Total Synthesis of 4,8-Didesmethyl Telithromycin

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Total Synthesis of 4,8Didesmethyl Telithromycin
Andrade, Rodrigo, ACS Med. Chem. Lett. 2012, 3, 1013
Kristen DeMeester
May 6, 2014
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/Andra
de%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
Desired Intermediate
Previous Work
ACS Med. Chem. Lett. 2012, 3, 1013
Forward Synthesis
ACS Med. Chem. Lett. 2012, 3, 1013
Forward Synthesis Continued
Nozaki-Hiyama-Kishi
Dess-Martin
Corey Kim
Oxidation
Amidation/Intramolecular Aza-Michael
ACS Med. Chem. Lett. 2012, 3, 1013
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

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