. Hydroxyl at the C-22position of pleuromutilin was activated with p-toluenesulfonylchloride30 to obtain intermediate
In the synthesis of pleuromutilin derivatives, p-toluenesulfonyl chloride was used to activate the C-22 hydroxyl group through nucleophilic substitution. This is a common strategy to make alcohols better leaving groups so further reactions can occur.
Thus,antibacterial activity can presumably be enhanced byintroducing appropriate hydrophobic chains and extendingthe distance between the urea bond and the aryl group. Asimilar phenomenon was reported in a previous study.31Substituents on the benzene ring also affected the antibacterialactivity.
Why is the antibacterial activity affected by the substitutions on the molecule? Does it have something to do with sterics or orientation?
Intermediate 2 was then reacted with 6-thioguanineand triethylamine (TEA) in dimethylformamide (DMF) toform intermediate 3 in an 85% yield, which was then reactedwith chloroformates and pyridine in dichloromethane (DCM)to form carbamate derivatives
The use of TEA and DMF to promote the reaction between tosylated pleuromutilin and thioguanine reminds me of the SN2 reactions from the first and second orgo quarters where a strong nucleophile displaces a good leaving group in polar aprotic solvent.