Formal synthesis of (?)-podophyllotoxin through the photocyclization of an axially chiral 3,4-bisbenzylidene succinate amide ester – a flow photochemistry approach?

Organic & Biomolecular Chemistry Pub Date: 2015-11-05 DOI: 10.1039/C5OB01844G

Abstract

We have developed a strategy for the stereoselective synthesis of cyclolignans related to podophyllotoxin and its derivatives. The crucial step of the synthesis is the photocyclization of a chiral atropoisomeric 1,2-bisbenzylidenesuccinate amide ester, which can be prepared from suitable aromatic aldehydes, diethyl succinate and L-prolinol. The photocyclization was found to be more efficient when irradiation was performed in a home-built continuous flow photochemical reactor. The in-flow irradiation also allowed us to perform the reaction on a multigram scale. The chiral auxiliary was removed by reductive cleavage with the Schwartz's reagent to give the cytotoxic 1R,2R-cis-podophyllic aldehyde, which in turn could be easily reduced to the corresponding alcohol, completing the formal synthesis of (?)-podophyllotoxin.

Graphical abstract: Formal synthesis of (?)-podophyllotoxin through the photocyclization of an axially chiral 3,4-bisbenzylidene succinate amide ester – a flow photochemistry approach
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