Chiral synthesis of functionalized tetrahydropyridines:: γ-Aminobutyric acid uptake inhibitor analogues

A convenient preparation of functionalized chiral tetrahydropyridine-3-carboxylates from nitriles in 68-90% enantiomeric excess (ee) via allylboration, followed by a conjugate addition-elimination and ring-closing metathesis, has been developed. Thus, the treatment of the acetate derived from vinylalumination of formaldehyde by use of [alpha-(ethoxycarbonyl)vinyl]diisobutylaluminum with chiral beta-substituted and beta-unsubstituted homoallylic amines, prepared in > 98% diastereomeric excess (de) and 68-90% ee via allylboration of the corresponding N-aluminoimines, furnished functionalized aminodienes, which underwent ring-closing metathesis to provide chiral C-5-C-6 disubstituted tetrahydropyridine-3-carboxylates. This methodology has been applied for the synthesis of a chiral C-6-substituted tetrahydropyridine with known GABA-inhibiting properties at low concentrations.