SolutionsRetrosynthesis examples
Exercise 1
In going from erythromycin to clarithromycin, an antibiotic patented by, among others, the author of this website, only one OH (that at C6) out of several must be methylated. What kind of problem is this and what tools from this topic help solve it?
It is a problem of chemo- and regioselectivity between groups of the same type. It is solved by protecting the other groups (in industrial routes, the OH groups of the sugars as silyl ethers or esters, the amine as a carbamate or N-oxide, the ketone as a protected oxime), methylating the C6 OH, less hindered in that conformation, and deprotecting at the end. The choice of protecting groups determines the yield of the process.
Exercise 2
In the synthesis of oseltamivir (Tamiflu) from shikimic acid, what are the advantages of starting from a chiral natural product? Give one practical drawback.
Shikimic acid already has the cyclohexene ring and three stereocentres with the right configuration: the synthesis comes down to transforming functional groups (FGI) with stereochemical control, without building the skeleton or resolving racemates. The drawback is dependence on supply: it was extracted from star anise, and the 2005 demand caused shortages, which spurred its production by fermentation and alternative routes.