RESUMEN
Supply of major metabolites such as γ-aminobutyric acid (GABA), ß-alanine and taurine is an essential instrument that shapes signalling, proper cell functioning and survival in the brain and peripheral organs. This background motivates the synthesis of novel classes of compounds regulating their selective transport through various fluid-organ barriers via the low-affinity γ-aminobutyric acid (GABA) transporter subtype 2 (GAT2). Natural and synthetic spirocyclic compounds or therapeutics with a range of structures and biological activity are increasingly recognised in this regard. Based on pre-validated GABA transport activity, straightforward and efficient synthesis method was developed to provide an azaspiro[4.5]decane scaffold, holding a variety of charge, substituent and 3D constrain of spirocyclic amine. Investigation of the azaspiro[4.5]decane scaffold in cell lines expressing the four GABA transporter subtypes led to the discovery of a subclass of a GAT2-selective compounds with acyl-substituted azaspiro[4.5]decane core.
Asunto(s)
Alcanos/química , Alcanos/farmacología , Compuestos Aza/química , Compuestos Aza/farmacología , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Acilación , Alcanos/síntesis química , Animales , Compuestos Aza/síntesis química , Humanos , Compuestos de Espiro/síntesis química , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Enantiopure trans-2,5-disubstituted trifluoromethylpyrrolidines were prepared on a several gram scale starting from a readily available chiral fluorinated oxazolidine (Fox). A pure oxazolopyrrolidine intermediate could be obtained after an efficient separation by selective diastereomer destruction. The addition of various Grignard reagents on this oxazolopyrrolidine provided disubstituted pyrrolidines with moderate to complete trans diastereoselectivity. The highly valuable compound (2S,5R)-5-trifluoromethylproline could be synthesized from the same oxazolopyrrolidine intermediate via a Strecker-type reaction.
Asunto(s)
Hidrocarburos Fluorados/síntesis química , Oxazoles/química , Prolina/análogos & derivados , Pirrolidinas/síntesis química , Hidrocarburos Fluorados/química , Indicadores y Reactivos/química , Estructura Molecular , Prolina/síntesis química , Prolina/química , Pirrolidinas/química , EstereoisomerismoRESUMEN
A highly efficient crystallization-induced dynamic resolution (CIDR) of trans-Fox (fluorinated oxazolidine) chiral auxiliary is reported. This chiral auxiliary was used for highly diastereoselective (>98% de) electrophilic fluorination of amide enolates. After removal of the chiral auxiliary, highly valuable enantiopure α-fluorocarboxylic acids and ß-fluoroalcohols are obtained.
Asunto(s)
Amidas/síntesis química , Oxazoles/química , Termodinámica , Amidas/química , Cristalización , Estructura Molecular , EstereoisomerismoRESUMEN
Using a trifluoromethylated oxazolidine (Fox) chiral auxiliary, the hydroxylation reaction of enolates was very efficiently performed under smooth and friendly conditions with molecular oxygen as oxidizer. This reaction occurred with an extremely high diastereoselectivity. After cleavage, the chiral auxiliary is efficiently recovered and highly valuable enantiopure oxygenated carboxylic acids and alcohols are released.