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Slimming vancomycin synthesis to make it big

New shorter synthesis makes way for scale-up

by Leigh Krietsch Boerner
September 19, 2020 | A version of this story appeared in Volume 98, Issue 36


Structure of the antibiotic vancomycin.

Like many antibiotics, vancomycin, used to treat methicillin-resistant Staphylococcus aureus, has an antibiotic-resistance problem. In earlier studies, Dale Boger designed a resistance-free version by changing one crucial atom. However, the synthesis involved 25 steps and could not be scaled up to make enough quantities to be tested. Now, Boger and coworkers at Scripps Research in California have streamlined their vancomycin synthesis, reducing it to 19 steps (J. Am. Chem. Soc. 2020, DOI: 10.1021/jacs.0c07433). This new, scalable design brings key challenging aspects of the synthesis under control, enabling industry chemists to potentially use it to make large quantities of the improved antibiotic. Because these modified versions remain active against bacteria, they need to go through clinical development before they’re deemed safe to use on people. “Enough material will certainly be able to be made this way to see if they live up to expectations,” Boger says. One of the tricky parts in making vancomycin is dealing with the three components in the core that are atropisomeric—isomeric because of a bulky part of the compound that can’t rotate. In the new synthesis, the researchers changed the design to make a single diastereomer of the core structure, eliminating the need for time-consuming purification. Boger has been working on this problem for 30 years. “Up to this point, it has been viewed as beautiful science but probably never going to be translatable because you can’t make them in the amounts needed,” he says. “Now we have the capability of doing that.”



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