Synthesis and Pharmacological Characterization at Glutamate Receptors of the Four Enantiopure Isomers of Tricholomic Acid

Abstract

The two enantiomeric pairs of erythro- and threo-amino-(3'-hydroxy-4',5'-dihydro-isoxazol-5'-yl)-acetic acids were synthesized via the 1,3-dipolar cycloaddition of bromonitrile oxide to ( R)- or ( S)-3-( tert-butoxycarbonyl)-2,2-dimethyl-4-vinyloxazolidine. The pharmacological profiles of the studied amino acids reflect the relationship between the activity/selectivity and the stereochemistry of the two stereogenic centers: while the (2 S,5' S) stereoisomer is an agonist at the AMPA and KA receptors, its (2 R,5' R) enantiomer interacts selectively with the NMDA receptors; the (2 S,5' R) stereoisomer is the only one capable to activate the mGluRs.

Synthesis and Biological Evaluation of CTP Synthetase Inhibitors as Potential Agents for the Treatment of African Trypanosomiasis

“…As for the synthesis of Acivicin and Br-Acivicin, previously reported by us, [8,9] the key-step for the synthesis of the isoxazoline analogues was a 1,3-dipolar cycloaddition of bromonitrile oxide, generated in situ by base-promoted dehydrohalogenation of the stable precursor dibromoformaldoxime, to ( S )-3-( tert -butoxycarbonyl)-2,2-dimethyl-4-vinyloxazolidine 10 (Scheme 1), producing the mixture of diastereoisomers 11a and 11b . [10] Compound (α S ,5 S )- 5 was obtained as previously described, [8] being a synthetic intermediate of Br-Acivicin 1 , while derivative (α S ,5 S )- 6 was simply prepared by treating compound (α S ,5 S )- 1 with benzylchloroformate in a mixture of tetrahydrofuran and water in the presence of NaHCO 3 (Scheme 1).…”

“…[8,9] Dibromoformaldoxime (DBF) was prepared according to a literature procedure. [18] The diastereomeric mixture of cycloadducts 11a and 11b was prepared as previously described [10] from DBF, and ( S )-3-( tert -butoxycarbonyl)-2,2-dimethyl-4-vinyloxazolidine ( S )- 10 . [19] Compound (α S ,5 S )- 5 was prepared as previously described.…”

Effects of 3‐Bromo‐4,5‐dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase‐1 Expression

“…The synthesis of derivatives 1 , 2 and 4 – 8 was based on the 1,3‐dipolar cycloaddition of bromonitrile oxide, generated in situ by dehydrohalogenation of the stable precursor dibromoformaldoxime (DBF) to the suitable dipolarophile, affording in all cases the 5‐substituted 3‐bromo‐isoxazoline derivative in very high yield. Derivatives 1 , 2 , 4 and 7 were previously described by us, compound 3 was obtained following a literature procedure whereas derivatives 5 , 6 and 8 were obtained according to Scheme .…”

Synthesis of nonracemic hydroxyglutamic acids

“…Diazotization of (2 R ,3 R )- 2 provided 2-deoxy-L-1,4-ribonolactone which was later transformed into 2'-deoxy-L-thymidine and other nucleosides [119]. Syntheses of all four enantiomers of tricholomic acid of interest as a flycidal compound as well as in receptor studies [120] were accomplished starting from enantiomeric 3-hydroxyglutamic acid, e.g., (2 S ,3 R )-3-hydroxyglutamic acid was converted in a few steps into (2 S ,5' S )-tricholomic acid [47]. The absolute configuration of ( R )-(−)-carnitine was established by enzymatic decarboxylation of (2 S ,3 R )-3-hydroxyglutamic acid followed by exhaustive methylation [121].…”