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.
Alkanes/chemistry , Alkanes/pharmacology , Aza Compounds/chemistry , Aza Compounds/pharmacology , GABA Plasma Membrane Transport Proteins/metabolism , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Acylation , Alkanes/chemical synthesis , Animals , Aza Compounds/chemical synthesis , Humans , Spiro Compounds/chemical synthesis , gamma-Aminobutyric Acid/metabolism
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.
Hydrocarbons, Fluorinated/chemical synthesis , Oxazoles/chemistry , Proline/analogs & derivatives , Pyrrolidines/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Indicators and Reagents/chemistry , Molecular Structure , Proline/chemical synthesis , Proline/chemistry , Pyrrolidines/chemistry , Stereoisomerism
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.
Amides/chemical synthesis , Oxazoles/chemistry , Thermodynamics , Amides/chemistry , Crystallization , Molecular Structure , Stereoisomerism
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.
Alcohols/chemical synthesis , Amides/chemistry , Carboxylic Acids/chemical synthesis , Ketones/chemistry , Oxazoles/chemistry , Oxygen/chemistry , Alcohols/chemistry , Carboxylic Acids/chemistry , Hydroxylation , Molecular Conformation , Stereoisomerism
