Concise Stereoselective Synthesis of (—)-Podophyllotoxin by an Intermolecular Iron(III)-Catalyzed Friedel-Crafts Alkylation

摘要

Owing to their diverse biological activities, in particular their cytotoxicity and antiviral properties, podophyllotoxin (1) and its derivatives are important members of the lignane class of natural products. The biological profile of these compounds, which has inspired the design of new drugs, has been investigated intensively. The biological activity of podophyllotoxin has generated strong interest in the development of synthetic routes to this natural product. Since the first synthesis of enantiomerically pure (—)-podophyllotoxin (1) by Meyers and co-workers in a 24-step sequence, another five syntheses of the enantiomerically pure natural product have been reported. Many additional studies have been concerned with the development of formal total syntheses and syntheses of racemic podophyllotoxin. In all synthetic approaches to podophyllotoxin, the modular generation of the tetracyclic backbone and the brevity of the sequence are of central importance. We report herein a six-step total synthesis of enantiomerically pure (—)-podophyllotoxin with an iron(III)-catalyzed Friedel-Crafts alkylation as a key step. Apart from the use of a terminal alkene as an aldehyde equivalent, no protecting-group manipulations were required in the entire synthetic sequence.