Synthesis of kainoid analogues

3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation

“…To prepare the desired 3-fluoro-4-hydroxy prolines, we envisaged a synthetic strategy based on electrophilic fluorination of an enolate or enolate equivalent of N -Boc-4-oxo- l -proline benzyl ester 1 , which is known to be regioselectively enolized at the C 3 under kinetic conditions. 54 In a first set of experiments, the lithium, sodium, and potassium enolate of 1 , generated by treatment of ketone 1 with the corresponding metal hexamethyldisylazides at −78 °C in tetrahydrofuran (THF), were reacted with N -fluorobenzenesulfonimide at −78 °C, and the reaction mixtures were allowed to slowly warm to room temperature overnight. In all cases, no fluorinated ketone was detected by 19 F NMR, and complex reaction mixtures were obtained.…”

“…We next attempted to prepare the trimethylsilyl enol ether 2 ( Scheme 1 ) by quenching the lithium enolate of 1 with trimethylsilyl chloride, as described previously. 54 Silyl enol ether 2 was isolated by pentane extraction and, after solvent removal, directly reacted with Selectfluor in acetonitrile at −30 °C. The reaction mixture was allowed to slowly warm to room temperature overnight, and we were pleased to observe a set of 19 F NMR signals compatible with a diastereoisomeric mixture of fluorinated ketones 3a , b in a ∼1.5:1 ratio and 50% overall isolated yield.…”

Excitatory amino acids

“…A related strategy to both of these approaches has been developed by Young and co-workers, who introduced the C-3 side chain by alkylation of 4-oxoproline derivatives, thereby providing access to a range of kainoid analogues. 62 Shirahama and co-workers have established a simple and readily applicable method for the stereochemical assignment of kainoid amino acids, based upon the H-2 and H-4 chemical shifts in D 2 O (for pD 3-8); the difference in chemical shifts is assumed to arise from the anisotropy of the substituents at these positions. 63 The binding of kainic acid to chiral 1,1 -binaphthyl molecular clefts has recently been investigated using NMR techniques.…”

Two separate and distinct syntheses of stereospecifically deuteriated samples of (2S)-proline

“…In our second synthesis, where stereoselectively b-monodeuteriated products were required, we used the silylenol ether 14, prepared during our work on the synthesis of analogues of kainic acid 14 as starting material. When this silylenol ether was prepared from a solution of the ketone 13 14 using excess trimethylsilyl chloride and the product was treated in situ with 2 H 2 O (Scheme 3), we observed remarkable stereoselectivity in deuteriation at C-3 in the resultant ketone 13a, since, although the 1 H NMR spectrum of the unpurified product was complicated by the conformational isomerism 13 shown by N-acylprolines, only one of the two multiplets at d 2.50 and 2.89 ppm (due to the diastereotopic protons at C-3) was absent in the 1 H NMR spectrum of the ketone 13a. Since the signal at d 2.89 ppm showed a 4.5% enhancement upon irradiation of the signal for H-2 at ca.…”