Attempted enantioselective total synthesis of podophyllotoxin.

Abstract

An enantioselective approach via an intramolecular Diels-Alder reaction to the total synthesis of podophyllotoxin, an antimitotic lignan, is described. The two requisite synthons, an o-quinodimethane precursor, and a chiral tether/dienophile derived from tartrate, were efficiently synthesized, but all attempts at effecting the convergent etherification step failed, likely due to a lack of nucleophilicity of the tartrate-derived primary alcohol. Very reproducible synthetic sequences were developed for the synthesis of a number of different chiral potential tether/dienophile molecules based on tartrate, but connection of these molecules to the diene precursor was never successful. Also described is some investigative work into the synthesis and use in synthesis of phosphonates as (Z)-selective Horner-Wadsworth-Emmons olefination reagents. An efficient synthesis of alkyl diphenyl phosphites and the success of subsequent Arbuzov reactions of these phosphites with halides has led to the synthesis of a number of new olefination reagents, for which evaluation of the (Z)-selectivity is ongoing.