2.08 – Pyridines and their Benzo Derivatives: (v) Synthesis

N-Carbathoxy-glycinester-natrium reagiert mit α,- β-ungesattigten Carbonsaure-estern RCHCHCO2C2H5 in Benzol unter Bildung von 1.3-Dicarbathoxy-pyrrolidonen-(4), die in 2-Stellung den Rest R tragen (40–70% d. Th.). Diese Reaktion macht das DL-γ-Oxo-prolin, das ammoniakalische Silberlosung und Fehlingsche Losung schon in der Kalte reduziert, gut zuganglich. Sie erschliest uberdies neue Wage zum DL-Hydroxy-prolin und DL-allo-Hydroxy-prolin und hat es ermoglicht, die 4-Athoxy-pyrrol-carbonsaure-(2) zu gewinnen. Die Abspaltung der Athoxygruppe gelang mit AlBr3 in Benzol. So gewonnene Losungen von 4-Hydroxy-pyrrol-carbonsaure-(2) zeigen wesentlich andere Eigenschaften als diejenigen, die T. Minagawa fur Oxyminalin angegeben hat. Dieser Substanz, die als Spaltstuck aus der prosthetischen Gruppe eines Ferments (Pectase) erhalten worden war, hatte man die Konstitution der 4-Hydroxy-pyrroll-carbonsaure-(2) zugeschrieben. Die von uns gewonnenen Losungen geben mit Oxydationsmitteln einen schwer loslichen tiefblauen Farbstoff.

Neue Synthese von β-Pyrrolidonen; Darstellung von dl-γ-Oxo-prolin, DL-allo-Hydroxy-prolin und 4-äthoxy-pyrrol-carbonsäure-(2)

Regioselective Dieckmann cyclisations using an N-acyloxazolidine derived from L-serine give substituted tetramic acids in high yield and enantioselectivity. The products are easily deprotected under mild conditions to give hydroxymethyltetramic acids.

Regioselective Dieckmann cyclisations leading to enantiopure highly functionalised tetramic acid derivatives

A series of (isoxazole)methylene-1-azacyclic compounds was prepared. The compounds were tested for affinity to central nicotinic acetylcholine receptors (nAChRs) and central muscarinic receptors. The compounds covered a broad range of affinities for the nAChRs (IC(50) = 0.32 to >1000 nM), with selectivities for the nAChRs over the muscarinic receptors in the range of 3-183. The high-affinity compound (Z)-26 (3-(4-methyl-5-isoxazolyl)methylene-1-azabicyclo[2.2. 2]octane, IC(50) = 3.2 nM) having only one energy minimum was used as the reference structure in a computational study. This ligand has enabled definition of an important distance parameter, and the existence of this parameter was supported by showing that other potent nicotinic ligands (for example, nicotine and epibatidine) fit the model.

Improving the Nicotinic Pharmacophore with a Series of (Isoxazole)methylene-1-azacyclic Compounds: Synthesis, Structure−Activity Relationship, and Molecular Modeling

S. M. McElvain

Papers

A Study of the Cyclization of a Series of ι,ι'-Dicarbethoxydialkylmethylamines through the Acetoacetic Ester Condensation