A practical synthesis of the anti-tumour agent 2-methyl-4-deoxyisopicropodophyllotoxin and related podophyllin analogues

Abstract

We describe an efficient, six-stage synthesis of 2-methyl-4-deoxyisopicropodophyllotoxin, which proceeds via a Diels–Alder cycloaddition between 2-methylmaleic anhydride and the orthoquinodimethane generated by treatment of 5-[1-acetoxy-1-(3′,4′,5′-trimethoxyphenyl)methyl]-6-trimethylsilylmethyl-1,3-benzodioxole with silica gel at 60 °C. The podophyllin was converted into a number of 4′-ester derivatives. This procedure was also used to prepare a diazapodophyllin via the use of 4-phenyl-1,2,4-triazoline-3,5-dione as dienophile.