A concise and efficient biomimetic synthesis of myrtucommulones D-E has been achieved, proceeding in just 6-7 linear steps from readily available biogenetic building blocks. The key feature of the synthesis was the Zn-mediated skeletal rearrangement reaction, without the need for rare metal photocatalysts and visible light. Based on this biomimetic synthesis, four compounds demonstrated moderate to excellent cytotoxic activities against osteosarcoma cells (U2OS and 143B).