Enantioselective Synthesis of Pactamycin , a Complex Antitumor Antibiotic

1. Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic Doug Kenny 05-06-14 Science, 12 April 2013

2. Jefferey S. Johnson • B.S. University of Kansas (1994) • Ph.D. Harvard University • NIH Postdoctoral Fellowship, UC Berkeley (1999-2001) • “My interests lie in the general area of chemical synthesis. I am particularly interested in the discovery of new organic transformations and their application to the total synthesis of architecturally challenging and biologically important natural products.”

3. Pactamycin Inhibits translocation: Stops the target ribosomal unit from continuing to move along the mRNA strand to which it is bound. While effective against bacteria, fungi and archaea, it is also highly toxic to human cells. Recent studies have shown that subtle changes to the structure of pactamycin can greatly alter its biological activity. Some natural derivatives show Improved selectivity for killing protozoans rather than humans. We need a way to make derivatives of this molecule!

4. Pactamycin “In the context of the work described herein, it is worth noting that Lu et al. contend that the structural complexity of pactamycin renders these and related structural modifications ‘inaccessible by synthetic organic chemistry.’ Conversely, we have porceeded from the hypothesis that the genetic engineering approach to pactamycin analogs might be inherently limited by the biosynthetic machinery.”

5. Previous Synthesis • Hanessian et al. 2011 32 steps

6. Retrosynthesis

7. Synthesis

8. Synthesis

9. Conclusion • 15 Steps • 1.9% overall yield • Modular synthesis with the ability to incorporate different functionalities.

10. Lewis Base Catalyst for Mannich Reaction

11. Epoxidation

12. Acylation- Proposed Mechanism