Title: Total synthesis of lycoperdic acid and its C4–epimer

URL: https://doi.org/10.1016/j.tetlet.2019.06.067

Ionotropic glutamate receptors (iGluRs) mediate majority of the fast excitatory neurotransmission in the central nervous system. To study and control the function of iGluRs, selective glutamate ligands have been developed and used actively.

In this paper, we report our enantiodivergent total synthesis of mushroom-derived glutamate, lycoperdic acid, and the (4R)–epimer. Key reaction is an asymmetric hydrogenation of racemic enamide ester using (R,S)–MeBoPhoz ligand. We found that both (4S)– and (4R)–enamides are excellent substrate for the hydrogenation to afford (2S,4S)– and (2R,4R)–amino acid esters. After separation, lycoperdic acid and the (4R)–epimer were synthesized in 5.7% and 1.2% total yield, respectively, for 11 steps each.

During the synthetic studies, we tested the possibility of configurational analysis based on experimental and calculated 13C NMR data. We also found that conventional two-step deprotection procedure A caused epimerization at the C2 position, which, however, was conveniently avoided by one-step deprotection (procedure B).

As mentioned above, artificial glutamate analogs are of use for neurochemical research. We have previously developed IKM–159 as an antagonist selective to AMPA-type iGluR [1]. The synthetic route described herein is, therefore, reasonably expected to be used for the synthesis of other isomers of lycoperdic acid, by using enantiomeric (S,R)–MeBoPhoz ligand.


[1] Juknaite, L.; Sugamata, Y.; Tokiwa, K.; Ishikawa, Y.; Takamizawa, S.; Eng, A.; Sakai, R.; Pickering, D. S.; Frydenvang, K.; Swanson, G. T.; Kastrup, J. S.; Oikawa, M., Studies on an (S)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid (AMPA) Receptor Antagonist IKM-159: Asymmetric Synthesis, Neuroactivity, and Structural Characterization. Journal of Medicinal Chemistry 2013, 56 (6), 2283-2293. (DOI: 10.1021/jm301590z)