Total Synthesis of 4,8-Didesmethyl Telithromycin

Total Synthesis of 4,8-Didesmethyl Telithromycin

Andrade, Rodrigo, ACS Med. Chem. Lett. 2012, 3, 1013

Kristen DeMeesterMay 6, 2014

Rodrigo AndradeB.A. 1996 Johns Hopkins

Ph.D. 2001 Massachusetts Institute of TechnologyAdvisor Peter Seeberger

NIH Postdoc Fellow 2003-2005 University of Texas, AustinAdvisor Stephen F. Martin

Assistant Professor of Chemistry, Temple University

https://chem.cst.temple.edu/~randrade/Andrade%20Lab/Home.html

Macrolide Antibiotics

Discovery of Novel Macrolide Antibiotics

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

Retrosynthesis

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

Setbacks

ACS Med. Chem. Lett. 2012, 3, 1013Previous Work

Desired Intermediate

Forward Synthesis

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

Forward Synthesis Continued

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

Nozaki-Hiyama-Kishi

Dess-Martin

Amidation/Intramolecular Aza-Michael

Corey Kim Oxidation

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 Didesmethyl Telithromycin

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

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