The Construction of the Chiral Quaternary Carbon in the Drug Discovery Directed towards the Novel Neuroprotective Agent E2050

Brain Ischemia is believed to induce neuronal damage by causing a [Ca2+] i overload and a sustained increase in the level of extracellular glutamate (Excitotoxicity theory). Based on the Excitotoxicity theory, inhibition of neuronal voltage-dependent calcium channels is expected to reduce excessive glutamate release at the presynaptic terminals, inhibit [Ca2+] i elevation in postsynaptic neurons, and protect neurons from cell death.E2050, which is derived from Verapamil, a known L-type calcium channel blocker, is a newly synthesized neuronal calcium channel blocker discovered at Eisai Tsukuba Research Laboratories. E2050 is an optically active compound in which the quaternary carbon center has a 2-isopropyl-2-phenyl-5-piperazinopentanitrile substituent. We report here two general routes for the preparation of enantiomerically pure E2050. First, we describe the preparation of the chiral 5-hydroxy-2-isopropyl-2-phenylpentanitrile which is the key intermediate by enzyme-catalyzed kinetic resolution. Second, we illustrate the practical asymmetric synthesis of E2050 by Sharpless epoxidation followed by MAD-induced rearrangement. We believe these methods are suitable for large-scale synthesis of E2050.