Induction of differentiation is a new and promising approach to leukemia therapy, well illustrated by the treatment of acute promyelocytic leukemia with 1,25-dihydroxyvitamin $D_3$ [1,25-$(OH)_2D_3$] or all-trans retinoic acid (ATRA). Using combination of either 1,25-$(OH)_2D_3$ or ATRA and chemotherapy, adverse effects 1,25-$(OH)_2D_3$ or ATRA such as hypercalcemic effects have decreased, and long-term survival has improved. In a previous study, we demonstrated that santonin could be chemically modified into a diacetoxy acetal derivative of santonin with strong differentiation-inducing activity. In this study, we further synthesized $C_6$-epimer derivatives of diacetoxy acetal derivative of santonin and tested their effects on HL-60 cell differentiation. Some of the $C_6$-epimer derivatives themselves induced increases in cell differentiation. Especially, (11S)-3,3-(ethylenedioxy) eudesmano-13-ol-$6{eta}$-acetate (7) was demonstrated to induce differentiation with larger than 80% of the cells attaining a differentiated phenotype. Importantly, 7 strongly enhanced differentiation of HL-60 cells in a dose-dependent manner when combined with either low doses of 1,25-$(OH)_2D_3$ or ATRA. The ability to enhance the differentiation potential of 1,25-$(OH)_2D_3$ or ATRA by 7 may improve outcomes in the therapy of acute promyelocytic leukemia.