Efficient synthesis of the anticancer drug etoposide 4 '-phosphate: Use ofbenzylic ether-protecting groups on the carbohydrate segment

The prodrug etoposide phosphate 2 is synthesized efficiently in three steps in 54.6% overall yield from 4'-demethylepipodophyllotoxin 3. The strategy pursued in the synthesis of 2 places the phosphate on 3 prior to coupling w ith the sugar and employs benzyl ether-protecting groups on both the phosph ate and the sugar, allowing easy removal in one step. The importance of sol vent, steric effects, and electronic effects in the coupling reaction is de monstrated. Two features of the synthesis are an unusual thermal anomerizat ion of the carbohydrate component 5a and completely diastereoselective, one -pot crystallization of the coupled product 6a-beta. The process has been d emonstrated on multi-kilogram scale.