An enantioselective synthesis of (-)-cis-2-aminomethylcyclopropanecarboxylic acid [(-)-CAMP] has been achieved in 2.5% total yield over ten steps starting from 2-furaldehyde. The synthesis features diastereoselective cyclopropane formation via diazene, followed by oxime formation and the reduction, for construction of the γ-aminobutyric acid (GABA) motif.

Here, we report a practical method for asymmetric synthesis of cyclopropane-fused GABA analogs. Starting from 2-furaldehyde, the cis-isomer (CAMP) was synthesized over 10 steps; (−)- and (+)-CAMP·HCl were synthesized by employing d- and l-menthol as the chiral auxiliary for total 2.5% and 1.3% yields, respectively. On the other hand, the trans-isomer (TAMP) was elaborated via double asymmetric induction, i.e. organocatalytic asymmetric cyclopropanation on chiral substrate. Thus, starting from l- and d-menthyl acrylate, in combination with quinidine-derived and quinine-derived organocatalysts, (−)- and (+)-TAMP·HCl were synthesized in total 6.6% and 3.7% yields, respectively, over 8 steps each. Configurational analysis of the synthetic intermediates based on 13C NMR is also reported. Preliminary oncological assays showed the weak but specific activities of CAMP and TAMP as the molecular basis of GABA analogs, which are still left unexplored.

An enantioselective synthesis of (-)-trans-2-aminomethylcyclopropanecarboxylic acid [(-)-TAMP], a partial agonist for GABAc receptor, has been achieved as the hydrochloride salt in 3.9% overall yield for total eight steps from L-menthol. The synthesis features double asymmetric cyclopropanation that employs cinchona alkaloid derived organocatalyst and L-menthyl chiral auxiliary.