A total synthesis of Calebin-A (1), a novel curcuminoid isolated from turmeric (Curcuma longa, Zingiberaceae) that has been demonstrated to protect neuronal cells from beta-amyloid insult, was successfully achieved in four steps. Elaborating on this synthetic route, 13 analogues were prepared for a structure-activity relationship (SAR) study. It was found that the parent compound 1 and derivatives 21, 28, and 30 protect PC12 rat pheocromocytoma and IMR-32 human neuroblastoma cells from beta-amyloid(25-35) insult. These results suggest that hydroxy group at para-position is most critical for the expression of biological activity.