Synthesis of cis-octahydroindoles via intramolecular 1,3-dipolar cycloaddition of 2-acyl-5-aminooxazolium salts.

A concise method for the diastereoselective synthesis of octahydroindoles is presented. The products contain 2-amido and 7-hydroxyl substituents. A series of 2-acyl-5-aminooxazoles were prepared in one step. Upon methylation of the oxazole nitrogen atom, the substrates underwent rapid intramolecular 1,3-dipolar cycloaddition with a tethered alkene and, after reduction with excess hydride, produced octahydroindoles with excellent diastereoselectivity. The method allows for the installation of α-quaternary stereogenic carbon atoms.

Synthesis and pharmacological in vitro and in vivo profile of 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68), a selective antagonist of the neuropeptide S receptor.

Neuropeptide S (NPS) has been shown to modulate arousal, sleep wakefulness, anxiety-like behavior, and feeding after central administration of the peptide agonist to mice or rats. We report here the chemical synthesis and pharmacological characterization of SHA 66 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid benzylamide) and SHA 68 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide), two closely related bicyclic piperazines with antagonistic properties at the NPS receptor (NPSR). The compounds block NPS-induced Ca2+ mobilization, and SHA 68 shows displaceable binding to NPSR in the nanomolar range. The antagonistic activity of SHA 68 seems to be specific because it does not affect signaling at 14 unrelated G protein-coupled receptors. Analysis of pharmacokinetic parameters of SHA 68 demonstrates that the compound reaches pharmacologically relevant levels in plasma and brain after i.p. administration. Furthermore, peripheral administration of SHA 68 in mice (50 mg/kg i.p.) is able to antagonize NPS-induced horizontal and vertical activity as well as stereotypic behavior. Therefore, SHA 68 could be a useful tool to characterize physiological functions and pharmacological parameters of the NPS system in vitro and in vivo.

Synthesis of a bis-amino acid that creates a sharp turn.

[reaction: see text] The synthesis of a new bis-amino acid 1 is presented. This monomer is designed to create a tightly curved structure when assembled into oligomers. The monomer is demonstrated to couple to the previously developed monomer 2 through pairs of amide bonds to create a strongly bent spiro-ladder oligomer. The structure of oligomer 3 was determined in aqueous solution using two-dimensional NMR.