Tuberculosis (TB) is a global health problem. Current Anti-TB drugs often have severe side effects, and additionally, multi-drug-resistant TB is a rising problem. New treatment options would, thus, be useful. Ilamycin E₁ (pictured) is a cyclopeptide isolated from marine bacteria with a very potent anti-tuberculosis activity. This natural product could serve as a lead compound for drug development.

Yian Guo, Tao Ye, and colleagues, Peking University, Shenzhen, China, have performed the first total synthesis of ilamycin E₁ and the related compound ilamycin F. The team used a convergent strategy, in which two fragments of the final compound were connected by an amidation and a macrolactonization to give the cyclopeptide structure. One fragment, a tripeptide, was synthesized starting from tryptophan in five steps, and the other, a tetrapeptide, was synthesized from glutamic acid in thirteen steps.

After the final lactonization, the cyclic product could be converted to ilamycin E₁ in two steps, which form the target compound’s piperidone unit. The same cyclic product can also be converted to ilamycin F by a different two-step process using a Pinnick oxidation. Interestingly, this last reaction can also be reversed, i.e., ilamycin F can be converted into a precursor for the synthesis of ilamycin E₁.

Since ilamycin F is more abundant in nature, but ilamycin E₁ is much more potent against TB, this is a particularly useful discovery. Overall, these developments can provide sufficient amounts of ilamycin E₁ for biological studies.

• Total Synthesis of Anti-tuberculosis Natural Products Ilamycins E1 and F,
  Yingying Cheng, Shoubin Tang, Yian Guo, Tao Ye,
  Org. Lett. 2018.
  https://doi.org/10.1021/acs.orglett.8b02643