Stereochemistry of gabapentin and several derivatives: solid state conformations and solution equilibria

Abstract

Gabapentin (1-(aminomethyl)cycloheaxaneacetic acid; Gpn) is a widely used anti-epileptic drug. The target site of action of Gpn remains controversial. Gpn can exist in two isomeric chair forms. The crystal structures of Gpn 1 and eight derivatives, Gpn hydrochloride 2, Gpn lactam 3, Boc-Gpn-OH 4, Ac-Gpn-OH 5, Piv- Gpn-OH 6, Tosyl-Gpn-OH 7, Boc-Gpn-OSu 8 and Boc-Gpn-NHMe 9, are described. The aminomethyl group occupies an axial position in 1, 3, 6 and 7, while it lies in an equatorial orientation in 2, 4, 5 and 8. The structure of Boc-Gpn-NHMe 9 reveals that the crystals contain both chair forms of the derivative in the ratio 0.7:0.3, favouring the aminomethyl group in an axial position. In all cases, the torsional angles about the C^α–C^β (θ₁) and C^β–C^γ (θ₂) bonds of the g-amino acid residue are characteristic of a gauche, gauche (g, g) conformation. In solution, NMR studies establish rapid conformational exchange, as anticipated, at room temperature. Low temperature NMR studies permit conformational freezing and determination of the freeenergy difference between the two 1,1-disubstituted cyclohexane conformers. The largest free-energy difference is observed in the free amino acid (0.38 kcal mol^–1), with the most stable conformer having the aminomethyl group in the equatorial position. The free-energy difference between the two forms is significantly reduced in the protected derivatives, with almost equal populations observed in solution for the fully protected neutral derivatives, Boc-Gpn-NHMe and Gpn lactam.