Design and synthesis of cyclic acylguanidines as BACE1 inhibitors

Based on the lead compound 1 reported in literature, a series of novel BACE1 inhibitors were designed and synthesized, among which compound 11 exhibited a 14-fold improvement in potency over the lead compound 1. This represents a good lead for the discovery of more promising BACE1 inhibitors for the potential treatment of AD.     

Validation of primary formaldehyde gas standards prepared by dynamic thermogravimetry through a tri-national comparison of gaseous formaldehyde amount fraction

A validation study for primary formaldehyde gas standards was performed at three National Metrology Institutes: the Korea Research Institute of Standards and Science (KRISS), the National Metrology Institute of Japan (NMIJ) and the National Institute of Metrology of China (NIM). The studied materials had a nominal amount fraction of 2 μmol/mol formaldehyde in nitrogen balance and were prepared in 10-L aluminum cylinders by KRISS. The impurities in the materials were analyzed using a gas chromatograph/atomic emission detector and a Fourier-transform infrared spectrometer (FTIR). The stability of the materials was assessed for 1 year by KRISS using paraformaldehyde as a source for the primary standard gas and a cavity ring-down spectrometer (CRDS) instrument as the measurement method. The amount fraction of formaldehyde in the materials decreased linearly by 0.74 % each month. The studied materials that exhibited similar linear rates of decline were distributed to the participants. After the measurement was completed by the participants, the materials were returned to KRISS and the stability analysis based on the primary standard maintained at KRISS was repeated. NMIJ analyzed the materials using paraformaldehyde as the source of the primary standard of formaldehyde and FTIR analysis, whereas NIM used trioxane as the primary standard gas source and CRDS analysis. The results of the comparison revealed good agreement between the results and were within the expanded uncertainty of 2 % although each of them used different combinations of methods in the generation of primary gas standards and measurements.     

Is PdII‐Promoted σ‐Bond Metathesis Mechanism Operative for the PdPEPPSI Complex‐Catalyzed Amination of Chlorobenzene with Aniline? Experiment and Theory

Reduction of the Pd?PEPPSI precatalyst to a Pd⁰ species is generally thought to be essential to drive Buchwald–Hartwig amination reactions through the well‐ documented Pd⁰/Pd^II catalytic cycle and little attention has been paid to other possible mechanisms. Considered here is the Pd?PEPPSI‐catalyzed aryl amination of chlorobenzene with aniline. A neat reaction system was used in new experiments, from which the potentially reductive roles of the solvent and labile ligand of the PEPPSI complex in leading to Pd⁰ species are ruled out. Computational results demonstrate that anilido‐containing Pd^II intermediates involving σ‐bond metathesis in pathways leading to the diphenylamine product have relatively low barriers. Such pathways are more favorable energetically than the corresponding reductive elimination reactions resulting in Pd⁰ species and other putative routes, such as the Pd^II/Pd^IV mechanism, single electron transfer mechanism, and halide atom transfer mechanism. In some special cases, if reactants/additives are inadequate to reduce a Pd^II precatalyst, a Pd^II‐involved σ‐bond metathesis mechanism might be feasible to drive the Buchwald–Hartwig amination reactions.