Excitatory amino acid transporters (EAATs) are essential CNS proteins that regulate glutamate levels. Excess glutamate release and alteration in EAAT expression are associated with several CNS disorders. Previously, we identified positive allosteric modulators (PAM) of EAAT2, the main CNS transporter, and have demonstrated their neuroprotective properties in vitro. Herein, we report on the structure-activity relationships (SAR) for the analogs identified from virtual screening and from our medicinal chemistry campaign. This work identified several selective EAAT2 positive allosteric modulators (PAMs) such as compounds 4 (DA-023) and 40 (NA-014) from a library of analogs inspired by GT949, an early generation compound. This series also provides nonselective EAAT PAMs, EAAT inhibitors, and inactive compounds that may be useful for elucidating the mechanism of EAAT allosteric modulation.

Asymmetric cycloaddition reactions have emerged as one of the powerful and reliable strategies for the construction of enantioenriched molecules, especially those with polycyclic frameworks. Herein, we report the asymmetric decarboxylative [3 + 2] cycloaddition of γ-methylidene-δ-valerolactones with nitroolefins under the cooperative catalysis of a palladium complex and a chiral urea-tertiary amine, delivering a variety of chiral spiro[2.4]heptanes in good yields with high enantioselectivities and moderate diastereoselectivities. The mild reaction conditions, in conjunction with good functional group tolerance, provided an easy access to multisubstituted chiral spiro[2.4]heptanes bearing three contiguous stereogenic centers including an all-carbon quaternary stereocenter. Moreover, this study reports the first asymmetric decarboxylative and dearomative [3 + 2] reaction of 2-nitrobenzofurans with 1,4-dipoles to afford complex polycyclic scaffolds. Large-scale synthesis and synthetic transformations of the product further demonstrate its synthetic utility.

Exposing 316 Stainless Steel pressure reactor bodies to an aqueous Bronstedt acidic solution (trifluoromethane sulfonic acid) at elevated temperatures (100-250 degrees C) under reducing atmosphere (hydrogen gas at 800 psi) leads to the formation of insoluble inorganic precipitates, identified as mixed chromium oxides by scanning electron microscopy X-ray fluorescence (SEM-XRP). A catalytically active metal surface is generated, that is, under these conditions the <100 angstrom thick chromium oxide layer that normally passivates 316 Stainless Steel (316SS) against corrosion is etched away, and the reactor body itself becomes an active hydrogenation catalyst. The effect is specific to aqueous acidic medium and therefore water-soluble substrates as encountered in biomass conversion, for example, sugar alcohols and levulinic acid, which can be deoxygenated to the corresponding alkanes and alkenes using only a Bronstedt acid and the reactor body as the catalyst. Control experiments in several different 316SS reactors built by different manufacturers from different batches of 316SS as well as inductively coupled plasma optical emission spectroscopy (ICP-OES) and mass spectrometry (ICP-MS) analysis of the chromium oxide precipitates formed and steel samples from the reactor body itself indicate that the catalytic activity is not caused by trace amounts of ruthenium or another hydrogenating metal such as Re, Rh, Ir, Pd, or Pt. The observed catalytic activity scales with the concentration of acid and the addition of 316SS added to the reaction mixture as a powder conclusively establishing 316SS as the active catalyst.

Biomass is characterized by a high oxygen content (typically ? 40 % w/w). Its conversion into feedstocks that can directly be used in existing petrochemical feed streams will therefore require an efficient and selective deoxygenation chemistry. Ruthenium or iron-based water/acid-tolerant and high-temperature stable metal complexes that are active ionic hydrogenation and hydrogenolysis catalysts maybe ideally suited for this purpose.