Practical Demethylation of Podophyllotoxin and Efficient Preparation of 4-Amino-4-deoxy-4′-demethylepipodophyllotoxin

Abstract

4′-Demethylepipodophyllotoxin (4′-DMEP) was readily available through demethylation of podophyllotoxin using methionine in methanesulfonic acid in the presence of TFA (or acetone/water). Thus, 4-amino-4-deoxy-4′-demethylepipodophyllotoxin was obtained in three steps in excellent yield by a Ritter reaction on 4′-DMEP, followed by treatment with thiourea in AcOH.

GRAPHICAL ABSTRACT

Keywords:

• 4-Amino-4-deoxy-4′-demethylepipodophyllotoxin
• demethylation
• 4′-DMEP
• methionine
• thiourea

ACKNOWLEDGMENTS

We thank Daniel Dauzonne and Claude Monneret from Institut Curie (Paris) for their interest and exploitation of the demethylation procedure.

Notes

^a Presence of 2% of 4c (4-epimer of starting material).

^b Presence of di- and tri-demethylated compounds 5a (1%) and 5b (0.5%).

^c Presence of di-demethylated compound 5a (0.5%).

^d In the absence of acetone/water.