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New enantiopure crown ethers containing either an ethyl diarylphosphinate moiety [(S,S)‐4 to (S,S)‐7] or a proton‐ionizable diarylphosphinic acid unit [(S,S)‐8 to (S,S)‐11] have been synthesized. Electronic circular dichroism (ECD) studies on the complexation of these new enantiopure crown ethers with the enantiomers of α‐(1‐naphthyl)ethylammonium perchlorate (1‐NEA) and with α‐(2‐naphthyl)ethylammonium perchlorate (2‐NEA) were also carried out. These studies showed appreciable enantiomeric recognition with heterochiral [(S,S)‐crown ether plus either (R)‐1‐ or (R)‐2‐NEA] preference. Theoretical calculations found three significant intermolecular hydrogen bonds in the complexes of (S,S)‐9. Furthermore, preference for heterochiral complexes was also observed, in good agreement with ECD results. Complex formation constants were determined by NMR titration for four selected crown ether/NEA pairs.

Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs) have been implicated as potential pharmacotherapy for psychiatric conditions. Screening our corporate compound deck, we identified a benzotriazole fragment (4) that was rapidly optimized to a potent and metabolically stable early lead (16). The highly lipophilic character of 16, together with its limited solubility, permeability, and high protein binding, however, did not allow reaching of the proof of concept in vivo. Since further attempts on the optimization of druglike properties were unsuccessful, the original hit 4 has been revisited and was optimized following the principles of fragment based drug discovery (FBDD). Lacking structural information on the receptor-ligand complex, we implemented a group efficiency (GE) based strategy and identified a new fragment like lead (60) with more balanced profile. Significant improvement achieved on the druglike properties nominated the compound for in vivo proof of concept studies that revealed the chemotype being a promising PAM lead targeting mGluR2 receptors.

Alkaloids U 0600Aromatic Electrophilic Substitutions on Vindoline. -Nitration of 10-bromo derivative (V) leads to the unexpected, anomalous 12-bromo-10-nitrovindoline (VI) and appears to be a further example of the rearrangement discovered by Reverdin. Nitration of the 10-chloro analogue (VII) leads to the expected derivative (VIII). -(GORKA-KERESKENYI, A.; SZABO, L.; HAZAI, L.; LENGYEL, M.; SZANTAY, C. J.; SANTA, Z.; KALAUS, G.; SZANTAY*, C.; Heterocycles 71 (2007) 7, 1553-1563; Dep. Org. Chem. Technol., Budapest Univ. Technol. Econ., H-1521 Budapest, Hung.; Eng.) -K. Woydowski 44-184

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