Synthesis of Podophyllotoxin and Related Compounds

Over 40 papers have so far been published dealing with the synthesis of podophyllotoxin and its isomers. The attention devoted to this relatively small group of compounds stems from the use of derivatives of 4′-demethylepipodophyllotoxin in cancer chemotherapy. At first glance it would appear that a wide variety of synthetic methods have been employed. However, closer scrutiny reveals that three, or at most four, common themes can be distinguished. The syntheses can therefore be classified, depending upon whether they involve either a γ-oxo ester or a dihydroxy acid as a key intermediate, or whether they involve a tandem conjugate addition or a Diels-Alder reaction as a key step. Since there is much ongoing activity in this area and a steady stream of papers being published, it is clear that no totally satisfactory solution has so far been found and that ingenuity has not been exhausted. The quest for improved therapeutic activity is an important stimulus for further work, and the need to produce compounds in enantiomerically pure form means that there is continued and indeed increasing interest in this area. 1. Introduction 2. The Oxo Ester Route 3. The Dihydroxy Ester Route 4. The Tandem Conjugate Addition Route 5. Use of the Diels-Alder Reaction 6. Synthesis of 2-Azapodophyllotoxins 7. Modifications of Podophyllotoxin Itself