Synthesis of analogues of GABA. VIII. Selective a-alkylation and γ-halogenation of the dianion from α,β-unsaturated nipecotic acid derivatives

Abstract

1,2,3,6-Tetrahydropyridine-3-carboxylic acid (3), the β, γ-unsaturated derivative of the GABA uptake inhibitor nipecotic acid (1), has been synthesized by deconjugation via the dilithium salt of the N-t-butyloxycarbonyl-protected intermediate (6). Substitution of the intermediate with alkylating agents or an aldehyde gave predominantly a-alkylated products but chlorination with N-chlorosuccinimide provided a route to the γ-substituted unsaturated amino acid (13a).

Synthesis of (±)-isofagomine and its stereoisomers from arecoline

“…It is known that arecoline (3) can be demethylated in high yields with various reagents including α-chloroethyl chloroformate 3 and 2,2,2-trichloroethyl chloroformate (TrocCl). 4 It is also known that the double bond in arecoline can be isomerised. 4, 5 It therefore seemed straightforward to perform these two steps and reduce the ester, thereby obtaining a potential precursor to isofagomine and its galacto analogue.…”

“…4, 5 It therefore seemed straightforward to perform these two steps and reduce the ester, thereby obtaining a potential precursor to isofagomine and its galacto analogue. Arecoline could be isomerised by following the known procedure 4 to give a 20 : 1 ratio of 4 and arecoline (3) in a quantitative yield (Scheme 1). The isomerized product 4 could not be separated chromatographically from the 5% content of arecoline (3) and was therefore used as such in the next step.…”

Synthesis of Methyl 5-(N-Benzoyl-N- methylamino)-2-methylpenta-2,4-dienoate by Ring-Opening Acylation of an N-Alkyltetrahydropyridine

“…In 1983, Allan and Fong reported the successful N-demethylation of 1 using (2,2,2-trichloroethoxy)carbonyl chloride . However, the intermediate (trichloroethyl)carbamate was known to be sensitive to dialkylamide bases, which posed limits on subsequent alkylation experiments we envisioned.…”

“…NMR spectra were recorded at room temperature. Arecoline 1 was prepared from commercially available arecoline hydrobromide (Aldrich Chemical Co.) using a known procedure …”

Synthesis of alkyl-substituted arecoline derivatives as .gamma.-aminobutyric acid uptake inhibitors

“…Ater workup, arecoline (6) was distilled off from the remaining oil in vacuo and the resulting gum was treated with ethyl acetate to give 10a (556 mg, 52%) as colorless crystals: mp 107-108 °C; IR (KBr) 1715 (s) cm"1; NMR (CDCla) 7. 19 (1 H, m), 5.05 (1 H, br s), 3.72…”