With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

The total synthesis of enantiomerically pure (+)-mesembrine is described. The central pyrrolidine moiety incorporating a quaternary, all-carbon-substituted stereocenter was constructed employing an asymmetric gold-catalyzed cycloisomerization of a 1,4-diynamide.

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N-Boc protected 1-aryl propargyl carbamates and acid chlorides can be readily transformed in a one-pot fashion by a coupling-isomerization-elimination (CIE) sequence into 4-substituted 5-(2-oxoethyl) oxazol-2(3H)-ones in moderate to good yield. † Dedicated to Professor Dr Barry M. Trost on the occasion of his 75 th birthday. ‡ Electronic supplementary information (ESI) available: 1 H and 13 C NMR spectra and analytical data of compounds 2, and 1 H and 13 C NMR spectra of compounds 3, cif file of the X-ray structure analysis of compound 3r. CCDC 1465496. For ESI and crystallographic data in CIF or other electronic format see Scheme 1 One-pot amidation-coupling-cyclization-isomerization (ACCI) synthesis of 4-substituted 5-(2-oxoethyl) oxazol-2(3H)-ones.Scheme 2 Competing formation of oxazol-2-ones in the three-component coupling-addition-cyclocondensation synthesis of N-Boc 2-substituted 4-iodopyrroles.Scheme 3 Optimization of the coupling-isomerization-elimination synthesis (CIE) of the 2-oxoethyl oxazol-2(3H)-one 3a. Research Article Organic Chemistry Frontiers 888 | Org. Chem. Front., 2016, 3, 887-896 This journal is

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