Parthenolide showed extensive bioactivities including selective eradication of AML stem cells. Herein we report protection-free semisyntheses of parthenolide and its cyclopropyl analogue (compound 10) from the abundant natural product costunolide with an overall yield of 55 and 60%, respectively. Compound 10 was more stable than parthenolide, and it maintained comparable activities against AML cell lines and AML stem cells. Therefore, compound 10 might be a superior small molecule than parthenolide as a tool for investigation of cancer stem cell biology.