Stereoselective synthesis of podophyllotoxin-related lignans

Lignans, a large family of secondary metabolites consisting of dimerized phenylpropanoid units, are widely distributed in the plant kingdom. Among them, the aryltetralin lignans are one of the most extensively studied groups of natural products due to their antiviral, antibacterial and antineoplastic properties. Particularly valuable in the chemotherapy of cancer is podophyllotoxin which served as a lead structure for the development of its semisynthetic derivatives etoposide and teniposide, both of which are currently in clinical use.

Res 4 Fig 1 EN (1)

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 atropisomeric 1,2-bisbenzylidenesuccinate amide ester, which can be prepared from the suitable aromatic aldehydes, diethyl succinate and L-prolinol. The photocyclization was found to be more efficient when the 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,2Rcis-podophyllic aldehyde, which in turn could be easily reduced to the corresponding alcohol, completing the formal synthesis of (-)-podophyllotoxin.

 

Res 4 Fig 2 (1)

 

Krawczyk K.K., Madej D., Maurin J.K., Czarnocki Z., „L-Prolinol as a chiral auxiliary in the photochemical synthesis of a new aryltetraline lignan analogue” Tetrahedron: Asymmetry 22 (10), 1103-1107 (2011)

Lisiecki K., Krawczyk K.K., Roszkowski P., Maurin J.K., Czarnocki Z., „Formal synthesis of (-)-podophyllotoxin through the photocyclization of an axially chiral 3,4-bisbenzylidene succinate amide ester – a flow photochemistry approach” Organic & Biomolecular Chemistry 14, 2, 460-469 (2015)

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