Efficient synthesis of the anticancer drug etoposide 4′-phosphate: Use of benzylic 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 with the sugar and employs benzyl ether-protecting groups on both the phosphate and the sugar, allowing easy removal in one step. The importance of solvent, steric effects, and electronic effects in the coupling reaction is demonstrated. Two features of the synthesis are an unusual thermal anomerization of the carbohydrate component 5a and completely diastereoselective, one-pot crystallization of the coupled product 6a-β. The process has been demonstrated on multi-kilogram scale.