboxylic esters afforded enantiomerically enriched 3-substituted glutamic acids of natural as well as unnatural stereochemistry. Alternatively, when the deprotection step was performed previously to the oxidation, cyclic aminocarbene complexes were formed, which finally led to optically active 3-substituted pyroglutamic acids.

Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.

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