Crambescin B decarboxylate is an inhibitor of voltage-gated sodium-channel and a potential biochemical tool. Herein, we report the asymmetric total synthesis of crambescin B decarboxylate using a new synthetic strategy. The key aspects of this new protocol include: 1) the use of an optically pure epoxide, synthesized by the Jacobsen hydrolytic kinetic resolution, as the starting material for guanidino-aziridine, and 2) the introduction of the THF ring through nucleophilic substitution using an acyl anion equivalent. The synthetic protocol reported herein is nine steps shorter than the previously reported shortest method. We determined the cytotoxicity and protective effects of crambescin B decarboxylate in mouse-hippocampus-derived neuronal HT22 cells with an MTS assay. Cell viability was observed to decrease in a concentration-dependent manner without cell detachment or shrinkage. In addition, crambescin B decarboxylate protected glutamate-induced cell death.