Total Synthesis of 4,8-Didesmethyl Telithromycin

1. Total Synthesis of 4,8-Didesmethyl Telithromycin Andrade, Rodrigo, ACS Med. Chem. Lett. 2012, 3, 1013 Kristen DeMeester May 6, 2014

2. Rodrigo Andrade B.A. 1996 Johns Hopkins Ph.D. 2001 Massachusetts Institute of Technology Advisor Peter Seeberger NIH Postdoc Fellow 2003-2005 University of Texas, Austin Advisor Stephen F. Martin Assistant Professor of Chemistry, Temple University https://chem.cst.temple.edu/~randrade/Andrade%20Lab/Home.html

3. Macrolide Antibiotics

4. Discovery of Novel Macrolide Antibiotics ACS Med. Chem. Lett. 2012, 3, 1013

5. Retrosynthesis ACS Med. Chem. Lett. 2012, 3, 1013

6. Setbacks Desired Intermediate Previous Work ACS Med. Chem. Lett. 2012, 3, 1013

7. Forward Synthesis ACS Med. Chem. Lett. 2012, 3, 1013

8. Forward Synthesis Continued Nozaki-Hiyama-Kishi Dess-Martin Corey Kim Oxidation Amidation/IntramolecularAza-Michael ACS Med. Chem. Lett. 2012, 3, 1013

9. Biochemical Results • Third-generation ketolide antibiotic • Less potent than Telithromycin • 8 times more active than 4, 8, 10-Tridesmethyl Telithromycin • 2 times more active than 4, 10 DidesmethylTelithromycin ACS Med. Chem. Lett. 2012, 3, 1013

10. Conclusions • 4, 8-Didesmethyl Telithromycin was prepared using intramolecular NHK in 36 steps (26 linear) • 4, 8-Didesmethyl Telithromycin analog was more potent than other synthetic derivatives synthesized in Andrade’s lab, which directly addresses antibacterial resistance to Telithromycin